Bolometer operating at the threshold for circuit quantum electrodynamics.

Radiation sensors based on the heating effect of absorbed radiation are typically simple to operate and flexible in terms of input frequency, so they are widely used in gas detection1, security2, terahertz imaging3, astrophysical observations4 and medical applications5. Several important applications are currently emerging from quantum technology and especially from electrical circuits that behave quantum mechanically, that is, circuit quantum electrodynamics6. This field has given rise to single-photon microwave detectors7-9 and a quantum computer that is superior to classical supercomputers for certain tasks10. Thermal sensors hold potential for enhancing such devices because they do not add quantum noise and they are smaller, simpler and consume about six orders of magnitude less power than the frequently used travelling-wave parametric amplifiers11. However, despite great progress in the speed12 and noise levels13 of thermal sensors, no bolometer has previously met the threshold for circuit quantum electrodynamics, which lies at a time constant of a few hundred nanoseconds and a simultaneous energy resolution of the order of 10h gigahertz (where h is the Planck constant). Here we experimentally demonstrate a bolometer that operates at this threshold, with a noise-equivalent power of 30 zeptowatts per square-root hertz, comparable to the lowest value reported so far13, at a thermal time constant two orders of magnitude shorter, at 500 nanoseconds. Both of these values are measured directly on the same device, giving an accurate estimation of 30h gigahertz for the calorimetric energy resolution. These improvements stem from the use of a graphene monolayer with extremely low specific heat14 as the active material. The minimum observed time constant of 200 nanoseconds is well below the dephasing times of roughly 100 microseconds reported for superconducting qubits15 and matches the timescales of currently used readout schemes16,17, thus enabling circuit quantum electrodynamics applications for bolometers.

Production and purification of lentiviral vectors generated in 293T suspension cells with baculoviral vectors.

Lentivirus can be engineered to be a highly potent vector for gene therapy applications. However, generation of clinical grade vectors in enough quantities for therapeutic use is still troublesome and limits the preclinical and clinical experiments. As a first step to solve this unmet need we recently introduced a baculovirus-based production system for lentiviral vector (LV) production using adherent cells. Herein, we have adapted and optimized the production of these vectors to a suspension cell culture system using recombinant baculoviruses delivering all elements required for a safe latest generation LV preparation. High-titer LV stocks were achieved in 293T cells grown in suspension. Produced viruses were accurately characterized and the functionality was also tested in vivo. Produced viruses were compared with viruses produced by calcium phosphate transfection method in adherent cells and polyethylenimine transfection method in suspension cells. Furthermore, a scalable and cost-effective capture purification step was developed based on a diethylaminoethyl monolithic column capable of removing most of the baculoviruses from the LV pool with 65% recovery.

Thermoelectric current in a graphene Cooper pair splitter.

Generation of electric voltage in a conductor by applying a temperature gradient is a fundamental phenomenon called the Seebeck effect. This effect and its inverse is widely exploited in diverse applications ranging from thermoelectric power generators to temperature sensing. Recently, a possibility of thermoelectricity arising from the interplay of the non-local Cooper pair splitting and the elastic co-tunneling in the hybrid normal metal-superconductor-normal metal structures was predicted. Here, we report the observation of the non-local Seebeck effect in a graphene-based Cooper pair splitting device comprising two quantum dots connected to an aluminum superconductor and present a theoretical description of this phenomenon. The observed non-local Seebeck effect offers an efficient tool for producing entangled electrons.

Matrix metalloproteinases-7, -8, -9 and TIMP-1 in the follow-up of diisocyanate-induced asthma.

BACKGROUND: Diisocyanate-induced asthma (DIA) is known to be associated with poor prognosis. We wished to clarify if matrix metalloproteinases (MMP)-7, -8 or -9 or tissue inhibitor of matrix metalloproteinases (TIMP-1) are associated with the functional or inflammatory outcome in DIA patients. METHODS: This is a longitudinal study where 17 patients with DIA diagnosed by a specific challenge test to diisocyanates were monitored. Exposure to diisocyanates was terminated seven (mean) months before the challenge test. The studies included spirometry, histamine challenge test and bronchoscopy. MMP-7, MMP-8, TIMP-1 [Enzyme-linked immunosorbent assay (ELISA)- and immunofluorometric assay-methods], MMP-9 (ELISA and zymography), interferon-gamma, tumour necrosis factor-alpha, interleukin-6, -8, -15, -17, CXCL-5/ENA-78, monocyte chemoattractant protein-1 and macrophage inhibitory factor (MIF) (ELISA) were assayed from bronchoalveolar lavage (BAL) fluid. Inhaled steroid therapy was initiated after the examinations, which were repeated at 6 months and at 3 years during the treatment. The results were compared with those of 15 healthy controls. RESULTS: Inhaled steroid medication increased BAL levels of MMP-9 and MMP-9/TIMP-1 and decreased MMP-7 and MMP-7/TIMP-1. The increase in MMP-9 levels was associated with a decline in the TH-2 type inflammation. CONCLUSIONS: Our data suggest that reduced TH-2 type inflammation in DIA after inhaled steroid medication is reflected as elevated MMP-9 and MMP-9/TIMP-1 levels in BAL. MIF may be the inducer of MMP-9. This might point to some protective role for MMP-9 in DIA.

Inflammation and functional outcome in diisocyanate-induced asthma after cessation of exposure.

BACKGROUND: The clinical outcome of diisocyanate-induced asthma has been found to be poor despite cessation of exposure. Our aim was to study the outcome of diisocyanate-induced asthma after initiation of inhaled steroid treatment at a mean period of 7 months (range 2-60 months) after cessation of exposure by following up lung function and bronchial inflammation. METHODS: Bronchoscopy was performed on 17 patients 2 days after a positive inhalation challenge test, after which budesonide 1600 mug a day was started. Bronchoscopy, spirometry, and histamine challenge tests were repeated at 6 months and on average 3 years. The results were also compared with those obtained from 15 healthy control subjects. RESULTS: Nonspecific bronchial hyperreactivity diminished significantly (P = 0.006); however, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values decreased, with a median yearly reduction of FEV1 of 79 ml. The count of mast cells in bronchial mucosa decreased (P = 0.012) and that of macrophages increased (P = 0.001). Interleukin-4 level in mucosa was during the first year significantly higher than in controls but its level decreased in the follow-up. Interleukin-6, interleukin-15, and tumour necrosis factor alpha messenger-RNA levels were significantly higher in hyperreactive patients than in nonhyperreactive patients at the end of the follow-up. CONCLUSION: Our results indicate that inflammation may persist in diisocyanate-induced asthma despite inhaled steroid medication. However, TH2-type inflammation diminished. Persistent nonspecific bronchial hyperreactivity was associated with proinflammatory acting cytokines produced mainly by macrophages. Considering the poor prognosis of the disease the findings could be utilized to develop the follow-up and treatment of diisocyanate-induced asthma.

Relationship between tracheal mucosal thickness and vascular resistance in dogs.

We have measured changes in tracheal mucosal thickness and tracheal vascular resistance in the dog. A probe was used to detect changes in height with time of the tracheal epithelium relative to an underlying cartilage. Tracheal vascular resistance was determined by perfusing a cranial tracheal artery at constant flow and measuring inflow pressure. Various drugs injected close-arterially were tested in 20 greyhounds anesthetized with pentobarbital sodium. Bradykinin, histamine, and methacholine significantly (P less than 0.01) decreased vascular resistance (-39.3 +/- 3.7, -47.3 +/- 4.2, and -22.5 +/- 5.2%, respectively) and increased the thickness of the mucosa (119.0 +/- 25.0, 61.9 +/- 25.0, and 46.3 +/- 6.4 micron). Substance P, vasoactive intestinal peptide, prostaglandin F2 alpha, and prostaglandin E, had large vasodilator actions (-31.4 +/- 5.0, -34.3 +/- 2.2, -21.9 +/- 2.8, and -31.5 +/- 2.4%) but only small effects on mucosal thickness (12.3 +/- 3.9, 13.0 +/- 3.4, 16.7 +/- 6.5, and 8.7 +/- 2.9 micron, respectively). Phenylephrine hydrochloride increased vascular resistance (19.8 +/- 1.7%) and decreased mucosal thickness (-23.9 +/- 3.1 micron). Thus airway vascular resistance and mucosal thickness always change in opposite directions, but drugs have different relative actions on the two variables. Even with large vasodilatations, the absolute changes in mucosal thickness were small and were unlikely to have an appreciable effect on tracheal airway resistance.

Effect of the Choice of Primary Chemotherapy on the Cumulative Length of Stay in Hospital for Multiple Myeloma.

The actual use of hospital beds for patients with multiple myeloma was calculated from a randomised trial of primary treatment with either melphalan and prednisone (MP, 66 patients) or intensive combination chemotherapy with vincristine, cyclophosphamide, lomustine, melphalan and methylprednisolone (MOCCA, 64 patients). The survival of the patients was similar in both arms, and the samples, 20 and 32 patients, respectively, were well representative for the whole arms. The average numbers of hospital days were similar fur both arms. For the first year MP 33.2 (SD 27.6) vs. MOCCA 32.1 (SD 19.0), and during the first to 4th years 78.5 (SD 45.9) vs. 67.8 (SD 34.1). For the year of death it was 50.4 (SD 33.1) vii. 36.3 (SD 27.0), respectivelly. Thus the choice of primary chemotherapy whether conventional or more aggressive had no influence on the actual number of in-patient hospital days concerned. When the combination chemotherapy schedule is well tolerated it can be administered just as well on an ambulatory basis or by using it with very short admissions. It seems that the need for inpatient care for patients with multiple myeloma is mostly related to the complications of the disease itself and to intercurrent disorders including infections.

In vitro determination of carcinogenicity of sixty-four compounds using a bovine papillomavirus DNA-carrying C3H/10T(1/2) cell line.

A new in vitro test for predicting rodent carcinogenicity is evaluated against a testing database of 64 chemicals including both genotoxic and nongenotoxic carcinogens and carcinogens that normally require addition of an S-9 microsomal fraction for detection in the bacterial mutagenicity assay. The assay uses focus formation in a stable, bovine papillomavirus type 1 (BPV-1) DNA carrying C3H/10T(1/2) mouse embryo fibroblast cell line (T1) that does not require transfection, infection with virus, isolation of primary cells from animals, or addition of a microsomal fraction. Of a total database of 64 compounds, 92% of the carcinogens, promoters, or noncarcinogens were correctly predicted. Based on previously reported results, the test of bacterial mutagenicity would have correctly predicted 58% of carcinogens, promoters or noncarcinogens and the Syrian hamster embryo test would have correctly predicted 87% of carcinogens, promoters, or noncarcinogens of this database. Of carcinogens that normally require addition of an S-9 fraction, T1 cells correctly predicted rodent carcinogenicity of polyaromatic hydrocarbons, aflatoxins, azo-compounds, nitrosamines, and hydrazine without the addition of an S-9 fraction. Of nongenotoxic carcinogens, T1 cells correctly predicted diethylstilbestroel, diethylhexylphthalate, acetamides, alkyl halides, ethyl carbamate, and phorbol ester tumour promoters.

Biopsy markers of airway inflammation and remodelling.

Bronchial inflammation is a consistent feature of asthma and its chronicity probably determines disease progression. Clinical evaluation of drugs with potential disease-modifying activity requires measurement of their effects on the inflammatory and remodelling process using a variety of techniques including bronchial biopsy, and analysis of sputum, bronchoalveolar lavage, blood, urine and exhaled air. Markers of the key components of the inflammatory process, such as the number and activation of T-cells. the number of mast cells, cytokine and chemokine release or gene expression, and eosinophil and neutrophil recruitment, can be determined in biopsy samples. Biopsies also allow assessment of the integrity and structure of the airway epithelium, the thickness of the reticular basement membrane and the numbers and ultrastructure of contractile cells. These and other markers may allow differentiation between subtypes of asthma patient according to atopic status and will help to distinguish asthma from chronic obstructive pulmonary disease. Airway remodelling may be a consequence of chronic bronchial inflammation and is a characteristic of chronic asthma, particularly in severe asthma and when there is progressive decline in lung function. There are changes in the surface epithelium, reticular basement membrane, bronchial smooth muscle, blood vessels and mucous glands. Reliable markers of remodelling need to be identified to improve our ability to evaluate chronic asthma therapy.

Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma.

Previous studies have shown both similar and distinct inflammatory changes in atopic and nonatopic asthma. This study was set to investigate the bronchial inflammatory cell infiltrate and subepithelial basement membrane (BM) tenascin deposition in subjects with newly diagnosed asthma and bronchial hyperresponsiveness (BHR). Seventy-nine asthmatic subjects (age 18-60 years) were recruited and 58 were atopic according to skin prick testing. The patients recorded asthma symptoms and peak flow measurements for 14 days. Lung function and BHR were measured by spirometry and histamine challenge. Serum eosinophil cationic protein (ECP) and blood eosinophils were assessed. Fiberoptic bronchoscopy was performed to obtain bronchial biopsies. Serum ECP was higher in the atopic group but eosinophil counts did not differ. There were no differences in inflammatory cells studied (activated eosinophils, T-lymphocytes, mast cells or macrophages) between nonatopic and atopic subjects. BM tenascin layer was significantly thicker in atopic compared with nonatopic subjects (7.6 vs 6.3 microm, P = 0.007). The thickness of tenascin correlated with eosinophil, T-lymphocyte, and macrophage counts, as well as with IL-4-positive cell counts and the correlation was seen only in atopic asthmatics. These findings suggest that inflammatory cells may have a regulatory role in tenascin expression in atopic asthma.

Regular albuterol or nedocromil sodium--effects on airway subepithelial tenascin in asthma.

Both albuterol and nedocromil sodium have been recognized to possess certain anti-inflammatory properties. However, there are no data on the impact of these drugs on the pathophysiology of the bronchial extracellular matrix in asthma characterized by enhanced tenascin (Tn) expression, known to occur proportional to the severity of asthma. This paper reports data from a morphometric study on the effects of regular treatment with inhaled albuterol or nedocromil sodium on the extent of bronchial subepithelial deposition of Tn, collagen types III, IV, and VII and mucosal infiltration with macrophages. Thirty-two patients (14 women) with chronic asthma, aged 38.7 years (median) with a median forced expiratory volume in 1 sec (FEV1) of 74.4% predicted, were selected to undergo fibre-optic bronchoscopy with bronchial biopsies before and after 12 weeks of treatment with either inhaled albuterol 0.2 mg or nedocromil sodium 4 mg four times daily according to a double-blind protocol. Cryostat sections of the biopsy specimens were studied by indirect immunostaining techniques using monoclonal antibodies and computer-assisted quantitative image analysis. Albuterol treatment significantly reduced the median thickness of subepithelial Tn expression from 9.7 to 6.3 microns (P = 0.023) and macrophage numbers in the epithelium (P = 0.034), lamina propria (P = 0.039) and entire mucosa (P = 0.033), whereas nedocromil sodium had no effect. Expression of the collagen types was not affected by either treatment. There was no identifiable statistical difference between the two treatments for any of the outcome variables measured. Nevertheless, the results demonstrate that even a short-acting beta 2-agonist may exert anti-inflammatory potential sufficient to interfere with the basic mechanisms of asthma as shown by reduction of subepithelial Tn content and mucosal macrophage count.

[Quality assurance in nursing in Finnish health care organizations]. / Hoitotyön laadunvarmistus terveyskeskuksissa ja sairaaloissa.

The purpose of this study is to describe the present situation in quality assurance in nursing in Finnish hospitals and health centers. The data was collected by questionnaires from the nurse leaders in 20 hospitals and in 28 health centers around Finland during the autumn 1987 and spring 1988. They were asked what has been done in their organizations in quality assurance in nursing; methods, areas, co-operators and problems they faced in their quality assurance programmes. Quality assurance in nursing is in the beginning. The nurses are discussing about the concepts of quality, quality assessment, quality assurance and measurements of quality in nursing. In 67% of organizations belonging to this study the nurses have begun to write the standards and criterias in nursing practice. Only in one hospital and in one health center nurses had measured the quality of nursing with some method.

[Standards in quality assurance in nursing]. / Laatuvaatimukset hoitotyön laadunvarmistuksessa.

The purpose of this article is to describe what kind of nursing standards have been written in Finland. The quality assurance process of nursing includes setting of nursing standards. They express the desired quality level of nursing. They would also guide the practice of nursing. The analysed nursing standards were collected from five university hospitals, 15 central hospitals and nine health centers. The standards were collected with the questionnaire studying the present situation of quality assurance of nursing in Finland. The total number of analysed nursing standards was 190. According to the results the standards were mostly set to evaluate and characterize the quality of nursing of the certain patient group (e.g. new born child, dying patient, cancer patient in chemotherapy) and to evaluate the realization of nursing principles. Safety and individuality of nursing and independence and autonomy of patient were the most often appeared nursing principles in the analysed standards. The standards were written in passive and the level of quality was the ideal optimum. The nursing standards were expressed often abstractively and in such a form that the measurement and evaluation of reached level of the standard is a very difficult task.

Autonomic innervation of the human respiratory tract as revealed by histochemical and ultrastructural methods.

The major findings and conclusions of this study are the following: Indirect evidence for the presence of the bronchoconstrictive transmitter acetylcholine in the human bronchial smooth muscle was obtained by demonstration of acetylcholinesterase-positive nerve fibers and nerve profiles of cholinergic type. Acetylcholinesterase-positive nerve fibers and nerve profiles of cholinergic type were found in human bronchial glands. A sparse adrenergic innervation of the human bronchial smooth muscle and glands was found by using catecholamine histofluorescence. This observation was supported by finding ultrastructurally adrenergic-like nerve profiles close to smooth muscle cells. Direct evidence for the presence of a new possible bronchodilating transmitter VIP (vasoactive intestinal peptide) in the human bronchial smooth muscle was obtained both by light microscopical demonstration of VIP immunoreactive nerve fibers and by localization of VIP like immunoreactivity in granules in nerve profiles. Nerve fibers containing VIP-immunoreactivity were found in the human bronchial glands by light microscopy. Substance P-immunoreactive nerves were found in the lower respiratory tract of the rabbit but not of man by light microscopy. Intraepithelial nerves were demonstrated in man from trachea to segmental bronchi and their concentration was established. The intraepithelial nerves seem to have two predominant locations: either close to the airway lumen or near the basement membrane. Nerves near the lumen were found only in larger airways e.g. trachea and lobar bronchi.

Ultrastructural organisation of intraepithelial nerves in the human airway tract.

Intraepithelial nerves of human airway tract were studied by electron microscopy after conventional glutaraldehyde fixation. Specimens were obtained from five patients at three different airway levels--the trachea, the right upper lobe bronchus, and segmental bronchus. Intraepithelial axon profiles were located either near the basement membrane or close to the lumen but were rare in the intermediate area of the epithelium. Axon profiles close to the lumen were seen only in the central airways (levels 1 and 2), while profiles close to the basement membrane were seen in all three levels.

[Quality of health care and costs]. / Laatu, terveydenhuolto ja raha.

The quality of health care is largely discussed issue among health care professionals in Finland. The purpose of this article is to point out some relations between the quality of nursing and the economical costs. The theme is mostly ignored in the published articles and books about quality of nursing and health care. In the previous studies of quality of nursing four main approaches have been introduced 1) practical approach, 2) professionalism, 3) client orientation and 4) research orientation. An important weakness in the approaches is that they are carried out from a point of view of a single profession at the time. Really multiprofessional projects are the exception. Additionally, economic costs have not been included in nursing quality concept or evaluation criterion. The need for quality in any health services is urgent, including nursing. That is because of decreasing resources and changing market oriented steering mechanisms in the Finnish health care system. In this situation the quality of nursing may arise as one important competition factor in the organizations and the units. The costs of poor quality of nursing are not well recognized among professionals. Collaboration between different professionals is a key issue to solve these kind of problems. We need more research about the relations between economic factors and quality of nursing and other health services.

Pathology of asthma.

Appreciation of the early damage that occurs to the respiratory epithelium has been limited by the use of autopsy specimens from fatally stricken asthmatics as a source of representative specimens. The use of bronchoscopy to obtain specimens from patients early in the course of their asthma has allowed a new understanding of the evolution of pathological changes that occur in asthma. Newly diagnosed, mild asthmatics have been shown to have bronchial goblet cell hyperplasia in addition to increased numbers of mast cells and eosinophils in the respiratory epithelium, and increased eosinophil granule protein deposition within the lamina propria. Endothelial gaps in postcapillary venules are greater in asthmatic airways, suggesting that increased plasma transudation may contribute to the known epithelial cell shedding characteristic of asthma attacks. Asthmatic inflammation, even early in the course of the disease, includes vascular permeability changes, inflammatory cell infiltration, epithelial cell shedding, and goblet cell hyperplasia, replacing the normal ciliated epithelium. Current investigation evaluating the effects of asthmatic inflammation on epithelial cell attachment to each other and to the extracellular matrix molecules regulated by adhesion glycoproteins will likely enhance further the understanding of the pathological changes that occur within the asthmatic airway.

Airway morphology: epithelium/basement membrane.

Morphologic studies have given important information about changes in the airways underlying the functional abnormalities in asthma. Recent biopsy studies have revealed that in asthma an airway inflammatory process is present even at a clinically early stage of the disease. This inflammatory response shows a particular cellular picture with concomitant vascular changes. It is widely thought that dramatic epithelial changes such as epithelial shedding are major mechanisms in the pathogenesis of asthma and bronchial hyper-responsiveness. Because of difficulties in obtaining proper biopsy specimens, it has not yet been established to what extent epithelial shedding really occurs in preterminal stages of asthma. Perhaps a more important aspect than epithelial shedding is a more continuous replacement of the ciliated epithelium by another type of epithelium in asthmatic patients' airways during the early disease stage. The airway epithelial cells, their surface receptors, and the underlying basement membrane seem to play an important role in maintaining the structural integrity of the epithelium and establishing functional permeability barriers. Disturbances in the structure may lead to events recognized as tissue damage and to the development of inflammation in asthma. We need to learn more about the adhesion mechanisms in asthma, both at the receptor and the ligand sites, to better assess the role of structural epithelial changes in this disease.