The good and the bad collagens of fibrosis - Their role in signaling and organ function.

Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or toxic liver injury, with reticular, chicken wire and bridging fibrosis. Importantly, the overall composition of the ECM, especially the relative amounts of the many types of collagens, which represent the most abundant ECM molecules and which centrally modulate cellular functions and physiological processes, changes dramatically during fibrosis progression. We hypothesize that there are good and bad collagens in fibrosis and that a change of location alone may change the function from good to bad. Whereas basement membrane collagen type IV anchors epithelial and other cells in a polarized manner, the interstitial fibroblast collagens type I and III do not provide directional information. In addition, feedback loops from biologically active degradation products of some collagens are examples of the importance of having the right collagen at the right place and at the right time controlling cell function, proliferation, matrix production and fate. Examples are the interstitial collagen type VI and basement membrane collagen type XVIII. Their carboxyterminal propeptides serve as an adipose tissue hormone, endotrophin, and as a regulator of angiogenesis, endostatin, respectively. We provide an overview of the 28 known collagen types and propose that the molecular composition of the ECM in fibrosis needs careful attention to assess its impact on organ function and its potential to progress or reverse. Consequently, to adequately assess fibrosis and to design optimal antifibrotic therapies, we need to dissect the molecular entity of fibrosis for the molecular composition and spatial distribution of collagens and the associated ECM.

Testing the near field/far field model performance for prediction of particulate matter emissions in a paint factory.

A Near Field/Far Field (NF/FF) model is a well-accepted tool for precautionary exposure assessment but its capability to estimate particulate matter (PM) concentrations is not well studied. The main concern is related to emission source characterization which is not as well defined for PM emitters compared to e.g. for solvents. One way to characterize PM emission source strength is by using the material dustiness index which is scaled to correspond to industrial use by using modifying factors, such as handling energy factors. In this study we investigate how well the NF/FF model predicts PM concentration levels in a paint factory. PM concentration levels were measured during big bag and small bag powder pouring. Rotating drum dustiness indices were determined for the specific powders used and applied in the NF/FF model to predict mass concentrations. Modeled process specific concentration levels were adjusted to be similar to the measured concentration levels by adjusting the handling energy factor. The handling energy factors were found to vary considerably depending on the material and process even-though they have the same values as modifying factors in the exposure models. This suggests that the PM source characteristics and process-specific handling energies should be studied in more detail to improve the model-based exposure assessment.

Airborne endotoxin associated with particles of different sizes and affected by water content in handled straw.

High exposures to endotoxin are observed in environments where organic materials are handled and lower exposures are found in e.g. indoor air. Inhaled endotoxin contributes significantly to the induction of airway inflammation and dysfunction. The size of an inhaled particle influences the deposition in the airways and the following health symptoms. The objective is to characterise the distribution of endotoxin on airborne particles of different sizes in straw storage halls with high exposure and in other environments with lower exposure levels to endotoxin. Furthermore we have studied the influence of water content of handled straw on the size distribution of endotoxin containing particles. Total, inhalable, thoracic and respirable endotoxin and particles have each been quantified in aerosols from boiler rooms and straw storage halls at 24 power plants, including 21 biofuel plants. Inhalable, thoracic and respirable endotoxin have been quantified in aerosols from offices and outdoor air. The endotoxin concentration was higher in airborne thoracic dust than in airborne 'total dust'. The median respirable fraction in the straw storage halls, boiler rooms at biofuel plants, boiler rooms at conventional plants, offices and outdoors was respectively 42%, 9%, 19%, 24% and 34%. Thoracic endotoxin per number of thoracic particles was higher than respirable endotoxin per number of respirable particles at the biofuel plants. In straw storage halls the fraction of endotoxin of respirable size was highest on the days with lowest water content in the received straw. Furthermore the exposures to all endotoxin fractions were highest on days with the lowest water content in the received straw. In conclusion the highest exposures and concentrations of endotoxin occur or tend to occur from thoracic dust. A high variation in endotoxin concentrations and in fractions of respirable or thoracic size is found in the different working areas. This is important in the risk assessment and makes attempts to influence the endotoxin exposure a possibility. Water content in straw affected the concentration, exposure level and size distribution of airborne endotoxin.

Wind-driven upwelling in the Southern Ocean and the deglacial rise in atmospheric CO2.

Wind-driven upwelling in the ocean around Antarctica helps regulate the exchange of carbon dioxide (CO2) between the deep sea and the atmosphere, as well as the supply of dissolved silicon to the euphotic zone of the Southern Ocean. Diatom productivity south of the Antarctic Polar Front and the subsequent burial of biogenic opal in underlying sediments are limited by this silicon supply. We show that opal burial rates, and thus upwelling, were enhanced during the termination of the last ice age in each sector of the Southern Ocean. In the record with the greatest temporal resolution, we find evidence for two intervals of enhanced upwelling concurrent with the two intervals of rising atmospheric CO2 during deglaciation. These results directly link increased ventilation of deep water to the deglacial rise in atmospheric CO2.

Exposure to dust and endotoxin of employees in cucumber and tomato nurseries.

Exposure to bioaerosols in occupational settings is associated with a range of adverse health effects. The aim of this study was to investigate the exposure levels to dust and endotoxin of people working in two cucumber nurseries and two tomato nurseries. Exposure was measured for greenhouse workers (n = 70) mainly working on harvesting cucumbers and tomatoes and clearing the plants after the harvest season. The people were exposed to between 0.2 and 15 mg inhalable dust m(-3) (median = 1.6 mg m(-3)) and between 0.5 and 400 ng inhalable endotoxin m(-3) (median = 32 ng m(-3)). The exposure to 'total dust' and endotoxin measured by stationary samplers (n = 30) in the greenhouses was low. Endotoxin was present in relatively high concentrations on cucumber leaves compared with leaves on pot plants. The Danish occupational exposure limit (OEL) for total organic dust is 3 mg m(-3) and 36% and 17% of the cucumber and tomato workers, respectively, were exposed to >3.0 mg inhalable dust m(-3). There is no OEL for endotoxin, but 'no effect levels' at approximately 15 ng m(-3) have been found. The majority of subjects (65%) were exposed to >15 ng m(-3). Significantly higher exposure was found for employees in cucumber nurseries than for employees in tomato nurseries. Clearing tomato plants after the harvest season caused a higher exposure to endotoxin than tomato harvesting. In conclusion, people working in cucumber and tomato nurseries were often exposed to high levels of inhalable dust and endotoxin. Cucumber harvest workers were exposed to significantly more dust and endotoxin than tomato harvest workers. The dust and endotoxin aerosolized during the working processes were only transported to other areas in the greenhouses to a very low degree. Cucumber and tomato leaves were identified as endotoxin reservoirs.

Albuminuria in ischemic heart disease.

Proteinuria associated with acute heart disease was studied prospectively in 160 patients admitted to the coronary care unit with suspected AMI. Series 1 comprised 150 patients, divided into the following groups: AMI, 27 UAP, 43 AP, 22 NIP and 18 excluded. Albumin and creatinine were measured in the first urine passed after admission (sample 1) and the first morning urine the following 2 days (samples 2 and 3). The ACR was significantly higher in the AMI and UAP groups than in the other patient groups (p < 0.0001). There was no significant difference of ACR between the AMI and UAP in sample 1 (p = 0.31). In the AMI, UAP and AP groups ACR was significantly higher in sample 1 than in samples 2 and 3 (p < 0.005). In the NIP group there were no significant differences between sample 1 versus samples 2 and 3 (p = 0.06). Series 2 comprised 10 patients: 8 AMI, 1 UAP and 1 AMYO. ACR were measured in all specimens voided during the period of observation. ACR can oscillate within hours between normal concentrations and concentrations well into or above the microalbuminuric range. We propose the term episodic albuminuria for this reversible, switch-like change in renal function. The albuminuric episodes lasted 90-600 minutes. Maximum values for ACR were between 133-790 mumol/mol or 78-466 mg/g. In healthy, resting individuals ACR is < 50 mumol/mol (< 30 mg/g). The rapid changes in glomerular permeability may reflect systemic changes in endothelial permeability in the affected individuals. We speculate that atrial natriuretic peptide (ANP) may be a mediator of this type of albuminuria.

Renal function after myocardial infarction and cardiac arrest in rats: role of ANP-induced albuminuria?

Renal function was measured by clearance technique before and after acute myocardial infarction (MI) induced by left coronary artery ligation in male Sprague-Dawley rats. The animals were anaesthetized with halothane-nitrous oxide, paralysed with pancuronium and artificially ventilated. All parameters were stable throughout the experiment in sham-operated time control animals (n = 8). After MI, rats developed left ventricular dysfunction with increased left ventricular end-diastolic pressure and decreased mean arterial pressure. MI produced antidiuresis and antinatriuresis without changes in glomerular filtration rate (GFR), lithium clearance or renal albumin excretion (n = 8). The antidiuretic and antinatriuretic responses to MI were similar in rats with chronic bilateral renal denervation (n = 5). Three additional rats with chronic bilateral renal denervation had cardiac arrest and were resuscitated with cardiac massage, i.v. lidocaine and intracardiac adrenaline administration. These animals showed a transient increase in urine flow rate, sodium and albumin excretion with maximum 30-60 min after resuscitation, while GFR and lithium clearance were normal. Since cardiac ischaemia and sympathetic stimulation are strong stimuli for the release of atrial natriuretic peptide (ANP), we examined if ANP (0.25, 0.50, and 1.00 microg kg(-1) min(-1), n = 8 per dose) affects urinary albumin excretion. ANP increased dose-dependently the urine/plasma concentration ratio of albumin relative to inulin, which suggests that ANP increases the glomerular permeability for albumin. We conclude that MI causes stimulation of renal tubular sodium and water reabsorption by a mechanism which is independent of intact renal innervation. MI does not produce any change in renal albumin excretion in rats, but transient albuminuria may be observed in rats following cardiac arrest and/or manoeuvres used in cardiac resuscitation. Since ANP produces albuminuria, we speculate that ANP may be an important mediator of albuminuria in states with elevated plasma concentrations of ANP.

The MICRAL test for diabetic microalbuminuria: predictive values as a function of prevalence.

The MICRAL test is an immunospecific dipstick for detection of low concentrations of albumin in urine (microalbuminuria). The test is intended to be used for screening in an ambulatory setting. The utility of the test depends on its ability to accurately predict which patients will be classified as either microalbuminuric or normoalbuminuric by means of a standard laboratory method for determination of albumin in urine. We have analysed data from studies with a total of 2904 samples of urine from diabetic patients. The data are from our own study (190 samples) and from a selected set of 10 publications. The results from standard laboratory measurements of albumin in urine were used as " gold standards". The sensitivity and specificity as calculated from the pooled data were 83.2 and 92.3%, respectively. The predictive values were calculated using simulated changes in the prevalence of microalbuminuria (MAU). At a prevalence of MAU of 1% the predictive value of a negative test is 99.9% but that of a positive test only 9.8%. At a prevalence of MAU of 80% the positive predictive value is 97.7% and the negative predictive value 57.9%. In general, any change in the prevalence will lead to a change in the predictive values. Thus the prevalence of MAU in the given clinical setting is a decisive factor in determining the utility of the MICRAL test.

Regulation of motilin release from isolated perfused pig duodenum.

The release of motilin from an isolated preparation of pig duodenum has been studied. There different types of stimuli were applied: electrical nerve stimulation, intraarterially administered peptides, and instillation of test solutions into the lumen of the duodenum. Furthermore extracts of 20 different regions of the pig digestive system have been analyzed for motilin content. Analysis of the extracts only detected significant presence of motilin in the pig duodenum and jejunum (79 +/- 15 and 60 +/- 19 pmol/g). The stimulation experiments showed: (1) a significant noncholinergic depression of motilin release during electrical stimulation of the vagus nerve (nadir at 74 +/- 5% of baseline level; (2) a significant elevation of motilin release in response to intraarterially administered vasoactive intestinal peptide (VIP) (peak at 330 +/- 35% of baseline level), and (3) a significantly elevated motilin release in response to instillation of autologuous bile (peak at 170 +/- 16% of baseline level) and hydrochloric acid (peak at 196 +/- 42% of baseline level) into the duodenal lumen. In conclusion, luminal acidification and bile are important factors in stimulation of motilin release, whereas the vagally stimulated VIP release was insufficient to overcome the general inhibitory effect of vagus stimulation.

[Metabolic disorders in the treatment of malignant hematologic diseases--the acute tumor lysis syndrome]. / Metaboliske forstyrrelser ved behandling af maligne haematologiske sygdomme--det akutte tumorlysesyndrom.

The acute tumor-lysis syndrome is a potentially fatal complication which characteristically arises during initial chemotherapy of malignant hematological diseases with large tumor burdens. The syndrome is characterized by hyperphosphatemia, hypocalcemia, hyperuricemia and often acute renal failure. Prior to chemotherapy the patient should be treated for 12-24 hour with intensified diuresis to ensure optimal renal function. The treatment of the fully developed syndrome is hemodialysis. Three cases of TLS which developed during initial chemotherapy of patients with acute lymnphoblastic leukemia and non-Hodgkin lymphoma are presented.