Hospital re-admission after critical care survival: a systematic review and meta-analysis.

Survivors of critical illness frequently require increased healthcare resources after hospital discharge. We undertook a systematic review and meta-analysis to assess hospital re-admission rates following critical care admission and to explore potential re-admission risk factors. We searched the MEDLINE, Embase and CINAHL databases on 05 March 2020. Our search strategy incorporated controlled vocabulary and text words for hospital re-admission and critical illness, limited to the English language. Two reviewers independently applied eligibility criteria and assessed quality using the Newcastle Ottawa Score checklist and extracted data. The primary outcome was acute hospital re-admission in the year after critical care discharge. Of the 8851 studies screened, 87 met inclusion criteria and 41 were used within the meta-analysis. The analysis incorporated data from 3,897,597 patients and 741,664 re-admission episodes. Pooled estimates for hospital re-admission after critical illness were 16.9% (95%CI: 13.3-21.2%) at 30 days; 31.0% (95%CI: 24.3-38.6%) at 90 days; 29.6% (95%CI: 24.5-35.2%) at six months; and 53.3% (95%CI: 44.4-62.0%) at 12 months. Significant heterogeneity was observed across included studies. Three risk factors were associated with excess acute care rehospitalisation one year after discharge: the presence of comorbidities; events during initial hospitalisation (e.g. the presence of delirium and duration of mechanical ventilation); and subsequent infection after hospital discharge. Hospital re-admission is common in survivors of critical illness. Careful attention to the management of pre-existing comorbidities during transitions of care may help reduce healthcare utilisation after critical care discharge. Future research should determine if targeted interventions for at-risk critical care survivors can reduce the risk of subsequent rehospitalisation.

Combined neurosurgical and orbital intervention for spheno-orbital meningiomas - the Manchester experience.

PURPOSE: Surgical resection of spheno-orbital meningioma (SOM) is challenging, requiring a multidisciplinary surgical approach. We present our experience of the surgical management of patients with SOM. METHODS: A retrospective analysis of patients with SOM who underwent joint neurosurgical and orbital surgical procedures between January 2000 and June 2017. Pre-operative clinical signs, indication for surgery, surgical complications and post-operative outcomes were recorded. RESULTS: Twenty-four operations were performed. Mean age was 49.5 years. Ninety-two percent of patients were female. Pre-operatively mean Snellen acuity vision was 6/12; 13 (54%) had an RAPD; 12 (50%) had reduced colour vision; 16 (67%) had a visual field defect. The majority (21 patients, 88%) had proptosis (average 4.5 mm ± 2.8 mm). The indication for surgery was evidence of visual dysfunction in 17 (71%), the remaining 7 (29%) had high risk of visual loss clinically or radiologically. Three-months post operatively, vision was stable in 13 (58%), improved in 6 (21%) and worse in 5 (17%). Average long-term follow-up was 82 months (1-220). Fourteen (58%) maintain improved or stable visual function. Four (17%) had reduced vision due to regrowth of the tumour at an average of 24 months. CONCLUSION: SOMs are very challenging to treat surgically. In this cohort the patients were predominantly young females with aggressive disease. Visual function was improved or stabilised in 79% of the patients.

First Report of the Armillaria Root-Disease Pathogen, Armillaria gallica, Associated with Several Woody Hosts in Three States of Mexico.

In September 2007, rhizomorphs with morphological characteristics of Armillaria were collected from woody hosts in forests of Mexico State, Veracruz, and Oaxaca, Mexico. Based on pairing tests, isolates were assigned to five somatically compatible genets or clones (MEX7R, MEX11R, MEX23R, MEX28R, and MEX30R). These genets were all identified as Armillaria gallica based on somatic pairing tests against known tester isolates and nucleotide sequences of the translation elongation factor 1α (tef-1α; GenBank Accession Nos. KF156772 to 76). Sequences of tef-1α for all genets showed a max identity of 97 to 99% to A. gallica (ST23, JF313125) (3,4). However, A. gallica comprises a genetically diverse complex that likely represents multiple cryptic species (3). In Mexico, this species has been previously reported in northeastern Morelos on Quercus sp., eastern Mexico State on Pinus hartwegii, and southwestern Mexico State on Prunus persica (1,2). This study identified associations with 10 new hosts within three states of Mexico, but only five hosts were diseased. Genet MEX7R comprised seven isolates collected in the University of Chapingo forest near Texcoco, Mexico State (19°18'10.764″ N, 98°42'14.147″ W, elevation 3441 m). Four MEX7R isolates were collected from diseased Alnus sp. including the root ball of a 130 cm dbh, root-disease killed tree, one isolate from a symptomless Senecio sp. s.l. (Roldana sp.) shrub and two isolates from symptomless Abies religiosa. Genet MEX11R comprised four isolates from a cloud forest near Xalapa, Veracruz (19°31'14.628″ N, 96°59'22.812″ W, elevation 1496 m). MEX11R isolates were collected from the roots of a root-disease killed Carpinus caroliniana, and from trees with no obvious symptoms (Miconia mexicana, Quercus xalapensis, and Liquidambar styraciflua). Two isolates of genet MEX23R were collected from the Jardin Botanico Francisco Javier Clavijero, Instituto de Ecologia, A.C., Xalapa, Veracruz (19°30'49.067″ N, 96°56'32.999″ W, elevation 1344 m). These isolates were from root-diseased Eriobotrya japonica (non-native fruit tree) that showed obvious symptoms (flaccid, chlorotic, and senescing leaves) and from an adjacent, infected Platanus mexicana that did not show readily observable symptoms. Two collections near Oaxaca, Oaxaca, included a single isolate MEX28R from the root ball of a recently root disease-killed Arbutus xalapensis within a small root disease center at Peña Prieta, in Parque La Cumbre, near Ixtepeji (17°09'42.084″ N, 96°38'15.936″ W, elevation 2853 m) and a single isolate MEX30R from the base of an asymptomatic Alnus acuminata near the El Carrizal fish hatchery 10 km northeast of San Miguel del Valle (17°06'45.036″ N, 96°24'03.743″ W, elevation 2594 m). Armillaria gallica has a circumpolar distribution with an extremely wide host range, and its ecological behavior varies greatly. Continued surveys are needed to better understand the distribution and ecological impacts of this pathogen in relation to Armillaria root disease in Mexico and the potential influences of climate change. Although A. gallica displays diverse ecological behavior, trees infected with A. gallica are less likely to survive the stresses of human activity and a changing climate (4). References: (1) D. Alvarado-Rosales and R. A. Blanchette. Phytopathology 84:1106, 1994. (2) R. D. Elias-Roman et al. For. Pathol. 43:390, 2013. (3) M.-S. Kim et al. Phytopathology 102:S4.63, 2012. (4) B. Marcais and N. Breda. J. Ecol. 94:1214, 2006.

Generic circumscriptions in Geoglossomycetes.

The class Geoglossomycetes is a recently created class of Ascomycota, currently comprised of one family (Geoglossaceae) and five genera (Geoglossum, Nothomitra, Sarcoleotia, Thuemenidium and Trichoglossum). These fungi, commonly known as earth tongues, have long been a subject of mycological research. However, the taxonomy within the group has historically been hindered by the lack of reliable morphological characters, uncertain ecological associations, and the inability to grow these fungi in culture. The phylogenetic relationships of Geoglossomycetes were investigated by conducting maximum likelihood and Bayesian analyses using a 4-gene dataset (ITS, LSU, MCM7, RPB1). Five well-supported monophyletic clades were found that did not correspond exactly with the currently recognised genera, necessitating a taxonomic revision of the group. Two new genera are proposed: Glutinoglossum to accommodate G. glutinosum and the newly described species G. heptaseptatum, and Sabuloglossum to accommodate S. arenarium. The type species of Thuemenidium, traditionally included within the Geoglossaceae, is confirmed as belonging to a separate lineage that is only distantly related to Geoglossomycetes.

Exercise knowledge, barriers and motivators among LRRK2 G2019S mutation carriers.

INTRODUCTION: People with a Gly2019Ser mutation in the leucine-rich repeat kinase 2 (LRRK2 G2019S) are at increased risk of developing Parkinson's disease (PD). Recent evidence suggests that exercise may delay or prevent the development of clinically overt symptoms of PD in people at risk of PD. We determined whether LRRK2 G2019S mutation carriers with and without manifest PD are aware of the relationship between exercise and PD and how they differ in awareness, barriers and motivators to exercise. METHODS: We deployed a survey among 4422 LRRK2 G2019S mutation carriers. In total, 505 (11.4%) of them completed the survey, of whom 105 had self-reported manifest PD. RESULTS: Ninety-two percent of the LRRK2 G2019S mutation carriers with manifest PD and 63% of those with non-manifest PD were aware of the relationship between exercise and PD. Lack of motivation was the top barrier for those without manifest PD, while having an injury/disability was the most common barrier for those with manifest PD. Improvement of body functioning was the top motivator for both. CONCLUSION: The fact that many at-risk individuals are not aware of the importance of exercise and would exercise more with fewer barriers creates opportunities for trials using exercise as a possible prevention strategy for PD.

Efficacy of trichloroacetic acid (95%) in the management of xanthelasma palpebrarum.

BACKGROUND: Xanthelasma palpebrarum (XP) is a commonly occurring benign eyelid disorder. AIM: To determine the efficacy of topical trichloroacetic acid (TCA) 95% in the management of XP. METHODS: This was a retrospective review of patients treated with TCA between June 2000 and July 2007. We recorded the outcomes of patients who attended the clinic at least 3 months after their treatment. We also contacted all patients with a minimum interval of 12 months between treatment and a telephone interview to assess for recurrence/persistence of the lesion(s). RESULTS: In total, 102 patients were enrolled in the study. Of these, 44 were reviewed in the clinic. There were nine persistent lesions and four recurrences recorded at a mean follow-up of 14.3 months. Telephone interviews were conducted with 51 patients (146 lesions). Of these 51 patients, 43 had been given bilateral TCA treatment. The mean number of TCA treatments was 1.68. Mean time from the past TCA treatment to the telephone interview was 31.8 months. Of the 51 patients, 17 patients reported no recurrence, 22 patients had experienced a recurrence, 9 patients had persistence of the lesion and 3 patients undergone surgical excision of the lesion since the last TCA treatment. Overall, the success rate for TCA was 61% at a mean follow-up of 31.8 months. CONCLUSIONS: XP has a strong history of recurrence. TCA treatment may be effective in XP and is a short, simple and cheap procedure that can be repeated. Although the requirement for retreatment is high, patient satisfaction with the procedure is also high.

First Report of Armillaria Root Disease Caused by Armillaria tabescens on Araucaria araucana in Veracruz, Mexico.

In September 2007, bark samples were collected from the root collar of a single Araucaria araucana tree that had recently died and was suspected of being killed by Armillaria root disease. Disease symptoms and signs included a thinning crown and fruiting bodies at the tree base over a several-year period before tree death. The tree was located in an isolated street-tree planting within a business district on Maestros Veracruzanos Street, Xalapa, Veracruz (19°31'52''N, 96°54'25''W, elevation 1,392 m). One fungal isolate (MEX21WF) was obtained, which possessed two sequence repeat types from the intergenic spacer-1 (IGS-1) region (GenBank Accession Nos. GQ335541 and GQ335542). On the basis of these IGS-1 sequences, this isolate from Mexico possessed 99% nucleotide sequence identities with North American Armillaria tabescens isolates (GenBank Accession Nos. AY695410 ≈ GQ335541 and AY773966 ≈ GQ335542). Somatic pairing tests of the isolate with other North American Armillaria species also identified it as A. tabescens (2). In addition, fruiting bodies were produced on the stump base in 2009 that matched morphological features of A. tabescens, e.g., exannulate, cespitose growth in clusters, brown-gray stipe to blackish toward the base, longitudinally fibrillose, basidiospores (6-) 7 to 9 × 4 to 5 (-5.5) µm, and other general morphology. On the basis of these three lines of taxonomic evidence, it was concluded that the isolate was A. tabescens. To our knowledge, this is the first confirmed report of A. tabescens causing Armillaria root disease in Mexico. Furthermore, this note represents the first report of A. tabescens on Araucaria araucana, which is native to Chile and Argentina. The other previous reports of A. tabescens in Mexico are based on herbarium specimens collected in 1965 (BPI 753040) from Valle de Bravo (approximately 350 km west of Xalapa) in the state of México and 1973 (BPI 753041) from near Monterrey (approximately 760 km north-northwest of Xalapa) in the state of Nuevo León (1). However, no host information or confirmation of taxonomic identification was reported for these herbarium specimens. Although this note confirms the presence of A. tabescens in Mexico, more surveys and monitoring are needed to determine the full distribution of this pathogen in Mexico. Because the climate and tree communities of eastern Mexico are similar to those of the southeastern United States, where A. tabescens has been reported as a common pathogen of oaks and fruit trees (3,4), it seems reasonable that A. tabescens may represent an existing or potential threat in eastern Mexico. References: (1) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology and Microbiology Laboratory. Online publication. ARS, USDA, 2010. (2) K. I. Mallett and Y. Hiratsuka. Can. J. Bot. 64:2588, 1986. (3) F. Miranda and A. J. Sharp. Ecology 31:313, 1950. (4) G. Schnabel et al. Mycol. Res. 109:1208, 2005.

Meteorite impact crater discovered in central alaska with landsat imagery.

Several supporting observations indicate that Sithylemenkat Lake, Alaska; occupies a meteorite impact crater formed near the end of the Wisconsinan glaciation. The initial identification with Landsat imagery is attributed to the unique perspective provided by such imagery.

Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors.

The host factor alpha isoform of the tripartite motif 5 (TRIM5alpha) restricts human immunodeficiency virus type 1 (HIV-1) infection in certain non-human primate species. Restriction of HIV-1 is enhanced by binding of the viral capsid to cyclophilin A (CypA) in target cells, although CypA is not absolutely required for restriction in rhesus macaque cells. Simian immunodeficiency virus (SIV) is not restricted by rhesus macaque TRIM5alpha and its capsid does not bind to CypA. Here, the effect of lentiviral CypA dependence on restriction in different tissues was examined by engineering an HIV-1 capsid quadruple mutant (V(86)P/H(87)Q/I(91)V/M(96)I) lentiviral vector (HIV(quad)) that is CypA-independent. Whereas HIV-1 was restricted in rhesus macaque and owl monkey epithelial cells, infection with the HIV(quad) vector was efficient at high viral concentrations. In contrast, HIV(quad) was largely restricted in primary rhesus macaque CD34(+) cells. Human epithelial and primary CD34(+) cells were permissive for HIV-1, HIV(quad) and SIV, whereas transduction of human T cells by HIV(quad) or SIV was impaired. The restrictive human cells did not express increased levels of TRIM5alpha, and restriction was not relieved by abolishing CypA, consistent with HIV(quad) and SIV being CypA-independent. Pseudotyping of lentiviral vectors with the gibbon ape leukemia virus envelope altered their sensitivity to perturbations of the virus-CypA interaction compared to pseudotyping with vesicular stomatitis virus glycoproteins, suggesting that the viral entry pathway modulates restriction. Together, these studies reveal that an HIV-1 capsid quadruple mutant can partially overcome lentiviral restriction in non-human primate epithelial cells, but not in hematopoietic cells. Similarly, human cells vary in their permissiveness for CypA-independent lentiviruses, and suggest the presence of tissue-specific factor(s) that can inhibit lentiviral transduction independently of viral interaction with TRIM5alpha and CypA.

The effect of altered sodium balance upon renal vascular reactivity to angiotensin II and norepinephrine in the dog. Mechanism of variation in angiotensin responses.

The mechanism whereby the vasoconstrictor response to angiotensin II (AII) is influenced by sodium balance or disease is unclear. To explore this question, the renal vascular responses (RVR) to intrarenal injections of subpressor doses of AII and norepinephrine were studied in dogs with an electromagnetic flowmeter. Acute and chronic sodium depletion increased plasma renin activity (PRA) and blunted the RVR to AII, while acute sodium repletion and chronic sodium excess plus desoxycorticosterone acetate decreased PRA and enhanced the RVR to AII. The magnitude of the RVR to AII was inversely related to PRA. The RVR to norepinephrine was unaffected by sodium balance and was not related to PRA. Inhibition of the conversion of angiotensin I to AII by SQ 20,881 during sodium depletion lowered mean arterial blood pressure (MABP), increased renal blood flow (RBF), and enhanced the RVR to AII but not to norepinephrine. Administration of bradykinin to chronically sodium-depleted dogs also lowered the MABP and increased RBF but had no effect on the RVR to AII. SQ 20,881 had no effect on MABP, RBF, or the RVR to AII in the dogs with chronic sodium excess and desoxycorticosterone acetate. Administration of indomethacin to chronically sodium-depleted dogs lowered RBF but did not influence the RVR to AII. The results indicate that the RVR to AII is selectively influenced by sodium balance and that the magnitude of the response is inversely related to the availability of endogenous AII. The data did not suggest that the variations in the RVR to AII were because of direct effects of sodium on vascular contraction, changes in the number of vascular AII receptors, or the renal prostaglandins. The results are consistent with the hypothesis that the vasoconstrictor effect of AII in the renal vasculature is primarily dependent upon the degree to which the AII vascular receptors are occupied by endogenous hormone.

Measurement of regional myocardial perfusion in man with 133 xenon and a scintillation camera.

A method was devised to quantitate regional capillary perfusion in the human heart by measuring the clearance constants (k) of Xenon-133 washout from multiple areas of the myocardium with a multiple-crystal scintillation camera. In 17 subjects, (133)Xe was injected into the right or left coronary artery or both and counts per second (cps) were recorded simultaneously on magnetic tape from each of 294 scintillation crystals viewing the precordium through a multichannel collimator. Data were processed by a digital computer. Crystals detecting the myocardial washout of (133)Xe were distinguished from those monitoring pulmonary excretion by positioning radioactive markers at the cardiac margins, and by a computer printout of the peak cps recorded by each crystal and its time after isotope injection into the coronary artery. The slopes of the initial segment of the multiple (133)Xe curves obtained in each study were calculated by the method of least squares using a monoexponential model. Myocardial blood flow rates in the cardiac regions viewed by the individual crystals were calculated (assuming a blood to myocardium partition coefficient of 0.72) along with the SD of every flow measurement. The pattern of myocardial perfusion rates so obtained was superimposed over a tracing of the subject's coronary arteriogram. Scintiphotographs showing the arrival and washout of isotope from various regions of myocardium and the area of tissue perfused by each coronary artery were obtained by replaying the data tape on an oscilloscope. Significant regional variations in local myocardial perfusion rates were observed in hearts with normal coronary arteries. When capillary flow measurements from crystals overlying the various cardiac chambers were averaged in each subject, the mean myocardial blood flow rate of the left ventricle in 17 patients, 64.1 +/-13.9 (SD) ml/100 g.min, significantly exceeded that of the right ventricle, 47.8 +/-10.9 ml/100 g.min, and of the right atrial region, 33.6 +/-10.3 ml/100 g.min. The approach may facilitate more objective assessment of: myocardial capillary perfusion in patients with angina pactoris, the pharmacology of antianginal drugs, and the efficacy of surgical procedures to revascularize ischemic myocardium.

Skin capillary blood flow in scleroderma.

Skin blood flow was measured by the clearance of radioactive xenon ((133)Xe) injected intracutaneously in eight patients with scleroderma and nine control subjects under conditions of controlled temperature and humidity. Scleroderma patients, on being cooled 1 hr at 18 degrees C, had a rate constant of (133)Xe clearance from the dorsal finger skin which was 0.04 +/-0.07 min(-1) (mean +/-SD), compared with 0.23 +/-0.15 min(-1) in normal subjects (P < 0.005). The corresponding mean cutaneous blood flows were 2.9 ml/100 g per min in the scleroderma patients and 16.4 ml/100 g per min in normal subjects. After reflex warming by waterbath, clearance was similar in the two groups (0.33 +/-0.1 vs. 0.40 +/-0.09); these data suggest that diminished clearance in scleroderma patients on cooling resulted, at least in part, from functional or reversible interruption of the circulation. The skin temperatures of scleroderma patients after reflex warming remained lower than those of normal subjects, despite similar increases in sublingual temperatures. The dissociation of (133)Xe clearance and skin temperature in scleroderma patients (i.e. subnormal skin temperatures with normal (133)Xe clearance after reflex warming) suggests either abnormal thermal properties of scleroderma skin or selective vasoconstriction of the vessels which regulate heat exchange. The demonstrated interruption of the capillary circulation on cooling of the skin in patients with scleroderma may be important in the pathogenesis of this disorder. After oral pretreatment with guanethidine, five patients with scleroderma had increased (133)Xe clearance and calculated blood flow on cooling, rising to normal in three of these patients. The potential of this technique for the quantitative sequential evaluation of skin blood flow in subjects with scleroderma and for the evaluation of empirical therapy is suggested.

Regional myocardial perfusion rates in patient with coronary artery disease.

Regional myocardial perfusion rates were estimated from the myocardial washout of (133)Xenon in 24 patients with heart disease whose coronary arteriograms were abnormal and 17 similar subjects whose coronary arteriograms were judged to be normal. Disappearance rates of (133)Xe from multiple areas of the heart were monitored externally with a multiple-crystal scintillation camera after the isotope had been injected into a coronary artery and local myocardial perfusion rates were calculated by the Kety formula. The mean myocardial perfusion rates in the left ventricle exceeded those in the right ventricle or atrial regions in subjects without demonstrable coronary artery disease. In this group there was a significant lack of homogeneity of local perfusion rates in left ventricular myocardium; the mean coefficient of variation of left ventricular local perfusion rates was 15.8%. In the patients with radiographically demonstrable coronary artery disease, a variety of myocardial perfusion patterns were observed. Local capillary blood flow rates were depressed throughout the myocardium of patients with diffuse coronary disease but were subnormal only in discrete myocardial regions of others with localized occlusive disease. Local myocardial perfusion rates were similar to those found in the group with normal coronary arteriograms in patients with slight degrees of coronary disease and in those areas of myocardium distal to marked coronary constrictions or occlusions which were well supplied by collateral vessels. In subjects with right coronary disease, the mean right ventricular perfusion rates were significantly subnormal; in seven subjects of this group perfusion of the inferior left ventricle by a dominant right coronary artery was absent or depressed. The average mean left ventricular perfusion rate of 12 subjects with significant disease of two or more branches of the left coronary artery was significantly lower than that of the group with normal left coronary arteriograms. In the patients with abnormal left coronary arteriograms, the average coefficient of variation of local left ventricular perfusion rates was significantly increased (24.8%). The studies provide evidence that coronary artery disease is associated with increased heterogeneity of local myocardial perfusion rates. They indicate that radiographically significant vascular pathology of the right or left coronary artery may be associated with significant reductions of myocardial capillary perfusion in the region supplied by the diseased vessel.

Increased renal secretion of norepinephrine and prostaglandin E2 during sodium depletion in the dog.

To determine whether vasoactive renal hormones modulate renal blood flow during alterations of sodium balance, simultaneous measurements of arterial and renal venous concentrations of norepinephrine and prostaglandin E2 (PGE2) and of plasma renin activity, as well as renal blood flow and systemic hemodynamics were carried out in 24 sodium-depleted and 28 sodium-replete anesthetized dogs. The mean arterial blood pressure of the sodium depleted dogs was not significantly different from that of the animals fed a normal sodium diet, but cardiac output was significantly lower (3.07 +/- 0.18 vs. 3.77 +/- 0.17 liters/min, mean +/- SEM; P < 0.01). Despite the higher total peripheral vascular resistance in the sodium-depleted dogs (46.1 +/- 2.9 vs. 37.0 +/- 2.1 arbitrary resistance U; P < 0.02), the renal blood flow and renal vascular resistance were not significantly different in the two groups. The arterial plasma renin activity and concentration of norepinephrine were higher in the sodium-depleted animals than in the controls; the arterial concentration of PGE2 was equal in both groups. The renal venous plasma renin activity was higher in the sodium-depleted dogs. Similarly, the renal venous norepinephrine concentration was higher in the sodium-depleted dogs than in the controls (457 +/- 44 vs. 196 +/- 25 pg/ml; P < 0.01); renal venous PGE2 concentration was also higher in the sodium depleted dogs (92 +/- 22 vs. 48 +/- 11 pg/ml; P < 0.01). Administration of indomethacin to five sodium-replete dogs had no effect on renal blood flow. In five sodium-depleted dogs indomethacin lowered renal blood flow from 243 +/- 19 to 189 +/- 30 ml/min (P < 0.05) and PGE2 in renal venous blood from 71 +/- 14 to 15 +/- 2 pg/ml (P < 0.02). The results indicate that moderate chronic sodium depletion, in addition to enhancing the activity of the renin-angiotensin system, also increases the activity of the renal adrenergic nervous system and increases renal PGE2 synthesis. In sodium-depleted dogs, inhibition of prostaglandin synthesis was associated with a significant decrease in renal blood flow. The results suggest that the renal blood flow is maintained during moderate sodium depletion by an effect of the prostaglandins to oppose the vasoconstrictor effects of angiotensin II and the renal sympathetic nervous system.

Respiratory adjustment to chronic metabolic alkalosis in man.

This study examined the ventilatory adjustment to chronic metabolic alkalosis induced under controlled conditions in normal human volunteers. Metabolic alkalosis induced by buffers (sodium bicarbonate, trishydroxymethylamine methane) or ethacrynic acid was associated with alveolar hypoventilation, as evidenced by a rise in arterial Pco(2), a fall in arterial Po(2), a reduced resting tidal volume, and a diminished ventilatory response to CO(2) inhalation. Alveolar hypoventilation did not occur when metabolic alkalosis was induced in the same subjects by thiazide diuretics or aldosterone despite comparable elevations of the arterial blood pH and bicarbonate concentration.The different ventilatory responses of the two groups could not be ascribed to differences among individuals comprising each group, pharmacological effects of the alkalinizing agents, differences in the composition of the lumber spinal fluid, changes in extracellular fluid volume, or sodium and chloride balance.The differences in ventilatory adjustments were associated with differences in the patterns of hydrogen and potassium ion balance during the induction of alkalosis. Alveolar hypoventilation occurred when hydrogen ions were buffered (sodium bicarbonate, trishydroxymethylamine methane) or when renal hydrogen ion excretion was increased (ethacrynic acid). Alveolar hypoventilation did not occur when induction of similar degrees of extracellular alkalosis was accompanied by marked potassium loss and no demonstrable increase in external hydrogen loss (thiazides and aldosterone).These observations suggest that respiratory depression does not necessarily accompany extracellular alkalosis but depends on the effect of the mode of induction of the alkalosis on the tissues involved in the control of ventilation.

Participation of the prostaglandins in the control of renal blood flow during acute reduction of cardiac output in the dog.

To determine whether renal prostaglandins participate in the regulation of renal blood flow during acute reduction of cardiac output, cardiac venous return was decreased in 17 anesthetized dogs by inflating a balloon placed in the thoracic inferior vena cava. This maneuver decreased cardiac output from 3.69+/-0.09 liters/min (mean+/-SEM) to 2.15+/-0.19 liters/min (P < 0.01) and the mean arterial blood pressure from 132+/-4 to 111+/-5 mm Hg (P < 0.01) and increased total peripheral vascular resistance from 37.6+/-2.5 to 57.9+/-4.8 arbitrary resistance units (RU) (P < 0.01). In marked contrast, only slight and insignificant decreases in the renal blood flow from 224+/-16 to 203+/-19 ml/min and renal vascular resistance from 0.66+/-0.06 to 0.61+/-0.05 arbitrary resistance units (ru) were observed during inflation of the balloon. Concomitant with these hemodynamic changes, plasma renin activity and plasma norepinephrine concentration increased significantly in both the arterial and renal venous bloods. Plasma concentration of prostaglandin E(2) in renal venous blood increased from 34+/-6 to 129+/-24 pg/ml (P < 0.01). The subsequent administration of indomethacin or meclofenamate had no significant effect on mean arterial pressure, cardiac output, and total peripheral vascular resistance, but reduced renal blood flow from 203+/-19 to 156+/-21 ml/min (P < 0.01) and increased renal vascular resistance from 0.61+/-0.05 to 1.05+/-0.21 ru (P < 0.01). Simultaneously, the plasma concentration of prostaglandin E(2) in renal venous blood fell from 129+/-24 to 19+/-3 pg/ml (P < 0.01). Administration of indomethacin to five dogs without prior obstruction of the inferior vena cava had no effect upon renal blood flow or renal vascular resistance. The results indicate that acute reduction of cardiac output enhances renal renin secretion and the activity of the renal adrenergic nerves as well as renal prostaglandin synthesis without significantly changing renal blood flow or renal vascular resistance. Inhibition of prostaglandin synthesis during acute reduction of cardiac output results in an increased renal vascular resistance and reduced renal blood flow. Accordingly, that data provide evidence that renal prostaglandins counteract in the kidney the vasoconstrictor mechanisms activated during acute reduction of cardiac output.

Human endometrial matrix metalloproteinase-2, a putative menstrual proteinase. Hormonal regulation in cultured stromal cells and messenger RNA expression during the menstrual cycle.

Proteinases are likely effectors of endometrial menstrual breakdown. We have investigated proteinase production by human endometrial stromal cells subjected in vitro to progesterone (P) withdrawal, the physiologic stimulus for menstruation. Culture media of cells exposed to estradiol, P, or estradiol plus P had low levels of proteolytic activity similar to cultures maintained in the absence of steroids. P withdrawal, or addition of RU486 to P-treated cultures, stimulated proteinase secretion. The stromal cell proteinase was characterized by gelatin zymography, inhibitor profile, and organomercurial activation, as a metalloproteinase present mostly as a 66-kD proenzyme with lower levels of a 62-kD active form. The P withdrawal-induced metalloproteinase was identified as matrix metalloproteinase-2 (MMP-2) by Western blotting. The increase of MMP-2 induced by P withdrawal was associated with the metalloproteinase-dependent breakdown of stromal cultures, involving dissolution of extracellular matrix and dissociation of stromal cells. Northern analysis showed the differential expression of MMP-2 mRNA in late secretory phase endometrium. These findings are consistent with the involvement of stromal cell-derived MMP-2 in the proteolysis of extracellular matrix promoting cyclic endometrial breakdown and the onset of menstrual bleeding.

Induction of myocardial nitric oxide synthase by cardiac allograft rejection.

Cardiac transplantation, effective therapy for end-stage heart failure, is frequently complicated by allograft rejection, the mechanisms of which remain incompletely understood. Nitric oxide (NO), a vasodilator which is cytotoxic and negatively inotropic, can be produced in large amounts by an inducible NO synthase (iNOS) in response to cytokines. To investigate whether iNOS is induced during cardiac allograft rejection, hearts from Lewis or Wistar-Furth rats were transplanted into Lewis recipients. At day 5, allogeneic grafts manifested reduced contractility and histologic evidence of rejection (inflammatory infiltrate, edema, necrosis of myocytes). The mRNA for iNOS and iNOS protein were detected in ventricular homogenates and in isolated cardiac myocytes from rejecting allogeneic grafts but not in tissue and myocytes from syngeneic control grafts. Immunocytochemistry showed increased iNOS staining in infiltrating macrophages and in microvascular endothelial cells and cardiac muscle fibers and also in isolated purified cardiac myocytes from the rejecting allografts. Using a myocardial cytosolic iNOS preparation, nitrite formation from L-arginine and [3H] citrulline formation from [3H]L-arginine were increased significantly in the rejecting allogeneic grafts (P < 0.01). Myocardial cyclic GMP was also increased significantly (P < 0.05). The data indicate myocardial iNOS mRNA, protein and enzyme activity are induced in infiltrating macrophages and cardiac myocytes of the rejecting allogeneic grafts. Synthesis of NO by iNOS may contribute to myocyte necrosis and ventricular failure during cardiac allograft rejection.