The effect of uterine stretch on first trimester abortions induced by extraovular prostaglandin impact

In 20 obstetrically normal 1st trimester pregnant volunteers abortion had been induced successfully in 19, by Prostaglandin-Impact (PGI) technique (1). A total average dose of 12.3±0.9 mg PG F2α, delivered into the extraovular (E.O.) space, reduced the plasma P levels from an initial value of 29.4±2.5 ng/ml to 12.8±1.6 ng/ml (P < 0.001) within 17.4±1.6 hours instillation-abortion time (IAT). Of the 20 women 13 aborted completely, 6 incompletely, and 1 progressed to 2 cm cervical dilatation: yielding an “Abortion Score” (AbS) of 86.0±4.6.Of the 20 gravidas, 10 only received PGI (Control Group), while the remaining 10 were exposed to uterine stretch, in addition to PGI (Experimental Group). Stretch had been accomplished by a “stretch balloon” filled with 200 ml saline. Comparing the Control and Experimental Groups revealed that stretch shortens the IAT and improves the AbS. This effect is very probably achieved through a stretch induced increase in the endogenous PG-synthesis of the uterus (1). This preliminary finding exposes the possibility, that pregnancy termination can be promoted by an increased involvement of endogenous PGs in the activation of the myometrium, provoked through stretch. The validity of this premise is under current examination.     

The efficacy of the extraovular “Prostaglandin-Impact” in provoking first trimester abortion

In good agreement with earlier findings (1–8) legal abortion had been induced successfully with Csapo's method of “Prostaglandin Impact” (PGI) in 44 out of 50 sedated patients. They were 25±1.1 years of age, 11.3±0.2 weeks pregnant, para 1.1±0.2. Only a PGI (10 mg PG F2α) was delivered into the extraovular space. In 44 women, this single PGI provoked 40% progesterone (P)-withdrawal in 3 hours (P < 0.001) and 64% P-withdrawal (P < 0.001) in 15.3±0.9 hours, when the patients aborted. The remaining 6 women, whose P-withdrawal was only 14% at 3 hours without continuation during 24 hours, failed to abort. Thus in PG-induced abortions the regulatory significance of rapid and continued P-withdrawal (1–8) had been verified.The side effects were mild, transient and acceptable. The “Abortion Score” was 86. There were no serious complaints or complications during the study and followup. Since even in the 6 cases of failure the cervix dilated sufficiently to allow curettage (without surgical dilatation), the therapeutic benefits of the single PGI technique should be further examined in those services, where constant medical supervision (for determining the necessity and timing of repeated PGI) is not available.     

Elucidation of Molecular Impediments in the α6 Subunit for in Vitro Expression of Functional α6β4* Nicotinic Acetylcholine Receptors

Explorations into the α6-containing nicotinic acetylcholine receptors (α6* nAChRs) as putative drug targets have been severely hampered by the inefficient functional expression of the receptors in heterologous expression systems. In this study, the molecular basis for the problem was investigated through the construction of chimeric α6/α3 and mutant α3 and α6 subunits and functional characterization of these co-expressed with β4 or β4β3 subunits in tsA201 cells in a fluorescence-based assay and in Xenopus oocytes using two-electrode voltage clamp electrophysiology. Substitution of a small C-terminal segment in the second intracellular loop or the Phe²²³ residue in transmembrane helix 1 of α6 with the corresponding α3 segment or residue was found to enhance α6β4 functionality in tsA201 cells significantly, in part due to increased cell surface expression of the receptors. The gain-of-function effects of these substitutions appeared to be additive since incorporation of both α3 elements into α6 resulted in assembly of α6β4* receptors exhibiting robust functional responses to acetylcholine. The pharmacological properties exhibited by α6β4β3 receptors comprising one of these novel α6/α3 chimeras in oocytes were found to be in good agreement with those from previous studies of α6* nAChRs formed from other surrogate α6 subunits or concatenated subunits and studies of other heteromeric nAChRs. In contrast, co-expression of this α6/α3 chimera with β2 or β2β3 subunits in oocytes did not result in efficient formation of functional receptors, indicating that the identified molecular elements in α6 could be specific impediments for the expression of functional α6β4* nAChRs.     

Immunoelectron microscopy studies with a monoclonal antibody directed against a receptor recognition site epitope in human α2-macroglobulin

α₂-Macroglobulin (α₂M) is a plasma proteinase inhibitor that binds up to 2 mole of proteinase per mole of inhibitor. Proteinase binding or reaction with small primary amines causes a major conformational change in α₂M. As a result of this conformational change, a new epitope recognized by monoclonal antibody 7H11D6 is exposed. The association of α₂M-proteinase or α₂M-methylamine with α₂M cellular receptors is prevented by 7H11D6. In this investigation, the binding of 7H11D6 to α₂M was studied by electron microscopy. 7H11D6 bound to α₂M-methylamine and α₂M-trypsin but not to native α₂M. The structure of α₂M after conformational change resembled the letter “H.” 7H11D6 epitopes were identified near the apices of the four arms in the α₂M “H” structure. 7H11D6 that was adducted to colloidal gold (7HAu) retained the specificity of the free antibody (binding to α₂M-trypsin but not to native α₂M). α₂M conformational change intermediates prepared by sequential reaction with a protein crosslinker and trypsin also bound 7HAu. These results suggest that a complete α₂M conformational change is not necessary for 7H11D6 epitope exposure and may not be required for receptor recognition. 7HAu was used to isolate a preparation consisting primarily of binary α₂M-trypsin (1 mole trypsin per mole α₂M instead of 2). Structures resembling the letter “H” were most common; however, each field showed some atypical molecules with arms that were compacted instead of thin and elongated. These incompletely transformed structures were similar to the α₂M conformational intermediates described previously (S. L. Gonias and N. L. Figler (1989) J. Biol. Chem. 264, 9565–9570). We propose that lateral arm extension is a critical step in α₂M conformational change. Failure of lateral arm extension is probably a common property of different α₂M conformational intermediates.     

The “interleukin 1 receptor antagonist” is a partial agonist of prostaglandin synthesis by human decidual cells

In many systems the interleukin-1 receptor antagonist opposes the effects of interleukin-1β. We considered that it might block interleukin-1β-stimulated prostaglandin production from human decidual cells. Very high levels of interleukin-1 receptor antagonist (>1000 pg/ml) had limited inhibitory effects on IL-1β-stimulated PGE2 synthesis, and lower levels of antagonist (<1000 pg/ml) increased the effects of IL-1β. Low concentrations of the antagonist alone (1–100 pg/ml) increased basal PGE2 production, whereas higher levels (10–100 ng/ml) had less effect. It seems, therefore, that in human decidua the “antagonist” is more accurately described as a partial agonist. It has been suggested that the IL-1 receptor antagonist could be used to inhibit decidual prostaglandin synthesis and thereby prevent preterm labor, but this report shows that caution should be exercised before using the receptor antagonist.     

Prostaglandin release from the guinea-pig uterus superfused in vitro. Effect of stage of estrous cycle, progesterone, estradiol, oxytocin and A23187

Prostaglandin (PG) E₂ was the major PG released from the superfused guinea-pig uterus on Day 7, followed by in descending order 6-oxo-PGF_1α, thromboxane (TX) B₂ and PGF_2α. However, the outputs of all four substances were low and were very similar. By Day 15, PGF_2α output from the superfused uterus had increased 21.9-fold, whereas the outputs of PGE₂, 6-oxo-PGF_1α and TXB₂ had increased only 1.8-, 2.9- and 1.2-fold, respectively. A mechanism is apparently “switched on” between Days 7 and 15 which causes a fairly specific increase in the release of PGF_2α from the uterus.Progesterone and/or estradiol had no effect on PG or TX release when superfused over the uterus on Day 7, nor did they have any effect on PG and TX release from the Day 15 uterus when administered separately. When administered together, however, they significantly inhibited PGF_2α, PGE₂ and 6-oxo-PGF_1α, but not TXB₂, release from the Day 15 uterus. Oxytocin had no effect on PG release from the Day 7 or Day 15 uterus, while A23187 stimulated PGF_2α, 6-oxo-PGF_1α and, to a lesser extent, PGE₂ release from the uterus on both Days 7 and 15 Oxytocin is apparently not important for stimulating PGF_2α release from the guinea-pig uterus in relation to luteolysis, whereas increasing intracellular free Ca⁺⁺ levels may be part of the mechanism for “switching on” uterine PG synthesis. Furthermore, changes in intracellular free Ca⁺⁺ levels in the endometrium may be responsible for the pulsatile nature of PGF_2α release from the uterus.     

An Enzyme-Linked Lectin Assay for α1,3-Galactosyltransferase

UDP-Gal:Galβ1-4GlcNAc α1,3-galactosyltransferase (α3GalT) is responsible for the synthesis of carbohydrate xenoantigen Galα1-3Galβ1-4GlcNAc. In this work a convenient and sensitive assay system for quantification of α3GalT activity by enzyme-linked lectin assay (ELLA) with colorimetric detection is described. Microtiter plate wells whose surface had been coated with the polyacrylamide conjugate of the disaccharide Galβ1-4GlcNAc (acceptor) are incubated with α3GalT in the presence of “cold” UDP-Gal as glycosyl donor. Formation of product by enzymatic extension of the glycan chain is detected by the biotinylated plant lectin Viscum album agglutinin. The standard curve for correct quantification of α3GalT activity is completed after running standard assays with no (background) or known quantities of enzyme activity. Product formation detected in this manner is proportional to enzyme activity and the concentrations of the acceptor and the glycosyl-donor UDP-Gal. In accordance with the known specificity of α3GalT, no enzymatic conversion of Le^x into GalαLe^x was observed using this assay. Human αGal antibodies were isolated using a disaccharide-exposing affinity adsorbent and their specificity was studied. Relative to the application of these natural immunoglobulins as product-detecting tool, the ELLA proved to be more sensitive.     

The abortifacient action of the extraovular “Prostaglandin impact” during the first half of human pregnancy

In 30 volunteers, 7 to 22 weeks pregnant, legal abortion had been induced successfully with the extraovular “Prostaglandin Impact” (PGI) (1). The patients were 24.8±1.1 years old (Means ± S.E.), para 1.6±0.3. At the 14.8±0.7 weeks of pregnancy and under sedation an initial dose of 10.0±0.0 mg PG F2α had been delivered transcervically into their extraovular (E.O.) space. This dose had been increased if accidental rupture of their fetal membranes resulted in intraamniotic (I.A.) treatment. The initial PGI of 16.0±2.0 mg was supplemented by additional PG doses, up to 27.0±2.9 mg, if clinical progress was slow. The patients responded to the initial PGI with sustained uterine contracture; rapid and continued progesterone (P) withdrawal, from 59.9±3.0 ng/ml to 30.7±2.1 ng/ml (49%); and with the progress of time high level cyclic intrauterine pressure (IUP). The 26% P-withdrawal, measured 3 hours after PGI was already significant (P < 0.001). Abortion was complete in 25 and incomplete in 4 patients, while 1 gravida had been curetted at 2 cm cervical dilatation. The instillation-abortion time (IAT) was short, only 13.0±1.1 hours. No side effects were observed in 17 patients, while 8 gravidas vomited (usually once) and 5 had transient increase in blood pressure. Extensive laboratory tests revealed no significant deviations from normality, during and after PG treatment. Blood transfusion was given to 2 patients (partly detached placentae and hemorrhage), antibiotics resolved 2 cases of endometritis and curettage removed (2 weeks after abortion) a small placental residue.The fetal membranes were accidentally ruptured in 11 patients and in these women the slow contracture response of the uterus signaled I.A. (rather than E.O.) PGI. The initial PG dose was increased, therefore, from 10.0±0.0 mg to 25.9±3.9 mg (P < 0.001) and the total dose from 20.0±2.0 to 42.3±4.8 mg (P < 0.001), to compensate for the lesser efficacious I.A. administration. In spite of this massive increase in the initial and total doses of PG, the rate and degree of P-withdrawal, the IAT, the incidence of side effects and the “Abortion Score” (AbS) of these 11 patients were similar to those of the 19 gravidas who received E.O. PGI. This finding, the good clinical outcome of the earlier (1) and the present study suggests that the transcervical E.O. PGI (regardless of accidental I.A. treatment) is a recommendable procedure for the non-surgical termination of pregnancy during the 1st half of gestation.     

Activated Rac1 Selectively Up-regulates the Expression of Integrin α6β4 and Induces Cell Adhesion and Membrane Ruffles of Nonadherent Colon Cancer Colo201 Cells

Functions of small GTPases in integrin expression were investigated when the interaction of nonadherent human colon carcinoma 201 cells with the extracellular matrix (ECM) was examined. By transfection of the constitutively active form of a small GTPase Rac1, Rac V12, adhesion of cells to the ECM increased with concomitant cell spreading and formation of membrane ruffles. Activated Cdc42 and Cdc42 V12, but not wild-type Rac1, Cdc42, or RhoA, also induced the adhesion and spreading of Colo201 cells. This adhesion is integrin β4 dependent since an antibody for integrin β4 inhibited the RacV12-dependent cell adhesion and numbers of adhesive cells on laminin-coated plates exceeded those on collagen- and fibronectin-coated plates. By immunofluorescence, in addition to clustering of integrin molecules, expression of integrin α6β4 on the cell surface of Rac V12- and Cdc42 V12-expressing cells was selectively up-regulated without an increase in biosynthesis of α6β4 integrin. Treatment of Rac V12-expressing cells with wortmannin or LY294002, specific inhibitors of phosphoinositide 3-OH kinase, decreased the up-regulated α6β4 and cell adhesion. In light of this evidence, we propose that the regulation of integrin α6β4 expression induced by Rac1 and Cdc42 may play an important role in cell adhesion and tumorigenesis of colon carcinoma cells.     

Glucuronic acid conjugates

The methods of assay in body fluids of 1-β-alkyl, 1-β-phenyl and 1-β-acyl glucuronic acids (“glucuronide conjugates”) have been reviewed. Most of the 78 references cited (from the literature of the period 1990–1997) concern the glucuronide conjugates of drug metabolites, and these have been considered, for reasons of accessibility, within sections of individual drug classes such as analgesics, anti-cancer agents and opioids. Other glucuronide conjugates are considered under “miscellaneous compounds”. A few gas chromatography and capillary electrophoresis methods are described, but the major technique of assay (62 citations) is reversed-phase high-performance liquid chromatography.     

Prostacycin production by arterialized autogenous venous grafts in dogs

Arteries are capable of producing significantly larger quantities of protacyclin than are veins. To test the hypothesis, whether prostacyclin production by the vessel wall is related to blood pressure and flow, we measured the amounts of PGI₂ released and synthesized by venous segments transplanted for 6 weeks into the arterial circulation. These results were compared with the production of prostacyclin by normal veins and arteries. In 20 dogs a segment of jugular vein was interposed into the carotid system; a sham dissection was done on the opposite side. “Arterialized” vein grafts showed prominent intima lined by endothelium, medial smooth muscle cell proliferation and fibrotic proliferation in adventitia. Spontaneous and arachidonic acid- stimulated prostacyclin production (measured by radioimmunoassay for 6-keto-PGF_1α) was not significantly different between arterialized venous autografts and jugular veins. Significantly larger amounts of prostacyclin were synthesized by the carotid artery. Thus, histologic changes and rheologic effects occurring in vein grafts transposed to the arterial site do not affect prostacyclin production.     

The effects of danazol mefanamic acid, norethistherone and a progesterone-impragnated coil on endometrial prostaglandin concentrations in women with monorrhagia

The effects of our four medical treatments have been assessed on menstrual blood loss (MBL) and endometrial prostaglandin (PG) concentrations in 30 women with objectively confirmed menorrhagia. Patients were randomly treated with danazol, 200mg daily (n=6), mefanamic acid, 500mg three times daily during menses (n=8), norethisterone, 5mg twice daily from day 15–25 of the cyle (n=8) or a progesterone-impregnated coil releasing 65ug progesterone daily (n=8). Endometrial biopsies were obtained in the mid-luteal phase before and after treatment in 23 cases, and assayed for PG content using radioimmunoassay. Treatment with norethisterone had no effect on either MBL or the concentration of PGs in the endometrium. MBL was significantly reduced after treatment with mefanamic acid (P=0.05, n=6) and the progesterone coil (P0.05, n=6), was reduced in each of 4 cases treated with danazol in whom endometrial biopsies were available. Although there was no consistent change in endometrial PG cocentrations in either the mefamic acid or danazol groups, the lower MBL after insertion of the progesterone coil was associated with a reduced endometrial content of PGE, PGF_2α and “total” PG (6oxo PGF_1α+PGE+PGE_2α)−P=0.05. Wherease the cyclooxygenase inhibitor mefenamic acid is likely to exert its effect on endometrial PGs at the time of menstruation itself, the continous administration of progesterone throught the menstrual cycle could result in both an impairment in estrogen receptor generation leading to reduced estrogen-mediated cyclooxygenase activity, and an increase in endometrial PG metabolism.     

Effect of Silodosin,an Alpha1A-Adrenoceptor Antagonist,on Ventral Prostatic Hyperplasia in the Spontaneously Hypertensive Rat

Background

A decreased prostatic blood flow could be one of the risk factors for benign prostatic hyperplasia/benign prostatic enlargement. The spontaneously hypertensive rat (SHR) shows a chronic prostatic ischemia and hyperplastic morphological abnormalities in the ventral prostate. The effect of silodosin, a selective alpha_1A-adrenoceptor antagonist, was investigated in the SHR prostate as a prostatic hyperplasia model focusing on prostatic blood flow.

Methods

Twelve-week-old male SHRs were administered perorally with silodosin (100 μg/kg/day) or vehicle once daily for 6 weeks. Wistar Kyoto (WKY) rats were used as normotensive controls and were treated with the vehicle. The effect of silodosin on blood pressure and prostatic blood flow were estimated and then the prostates were removed and weighed. The tissue levels of malondialdehyde (MDA), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 1/cytokine-induced neutrophil chemoattractant 1 (CXCL1/CINC1), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta 1 (TGF-β1), basic fibroblast growth factor (bFGF) and alpha-smooth muscle actin (α-SMA) were measured. The histological evaluation was also performed by hematoxylin and eosin staining.

Results

There was a significant increase in blood pressure, prostate weight, prostate body weight ratio (PBR), tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA in the SHR compared to the WKY rat. The ventral prostate in the SHR showed the morphological abnormalities compared to the WKY rat. Prostatic blood flow was decreased in the SHR. However, treatment with silodosin significantly restored the decreased prostatic blood flow in the SHR. Moreover, silodosin normalized tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA, and it ameliorated ventral prostatic hyperplasia in the SHR excluding blood pressure. Silodosin decreased PBR but not prostate weight in the SHR.

Conclusions

Silodosin can inhibit the progression of prostatic hyperplasia through a recovery of prostatic blood flow.     

The mechanism of prostaglandin action on the early pregnant human uterus

To extend observations in 11 weeks pregnant patients⁽¹⁾ the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 g (15S)-methyl PGF2α methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 g 16-phenoxy-ω-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 ± 154 g.The PGF2α and PGE₂-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversibly compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the “ideal” method of non-surgical menstrual induction.     

Anergic Pulmonary Tuberculosis Is Associated with Contraction of the Vd2+T Cell Population,Apoptosis and Enhanced Inhibitory Cytokine Production

Objective

To study the association of anergic pulmonary tuberculosis with Vδ2⁺ T cells and related cytokine levels.

Methods

82 pulmonary tuberculosis patients were divided into two groups according to their purified protein derivative tuberculin skin test (TST) results: 39 with TST-negative anergic pulmonary tuberculosis and 43 with TST-positive pulmonary tuberculosis, while 40 healthy volunteers were used as control. Based on chest X-ray results, the tuberculosis lesions were scored according to their severity, with a score of ≤ 2.5 ranking as mild, 2.5-6 as moderate and ≥ 6 as severe. The Vδ2⁺ T cell percentage and their expression levels of the apoptosis-related membrane surface molecule FasL in peripheral blood and bronchoalveolar lavage fluids (BALF) were analyzed by flow cytometry, while IL-2, IL-4, IL-6 and IL-10 cytokine and γ-interferon (γ-IFN) concentrations in peripheral blood were determined by ELISA.

Results

Most of the patients with chest X-ray lesion scores higher than 6 belonged to the anergic tuberculosis group (P<0.05). Anergic pulmonary tuberculosis patients displayed reduced peripheral blood Vδ2⁺ T cell counts (P<0.05) and higher FasL expression in peripheral blood Vδ2 ⁺ T cells (P <0.05). The Vδ2⁺ T cell percentages in the BALF of all tuberculosis patients were lower than in their peripheral blood (P <0.05), and IL-4 and IL-10 concentrations in peripheral blood of anergic tuberculosis patients were higher than in TST-positive tuberculosis patients and healthy controls (P <0.05).

Conclusion

Anergic pulmonary tuberculosis is accompanied by reduced Vδ2⁺ T cell percentage, and elevated Vδ2⁺ T cell FasL expression as well as enhanced IL-4 and IL-10 levels in peripheral blood.     

Disturbance of the OPG/RANK/RANKL pathway and systemic inflammation in COPD patients with emphysema and osteoporosis

Background

Osteoporosis is one of the systemic features of COPD. A correlation between the emphysema phenotype of COPD and reduced bone mineral density (BMD) is suggested by some studies, however, the mechanisms underlying this relationship are unclear. Experimental studies indicate that IL-1β, IL-6 and TNF-α may play important roles in the etiology of both osteoporosis and emphysema. The OPG/RANK/RANKL system is an important regulator of bone metabolism, and participates in the development of post-menopausal osteoporosis. Whether the OPG/RANK/RANKL pathway is involved in the pathogenesis of osteoporosis in COPD has not been studied.

Methods

Eighty male patients (current or former smokers) completed a chest CT scan, pulmonary function test, dual x-ray absorptiometry measurements and questionnaires. Among these subjects, thirty patients with normal BMD and thirty patients with low BMD were selected randomly for measurement of IL-1β, IL-6, TNF-α (flow cytometry) and OPG/RANK/RANKL (ELISA). Twenty age-matched healthy volunteers were recruited as controls.

Results

Among these eighty patients, thirty-six had normal BMD and forty-four had low BMD. Age, BMI and CAT score showed significant differences between these two COPD groups (p < 0.05). The low-attenuation area (LAA%) in the lungs of COPD patients was negatively correlated with lumbar vertebral BMD (r = 0.741; p < 0.0001). Forward logistic regression analysis showed that only LAA% (p = 0.005) and BMI (p = 0.009) were selected as explanatory variables. The level of IL-1β was significantly higher in the COPD patients as compared to the normal controls (p < 0.05), but the difference between the two COPD groups did not reach significance. The levels of IL-6 and TNF-α among the three groups were significantly different (p < 0.05). The level of RANKL and the RANKL/OPG ratio were significantly higher in COPD patients with low BMD compared to those with normal BMD and the normal controls (p < 0.05), and correlated negatively with lumbar vertebral BMD, but positively with LAA%.

Conclusions

Radiographic emphysema is correlated with low BMD in current and former smokers with COPD. IL-1β, IL-6, TNF-α, and the osteoporosis-related protein system OPG/RANK/RANKL may have some synergetic effects on emphysema and bone loss in COPD.     

Effects of prostaglandins on the cerebral circulation in the goat

The role of prostaglandins in producing cerebrovasodilation during hypercapnia was tested in goats. Cerebral blood flow (CBF) changes with increasing arterial PCO2 were measured before and after prostaglandin synthesis inhibition with indomethacin or ibuprofen. Both drugs produced significant decreases in CBF under control anesthetized conditions but had no significant effect on the cerebrovascular response to increased arterial PCO2. The effects of direct intracerebrovascular infusion of prostaglandin E₂ (PGE2), prostaglandin F2α (PGF2α) and prostacyclin were also measured. In the dose range tested (0.1–1 ug/min) PGF2α had no significant effect on cerebral blood flow (CBF). Both PGE2 and PGI2 produced an increase in CBF and the increase produced by PGI2 was significantly greater than that produced by PGE2. The effectiveness of each compound in producing cerebrovascular changes is consistent with the endogenous distribution of prostaglandins within the brain. These results suggest that prostaglandins, particularly PGI1, may be important in modulating cerebrovascular tone but have no role in increasing CBF during hypercapnia.     

The fast–slow continuum and mammalian life-history patterns: an empirical evaluation

The fast–slow continuum hypothesis has been proposed to explain the diversity of life-history patterns exhibited by biological populations, but the quantification and population-dynamic consequences of the continuum has remained unclear. I used the ratio of fertility rate to age at first reproduction (F/α ratio) to quantify the tempo of life-history of 138 populations of mammals, and investigated the life-history and population-dynamic consequences of being “fast” or “slow”. “Fast” mammals (F/α>0.60) were characterized by early maturity, short lifespans, low survival rates, and high fertility and projected population growth rate (λ) compared to “slow” (F/α<0.15) mammals. In “fast” populations, λ was overwhelmingly most sensitive to changes in reproductive parameters (age at first reproduction and fertility rates) and relatively insensitive to changes in survival rates. In “slow” populations, λ was very sensitive to changes in juvenile or adult survival rates, and relatively insensitive to changes in reproductive parameters. The pattern of relationships between the F/α ratio and life-history variables, λ, and elasticity of λ to changes in life-history variables persisted even after the effects of body size and phylogeny were statistically removed. These results suggest that fast–slow continuum in mammalian life-history is independent of body size or phylogeny, that the F/α ratio adequately quantifies the position of a population along a fast–slow continuum, and that the tempo of life- histories has substantial population-dynamic consequences.

Zusammenfassung

Die r-K-Kontinuum-Hypothese wurde aufgestellt, um die Diversität von ,,life-history“-Mustern biologischer Populationen zu erklären, aber die Quantifizierung und die Kosnsequenzen für die Populationsdynamik des Kontinuums blieben unklar. Ich benutze das verhältnis der Fortpflanzungsrate zum Fortpflanzungsalter (F/α-Verhältnis) um die Geschwindigkeit der ,,life-history“ von 138 Populationen von Säugetieren zu quantifizieren und untersuchte die Konsequenzen fur die Lebensweise sowie die Populationsdynamik des,,schnell“oder,,langsam “-Seins. ,,Schnelle“Säugetiere (F/α>0.60) waren durch eine frühe Reife, kurze Lebenszeiten, geringe Überlebensraten sowie durch eine große Fertilität und hochgerechnete Populationswachstumsrate (λ) im Vergleich zu ,,langsamen“(F/α<0.15) Säugetieren charakterisiert. In ,,schnellen“ Population reagierte (λ) überwältigend sensibel auf Änderungen in den Fortpflanzungsparametern (Fortpflanzunsalter und Fertilitätsrate) und relativ gering auf Veräanderungen in der Überlebensrate. In ,,langsamen“ Populationen reagierte (λ) sehr sensibel auf Veräanderungen in den reproduktiven Parametern. Das Muster der Beziehung zwischen dem (F/α-Verhältnis) und den Variablen der ,,life-history“,λ, und die Elastizität von λ gegenüber Veränderungen in den variablen der Lebensweise bliev sogar bestehen, nachdem die Effekte von Körpergröße und Phylogenese statistisch eliminiert wurden. Diese Ergebnisse lassen vermuten, dass das r-K-Kontinuum in der ,,life-history“der Säugetiere unabhängig von der Körpergröße und Phylogenie ist, dass das F/α-Verhältnis die Position einer Population im r-K-Kontinuum quantifiziert und dass die Geschwindigkeit der,,life-history“beachtliche konsequenzen fur die Populationsdynamik hat.     

Ocular blood flow decreases during passive heat stress in resting humans

Background

Heat stress induces various physiological changes and so could influence ocular circulation. This study examined the effect of heat stress on ocular blood flow.

Findings

Ocular blood flow, end-tidal carbon dioxide (P_ETCO₂) and blood pressure were measured for 12 healthy subjects wearing water-perfused tube-lined suits under two conditions of water circulation: (1) at 35°C (normothermia) for 30 min and (2) at 50°C for 90 min (passive heat stress). The blood-flow velocities in the superior temporal retinal arteriole (STRA), superior nasal retinal arteriole (SNRA), and the retinal and choroidal vessels (RCV) were measured using laser-speckle flowgraphy. Blood flow in the STRA and SNRA was calculated from the integral of a cross-sectional map of blood velocity. P_ETCO₂ was clamped at the normothermia level by adding 5% CO₂ to the inspired gas. Passive heat stress had no effect on the subjects’ blood pressures. The blood-flow velocity in the RCV was significantly lower after 30, 60 and 90 min of passive heat stress than the normothermic level, with a peak decrease of 18 ± 3% (mean ± SE) at 90 min. Blood flow in the STRA and SNRA decreased significantly after 90 min of passive heat stress conditions, with peak decreases of 14 ± 3% and 14 ± 4%, respectively.

Conclusion

The findings of this study suggest that passive heat stress decreases ocular blood flow irrespective of the blood pressure or arterial partial pressure of CO₂.     

Linking Power Doppler Ultrasound to the Presence of Th17 Cells in the Rheumatoid Arthritis Joint

Background

Power Doppler ultrasound (PDUS) is increasingly used to assess synovitis in Rheumatoid Arthritis (RA). Prior studies have shown correlations between PDUS scores and vessel counts, but relationships with T cell immunopathology have not been described.

Methodology/Principal Findings

PBMC were isolated from healthy controls (HC) or RA patients and stimulated ex vivo with PMA and ionomycin for 3 hours in the presence of Golgistop. Paired synovial fluid (SF) or synovial tissue (ST) were analysed where available. Intracellular expression of IL-17, IFNγ, and TNFα by CD4+ T cells was determined by flow cytometry. Synovial blood flow was evaluated by PDUS signal at the knees, wrists and metacarpophalangeal joints of RA patients. Serum, SF and fibroblast culture supernatant levels of vascular endothelial growth factor-A (VEGF-A) were measured by ELISA. The frequency of IL17+IFNγ-CD4+ T cells (Th17 cells) was significantly elevated in peripheral blood (PB) from RA patients vs. HC (median (IQR) 0.5 (0.28–1.59)% vs. 0.32 (0.21–0.54)%, p = 0.005). Th17 cells were further enriched (mean 6.6-fold increase) in RA SF relative to RA PB. Patients with active disease had a higher percentage of IL-17+ T cells in ST than patients in remission, suggesting a possible role for Th17 cells in active synovitis in RA. Indeed, the percentage of Th17 cells, but not Th1, in SF positively correlated with CRP (r = 0.51, p = 0.04) and local PDUS-defined synovitis (r = 0.61, p = 0.002). Furthermore, patients with high levels of IL-17+CD4+ T cells in SF had increased levels of the angiogenic factor VEGF-A in SF. Finally, IL-17, but not IFNγ, increased VEGF-A production by RA synovial fibroblasts in vitro.

Conclusions/Significance

Our data demonstrate a link between the presence of pro-inflammatory Th17 cells in SF and local PDUS scores, and offer a novel immunological explanation for the observation that rapid joint damage progression occurs in patients with persistent positive PDUS signal.