Autumn Weather and Winter Increase in Cerebrovascular Disease Mortality.

Mortality from cerebrovascular disease increases in winter but the cause is unclear. Ireland's oceanic climate means that it infrequently experiences extremes of weather. We examined how weather patterns relate to stroke mortality in Ireland. Seasonal data for Sunshine (% of average), Rainfall (% of average) and Temperature (degrees Celsius above average) were collected for autumn (September-November) and winter (December-February) using official Irish Meteorological Office data. National cerebrovascular mortality data was obtained from Quarterly Vital Statistics. Excess winter deaths were calculated by subtracting (nadir) 3rd quarter mortality data from subsequent 1st quarter data. Data for 12 years were analysed, 2002-2014. Mean winter mortality excess was 24.7%. Winter mortality correlated with temperature (r=.60, p=0.04). Rise in winter mortality correlated strongly with the weather in the preceding autumn (Rainfall: r=-0.19 p=0.53, Temperature: r=-0.60, p=0.03, Sunshine, r=0.58, p=0.04). Winter cerebrovascular disease mortality appears higher following cool, sunny autumns.

In-hospital stroke: characteristics and outcomes.

In-hospital stroke (IS) made up 6.5% of strokes recorded in the Irish National Stroke Register in 2012. International research has demonstrated poorer outcomes post IS compared to out of hospital stroke (OS). We aimed to profile all IS and OS over a 22 month period and compare the two groups by gathering data from the HIPE portal stroke register. The study site is a primary stroke centre. IS represented 11% (50/458) of total strokes with over half (27/50, 54%) admitted initially with medical complaints. IS patients had a significantly longer length of stay (79.2 +/- 87.4 days vs. 21.9 +/- 45.9 days, p < 0.01) and higher mortality (13/50 vs. 39/408, p < 0.01). Patients in the IS group were also less likely to receive stroke unit care (1/50 vs. 136/408, p < 0.01). This study demonstrates the significant morbidity and mortality associated with IS and highlights the need for efforts to be made to optimize identification and management of acute stroke in this cohort.

The role of professional associations in reducing maternal mortality worldwide.

The death of hundreds of thousands of women due to pregnancy-related complications casts a shadow over the modern obstetrical world. This paper examines the potential roles and responsibilities of professional obstetrical and midwifery associations in addressing this tolerated tragedy of maternal deaths. We examine the successes and challenges of obstetrical and midwifery associations and encourage the growth and development of active associations to address maternal mortality within their own borders. Professional associations can play a vital role in the reduction of maternal mortality worldwide. Their roles include lobbying for women's health and rights, setting standards of practice, raising awareness and team building. Associations from developed countries can influence and strengthen their colleagues within developing countries; for example, the FIGO Save the Mothers initiative. Professional associations should be encouraged to play an active role in reducing maternal mortality within their own country and abroad.

Lying in the bed we've made: reflection on some unintended consequences of clinical practice guidelines in the courts.

Evidence on the use of clinical practice guidelines to aid in the legal determination of negligence is increasing, specifically where they affect determinations of the standard of care and causation. So too is evidence that some clinical practice guidelines are of poor quality. An action alleging the negligent failure to diagnose and treat gestational diabetes in 1988, in which the neonate suffered permanent brachial plexus injury, entered into evidence a 1984 clinical practice guideline authored by the Society of Obstetricians and Gynaecologists of Canada. No "experts" were called to adjudicate the quality of this guideline, which cited no evidence or rationale in support of its recommendations. The standard as laid out in the guideline was judged by the court to reflect a prevailing standard of care, and a finding of negligence was rendered. As the courts pay increased attention to clinical practice guidelines, critical appraisal by the professional organizations developing these documents must occur to assure methodological rigour. Further, the quality of clinical practice guidelines should receive critical scrutiny by the courts if they are to be relied upon, even partially, to assist with legal determinations of the standard of care or issues under causation.

The quality of obstetrical clinical practice guidelines promulgated by a specialty society.

OBJECTIVE: To review the methodologic quality of all obstetrical clinical practice guidelines developed by the Society of Obstetricians and Gynaecologists of Canada (SOGC) from 1992 to August 2001. METHODS: Three reviewers independently assessed each of 37 guidelines according to a validated and reliable 37-item appraisal tool. A mean "global" score as well as three "dimension" scores were calculated for each guideline. The appraisal tool assessed each document according to three dimensions, which related to the rigour of its development (Dimension 1), its context and content (Dimension 2), and its application (Dimension 3). A repeated-measures analysis of variance was used to derive the interclass correlation coefficient. RESULTS: Mean global quality scores ranged from 8.1% to 54.0%. Only two guidelines were given a mean global score above 50% and 21 of the guidelines (56.8%) had mean global scores of less than 30%. Mean dimension scores were 19.9% for Dimension 1, relating to rigour of development, 47.3% for Dimension 2, relating to context and content, and 27.2% for Dimension 3, relating to application. The interclass correlation coefficient using a fixed-effects model was 0.72, reflecting reasonable agreement between the reviewers. CONCLUSION: Both the mean global scores and mean dimension-specific scores for the obstetrical clinical practice guidelines were lower than optimal. We were unable to reveal statistically significant improvements in guideline quality over time given the limited number of documents, but the scores for more recently drafted guidelines appear generally higher than earlier guidelines. This finding is consistent with new editorial policy adopted by the SOGC regarding guideline development. A broader review should be conducted by the SOGC on guidelines in development and under revision.

Platelet count may predict abnormal bleeding time among pregnant women with hypertension and preeclampsia.

BACKGROUND: Anesthesiologists often require laboratory data to estimate the bleeding risk among hypertensive pregnant women prior to administering regional anesthesia. Many rely on the bleeding time (BT) in making this determination. We examined whether the platelet count can adequately predict BT among a group of hypertensive parturients. METHODS: This retrospective subgroup analysis, taken from a cohort of 2,051 hypertensive pregnant women, comprises 87 individuals who underwent both a BT and platelet count prior to delivery. We calculated the correlation between the platelet count and BT at three platelet cut-off points with respect to prolonged BT of eight minutes or more. RESULTS: There was a significant negative correlation between platelet count at delivery and BT [r= -0.45, 95% confidence interval (CI) -0.26 to -0.60; P <0.0001]. All three platelet cut-off points had a sensitivity of less than 66% with negative predictive values below 75% for an abnormal BT. A platelet count > or =75 x 109/L [corrected] was specific for the presence of an abnormal BT (specificity 97.8%, 95% CI 91.7-100.0), with a positive predictive value of 95.5% (95% CI 83.1-100.0) and a positive likelihood ratio of 24 (95% CI 3.3-168). CONCLUSIONS: In a group of hypertensive parturients, the platelet count appears to be very specific for predicting a prolonged BT The platelet count may aid the anesthesiologist in determining the risk of bleeding from regional anesthesia. Given the study's potential for bias future research is needed to validate these findings.

Detection of [U-13C]eicosapentaenoic acid in rat liver lipids using 13C nuclear magnetic resonance spectroscopy.

Fatty acid carbons are well-resolved in 13C nuclear magnetic resonance (NMR) spectra of lipid extracts, but application of this methodology to the metabolism of 13C-labelled fatty acids has not yet been reported. In the present study, 13C NMR was used to monitor the presence of 98% [U-13C]eicosapentaenoic acid (EPA) in liver and carcass lipids 24 h after it had been injected into the stomach of a rat. Natural abundance 13C NMR spectra of liver total fatty acid extracts were obtained from four control rats for comparison. At 24 h post-injection, quantitative high resolution 13C NMR showed 13C enrichment in liver fatty acid extracts was present mainly at olefinic and at the n-1 to n-4 carbons, but 13C signal intensities for C-1 to C-4 of [U-13C]EPA were markedly reduced or absent. Small 13C resonances, possibly indicative of some 13C incorporation into docosahexaenoic acid and saturated or monounsaturated fatty acids, were present in spectra of liver fatty acids. Liver and carcass fatty acid composition was similar in both the controls and the EPA-injected rat, suggesting little accumulation of the injected [U-13C]EPA after 24 h. We conclude that the carbon-specific data provided by 13C NMR of lipid extracts may be useful in monitoring the fate of individual carbons during tracer studies using 13C-labelled fatty acids.

Immunochemical studies of human factor XIII.

Plasma factor XIII circulates as a noncovalently associated, tetrameric zymogen (a2b2). The b subunit may act as a carrier protein for the a subunit, which possesses the potential catalytic function. In order to define interactions that occur between the two subunits, a sensitive and specific RIA for the b subunit has been developed. Purified plasma factor XIII was incubated with thrombin and chromatographed on organomercurial agarose to separate the subunits. Pure b chain eluted in buffer containing CaCl2. This material was used as the standard b preparation, both for preparing a monospecific antiserum and for establishing the assay. The linear range of the assay is 7 to 700 ng/ml (Ca. 0.1 to 10 nM b subunit), with a minimum detectable dose of l. Data were analyzed by use of the logit-log transformation of antigen-binding curves. The dose-response slope for standard b is -2.76 + or - 0.20, with a potency (ED50) of 74.9 + or - 6.5 ng/ml. This RIA is also valid for determining b subunit concentration of plasma and serum. The dose-response slope for the plasma system is -2.69 + or - 0.20 with an ED50 identical to that of the purified system. By this method the mean b subunit concentration in normal human plasma (corrected for anticoagulant) is 13.8 micro g/ml (ca. 0.15 micro M). The concentration in serum is 13.6 micro g/ml, which shows that b subunit is quantitatively recovered after coagulation has occurred.

In vivo radiolabeling of platelet proteins: a new method with identification of platelet factor XIII.

A method for radiolabeling platelets in vivo was developed in which 3H-arginine was injected into the bone marrow of normal dogs. On the third day after injection, a maximum of 6%--7% of the radioactivity had been incorporated into the total platelet mass. This method of isotope administration resulted in a 50--60-fold increase in maximum uptake of radiolabel by platelets, as compared to values obtained by others using intravenous injections of various radioactive compounds. Tritium-labeled platelets were harvested from the animals and then were washed to remove unbound 3H-arginine. On polyacrylamide gel electrophoresis 7 labeled protein bands, with molecular weights ranging from 29,000to 132,000, were obtained from the platelet-soluble fraction. One 3H-containing protein with a molecular weight of 81,000 was identified immunologically and enzymatically as platelet factor XIII.

Fibrinogen Chapel Hill: hypodysfibrinogenemia with a tertiary polymerization defect.

A patient with a functionally defective fibrinogen (fibrinogen Chapel Hill) has been investigated. Fibrinogen Chapel Hill is characterized by hypofibrinogenemia, with a plasma concentration about one third of normal, as measured both functionally and immunochemically. Fibrinogen survival is normal; so also is fibrinopeptide release. A polymerization defect in this fibrinogen results in the delay of fibrin fibrils in solution to form a normal three-dimensional gel. This defect is not associated with end-to-end aggregation or with lateral associations in solution. Delayed gelation results from an abnormality in a tertiary contact site involved in network branching, which is associated with the hydrophilic, carboxy-terminal segment of the alpha chain. Fibrinogen Chapel Hill exhibits two additional abnormal responses, which are also associated with the same region. The early plasmin cleavages of fibrinogen and fragment X are delayed, and there is a concomitant delay in the appearance of fragments Y, D, and E. This fibrinogen also has an unusual sensitivity to Ancrod proteolysis, whereby Ancrod cleaves a large carboxy-terminal segment of the alpha chain more rapidly than in normal fibrinogen. The abnormalities in fibrinogen Chapel Hill can be explained by a structural abnormality which is functionally related to an alpha chain associated polymerization domain.

Difference between type I autoimmune inhibitors of fibrin stabilization in two patients with severe hemorrhagic disorder.

Inhibitors of fibrin stabilization of apparently autoimmune origin, found in two severely bleeding unrelated patients (W. G. and G. A.), were compared with regard to their biological target specificities, potencies and immunological characteristics. Both interfered only with the activation of fibrin stabilizing factor (coagulation Factor XIII) and, while totally preventing the conversion of this zymogen to the functional transamidating enzyme, fibrinoligase (Factor XIII(a)), they showed very little inhibition toward the enzyme itself. Thus, according to the classification of Lorand concerning biological specificities, both can be characterized as Type I inhibitors of fibrin stabilization. Potencies of the two inhibitors were quite similar when measured in conjunction with the plasma zymogen, but they differed remarkably in tests with platelet Factor 13. The inhibitor of patient W. G. prevented the activation of the zymogen from platelets, but that of G. A. had no effect on the platelet factor. It may therefore be concluded that the inhibitor of W. G. is directed exclusively against the a subunit which is a common constituent of plasma as well as platelet factors. The inhibitor of G. A., however, must be targeted against determinants uniquely characteristic for the ab ensemble of the plasma zymogen including the b subunit. On the basis of this difference in target specificity, the inhibitor of W. G. is designated as Type I-1 and that of G. A. as Type I-2. The inhibitors of both patients were isolated as immunoglobulins, and neutralization tests revealed that the antibody of W. G. comprised mainly heavy chains of the IgG1 and light chains of the kappa class. The antibody of G. A. proved to be considerably more heterogeneous and contained IgG1 and IgG3 heavy chains as well as kappa- and lambda-light chains. The finding that the antibody of W. G. inhibited conversion of platelet Factor 13 and also its thrombinmodified form, but had no effect on the thrombin and Ca(2+)-activated factor, is an indication that antigenic determinants existing both on the native zymogen and on its hydrolytically modified form become buried in the Ca(2+)-dependent step of activation. This is clear evidence for the occurrence of a significant conformational change in the protein structure attendant to the process of unmasking of its enzymic activity.

Role of fibrinopeptide B release: comparison of fibrins produced by thrombin and Ancrod.

The gelation time, opacity, light scattering, and elastic moduli of human fibrin gels clotted in the presence of thrombin, Ancrod, and Reptilase have been compared. At low ionic strength lateral association to thick fibers is observed in all cases. At all ionic strengths thrombin fibrin forms thicker fibers than does Ancrod fibrin. We have demonstrated that an increase in the extent of lateral association is linked to an increase in its velocity and to a decrease in the gelation time. One may consider the removal of fibrinopeptide B to act as a switch: after it is removed fibrin assembles rapidly to thick fibers and gelation is fast; but when this peptide is still attached, there is a slow assembly of thin fibers, and gelation, especially of dilute fibrin, is delayed. We believe that this delay is critical for the complete digestion by plasmin of fibrin formed during in vivo defibrination with Ancrod and of fibrin produced by very small amounts of thrombin (which would still contain fibrinopeptide B), and that slow release of fibrinopeptide B is part of a control mechanism for the regulation of fibrin formation and the prevention of intravascular coagulation.

Affinity chromatography of human plasma and platelet factor XIII on organomercurial agarose.

A method for affinity chromatography of plasma and platelet factor XIII has been developed, based on known structural characteristics of these molecules. Plasma factor XIII is composed of a and b subunits which are held together by noncovalent interactions; platelet factor XIII has only a subunits. a subunit contains free sulfhydryl groups, while in b subunit all the cystines form disulfide bonds. The affinity gel is an organomercurial agarose with p-chloromercuribenzoate as the reactive group. Both the zymogen and activated forms of a subunit reversibly bind to the ligand by forming covalent mercaptide bonds and are eluted by reducing agents. b subunit does not bind to the affinity gel and is held to it only through interaction with a subunit. Affinity chromatography can be used to purify plasma and platelet factor XIII and to study interactions of the subunits. Experiments on the affinity chromatography of purified plasma factor XIII in several stages of activation agree with earlier observations that activation is a two-step procedure in which b subunit is not quantitatively released from the complex until the final stage of activation by Ca2+.

Purification and immunochemical characterization of human plasma factor XIII.

A detailed study of the conditions for purification of plasma factor XIII was undertaken and an optimal procedure developed. This procedure involves adsorption with aluminum hydroxide, repeated fractionation with ammonium sulfate, heat denaturation of fibrinogen, precipitation with polyethylene glycol, cryoprecipitation, and chromatography on DEAE-cellulose with gradient elution. The specific activity of the final product, as measured by the fluorescent amine incorporation assay for factor XIII, averages about 3,000-4,000 mumol dansylcadaverine incorporation/mg protein. The yield is about 20%. In SDS electrophoresis the final product has two bands under nonreducing conditions, characteristic of the a and b subunits.