bluuebunny/crossref_metadata_2025 huggingface dataset:
Ac-SDKP Reverses Inflammation and Fibrosis in Rats With Heart Failure After Myocardial Infarction
Authors: Yang Fang , Yang Xiao-Ping , Liu Yun-He , Xu Jiang , Cingolani Oscar , Rhaleb Nour-Eddine , Carretero Oscar A.
Published: December 2003

Inflammation may play an important role in the pathogenesis of cardiac fibrosis in heart failure (HF) after myocardial infarction (MI).
N
-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4- to 5-fold by angiotensin-converting enzyme inhibitors. We tested the hypothesis that in rats with HF after MI, Ac-SDKP acts as an anti-inflammatory cytokine, preventing and also reversing cardiac fibrosis in the noninfarcted area (reactive fibrosis), and thus affording functional improvement. We found that Ac-SDKP significantly decreased total collagen content in the prevention group from 23.7±0.9 to 15.0±0.7 μg/mg and in the reversal group from 22.6±2.2 to 14.4±1.6 (
P
<0.01). Interstitial collagen volume fraction and perivascular collagen were likewise significantly reduced. We also found that infiltrating macrophages were reduced from 264.7±8.1 to 170.2±9.2/mm
2
,
P
<0.001 (prevention), and from 257.5±9.1 to 153.1±8.5 mm
2
,
P
<0.001 (reversal), while transforming growth factor (TGF)-β-positive cells were decreased from 195.6±8.4 to 129.6±5.7/mm
2
,
P
<0.01 (prevention), and from 195.6±8.4 to 130.7±10.8/mm
2
,
P
<0.01 (reversal). Ac-SDKP did not alter either blood pressure or left ventricular hypertrophy (LVH); however, it depressed systolic cardiac function in the prevention study while having no significant effect in the reversal group. We concluded that Ac-SDKP has an anti-inflammatory effect in HF that may contribute to its antifibrotic effect; however, this decrease in fibrosis without changes in LVH was not accompanied by an improvement in cardiac function.
Association Between Physical Activity and Blood Pressure Is Modified by Variants in the G-Protein Coupled Receptor 10
Authors: Franks Paul W. , Bhattacharyya Sumit , Luan Jian’an , Montague Carl , Brennand John , Challis Benjamin , Brage Søren , Ekelund Ulf , Middelberg Rita P.S. , O’Rahilly Stephen , Wareham Nicholas J.
Published: December 2003

Hypertension is strongly related to cardiovascular disease and all-cause mortality. Exercise reduces blood pressure but the response varies between individuals. The mechanisms by which physical activity energy expenditure (PAEE) modifies blood pressure are not fully defined but include modulation of sympathetic tone. Novel polymorphisms in the G-protein coupled receptor (GPR10) have been linked with high blood pressure. GPR10 may mediate the relationship between PAEE and blood pressure via central nervous mechanisms. We examined whether two GPR10 polymorphisms (
G
-62A and C914T) modify the association between PAEE and blood pressure in the MRC Ely study (N=687). When stratified by the C914T genotype, there were between-group differences for body mass index (BMI) (
P
=0.05), diastolic blood pressure (DBP) (
P
=0.006), and systolic blood pressure (SBP) (
P
=0.005). No differences were found between
G
-62A genotypes. The previously reported inverse relationship between PAEE and blood pressure was not observed in minor allele carriers for either polymorphism (A62 carriers: DBP β-1.11,
P
=0.52; SBP β-1.66,
P
=0.52. T914 carriers: SBP β=3.27;
P
=0.60) but was in common allele homozygotes (G62G: DBP β-6.18
P
=0.00001; SBP β-8.54
P
=0.0001. C914C: SBP β-7.07;
P
=0.00001). This corresponded to a significant interaction between PAEE and GPR10 polymorphisms on DBP (
G
-62A:
P
=0.006) and SBP (
G
-62A:
P
=0.008. C914T:
P
=0.068). Significant interactions were observed between haplotype (derived from
G
-62A and C914T), PAEE, and blood pressure (DBP:
P
=0.08; SBP:
P
=0.023). The effect of physical activity on blood pressure is highly variable at population level. Knowledge of GPR10 genotype may define those who are least likely to benefit from physical activity. These findings may have relevance in the targeted treatment of hypertensive disease.
Forced Homodimerization by Site-Directed Mutagenesis Alters Guanylyl Cyclase Activity of Natriuretic Peptide Receptor B
Authors: Langenickel Thomas , Buttgereit Jens , Pagel Ines , Dietz Rainer , Willenbrock Roland , Bader Michael
Published: December 2003

Natriuretic peptides mediate their physiologic effects through activation of membrane-bound, guanylyl cyclase–coupled receptors (NPRs). Receptor dimerization is an important feature of signal transduction. This study was aimed at characterizing structurally important residues of the extracellular ligand-binding domain of NPR-B for receptor dimerization and cGMP generation. Deletion mutagenesis was used to replace cysteine residues at positions 53 (C53S), 417 (C417S), and 426 (C426S) by serine. Receptor expression, dimerization, whole-cell cGMP response, and guanylyl cyclase activity of membrane fractions were determined in stably transfected COS-7 cells. C53S, C417S, and C426S mutants were expressed and found to form disulfide-bridged covalent dimers. In contrast to NPR-B and C53S, C417S and C426S mutants displayed constitutive activity in whole cells (C417S, 146±12%,
P
<0.01; C426S, 153±7% of ligand-independent NPR-B cGMP generation,
P
<0.01). The cGMP response of C417S and C426S mutants in whole cells was dose dependent and ≈4 times lower than that in NPR-B, whereas it was blunted in C53S-transfected cells (1 μmol/L CNP, NPR-B 2868±436%; C53S, 206±16% of control,
P
<0.001 vs NPR-B, C417S, and C426S). Guanylyl cyclase assay in transfected cells confirmed the constitutive activity of C417S and C426S mutants. These data suggest that receptor dimerization by covalent disulfide bridges alters ligand-independent as well as ligand-dependent receptor activity. Localization of the crosslink in relation to the cell membrane is important for configuration of the extracellular domain and the consecutive signal transduction.
Apamin-Sensitive K
+
Currents Mediate Arachidonic Acid-Induced Relaxations of Rabbit Aorta
Authors: Gauthier Kathryn M. , Spitzbarth Nancy , Edwards Erik M. , Campbell William B.
Published: December 2003

Arachidonic acid induces an endothelium-dependent relaxation of the rabbit aorta that is blocked by lipoxygenase inhibitors. The cellular vasodilatory mechanisms activated by arachidonic acid metabolites remain undefined. In rabbit thoracic aortic rings pretreated with indomethacin (10 μmol/L) and contracted with phenylephrine, arachidonic acid (0.1 to 100 μmol/L) induced concentration-dependent relaxations. Maximal relaxations averaged 45±3% and were inhibited by increasing extracellular K
+
(30 mmol/L, 15±5%;
P
<0.001) or incubation with apamin (100 nmol/L, 26±7%;
P
<0.05) but not incubation with charybdotoxin (100 nmol/L, 41±5%). In aortic strips with an intact endothelium that were treated with phenylephrine, arachidonic acid (10 μmol/L) increased the membrane potential from −28.7±1.3 to −37.8±3.0 mV (
P
<0.01). Preincubation with apamin did not alter basal membrane potential but inhibited arachidonic acid-induced hyperpolarization (−31.5±1.5 mV). Incubation of rabbit aortic segments with apamin or charybdotoxin did not alter [
14
C]arachidonic acid metabolism. Whole-cell outward K
+
currents from isolated rabbit aortic smooth muscle cells averaged 43.0±4.8 pA/pF at 60 mV and were significantly decreased to 35.7±4.2 pA/pF by apamin (
P
<0.001). Subsequent addition of charybdotoxin further decreased maximal currents to 14.4±2.3 pA/pF. Addition of 11,12,15-trihydroxyeicosatrienoic acid increased the outward whole-cell K
+
current. In inside-out patches of aortic smooth muscle, apamin inhibited the calcium activation (100 to 300 nmol/L;
P
<0.001) of a small-conductance K
+
channel (≈24 pS). These results suggest that arachidonic acid induces endothelium-dependent hyperpolarization and relaxation of rabbit aorta through activation of smooth muscle, apamin-sensitive K
+
currents.
Development of Proximal Coronary Arteries in Quail Embryonic Heart
Authors: Ando Katsumi , Nakajima Yuji , Yamagishi Toshiyuki , Yamamoto Sadamu , Nakamura Hiroaki
Published: December 2003

Studies have shown that the proximal coronary artery (PCA) develops via endothelial ingrowth from the peritruncal ring (PR) of the coronary vasculature. However, the details of PCA formation remain unclear. We examined the development of PCAs in quail embryonic hearts from 5 to 9 days of incubation (embryonic day [ED]) using double-immunostaining for QH1 (quail endothelial marker) and smooth muscle α-actin. At 6 to 7 ED, several QH1-positive endothelial strands from the PR penetrated the facing sinuses, and in some embryos, several endothelial strands penetrated the posterior (noncoronary) sinus. At 7 to 8 ED, the endothelial strands penetrating the facing sinuses seemed to fuse, forming a proximal coronary stem that was demarcated from the aortic wall by the nascent smooth muscle layer of the coronary artery. By 9 ED, two coronary stems were completely formed, and the endothelial strands previously penetrating the noncoronary sinus had disappeared. Confocal microscopy at 6 ED revealed discontinuous QH1-positive endothelial progenitors in the aortic wall at sites where the endothelial strands would later develop. Observations demonstrate that during the formation of the PCA, endothelial strands from the PR penetrate the facing sinuses and then fuse, whereas those strands penetrating the noncoronary sinus disappear. Thereafter, the coronary artery tunica media demarcates the definitive PCA from the aortic media.
Superoxide Is Involved in the Central Nervous System Activation and Sympathoexcitation of Myocardial Infarction–Induced Heart Failure
Authors: Lindley Timothy E. , Doobay Marc F. , Sharma Ram V. , Davisson Robin L.
Published: December 2003

Increased angiotensin II signaling in the brain has been shown to play a critical role in the excessive sympathoexcitation and development of heart failure (HF) after myocardial infarction (MI). We have recently demonstrated that reactive oxygen species mediate the actions of angiotensin II in the brain. In this study, we tested the hypothesis that increased redox signaling in central cardiovascular control regions is a key mechanism in the neurocardiovascular dysregulation that follows MI. Ligation of the left coronary artery induced a large MI and subsequent HF in adult C57BL/6 mice, as demonstrated by cardiac hypertrophy, hydrothorax, and ascites. Immunohistochemical analysis of Fos, a marker of neuronal activation, revealed a significant increase in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 and 4 weeks after MI compared with sham mice. Intracerebroventricular injection of an adenoviral vector encoding superoxide dismutase (Ad-Cu/ZnSOD) caused a significant decrease in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 weeks after MI compared with mice receiving either saline or a control vector (Ad-LacZ). There was also a diminished role of sympathetic drive in post-MI mice treated centrally with Ad-Cu/ZnSOD, as demonstrated by significantly attenuated falls in heart rate and mean arterial pressure to the ganglionic blocker hexamethonium and decreased urinary norepinephrine levels in these mice compared with Ad-LacZ–treated MI mice. These results suggest that superoxide plays a key role in the central activation and sympathetic hyperactivity after MI in mice and that oxygen radicals in the brain may be important new targets for therapeutic treatment of heart failure.
Spasticity After Stroke
Authors: Sommerfeld Disa K. , Eek Elsy U.-B. , Svensson Anna-Karin , Holmqvist Lotta Widén , von Arbin Magnus H.
Published: December 2003

Background and Purpose—

There is no consensus concerning the number of patients developing spasticity or the relationship between spasticity and disabilities after acute stroke. The aim of the present study was to describe the extent to which spasticity occurs and is associated with disabilities (motor impairments and activity limitations).

Methods—

Ninety-five patients with first-ever stroke were examined initially (mean, 5.4 days) and 3 months after stroke with the Modified Ashworth Scale for spasticity; self-reported muscle stiffness; tendon reflexes; Birgitta Lindmark motor performance; Nine Hole Peg Test for manual dexterity; Rivermead Mobility Index; Get-Up and Go test; and Barthel Index.

Results—

Of the 95 patients studied, 64 were hemiparetic, 18 were spastic, 6 reported muscle stiffness, and 18 had increased tendon reflexes 3 months after stroke. Patients who were nonspastic (n=77) had statistically significantly better motor and activity scores than spastic patients (n=18). However, the correlations between muscle tone and disability scores were low, and severe disabilities were seen in almost the same number of nonspastic as spastic patients.

Conclusions—

Although spasticity seems to contribute to disabilities after stroke, spasticity was present in only 19% of the patients investigated 3 months after stroke. Severe disabilities were seen in almost the same number of nonspastic as spastic patients. These findings indicate that the focus on spasticity in stroke rehabilitation is out of step with its clinical importance. Careful and continual evaluation to establish the cause of the patient’s disabilities is essential before a decision is made on the most proper rehabilitation approach.
Acquired Immunodeficiency Syndrome and the Risk of Stroke
Authors: Cole John W. , Pinto Amelia N. , Hebel J. Richard , Buchholz David W. , Earley Christopher J. , Johnson Constance J. , Macko Richard F. , Price Thomas R. , Sloan Michael A. , Stern Barney J. , Wityk Robert J. , Wozniak Marcella A. , Kittner Steven J.
Published: December 2003

Background and Purpose—

Although acquired immunodeficiency syndrome (AIDS) is thought to increase the risk of stroke, few data exist to quantify this risk. This is the first population-based study to quantify the AIDS-associated risk of stroke.

Methods—

We identified all incident ischemic stroke (IS) and intracerebral hemorrhage (ICH) cases among young adults 15 to 44 years of age in central Maryland and Washington, DC, who were discharged from any of the 46 hospitals in the study area in 1988 and 1991. Using data from the medical records, 2 neurologists reviewed each case to confirm the diagnosis. Cases of AIDS among these patients with stroke were defined using Centers for Disease Control and Prevention criteria (1987). The number of cases of AIDS in the central Maryland and Washington population during 1988 and 1991 was determined from regional health departments working with the Centers for Disease Control and Prevention. Poisson regression was used to estimate the age-, race-, and sex-adjusted relative risk of stroke associated with AIDS.

Results—

There were 385 IS cases (6 with AIDS) and 171 ICH cases (6 with AIDS). The incidences of IS and ICH among persons with AIDS were both 0.2% per year. AIDS conferred an adjusted relative risk of 13.7 (95% confidence interval [CI], 6.1 to 30.8) for IS and 25.5 (95% CI, 11.2 to 58.0) for ICH. After exclusion of 5 cases of stroke in AIDS patients in whom other potential causes were identified, AIDS patients continued to have an increased risk of stroke with an adjusted relative risk of 9.1 (95% CI, 3.4 to 24.6) for IS and 12.7 (95% CI, 4.0 to 40.0) for ICH.

Conclusions—

This population-based study found that AIDS is strongly associated with both IS and ICH.
Multi-Slice CT Angiography in Diagnosing Total Versus Near Occlusions of the Internal Carotid Artery
Authors: Chen Chi-Jen , Lee Tsong-Hai , Hsu Hui-Ling , Tseng Ying-Chi , Lin Shinn-Kuang , Wang Li-Jen , Wong Yon-Cheong
Published: December 2003

Background and Purpose—

To determine the accuracy of multislice computed tomographic (CT) angiography in diagnosing total versus near occlusions of the internal carotid artery (ICA).

Methods—

Fifty-seven ICA total or near occlusions identified by catheter angiography were studied with multislice CT angiography 1 to 3 days after catheter angiography. CT angiography in diagnosing total versus near occlusions was analyzed by 2 radiologists independently. The results were compared with those of catheter angiography.

Results—

Catheter angiography depicted 31 total occlusions, including 10 without a stump, 19 with a stump <2 cm, and 2 with a stump >2 cm. Among them, 22 had a downward extent of the retrograde ICA flow at or above the carotid siphon, 8 at the carotid canal, and 1 at the distal cervical ICA. Catheter angiography depicted 26 near occlusions, including 21 with a tight stenosis at the proximal third cervical ICA, 1 at the middle third, and 4 at the carotid canal or siphon. CT angiography correctly depicted all total and near occlusions. In total occlusions, the length of the stump and the retrograde flow were all accurately described by CT angiography. In near occlusions, the sites of tight stenoses were also correctly identified by CT angiography.

Conclusions—

Multislice CT angiography had an excellent correlation with catheter angiography in diagnosing total versus near occlusion of the ICA. It may be considered as a substitute of catheter angiography in confirming the ultrasonographic results in diagnosing total versus near occlusions of the ICA.
Age and National Institutes of Health Stroke Scale Score Within 6 Hours After Onset Are Accurate Predictors of Outcome After Cerebral Ischemia
Authors: Weimar C. , König I.R. , Kraywinkel K. , Ziegler A. , Diener H.C.
Published: December 2003

Background and Purpose—

To date, no validated, comprehensive, and practicable model exists to predict functional recovery within the first hours of cerebral ischemic symptoms. The purpose of this study was to externally validate 2 prognostic models predicting functional outcome and survival at 100 days within the first 6 hours after onset of acute cerebral ischemia.

Methods—

On admission to a participating hospital, patients were registered prospectively and included according to defined criteria. Follow-up was performed 100 days after the event. With the use of prospectively collected data, 2 prognostic models were developed and internally calibrated in 1079 patients and externally validated in 1307 patients. By means of age and National Institutes of Health Stroke Scale (NIHSS) score as independent variables, model I predicts incomplete functional recovery (Barthel Index <95) versus complete functional recovery, and model II predicts mortality versus survival.

Results—

In the validation data set, model I correctly predicted 62.9% of the patients who were incompletely restituted or had died and 83.2% of the completely restituted patients, and model II correctly predicted 57.9% of the patients who had died and 91.5% of the surviving patients. Both models performed better than the treating physicians’ predictions made within 6 hours after admission.

Conclusions—

The resulting prognostic models are useful to correctly stratify treatment groups in clinical trials and should guide inclusion criteria in clinical trials, which in turn increases the power to detect clinically relevant differences.
Improved Detection of Microbubble Signals Using Power M-Mode Doppler
Authors: Saqqur Maher , Dean Naeem , Schebel Marcia , Hill Michael D. , Salam Abdul , Shuaib Ashfaq , Demchuk Andrew M.
Published: December 2003

Background—

Power motion-mode transcranial Doppler (TCD) (PMD) is a new, multigated technique that may simplify and enhance detection of embolus. We developed criteria for emboli detection using PMD. Then, we performed a blinded comparison of transcranial PMD with single-gate spectral TCD in TCD bubble study patients.

Methods—

Patients with right-to-left shunt as detected with standard TCD were selected for this study. The international emboli criteria for spectral TCD were used. We defined novel PMD criteria for detecting emboli signature on PMD as follows: (1) signature at least 3 dB higher than the highest spontaneous PMD display of background blood flow; (2) embolic signature reflects motion in one direction at a minimum spatial extent of 7.5 mm and temporal extent of 30 ms; (3) embolus must traverse a prespecified depth. Each study was blindly assessed for microbubble signals (MBS) count on either modality.

Results—

Thirty-six patients were included in the study. Mean age was 44.4 (SD 14.4), 50% were male, and median time from stroke onset to TCD bubble test was 12 days. Median MBS count in middle cerebral arteries (MCA) was 4 on both modalities. Spectral TCD MBS counts were highly correlated (ρ=0.97) with PMD MBS counts in MCA and similarly in anterior cerebral arteries (ACA) (ρ=0.79). When PMD microbubble counts in the ACA and MCA were summed, a clear 2-fold difference emerged between 2 modalities (
P
<0.001).

Conclusion—

When compared with spectral TCD, PMD detects more MBS with higher counts by identifying ACA as well as MCA emboli. Pitfalls of overcounting emboli with PMD can be avoided by following such criteria.
Systematic Review of Methods and Results of Studies of the Genetic Epidemiology of Ischemic Stroke
Authors: Floßmann Enrico , Schulz Ursula G.R. , Rothwell Peter M.
Published: December 2003

Background and Purpose—

To design appropriate molecular genetic studies, we first need to understand the genetic epidemiology of stroke. We therefore performed a systematic review of the literature to assess the heritability of stroke according to methodological quality of studies and to determine any heterogeneity in findings between studies and possible publication bias.

Methods—

We searched for twin studies and studies of family history of stroke using bibliographic databases and by hand-searching reference lists and journals. Odds ratios (ORs) for family history as a risk factor for stroke were calculated within studies and combined by meta-analysis. Heterogeneity between studies, methodological quality of studies, and the influence of the age at which stroke occurred in both probands and relatives were assessed.

Results—

We identified 53 independent studies (3 twin, 33 case-control, and 17 cohort). Monozygotic twins were more likely to be concordant than dizygotic twins (OR, 1.65; 95% CI, 1.2 to 2.3;
P
=0.003). A positive family history was a risk factor for stroke in both case-control (OR, 1.76; 95% CI, 1.7 to 1.9;
P
<0.00001) and cohort (OR, 1.30; 95% CI, 1.2 to 1.5;
P
<0.00001) studies. However, there was major heterogeneity between studies (cohort
P
=0.0001; case-control
P
<0.00001), with much stronger associations in small studies and methodologically less rigorous studies. Moreover, studies that reported insufficient data to allow meta-analysis tended to have found weaker associations. Family history of stroke was more frequent in studies that were confined to probands or relatives aged <70 years. However, few studies considered the number of affected and unaffected relatives, only 2 studies considered stroke phenotypes in detail, and only 19 studies (38%) adjusted associations for intermediate phenotypes. No twin study, only 5 cohort studies (26%), and 20 case-control studies (61%) differentiated between ischemic and hemorrhagic stroke in the proband. Family history of stroke was more frequent in large- and small-vessel stroke than in cardioembolic stroke. There were very few data on the influence of family history on stroke severity and no data on stroke recovery.

Conclusions—

Twin studies suggest a small genetic contribution to stroke, but reliable interpretation of published family history studies is undermined by major heterogeneity, insufficient detail, and potential publication and reporting bias. More detailed large-scale genetic epidemiology is required.
Preventive Antibacterial Treatment Improves the General Medical and Neurological Outcome in a Mouse Model of Stroke
Authors: Meisel Christian , Prass Konstantin , Braun Johann , Victorov Ilya , Wolf Tilo , Megow Dirk , Halle Elke , Volk Hans-Dieter , Dirnagl Ulrich , Meisel Andreas
Published: December 2003

Background and Purpose—

Epidemiological studies have demonstrated a high incidence of infections after severe stroke and their prominent role in morbidity and mortality in stroke patients. In a mouse model, it has been shown recently that stroke is coupled with severe and long-lasting immunosuppression, which is responsible for the development of spontaneous systemic infections. Here, we investigated in the same model the effects of preventive antibiotic treatment on survival and functional outcome of experimental stroke.

Methods—

Mice were subjected to experimental stroke by occlusion of the middle cerebral artery (MCAO) for 60 minutes. A group of mice received moxifloxacin (6×100 mg/kg body weight every 2 hours over 12 hours) either immediately or 12 hours after MCAO. Control animals received the vector only. Behavior, neurological deficit, fever, survival, and body weight were monitored over 14 days. In a subgroup, infarct volume was measured 4 days after MCAO. Microbiological assessment was based on cultures of lung tissue, blood, and feces of animals 3 days after stroke. For a dose-response study, moxifloxacin was given immediately after MCAO in different doses and at different time points.

Results—

Microbiological analyses of blood and lung tissue demonstrated high bacterial burden, mainly
Escherichia coli
, 3 days after stroke. Accordingly, we observed clinical and histological signs of septicemia and pneumonia. Moxifloxacin prevented the development of infections and fever, significantly reduced mortality, and improved neurological outcome.

Conclusions—

Preventive antibiotic treatment may be an important new therapeutical approach to improve outcome in patients with severe stroke.
Fertility and Contraception during the Demographic Transition: Qualitative and Quantitative Approaches
Authors: Szreter Simon , Nye Robert A. , Poppel Frans van
Published: December 2003

Demographic, cultural, and oral-history approaches to the study of falling fertility in nineteenth-and twentieth-century France, Canada, Britain, Holland, Norway, and Finland confirm the importance of the persistent usage of “traditional” methods of birth control—such as coitus interruptus, abortion, and forms of periodic abstinence—throughout the period when fertility fell, though fertility fell in each case at a different point in time. These studies also use qualitative evidence that provides insight into the reasons for contraceptive preference, thereby combining the history of changing sexualities with the analysis of demographic change.
Physicians and Fertility Control in the Netherlands
Authors: Poppel Frans van , Röling Hugo
Published: December 2003

Personal documents, articles in medical journals, brochures, and newspaper articles, and reports of public meetings suggest that the medical profession in the Netherlands harbored a negative attitude toward birth control during the 1870s and 1880s; during the 1890s and thereafter, it maintained steadfast silence on birth-control matters. Population-register data and vital registration information show, however, that despite their reticence on the subject, medical men were among the most effective birth controllers in the population, despite marrying relatively young wives. They stopped having children once they had reached their desired total number. The profession's fear of losing its hardearned respectability and status by becoming connected with contraception-related issues, such as prostitution and venereal disease, may well have caused its public disapproval of birth control.
Women, Priests, and Physicians: Family Limitation in Quebec, 1940–1970
Authors: Gervais Diane , Gauvreau Danielle
Published: December 2003

The fertility transition occurred relatively later, and at a much slower pace, in Quebec than in most industrializing countries. Quantitative data can help to situate the general trends and the contributing factors. Qualitative data reveal the hostile context in which Catholic couples tried to fulfill their aspirations to have smaller families. They also show variability in the practices of clergy members.
CLIMATE CHANGE SCENARIOS FOR THE U.S. NATIONAL ASSESSMENT
Authors: MacCracken Michael C. , Barron Eric J. , Easterling David R. , Felzer Benjamin S. , Karl Thomas R.
Published: December 2003

In support of the U.S. National Assessment of the Potential Consequences of Climate Variability and Change, climate scenarios were prepared to serve as the basis for evaluating the vulnerability of environmental and societal systems to changes projected for the twenty-first century. Since publication of the results of the assessment at the end of 2000, the National Research Council's report Climate Change Science: An Analysis of Some Key Questions, and the U.S. government's U.S. Climate Action Report—2002 have both relied on the assessment's findings. Because of the importance of these findings, it is important to directly address questions regarding the representativeness and usefulness of the model-based projections on which the findings were based. In particular, criticisms have focused on whether the climate models that were relied upon adequately represented twentieth-century conditions and whether their projections of conditions for the twenty-first century were outliers. Reexamination of the approach used in developing and evaluating the climate scenarios indicates that the results from the two primary climate modeling groups that were relied upon allowed the generation of climate scenarios that span much of the range of possible future climatic conditions projected by the larger set of model simulations, which was compiled for the IPCCs Third Assessment Report. With the set of models showing increasing agreement in their simulations of twentieth-century trends in climate and of projected changes in climate on subcontinental to continental scales, the climate scenarios that were generated seem likely to provide a plausible representation of the types of climatic conditions that could be experienced during the twenty-first century. Warming, reduced snow cover, and more intense heavy precipitation events were projected by all models, suggesting such changes are quite likely. However, significant differences remain in the projection of changes in precipitation and of the regional departures in climate from the larger-scale patterns. For this reason, evaluating potential impacts using climate scenarios based on models exhibiting different regional responses is a necessary step to ensuring a representative analysis. Utilizing an even more encompassing set of scenarios in the future could help move from mainly qualitative toward more certain and quantitative conclusions.
Climate Research and Seasonal Forecasting for West Africans: Perceptions, Dissemination, and Use?
Authors: Tarhule Aondover , Lamb Peter J.
Published: December 2003

Beginning in response to the disastrous drought of 1968–73, considerable research and monitoring have focused on the characteristics, causes, predictability, and impacts of West African Soudano–Sahel (10°–18°N) rainfall variability and drought. While these efforts have generated substantial information on a range of these topics, very little is known of the extent to which communities, activities at risk, and policy makers are aware of, have access to, or use such information. This situation has prevailed despite Glantz's provocative BAMS paper on the use and value of seasonal forecasts for the Sahel more than a quarter century ago. We now provide a systematic reevaluation of these issues based on questionnaire responses of 566 participants (in 13 communities) and 26 organizations in Burkina Faso, Mali, Niger, and Nigeria. The results reveal that rural inhabitants have limited access to climate information, with nongovernmental organizations (NGOs) being the most important source. Moreover, the pathways for information flow are generally weakly connected and informal. As a result, utilization of the results of climate research is very low to nonexistent, even by organizations responsible for managing the effects of climate variability. Similarly, few people have access to seasonal climate forecasts, although the vast majority expressed a willingness to use such information when it becomes available. Those respondents with access expressed great enthusiasm and satisfaction with seasonal forecasts. The results suggest that inhabitants of the Soudano–Sahel savanna are keen for changes that improve their ability to cope with climate variability, but the lack of information on alternative courses of action is a major constraint. Our study, thus, essentially leaves unchanged both Glantz's negative “tentative conclusion” and more positive “preliminary assessment” of 25 years ago. Specifically, while many of the infrastructural deficiencies and socioeconomic impediments remain, the great yearning for climate information by Soudano–Sahalians suggests that the time is finally ripe for fostering increased use. Therefore, a simple model for improved dissemination of climate research and seasonal climate forecast information is proposed. The tragedy is that a quarter century has passed since Glantz's clarion call.
Evaluation of the IRI'S “Net Assessment” Seasonal Climate Forecasts: 1997–2001
Authors: Goddard L. , Barnston A. G. , Mason S. J.
Published: December 2003

The International Research Institute for Climate Prediction (IRI) net assessment seasonal temperature and precipitation forecasts are evaluated for the 4-yr period from October–December 1997 to October–December 2001. These probabilistic forecasts represent the human distillation of seasonal climate predictions from various sources. The ranked probability skill score (RPSS) serves as the verification measure. The evaluation is offered as time-averaged spatial maps of the RPSS as well as area-averaged time series. A key element of this evaluation is the examination of the extent to which the consolidation of several predictions, accomplished here subjectively by the forecasters, contributes to or detracts from the forecast skill possible from any individual prediction tool.

Overall, the skills of the net assessment forecasts for both temperature and precipitation are positive throughout the 1997–2001 period. The skill may have been enhanced during the peak of the 1997/98 El Niño, particularly for tropical precipitation, although widespread positive skill exists even at times of weak forcing from the tropical Pacific. The temporally averaged RPSS for the net assessment temperature forecasts appears lower than that for the AGCMs. Over time, however, the IRI forecast skill is more consistently positive than that of the AGCMs. The IRI precipitation forecasts generally have lower skill than the temperature forecasts, but the forecast probabilities for precipitation are found to be appropriate to the frequency of the observed outcomes, and thus reliable. Over many regions where the precipitation variability is known to be potentially predictable, the net assessment precipitation forecasts exhibit more spatially coherent areas of positive skill than most, if not all, prediction tools. On average, the IRI net assessment forecasts appear to perform better than any of the individual objective prediction tools.
Multimodel Ensembling in Seasonal Climate Forecasting at IRI
Authors: Barnston Anthony G. , Mason Simon J. , Goddard Lisa , DeWitt David G. , Zebiak Stephen E.
Published: December 2003

The International Research Institute (IRI) for Climate Prediction seasonal forecast system is based largely on the predictions of ensembles of several atmospheric general circulation models (AGCMs) forced by two versions of an SST prediction—one consisting of persisted SST anomalies from the current observations and one of evolving SST anomalies as predicted by a set of dynamical and statistical SST prediction models. Recently, an objective multimodel ensembling procedure has replaced a more laborious and subjective weighting of the predictions of the several AGCMs. Here the skills of the multimodel predictions produced retrospectively over the first 4 years of IRI forecasts are examined and compared with the skills of the more subjectively derived forecasts actually issued. The multimodel ensemble predictions are generally found to be an acceptable replacement, although the precipitation forecasts do benefit from inclusion of empirical forecast tools. Planned pattern-level model output statistics (MOS) corrections for systematic biases in the AGCM forecasts may render them more sufficient in their own right.
Nuclear factor–κB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis
Authors: Bharti Alok C. , Shishodia Shishir , Reuben James M. , Weber Donna , Alexanian Raymond , Raj-Vadhan Saroj , Estrov Zeev , Talpaz Moshe , Aggarwal Bharat B.
Published: December 2003

Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor–κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-κB and STAT3 and if their suppression induces apoptosis. We assayed CD138+ cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-κB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-κB and STAT3 but to a variable degree (NF-κB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-κB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-κB and STAT3 were absent in cells from healthy individuals. Suppression of NF-κB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-κB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-κB and STAT3, and suppression of these transcription factors inhibits the survival of the cells. (Blood. 2004;103:3175-3184)
CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis
Authors: Boyer Olivier , Saadoun David , Abriol Julien , Dodille Mélanie , Piette Jean-Charles , Cacoub Patrice , Klatzmann David
Published: December 2003

Patients who are chronically infected with hepatitis C virus (HCV) often develop mixed cryoglobulinemia (MC), a B-cell proliferative disorder with polyclonal activation and autoantibody production. We investigated if MC is associated with a deficit of CD4+CD25+ immunoregulatory T (Treg) cells, which have been shown to control autoimmunity. Because Treg cells express higher amounts of CD25 than activated CD4+ T cells, we analyzed blood CD4+CD25high Treg cells in 69 untreated patients chronically infected with HCV. Treg cell frequency in patients without MC (8.8% ± 2.3%) or with asymptomatic MC (7.4% ± 2.1%) was comparable to that of healthy controls (7.9% ± 1.3%). In contrast, it was significantly reduced in symptomatic MC patients (2.6% ± 1.2%, P < .001) even when compared to a panel of untreated HCV- patients with different inflammatory disorders (6.2% ± 0.8%, P < .0001). In symptomatic MC patients, the purified remaining CD4+CD25+ T cells retained suppressive activity in vitro. These results, together with experimental data showing that depletion of Treg cells induces autoimmunity, suggest a major role of Treg cell deficiency in HCV-MC vasculitis and this is the first report of a quantitative Treg cell deficiency in virus-associated autoimmunity. (Blood. 2004; 103:3428-3430)
GPIb-dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP-dependent kinase
Authors: Marshall Stuart J. , Senis Yotis A. , Auger Jocelyn M. , Feil Robert , Hofmann Franz , Salmon Gary , Peterson J. Thomas , Burslem Frank , Watson Steve P.
Published: December 2003

Glycoprotein Ib-IX-V (GPIb-IX-V) mediates platelet tethering to von Willebrand factor (VWF), recruiting platelets into the thrombus, and activates integrin αIIbβ3 through a pathway that is dependent on Src kinases. In addition, recent reports indicate that activation of αIIbβ3 by VWF is dependent on protein kinase G (PKG) and mitogen-activated protein (MAP) kinases. The present study compares the importance of these signaling pathways in the activation of αIIbβ3 by GPIb-IX-V. In contrast to a recent report, VWF did not promote an increase in cyclic guanosine monophosphate (cGMP), while agents that elevate cGMP, such as the nitrous oxide (NO) donor glyco–SNAP-1 (N-(β-D-glucopyranosyl)-N2-acetyl-S-nitroso-D,L-penicillaminamide) or the type 5 phosphosdiesterase inhibitor, sildenafil, inhibited rather than promoted activation of αIIbβ3 by GPIb-IX-V and blocked aggregate formation on collagen at an intermediate rate of shear (800 s-1). Additionally, sildenafil increased blood flow in a rabbit model of thrombus formation in vivo. A novel inhibitor of the MAP kinase pathway, which is active in plasma, PD184161, had no effect on aggregate formation on collagen under flow conditions, whereas a novel inhibitor of Src kinases, which is also active in plasma, PD173952, blocked this response. These results demonstrate a critical role for Src kinases but not MAP kinases in VWF-dependent platelet activation and demonstrate an inhibitory role for cGMP-elevating agents in regulating this process.
Dynamic reorganization of chromatin structure and selective DNA demethylation prior to stable enhancer complex formation during differentiation of primary hematopoietic cells in vitro
Authors: Tagoh Hiromi , Melnik Svitlana , Lefevre Pascal , Chong Suyinn , Riggs Arthur D. , Bonifer Constanze
Published: December 2003

In order to gain insights in the true molecular mechanisms involved in cell fate decisions, it is important to study the molecular details of gene activation where such decisions occur, which is at the level of the chromatin structure of individual genes. In the study presented here we addressed this issue and examined the dynamic development of an active chromatin structure at the chicken lysozyme locus during the differentiation of primary myeloid cells from transgenic mouse bone marrow. Using in vivo footprinting we found that stable enhancer complex assembly and high-level gene expression are late events in cell differentiation. However, even before the onset of gene expression and stable transcription factor binding, specific chromatin alterations are observed. This includes changes in DNA topology and the selective demethylation of CpG dinucleotides located in the cores of critical transcription factor binding sites, but not in flanking DNA. These results firmly support the idea that epigenetic programs guiding blood cell differentiation are engraved into the chromatin of lineage-specific genes and that such chromatin changes are implemented before cell lineage specification. (Blood. 2004;103:2950-2955)
Impact of Obesity on Biochemical Control After Radical Prostatectomy for Clinically Localized Prostate Cancer: A Report by the Shared Equal Access Regional Cancer Hospital Database Study Group
Authors: Freedland Stephen J. , Aronson William J. , Kane Christopher J. , Presti Joseph C. , Amling Christopher L. , Elashoff David , Terris Martha K.
Published: December 2003

Purpose

Given the limited information regarding the impact of obesity on treatment outcomes for prostate cancer, we sought to examine the relationship between body mass index (BMI) and cancer control after radical prostatectomy (RP).

Patients and Methods

We compared clinicopathologic and biochemical outcome information across BMI groups from 1,106 men treated with RP between 1988 and 2002. Multivariate analysis was used to determine if BMI significantly predicted adverse pathology or biochemical recurrence.

Results

Obesity was related to year of surgery (P < .001) and race (P < .001), with black men having the highest obesity rates. Obese patients had higher biopsy and pathologic grade tumors (P < .001). On multivariate analysis, BMI ≥ 35 kg/m2 was associated with a trend for higher rates of positive surgical margins (P = .008). Overweight patients (BMI, 25 to 30 kg/m2) had a significantly decreased risk of seminal vesicle invasion (P = .039). After controlling for all preoperative clinical variables including year of surgery, BMI ≥ 35 kg/m2 significantly predicted biochemical failure after RP (P = .002). After controlling for surgical margin status, BMI ≥ 35 kg/m2 remained a significant predictor of biochemical failure (P = .012). There was a trend for BMI ≥ 35 kg/m2 to be associated with higher failure rates than BMI between 30 and 35 kg/m2 (P = .053).

Conclusion

The percentage of obese men undergoing RP in our data set doubled in the last 10 years. Obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates among men treated with RP. A BMI ≥ 35 kg/m2 was associated with a higher risk of failure than a BMI between 30 and 35 kg/m2.
Immunopharmacologic Analysis of an Autologous, Hapten-Modified Human Melanoma Vaccine
Authors: Berd David , Sato Takami , Maguire Henry C. , Kairys John , Mastrangelo Michael J.
Published: December 2003

Purpose

We have previously reported a clinical trial of a human cancer vaccine consisting of autologous tumor cells modified with the hapten, dinitrophenyl (DNP), in patients with clinical stage III melanoma. Here we present a follow-up report expanded to 214 patients with 5-year follow-up.

Patients and Methods

Two hundred fourteen patients with clinical stage III melanoma (117 patients with stage IIIC and 97 patients with stage IIIB) who were melanoma-free after standard lymphadenectomy were treated with multiple intradermal injections of autologous, DNP-modified vaccine mixed with bacille Calmette-Guérin. Four vaccine dosage schedules were tested sequentially, all of which included low-dose cyclophosphamide. Patients were tested for delayed-type hypersensitivity (DTH) to autologous melanoma cells, both DNP-modified and unmodified, and to control materials.

Results

The 5-year overall survival (OS) rate of the 214 patients was 44%. DTH responses to unmodified autologous melanoma were induced in 47% of patients. The OS of this DTH-positive group was double that of DTH-negative patients (59.3% v 29.3%; P < .001). In contrast, positive DTH responses to DNP-modified autologous melanoma cells and to purified protein derivative developed in almost all patients but did not affect OS. Surprisingly, the OS after relapse was also significantly longer in patients who developed positive DTH to unmodified tumor cells (25.2% v 12.3%; P < .001). Finally, the development of DTH was dependent on the schedule of administration of the vaccine, specifically, the timing of an induction dose administered at the beginning of the treatment program.

Conclusion

This study underscores the importance of the immunopharmacology of the autologous, DNP-modified vaccine and may be relevant to other cancer vaccine technologies.