bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid vegetation change during the early Holocene in the Faroe Islands detected in terrestrial and aquatic ecosystems
Authors: Hannon Gina E. , Bradshaw Richard H. W. , Wastegård Stefan
Published: September 2003

High‐resolution pollen, plant macrofossil and sedimentary analyses from early Holocene lacustrine sediments on the Faroe Islands have detected a significant vegetation perturbation suggesting a rapid change in climate between ca. 10 380 cal. yr BP and the Saksunarvatn ash (10 240±60 cal. yr BP). This episode may be synchronous with the decline in δ18O values in the Greenland ice‐cores. It also correlates with a short, cold event detected in marine cores from the North Atlantic that has been ascribed to a weakening of thermohaline circulation associated with the sudden drainage of Lake Agassiz into the northwest Atlantic, or, alternatively, a period with distinctly decreased solar forcing.

The vegetation sequence begins at ca. 10 500 cal. yr BP with a succession from tundra to shrub‐tundra and increasing lake productivity. Rapid population increases of aquatic plants suggest high summer temperatures between 10 450 and 10 380 cal. yr BP. High pollen percentages, concentrations and influx of Betula, Juniperus and Salix together with macrofossil leaves indicate shrub growth around the site during the initial phases of vegetation colonisation. Unstable conditions followed ca. 10 380 cal. yr BP that changed both the upland vegetation and the aquatic plant communities. A decrease in percentage values of shrub pollen is recorded, with replacement of both aquatics and herbaceous plants by pioneer plant communities. An increase in total pollen accumulation rates not seen in the concentration data suggests increased sediment delivery. The catchment changes are consistent with less seasonal, moister conditions. Subsequent climatic amelioration reinitiated a warmth‐driven succession and catchment stabilisation, but retained high precipitation levels influencing the composition of the post‐event communities. Copyright © 2003 John Wiley & Sons, Ltd.
Dating the introduction of cereal cultivation to the British Isles: early palaeoecological evidence from the Isle of Man
Authors: Innes James B. , Blackford Jeffrey J. , Davey Peter J.
Published: September 2003

The adoption of cereal cultivation is a key benchmark in the transition from Mesolithic hunter–gatherer foraging to Neolithic farming economies, but the nature, timing and ecological–cultural context of the earliest cereal use in the British Isles and northwest Europe is still uncertain. We present AMS radiocarbon dating and fine‐resolution pollen evidence from the Isle of Man for cereal growing in the latter stages of a distinct episode of forest disturbance at almost 6000 yr BP (uncalibrated). The coherent ecological structure of this phase at the fine resolution level suggests that it records cereal cultivation well before the Ulmus decline, rather than wild grass pollen grains. This example is one of a cluster of early dates for cereal‐type pollen near the start of the sixth millenium BP, including several around the Irish Sea, which indicate that the introduction of cereal agriculture probably occurred as early in the central British Isles as in the northern European plain. This early cereal phase is followed later by a probable phase of pre‐Ulmus decline pastoral activity. We also report Mesolithic age woodland disturbance around 7000 yr BP (uncalibrated) and the first radiocarbon dates for mid‐Holocene forest history of the Isle of Man. Copyright © 2003 John Wiley & Sons, Ltd.
Post‐glacial vegetation reconstruction and a possible 8200 cal. yr BP event from the low arctic of continental Nunavut, Canada
Authors: Seppä Heikki , Cwynar Les C. , MacDonald Glen M.
Published: September 2003

Climate models suggest that the global warming during the early to mid‐Holocene may have partly resulted from the northward advance of the northern treeline and subsequent reduction of the planetary albedo. We investigated the Holocene vegetation history of low arctic continental Nunavut, Canada, from a radiocarbon‐dated sediment core from TK‐2 Lake, a small‐lake ca. 200 km north of the limit of the forest‐tundra. The pollen and loss‐on‐ignition data indicate the presence of dwarf shrub tundra in the region since the beginning of organic sedimentation at ca. 9000 cal. yr BP with dominance of Betula, especially since 8700 cal. yr BP. At 8100–7900 cal. yr BP the dominance of the shrub tundra was punctuated by a transient decline of Betula and coincident increases of Ericaceae undiff., Vaccinium‐type, and Gramineae. This suggests an abrupt disturbance of the Betula glandulosa population, approximately simultaneously with the sudden 8200 cal. yr BP event in the North Atlantic. However, in the absence of other sites studied in the area, linkage to the 8200 cal. yr BP event remains tentative. The lack of any evidence of forest‐tundra in the region constrains the northern limit of the mid‐Holocene advance of the forest‐tundra boundary in central northern Canada. Consequently, our results show that the climate models imposing a mid‐Holocene advance of the limit of the forest‐tundra to the arctic coast of Canada may have overestimated the positive climatic feedback effects that can result from the replacement of tundra by the boreal forest. Copyright © 2003 John Wiley & Sons, Ltd.
Syntheses and UV–visible spectroscopic properties of two new hydrophilic 2,6‐di(carbamoyl)‐substituted solvatochromic pyridinium N‐phenolate betaine dyes
Authors: Reichardt Christian , Röchling Andreas , Schäfer Gerhard
Published: September 2003

Syntheses and negative solvatochromism of t wo 2,6‐di(carbamoyl)‐substituted pyridinium N‐phenolate betaines dyes, 3 and 4, are described for the purpose of obtaining more hydrophilic zwitterionic dyes which are better soluble in water and other aqueous media (such as binary water–solvent mixtures or aqueous ionophore solutions) than the rather hydrophobic standard betaine dyes 1 and 2, which have been used to establish an empirical scale of solvent polarity, called the ET(30) or $E_{\rm{T}}^{\rm{N}}$ scale. Copyright © 2003 John Wiley & Sons, Ltd.
The collective invention of language to access the universe of possible ideas
Authors: Baumeister Roy F. , Vohs Kathleen D.
Published: September 2003

Thought uses meaning but not necessarily language. Meaning, in the form of a set of possible concepts and ideas, is a nonphysical reality that lay waiting for brains to become smart enough to represent these ideas. Thus, the brain evolved, whereas meaning was discovered, and language was invented – collectively – as a tool to help the brain use meaning.
Nativism, neuroconstructivism, and developmental disorder
Authors: Gerrans Philip
Published: September 2003

Either genetically specified modular cognitive architecture for syntactic processing does not exist (neuroconstructivism), or there is a module but its development is so abnormal in Williams syndrome (WS) that no conclusion can be drawn about its normal architecture (moderate nativism). Radical nativism, which holds that WS is a case of intact syntax, is untenable. Specific Language Impairment and WS create a dilemma that radical nativism cannot accommodate.
Dancing with humans: Interaction as unintended consequence
Authors: Locke John L.
Published: September 2003

Parallels to Shanker & King's (S&K's) proposal for a model of language teaching that values dyadic interaction have long existed in language development, for the neotenous human infant requires care, which is inherently interactive. Interaction with talking caregivers facilitates language learning. The “new” paradigm thus has a decidedly familiar look. It would be surprising if some other paradigm worked better in animals that have no evolutionary linguistic history.
Viewing cognitive mechanisms in the context of biology
Authors: Hermer-Vazquez Linda
Published: September 2003

Cognitive mechanisms are based in organisms’biology, and results from biological studies suggest that there is unlikely to be a single mechanism for reorienting or for combining information across modules or domains. Rather, there are likely to be multiple, partly overlapping systems for accomplishing nearly all cognitive and behavioral goals, as is the case for biological mechanisms more generally.
The role of working memory in skilled and conceptual thought
Authors: Wynn Thomas , Coolidge Fred
Published: September 2003

Models of working memory challenge some aspects of Carruthers’ account but enhance others. Although the nature of the phonological store and central executive appear fully congruent with Carruthers’ proposal, current models of the visuo-spatial sketchpad provide a better account of skilled action. However, Carruthers’ model may provide a way around the homunculus problem that has plagued models of working memory.
Production of short microwave pulses with a peak power exceeding
the driving electron beam power
Authors: ELTCHANINOV ANTON A. , KOROVIN SERGEI D. , ROSTOV VLADISLAV V. , PEGEL IGOR V. , MESYATS GENNADY A. , RUKIN SERGEI N. , SHPAK VALERY G. , YALANDIN MICHAEL I. , GINZBURG NAUM S.
Published: September 2003

This article presents results of theoretical and experimental
studies on the production of ultrashort (a few RF cycles duration)
microwave pulses of gigawatt peak powers based on superradiance
from high-current electron beams. With the Cherenkov
backward-wave–electron-beam interaction in a low-dispersion
slow-wave structure, microwave pulses with a peak power greater
than the peak power of the driving electron beam have been produced
for the first time. In an experiment using the SINUS-150 compact
high-current electron accelerator, with a 2.6-kA injected beam
current and a 330-kV electron energy, microwave pulses of 1.2
GW peak power and ∼0.5 ns duration (FWHM) were generated
in the X-band. Production of superradiance pulses in a repetitive
regime (3500 Hz) in the Ka-band has been demonstrated using
a compact hybrid SOS-modulator. The effect of spatial accumulation
of microwave energy in extended slow-wave structures with
substantially nonuniform coupling has been demonstrated. In
an experiment using the SINUS-200 compact accelerator, X-band
pulses of ∼3 GW peak power and 0.6–0.7 ns width (FWHM)
were produced with a power conversion efficiency of 150–180%
and an energy efficiency of ∼15%.
Cowden Syndrome
Authors: Eng Charis
Published: September 2003

Cowden syndrome is an autosomal dominant inherited cancer syndrome characterized by multiple hamartomas which may develop in any organ. Mucocutaneous papillomas and trichilemmomas are hallmarks of the syndrome. Affected individuals are at high risk of developing both benign and malignant disease of the thyroid and breast. Epithelial thyroid carcinoma occurs in 3–10% of affected individuals while women have a 25–50% lifetime risk of developing adenocarcinoma of the breast. Because of the cancer risk, it is imperative that health care providers recognize Cowden syndrome. The susceptibility gene has been localized to 10q22‐23 and preliminary studies demonstrate no genetic heterogeneity.
Clinical course of chronic periodontitis
Authors: Heitz‐Mayfield Lisa J. A. , Schätzle Marc , Löe Harald , Bürgin Walter , Ånerud Åge , Boysen Hans , Lang Niklaus P.
Published: September 2003

Aim: The purpose of this study was to assess the initiation and progression of periodontal disease during adult life.

Materials and Methods: In a 26‐year longitudinal investigation of the initiation and progression of chronic periodontitis that started in 1969 and included 565 men of Norwegian middle class, 223 who had participated in some, but not all, intermediate examinations presented at the last survey in 1995. Fifty‐four individuals were available for examination in all seven surveys.

Results: Covering the age range from 16 to 60 years, the study showed that at 16 years of age, 5% of the participants had initial loss of periodontal attachment (ILA2 mm) at one or more sites. Both the subject incidence and the site incidence increased with time, and by 32 years of age, all individuals had one or more sites with loss of attachment. As age progressed, new lesions affected sites, so that as these men approached 60 years of age approximately 50% of all available sites had ILA.

An assessment of the intraoral distribution of the first periodontal lesion showed that, regardless of age, molars and bicuspids were most often affected. At and before the age of 40 years, the majority of ILA was found in buccal surfaces in the form of gingival recession. By 50 years, however, a greater proportion of sites presented with attachment loss attributed to pocket formation or a combination of pocket formation and gingival recession. As individuals neared 60 years of age, approximately half of the interproximal areas in posterior teeth had these lesions.

Conclusion: This investigation has shown that, in a well‐maintained population who practises oral home care and has regular check‐ups, the incidence of incipient periodontal destruction increases with age, the highest rate occurs between 50 and 60 years, and gingival recession is the predominant lesion before 40 years, while perio‐dontal pocketing is the principal mode of destruction between 50 and 60 years of age.
The Experience of Recovery from Schizophrenia: Towards an Empirically Validated Stage Model
Authors: Andresen Retta , Oades Lindsay , Caputi Peter
Published: September 2003

Objective: The consumer movement is advocating that rehabilitation services become recovery-orientated. The objectives of this study are to gain a better understanding of the concept of recovery by: (i) identifying a definition of recovery that reflects consumer accounts; and (ii) developing a conceptual model of recovery to guide research, training and inform clinical practice.

Method: A review was conducted of published experiential accounts of recovery by people with schizophrenia or other serious mental illness, consumer articles on the concept of recovery, and qualitative research and theoretical literature on recovery. Meanings of recovery used by consumers were sought to identify a definition of recovery. Common themes identified in this literature were used to construct a conceptual model reflecting the personal experiences of consumers.

Results: The definition of recovery used by consumers was identified as psychological recovery from the consequences of the illness. Four key processes of recovery were identified: (i) finding hope; (ii) re-establishment of identity; (iii) finding meaning in life; and (iv) taking responsibility for recovery. Five stages were identified: (i) moratorium; (ii) awareness; (iii) preparation; (iv) rebuilding; and (v) growth.

Conclusion: A five-stage model compatible with psychological recovery is proposed, which offers a way forward for attaining recovery-orientated outcomes. After further empirical investigation, a version of this model could be utilized in quantitative research, clinical training and consumer education.
Attention Deficit Hyperactivity Disorder, Combined Type: Better Executive Function Performance With Longer-Term Psychostimulant Medication
Authors: Vance Alasdair L. A. , Maruff Paul , Barnett Rebecca
Published: September 2003

Objective: Executive function deficits are evident in primary school-age children with attention deficit hyperactivity disorder, combined type (ADHD-CT) and are possibly improved by longer-term psychostimulant medication. In contrast, a substantial subgroup of children with ADHD-CT become symptomatic despite longer-term psychostimulant medication use. We investigated the hypothesis that better executive function performance is associated with the use of longer-term psychostimulant medication in primary school-age children with ADHD-CT who are again symptomatic of ADHD-CT, despite its use.

Method: A cross-sectional study of 40 primary school-age psychostimulant medicationnaïve children with ADHD-CT, 26 with symptomatic ADHD-CT and treated with psychostimulant medication, and 26 control children without ADHD-CT was conducted. Nonverbal tasks of executive function were compared across the three groups.

Results: The longer-term psychostimulant medication-treated group had a better executive function performance, despite being symptomatic for ADHD-CT, than the psychostimulant medication-naïve group.

Conclusion: Improved executive function may be a marker of psychostimulant medication effect in children with ADHD-CT treated in the longer term. This improvement may not correlate with that of the ADHD-CT symptoms. Longitudinal studies are required.
Disseminated histoplasmosis with atypical cutaneous lesions in an Italian HIV‐infected patient: another autochtonous case
Authors: Calza L , Manfredi R , Donzelli C , Marinacci G , Colangeli V , Chiodo F
Published: September 2003

Disseminated histoplasmosis is recognized as a common AIDS‐defining opportunistic disease in endemic areas (Americas, Africa, East Asia), while it is rarely described in Europe, usually in individuals returning from endemic regions, or following endogenous reactivation of a latent infection imported long before from overseas countries. However, reports of autochtonous cases in Europe suggest the possible, endemic presence of Histoplasma capsulatum in some European regions, such as the South of France or the Po valley in Italy. A case of disseminated histoplasmosis with atypical, papular and ulcerate skin lesions in an Italian HIV‐infected patient, without history of travels outside his native region, is described. Our patient represents the fifth autochtonous case of AIDS‐associated histoplasmosis described in Italy.
Ubiquitination, Protein Turnover, and Long-Term Synaptic Plasticity
Authors: Schwartz James H.
Published: September 2003

For at least half a century, alteration of synaptic strength through growth at specific nerve terminals has been favored as the mechanism underlying long-term changes in behavior and synaptic plasticity. Although new proteins for synapses can either be synthesized locally or transported from the cell body, recent work on the postsynaptic element (dendritic spines) of cortical excitatory synapses indicates that transmission can also be modified by controlling the density of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors (AMPARs) in the postsynaptic density (PSD). This regulation is mediated by mono-ubiquitination, which governs turnover of AMPAR subunits by determining whether the endocytosed subunits are sent to lysosomes to be degraded or recycled back to the membrane by exocytosis. Also important is activity-dependent multi-ubiquitination and degradation of proteins that make up the scaffolding complexes that confine receptors to the PSD.
Pattern of Melatonin Secretion Mediates Transfer of Photoperiod Information from Mother to Fetus in Mammals
Authors: Goldman Bruce D.
Published: September 2003

Studies performed over the past 20 years have revealed that mother rodents can provide photoperiod information to their developing fetuses. In adult mammals, the pattern of pineal melatonin secretion changes in relation to changes in day length, and the melatonin pattern is a key part of the photoperiodic mechanism. Melatonin crosses the placenta, and fetal rodents can respond to the maternal melatonin rhythm. Thus, the mother's melatonin rhythm provides day-length information to the fetus, and this information is used, along with photoperiod information that is obtained after birth, to influence juvenile development. The transfer of photoperiod information from mother to fetus may be part of an adaptive system. When young are born early in the spring or summer breeding season, the increase in day length between the times of fetal and postnatal life results in rapid reproductive maturation, allowing these early-born animals to reproduce later during the same breeding season. In contrast, for young born late in the breeding season, the decrease in photoperiod between fetal and postnatal life results in delayed maturation of the gonads, and reproduction is delayed until the beginning of the next year's breeding season.
Novel
bis
-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro
Authors: Koh Yasuhiro , Nakata Hirotomo , Maeda Kenji , Ogata Hiromi , Bilcer Geoffrey , Devasamudram Thippeswamy , Kincaid John F. , Boross Peter , Wang Yuan-Fang , Tie Yunfeng , Volarath Patra , Gaddis Laquasha , Harrison Robert W. , Weber Irene T. , Ghosh Arun K. , Mitsuya Hiroaki
Published: September 2003

We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(
R
),3a(
S
),6a(
R
)-
bis
-tetrahydrofuranylurethane (
bis
-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC
50
], ∼0.003 μM; IC
90
, ∼0.009 μM) with minimal cytotoxicity (50% cytotoxic concentration for CD4
+
MT-2 cells, 74 μM). UIC-94017 blocked the infectivity and replication of each of HIV-1
NL4-3
variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 μM (IC
50
s, 0.003 to 0.029 μM), although it was less active against HIV-1
NL4-3
variants selected for resistance to amprenavir (IC
50
, 0.22 μM). UIC-94017 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections.
PCR and Restriction Endonuclease Assay for Detection of a Novel Mutation Associated with Sulfonamide Resistance in
Neisseria meningitidis
Authors: Bennett Désirée E. , Cafferkey Mary T.
Published: September 2003

We identified a previously undocumented mutation in the dihydropteroate synthase (
folP
) gene associated with
Neisseria meningitidis
sulfonamide resistance. A PCR-based assay to detect this mutation, which is 100% predictive of sulfonamide resistance, was developed.
Liposomal Amphotericin B, and Not Amphotericin B Deoxycholate, Improves Survival of Diabetic Mice Infected with
Rhizopus oryzae
Authors: Ibrahim Ashraf S. , Avanessian Valentina , Spellberg Brad , Edwards John E.
Published: September 2003

The efficacies of liposomal amphotericin B (LAmB) and amphotericin B deoxycholate (AmB) were compared in a diabetic murine model of hematogenously disseminated
Rhizopus oryzae
infection. At 7.5 mg/kg of body weight twice a day (b.i.d.), LAmB significantly improved overall survival compared to the rates of survival in both untreated control mice (
P
= 0.001) and mice treated with 0.5 mg of AmB per kg b.i.d. (
P
= 0.047). These data indicate that high-dose LAmB is more effective than AmB in treating murine disseminated zygomycosis.
Ciprofloxacin Transport by Chemoattractant-Activated Polymorphonuclear Leukocytes: Regulation by Priming and Protein Kinase C
Authors: Walters John D. , Nakkula Robin J.
Published: September 2003

At infection sites, polymorphonuclear leukocyte (PMN) function is enhanced (“primed”) by granulocyte-macrophage colony-stimulating factor (GM-CSF) or lipopolysaccharide (LPS) and activated by formyl peptides. In this study, GM-CSF or LPS alone had no significant effects on PMN ciprofloxacin transport. Through a mechanism involving protein kinase C, activation byformyl-Met-Leu-Phe (fMLP) significantly decreased theKmof ciprofloxacin transport and enhanced ciprofloxacin accumulation. This effect was dramatically enhanced when PMNs were primed with GM-CSF or LPS prior to activation by fMLP.
Gas stove use and respiratory health among adults with asthma in NHANES III
Authors: Eisner M D , Blanc P D
Published: September 2003

Background:Gas stoves release respiratory irritants, such as nitrogen dioxide and other combustion by-products. Adults with asthma may be susceptible to the effects of gas stove exposure because of their underlying airway hyperresponsiveness, but this association has been difficult to establish.

Aims:To examine the association between gas stove use and respiratory health.

Methods:The analysis used data from the US Third National Health and Nutrition Examination Survey among 445 adults with asthma (representing 4.8 million persons with the condition).

Results:Nearly half of the adults with asthma had a gas stove in their home (47.1%). There was no association between gas stove use and FEV1(mean change 146 ml; 95% CI −50 to 342 ml), FVC (0 ml; 95% CI −151 to 152 ml), or FEF25%–75%(357 ml; 95% CI −7 to 722 ml). There was also no relation between gas stove use and the risk of self reported cough (OR 0.8; 95% CI 0.4 to 1.7), wheeze (OR 1.5; 95% CI 0.7 to 3.2), or other respiratory symptoms. Controlling for sociodemographic, smoking, housing, and geographic factors did not appreciably affect these results.

Conclusions:Among adults with asthma, there was no apparent impact of gas stove use on pulmonary function or respiratory symptoms. These results should be reassuring to adults with asthma and their health care providers.
Workplace bullying and the risk of cardiovascular disease and depression
Authors: Kivimäki M , Virtanen M , Vartia M , Elovainio M , Vahtera J , Keltikangas-Järvinen L
Published: September 2003

Aims:To examine exposure to workplace bullying as a risk factor for cardiovascular disease and depression in employees.

Methods:Logistic regression models were related to prospective data from two surveys in a cohort of 5432 hospital employees (601 men and 4831 women), aged 18–63 years. Outcomes were new reports of doctor diagnosed cardiovascular disease and depression during the two year follow up among those who were free from these diseases at baseline.

Results:The prevalence of bullying was 5% in the first survey and 6% in the second survey. Two per cent reported bullying experiences in both surveys, an indication of prolonged bullying. After adjustment for sex, age, and income, the odds ratio of incident cardiovascular disease for victims of prolonged bullying compared to non-bullied employees was 2.3 (95% CI 1.2 to 4.6). A further adjustment for overweight at baseline attenuated the odds ratio to 1.6 (95% CI 0.8 to 3.5). The association between prolonged bullying and incident depression was significant, even after these adjustments (odds ratio 4.2, 95% CI 2.0 to 8.6).

Conclusions:A strong association between workplace bullying and subsequent depression suggests that bullying is an aetiological factor for mental health problems. The victims of bullying also seem to be at greater risk of cardiovascular disease, but this risk may partly be attributable to overweight.
Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial Disease
Authors: Rajagopalan Sanjay , Mohler Emile R. , Lederman Robert J. , Mendelsohn Farrell O. , Saucedo Jorge F. , Goldman Corey K. , Blebea John , Macko Jennifer , Kessler Paul D. , Rasmussen Henrik S. , Annex Brian H.
Published: September 2003

Background—

“Therapeutic angiogenesis” seeks to improve perfusion by the growth of new blood vessels. The Regional Angiogenesis with Vascular Endothelial growth factor (RAVE) trial is the first major randomized study of adenoviral vascular endothelial growth factor (VEGF) gene transfer for the treatment of peripheral artery disease (PAD).

Methods and Results—

This phase 2, double-blind, placebo-controlled study was designed to test the efficacy and safety of intramuscular delivery of AdVEGF121, a replication-deficient adenovirus encoding the 121-amino-acid isoform of vascular endothelial growth factor, to the lower extremities of subjects with unilateral PAD. In all, 105 subjects with unilateral exercise-limiting intermittent claudication during 2 qualifying treadmill tests, with peak walking time (PWT) between 1 to 10 minutes, were stratified on the basis of diabetic status and randomized to low-dose (4×10
9
PU) AdVEGF121, high-dose (4×10
10
PU) AdVEGF121, or placebo, administered as 20 intramuscular injections to the index leg in a single session. The primary efficacy end point, change in PWT (ΔPWT) at 12 weeks, did not differ between the placebo (1.8±3.2 minutes), low-dose (1.6±1.9 minutes), and high-dose (1.5±3.1 minutes) groups. Secondary measures, including ΔPWT, ankle-brachial index, claudication onset time, and quality-of-life measures (SF-36 and Walking Impairment Questionnaire), were also similar among groups at 12 and 26 weeks. AdVEGF121 administration was associated with increased peripheral edema.

Conclusions—

A single unilateral intramuscular administration of AdVEGF121 was not associated with improved exercise performance or quality of life in this study. This study does not support local delivery of single-dose VEGF
121
as a treatment strategy in patients with unilateral PAD.
Increased Angiotensin-(1-7)–Forming Activity in Failing Human Heart Ventricles
Authors: Zisman Lawrence S. , Keller Rebecca S. , Weaver Barbara , Lin Qishan , Speth Robert , Bristow Michael R. , Canver Charles C.
Published: September 2003

Background—

The formation of angiotensin-(1-7) from either angiotensin (Ang) I or Ang II in failing human hearts is not well understood.

Methods and Results—

Angiotensinase activity in left and right ventricular membranes from 14 idiopathic dilated cardiomyopathy (IDC), 8 primary pulmonary hypertension (PPH), and 13 nonfailing human hearts was measured with either
125
I-Ang I or
125
I-Ang II as substrate. Ang-(1-7)–forming activity from
125
I-Ang I was inhibited by thiorphan. With
125
I-Ang II as substrate, Ang-(1-7) formation was inhibited by the ACE2-specific inhibitor C16. Western blotting with an anti-ACE2 antibody confirmed the presence of ACE2. Angiotensinase activity with
125
I-Ang I as substrate was increased in failing IDC left ventricles (LVs) compared with nonfailing LVs (
P
<0.001). Ang-(1-7)–forming activity with
125
I-Ang II as substrate was increased in both failing LVs and right ventricles (RVs) of IDC hearts and only in failing RVs of PPH hearts (PPH LV, 51.12±5.25; PPH RV, 89.97±11.21; IDC LV, 139.7±21.96; and IDC RV, 192.7±5.43; NF LV, 32.89±5.38; NF RV 40.49±10.66 fmol/min per milligram (
P
<0.05 PPH RV versus PPH LV;
P
<0.05 PPH RV versus NF RV;
P
<0.001 IDC LV versus NF LV;
P
<0.001 IDC RV versus NF RV).

Conclusions—

Ang-(1-7)–forming activity from both Ang I and Ang II was increased in failing human heart ventricles but was mediated by at least two different angiotensinases. The first, which demonstrated substrate preference for Ang I, was neutral endopeptidase (NEP)-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C16.
Chlamydia pneumoniae
Stimulates Proliferation of Vascular Smooth Muscle Cells Through Induction of Endogenous Heat Shock Protein 60
Authors: Hirono Satoru , Dibrov Elena , Hurtado Cecilia , Kostenuk Annette , Ducas Robin , Pierce Grant N.
Published: September 2003

Chlamydia pneumoniae
infection has been linked with atherosclerosis. However, the mechanism responsible for the atherogenic effects of
C pneumoniae
remains unclear. Heat shock proteins (HSPs) have been found in atherosclerotic lesions. HSPs of HSP70 and HSP90 families are involved in the regulation of cell cycle progression and cell proliferation. We assessed the hypothesis that HSP60 is induced in vascular cells infected with
C pneumoniae
and stimulates cell proliferation. Rabbit vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were infected with
C pneumoniae
. Western blot analysis demonstrated the induction of endogenous HSP60 expression in
C pneumoniae
-infected VSMCs.
C pneumoniae
infection significantly increased the number of VSMCs, and the mitogenic effect correlated with the expression level of endogenous HSP60. In contrast to VSMCs,
C pneumoniae
infection had no effect on the expression level of HSP60 and did not stimulate cell proliferation in HUVECs. Exogenous addition of recombinant chlamydial HSP60 had no mitogenic effect on VSMCs and HUVECs. However, overexpression of HSP60 within VSMCs by infection with adenovirus encoding human HSP60 resulted in a significant increase in cell numbers compared with uninfected VSMCs. These results suggest that overexpression of endogenous HSP60 may be a central intracellular event responsible for the mitogenic effects induced by
C pneumoniae
infection. In addition to
C pneumoniae
, other infectious agents and atherogenic risk factors may also stimulate VSMC proliferation and contribute to the lesion formation through the induction of HSP60.
Selective inactivation of p27Kip1 in hematopoietic progenitor cells increases neointimal macrophage proliferation and accelerates atherosclerosis
Authors: Díez-Juan Antonio , Pérez Paloma , Aracil Miguel , Sancho David , Bernad Antonio , Sánchez-Madrid Francisco , Andrés Vicente
Published: September 2003

Excessive proliferation of immune cells and vascular smooth myocytes (VSMCs) contributes to atherosclerosis. We have previously shown that whole-body inactivation of the growth suppressor p27 exacerbates atherosclerosis in apolipoprotein E-null mice (apoE–/–), and this correlated with increased proliferation of arterial macrophages and VSMCs. In the present study, we postulated that targeted disruption of bone marrow (BM) p27 is sufficient to enhance arterial macrophage proliferation and atherosclerosis. To test this hypothesis, sublethally irradiated apoE–/– mice with an intact p27 gene received a BM transplant from either apoE–/– or p27–/–apoE–/– doubly deficient donor mice and challenged with a high-cholesterol diet. Compared with mice that received an apoE–/– BM transplant, reconstitution with p27–/–apoE–/– doubly deficient marrow increased the expression of proliferating cell nuclear antigen in neointimal macrophages and accelerated aortic atherosclerosis, and this correlated with augmented aortic expression of the inflammatory cytokines CCL2/MCP-1 (monocyte chemoattractant protein 1) and CCL5/RANTES (regulated on activation, normal T-cell expressed and secreted). Overall, these findings provide evidence that p27 deficiency in hematopoietic progenitor cells enhances the inflammatory/proliferative response induced by dietary cholesterol and accelerates atherosclerosis.
Prostaglandin E2in the expired breath condensate of patients with asthma
Authors: Kostikas K. , Papatheodorou G. , Psathakis K. , Panagou P. , Loukides S.
Published: September 2003

Inhaled prostaglandin (PG)E2has been found to cause bronchodilation in asthmatics, although it does not have bronchodilative effects in normal subjects. The aim of this study was to investigate the levels of PGE2in the expired breath condensate of patients with asthma, the possible contribution of smoking habit to its levels and the possible relationship between PGE2and the degree of bronchial hyperresponsiveness, as assessed by the provocation dose of histamine causing a 20% fall in forced expiratory volume in one second (FEV1) (PD20).

A total of 30 mild asthmatics (15 smokers, all steroid-naive, FEV188±6 (%±sd)) and 20 healthy control subjects (10 smokers) were studied. Histamine challenge testing was performed in all subjects and the PD20was determined.

The results showed that asthmatic smokers had significantly higher values of PGE2compared to asthmatic nonsmokers and control subjects (40±21versus14.5±4.5versus11.7±3 pg·mL−1, respectively). Further analysis showed that PGE2levels were significantly higher in asthmatic smokers compared to smoker and nonsmoker controls (40±21versus11.6±2versus11.7±4 pg·mL−1, respectively). No significant difference was observed between asthmatic nonsmokers and both control smokers and control nonsmokers. No significant correlation was found between PGE2levels and PD20in all groups of asthmatics, irrespective of smoking habit.

In conclusion, the elevation of prostaglandin E2in the expired breath condensate of patients with asthma is mainly attributed to smoking habit and prostaglandin E2levels do not predict the degree of bronchial hyperresponsiveness.
Trends in antimalarial drug deployment in sub-Saharan Africa
Authors: Bloland P. B. , Kachur S. P. , Williams H. A.
Published: September 2003

Antimalarial drug resistance is forcing newly developed pharmaceuticals into widespread use at an accelerating pace. To have the greatest public health impact, new pharmaceuticals will need to be deployed effectively in sub-Saharan Africa. Achieving effective antimalarial drug deployment over the short- to medium-term will require an appreciation of how drugs are currently used in Africa and the development of innovative approaches to optimize that use. Over the long-term, fundamental changes in the way that drugs are deployed will probably be required. There are many new strategies and initiatives that, to a greater or lesser degree, will influence how drugs are used. These influences may have a positive or negative effect on reducing malaria morbidity and mortality. The concept of analyzing and monitoring programmatic effectiveness allows for a more holistic understanding of these influences and allows for more unbiased, evidence-based decision making related to drug policy and deployment.
Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuatedPlasmodium falciparumsporozoite vaccine
Authors: Luke Thomas C. , Hoffman Stephen L.
Published: September 2003

Annually, malaria causes >300 million clinical cases and 1 million deaths, is responsible for the loss of >1% of gross domestic product (GDP)in Africa and is a serious concern for travelers. An effective vaccine could have a dramatic impact on the disease. For 20 years, scientists have tried to develop modern, recombinant `subunit' malaria vaccines. This has been difficult. In fact, there is only one recombinant protein vaccine on the market for any disease, and no vaccines based on synthetic peptides,recombinant viruses, recombinant bacteria or DNA plasmids. Most vaccines are based on attenuated or inactivated whole pathogens or material derived directly from the infectious agent. It is in that context that our recent report summarizing the protection of humans with attenuated Plasmodium falciparum (Pf) sporozoites produced at four different sites over 25 years is important. In studies utilizing live mosquitoes as the vaccine delivery mechanism, there was complete protection against malaria in 93% of volunteers (13/14) and 94% of challenges (33/35). Sanaria's goal is to develop and commercialize a non-replicating, metabolically active Pfsporozoite vaccine.

Three practical questions must be addressed before manufacturing for clinical trials: (1) can one administer the vaccine by a route that is clinically practical; (2) can one produce adequate quantities of sporozoites;and (3) can sporozoites be produced with the physical characteristics that meet the regulatory, potency and safety requirements of regulatory authorities? Once these questions have been answered, Sanaria will demonstrate that the vaccine protects >90% of human recipients against experimental challenge with Pf sporozoites, can be produced with an efficiency that makes it economically feasible, and protects >90% of African infants and children from infection, and thus from severe morbidity and mortality. By producing a vaccine for travelers, Sanaria will provide the infrastructure,regulatory foundation and funds necessary to speed licensure, manufacturing and deployment of the vaccine for the infants and children who need it most.
Research approaches in the development of interventions against vector-borne infection
Authors: Spielman Andrew
Published: September 2003

The conceptual basis of public health entomology developed at the turn of the twentieth century with the seminal experiments that guided the first vector-directed interventions. Within 50 years, technological advances built confidence in the power of research to resolve threats posed by vector-borne pathogens. Hope that the resulting diseases might be eliminated by time-limited interventions, however, soon became remote, thereby intensifying research efforts in vector biology. Beginning in the 1960s, US investigator-initiated grant proposals in vector biology were reviewed by a panel of the National Institutes of Health (NIH) that considered all proposals relating to `Tropical Medicine and Parasitology' (TMP). Following the recommendation of a conference held in 1978, proposals relating to insect physiology came to be reviewed by TMP. A standing `ad hoc entomology'study section was formed in 1982 to deal with this influx of proposals. Another conference, held in 1993, encouraged consideration of proposals relating to vector transgenics by that study section. By 1994, this diversion caused the community of US public health entomologists to petition, in vain,for a return to the original concept of vector biology. By 2003, so many molecular proposals were submitted that entomological studies containing a field component were removed to an epidemiological study section distinct from TMP. In 2002, only half as many vector biology training programs could be identified in the US as in 1982, with a proportionate loss of associated faculty. A conference convened by the Institute of Medicine in 2003 concluded that the `human resource capacity' in the US suitable for dealing with vector-related issues in health should be rebuilt. Although the development of such a discipline would depend largely on the system of investigator-initiated research proposals awarded by NIH, private donors and foundations seem likely to play an important role in this dynamic. The meld of vector biology, insect physiology and vector transgenics that will characterize the faculty that produces this new generation of public health entomologists remains to be defined.
Pre-donated autologous blood transfusion in scoliosis surgery
Authors: Ridgeway S. , Tai C. , Alton P. , Barnardo P. , Harrison D. J.
Published: September 2003

We studied the use of autologous pre-donated blood transfusion in surgery for scoliosis in 45 patients who were divided into two groups; 27 who pre-donated autologous blood (group 1) and 18 who were planned recipients of allogenic blood (group 2). Normovolaemic haemodilution and intra-operative blood salvage was used in six patients in group 1 and three patients in group 2.

The two groups did not differ significantly with respect to age, American Society of Anaesthesiologists score, mean operative time, number of vertebral segments fused, total blood loss, length of stay in intensive care and length of stay in hospital. The risk of requiring allogenic blood transfusion was found to be significantly less in group 1 (7.4% ν 88.9%, p < 0.001). Only 5.21% of autologous units were wasted. Although intra-operative blood salvage reduced the total blood loss in both groups, it did not affect the need for subsequent allogenic transfusion or reduce the number of pre-donated autologous units which were given (p < 0.67). Autologous blood transfusion required extra time, personnel, resources and cost £28.88 per patient more than allogenic transfusion, however, the projected costs at May 2002 make this programme cost-effective by £51.54 per patient.

Pre-donated autologous blood transfusion is acceptable and safe in scoliosis surgery. It significantly reduces the subsequent requirement of allogenic transfusion. Although the cost is currently more than allogenic transfusion, with the increase in the costs of the latter and the decrease in potential donors which is anticipated, pre-donation of autologous blood will become comparatively cost-effective.
Survival analysis of hips treated with flexion osteotomy for femoral head necrosis
Authors: Drescher W. , Fürst M , Hahne H. J. , Helfenstein A. , Petersen W. , Hassenpflug J.
Published: September 2003

The treatment of osteonecrosis of the femoral head (FHN) is controversial. It mainly occurs in young patients in whom total hip replacement is best avoided because of an increased risk of revision. The objective of this long-term follow-up study was to evaluate the outcome of intertrochanteric flexion osteotomy as a hip joint preserving operation for FHN.

Over a 19-year period we carried out 70 intertrochanteric flexion osteotomies for FHN in 64 patients. The mean follow-up was 10.4 years (3.0 to 20.3). The overall mean Harris hip score increased from 51 points preoperatively to 71 points postoperatively. Six patients (9%) developed early postoperative complications. A total of 19 hips (27%) underwent total hip arthroplasty at a mean of 8.7 years after osteotomy. The five-year survival rate was 90%. Survival rates of hips in Ficat stage 2 were higher than those in stages 3 or 4. Hips with a preoperative necrotic angle of < 200° had a better survival probability than those with a necrotic angle > 200°. Our findings suggest that flexion osteotomy is a safe and effective procedure in Ficat stage 2 and 3 FHN, preferably with a necrotic angle of < 200°.
Electron Orbital Hybridization‐Enhanced Copper‐Nanocatalysis for Anti‐Infection
Authors: Luo Yao , Ruan Zesong , Guo Zhao , Chen Yunfeng , Lin Han , Ge Min , Zhu Chen
Published: January 2024

Recurrent bacterial infections, impenetrable microbial biofilms, and irremediable antibiotic resistance are the most perilous threats in orthopedic implant‐associated infections (IAIs). Recently, chemodynamic therapy (CDT) has been considered a promising therapy, while the clinical practices for existing CDT agents are limited by the low therapeutic efficiency in physiological circumstances. Herein, it is demonstrated that silica‐copper nanosheets (Si@Cu NSs) exhibit a combined therapeutic photothermal‐chemodynamic strategy for IAIs treatment with superior capacity and biocompatibility. This unique design endows the nanostructure with enhanced copper‐based Fenton‐like properties via p‐d orbital hybridization by incorporating copper nanoclusters (Cu NCs) on silicene nanosheets (Si NSs) matrix, integrating inherent photothermal performance of Si NSs with specific catalytic anti‐infection of Cu NCs against planktonic bacteria and biofilms both in vitro and in vivo. This study not only reveals the promising bio‐application prospects of 2D nanocatalytic biomaterials but also demonstrates the feasibility of constructing novel CDT agents by orbital hybridization for the catalytic treatment of IAIs.
A Paper‐Like Hydrogel for Versatile Information Encryption and Decryption Via Chemical‐Induced Phase Separation
Authors: Hou Jun‐Bo , Chen Xin‐Shi , Zhao Yue
Published: January 2024

Information coding, recording, encryption, and decryption are of great importance in the field of anti‐counterfeiting, especially in the current AI information era. Herein, a paper‐like hydrogel composed of solely H‐bonded poly(vinyl alcohol) (PVA) and poly(n‐vinylcaprolactam) (PNVCL), namely VAPN, is developed for multiple ways of encryption and decryption based on chemical‐induced phase separation. It not only exhibits excellent ability of ink absorption and retention by the noncovalent H‐bonds and n−π* interactions and good mechanical strength but also maintains a negligible volume change during the phase separation that is crucial for the information fidelity. Given that the noncovalent interactions are the driving force to trigger the phase separation in the hydrogel, available chemical inks are numerous ranging from small molecules to polymers. Furthermore, together with thermally induced phase separation, the different dynamic processes of the association and dissociation between ink molecules and the hydrogel endow the latter with reversible information recording and self‐erasing, temporary or permanent, and customized encryption and decryption.