bluuebunny/crossref_metadata_2025 huggingface dataset:
Agent‐based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor‐β1
Authors: Mi Qi , Rivière Beatrice , Clermont Gilles , Steed David L. , Vodovotz Yoram
Published: September 2007

Inflammation and wound healing are inextricably linked and complex processes, and are deranged in the setting of chronic, nonhealing diabetic foot ulcers (DFU). An ideal therapy for DFU should both suppress excessive inflammation while enhancing healing. We reasoned that biological simulation would clarify mechanisms and help refine therapeutic approaches to DFU. We developed an agent‐based model (ABM) capable of reproducing qualitatively much of the literature data on skin wound healing, including changes in relevant cell populations (macrophages, neutrophils, fibroblasts) and their key effector cytokines (tumor necrosis factor‐α [TNF], interleukin [IL]‐1β, IL‐10, and transforming growth factor [TGF]‐β1). In this simulation, a normal healing response results in tissue damage that first increases (due to wound‐induced inflammation) and then decreases as the collagen levels increase. Studies by others suggest that diabetes and DFU are characterized by elevated TNF and reduced TGF‐β1, although which of these changes is a cause and which one is an effect is unclear. Accordingly, we simulated the genesis of DFU in two ways, either by (1) increasing the rate of TNF production fourfold or (2) by decreasing the rate of TGF‐β1 production 67% based on prior literature. Both manipulations resulted in increased inflammation (elevated neutrophils, TNF, and tissue damage) and delayed healing (reduced TGF‐β1 and collagen). Our ABM reproduced the therapeutic effect of platelet‐derived growth factor/platelet releasate treatment as well as DFU debridement. We next simulated the expected effect of administering (1) a neutralizing anti‐TNF antibody, (2) an agent that would increase the activation of endogenous latent TGF‐β1, or (3) latent TGF‐β1 (which has a longer half‐life than active TGF‐β1), and found that these therapies would have similar effects regardless of the initial assumption of the derangement that underlies DFU (elevated TNF vs. reduced TGF‐β1). In silico methods may elucidate mechanisms of and suggest therapies for aberrant skin healing.
Cell suspension cultures of allogenic keratinocytes are efficient carriers for ex vivo gene transfer and accelerate the healing of full‐thickness skin wounds by overexpression of human epidermal growth factor
Authors: Vranckx Jan Jeroen , Hoeller Daniela , Velander Patrik E. M. , Theopold Christoph F. P. , Petrie Nicola , Takedo Akira , Eriksson Elof , Yao Feng
Published: September 2007

The concept of using growth factor therapy to induce wound repair has been endorsed in studies that show reduced growth factors in wound fluid from chronic and aged wounds. In this study, we used cell suspensions of allogenic keratinocytes as gene‐delivery vehicles for human epidermal growth factor (hEGF) and analyzed their impact on wound repair in a porcine wound‐healing model. Full‐thickness wounds were created on the backs of six Yorkshire pigs and covered with a wound chamber to create a wet wound‐healing environment. First, 5 × 105 allogenic, autogenic, or mixed keratinocytes were transplanted into wounds and healing parameters were analyzed. Second, we measured long‐term reepithelialization and contraction rates from day 8 until day 35. In the third experiment, allogenic keratinocytes were transfected with an hEGF‐expressing plasmid pCEP‐hEGF and transplanted in full‐thickness wounds to improve repair. Wounds treated with autogenic, allogenic, or mixed keratinocytes showed a significantly higher rate of reepithelialization relative to saline‐treated control wounds. Repetitive biopsies indicated that the use of allogenic keratinocytes did not lead to long‐term wound breakdown. Wounds treated with hEGF‐expressing allogenic keratinocytes reepithelialized faster than wounds treated with allogenic keratinocytes or control wounds. With a peak hEGF expression of 920.8 pg/mL, hEGF was detectable until day 5 after transplantation compared with minimal hEGF expression in control wounds. This study shows that allogenic keratinocytes can serve as efficient gene transfer vehicles for ex vivo growth factor delivery to full‐thickness wounds and overexpression of hEGF further improves reepithelialization rates.
db/db mice exhibit severe wound‐healing impairments compared with other murine diabetic strains in a silicone‐splinted excisional wound model
Authors: Michaels Joseph , Churgin Samara S. , Blechman Keith M. , Greives Matthew R. , Aarabi Shahram , Galiano Robert D. , Gurtner Geoffrey C.
Published: September 2007

The pathophysiology of diabetic wound healing and the identification of new agents to improve clinical outcomes continue to be areas of intense research. There currently exist more than 10 different murine models of diabetes. The degree to which wound healing is impaired in these different mouse models has never been directly compared. We determined whether differences in wound impairment exist between diabetic models in order to elucidate which model would be the best to evaluate new treatment strategies. Three well‐accepted mouse models of diabetes were used in this study: db/db, Akita, and streptozocin (STZ)‐induced C57BL/6J. Using an excisional model of wound healing, we demonstrated that db/db mice exhibit severe impairments in wound healing compared with STZ and Akita mice. Excisional wounds in db/db mice show a statistically significant delay in wound closure, decreased granulation tissue formation, decreased wound bed vascularity, and markedly diminished proliferation compared with STZ, Akita, and control mice. There was no difference in the rate of epithelialization of the full‐thickness wounds between the diabetic or control mice. Our results suggest that splinted db/db mice may be the most appropriate model for studying diabetic wound‐healing interventions as they demonstrate the most significant impairment in wound healing. This study utilized a novel model of wound healing developed in our laboratory that stents wounds open using silicone splints to minimize the effects of wound contraction. As such, it was not possible to directly compare the results of this study with other studies that did not use this wound model.
Effects of decreased insulin‐like growth factor‐1 stimulation on hypoxia inducible factor 1‐α protein synthesis and function during cutaneous repair in diabetic mice
Authors: Yu Diana H. , Mace Kimberly A. , Hansen Scott L. , Boudreau Nancy , Young David M.
Published: September 2007

Insulin‐like growth factor‐1 (Igf‐1), a critical mediator of tissue repair, is significantly decreased in diabetic wounds. Furthermore, decreased levels of hypoxia‐inducible factor 1‐α (Hif‐1α) and its target genes are also associated with impaired wound healing in diabetic mice. The aim of our study was to examine whether the reduced levels of Igf‐1 are responsible for the reduction in Hif‐1α protein synthesis and activity in diabetic wounds. We provide evidence that Igf‐1 regulates Hif‐1α protein synthesis and activity during wound repair. In addition, Igf‐1 stimulated phosphytidylinositol 3‐kinase activity in diabetic fibroblasts, which, in turn, increased activation of the translational regulatory protein, p70 S6 kinase. Moreover, improved healing of diabetic wounds by addition of recombinant IGF‐1 protein was associated with an increase in Hif‐1α protein synthesis and function in vivo.
Enhancement of keratinocyte performance in the production of tissue‐engineered skin using a low‐calcium medium
Authors: Hernon Catherine A. , Harrison Caroline A. , Thornton Daniel J. A. , MacNeil Sheila
Published: September 2007

The success of laboratory‐expanded autologous keratinocytes for the treatment of severe burn injuries is often compromised by their lack of dermal remnants and failure to establish a secure dermo‐epidermal junction on the wound bed. We have developed a tissue‐engineered skin substitute for in vivo use, based on a sterilized donor human dermis seeded with autologous keratinocytes and fibroblasts. However, culture rates are currently too slow for clinical use in acute burns. Our aim in this study was to increase the rate of production of tissue‐engineered skin. Two approaches were explored: one using a commercial low‐calcium media and the other supplementing well‐established media for keratinocyte culture with the calcium‐chelating agent ethylene glutamine tetra‐acetic acid (EGTA). Using commercial low‐calcium media for both the initial cell culture and subsequent culture of tissue‐engineered skin did not produce tissue suitable for clinical use. However, it was possible to enhance the initial proliferation of keratinocytes and to increase their horizontal migration in tissue‐engineered skin by supplementing established culture medium with 0.04 mM EGTA without sacrificing epidermal attachment and differentiation. Enhancement of keratinocyte migration with EGTA was also maximal in the absence of fibroblasts or basement membrane.
Increased apoptosis at the late stage of tendon healing
Authors: Lui Pauline Po Yee , Cheuk Yau Chuk , Hung Leung Kim , Fu Sai Chuen , Chan Kai Ming
Published: September 2007

The mechanism for the clearance of excess healing fibroblasts at the end of tendon healing has not been reported despite the importance of maintaining tissue homeostasis. This study investigated the role of apoptosis in cell turnover in a rat central 1/3 patellar tendon donor site injury model. At days 4, 7, 14, 28, months 2 and 6, the rats were killed. Patellar tendons without injury served as control. Apoptotic cells were determined by an in situ terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end‐labeling (TUNEL) assay and anti‐active caspase‐3 antibodies, while proliferating cells were determined by anti‐proliferating cell nuclear antigen antibodies. The total fibroblast‐like cell density in the center of the wound increased from day 4 and thereafter steadily returned to normal. In situ TUNEL assay showed few positive staining cells in the wound at days 4 and 7. The percentages of TUNEL‐positive fibroblast‐like cells showing morphological characteristics of apoptosis increased sharply and reached the maximum on day 28 (median %: 31.38%). No fibroblast‐like cell was stained at month 6 and the healed tissue was similar to that in a normal uninjured tendon. A similar trend was observed with active caspase‐3 immunohistochemistry. In conclusion, an increase in apoptosis at the end of tendon healing coincided with a decrease in cellularity.
Stromal progenitor cell therapy corrects the wound‐healing defect in the ischemic rabbit ear model of chronic wound repair
Authors: Volk Susan W. , Radu Antoneta , Zhang Liping , Liechty Kenneth W.
Published: September 2007

Chronic wounds create a formidable clinical problem resulting in considerable morbidity and healthcare expenditure. The etiology for wound healing impairment appears to be multifactorial; however, ischemia is a common factor in most types of chronic wounds. Ideal therapy for such wounds would be to correct deficiencies in growth factors and matrix components and provide cellular precursors required for timely wound closure. We hypothesized that stromal progenitor cell (SPC) therapy could correct the ischemic wound‐healing defect through both direct and indirect mechanisms. To test this hypothesis, we used the ischemic rabbit ear model of chronic wound healing. We found that treatment of the wounds with SPCs was able to reverse the ischemic wound‐healing impairment, with improved granulation tissue formation and reepithelialization compared with vehicle or bone marrow mononuclear cell controls. In vitro, SPCs were found to produce factors involved in angiogenesis and reepithelialization, and extracellular matrix components, providing evidence for both direct and indirect mechanisms for the observed correction of the healing impairment in these wounds. Treatment of ischemic wounds with SPCs can dramatically improve wound healing and provides a rationale for further studies focused on SPCs as a potential cellular therapy in impaired wound healing.
Sustained expression of Hif‐1α in the diabetic environment promotes angiogenesis and cutaneous wound repair
Authors: Mace Kimberly A. , Yu Diana H. , Paydar Keyianoosh Z. , Boudreau Nancy , Young David M.
Published: September 2007

Impaired wound healing in diabetic patients is associated with deficiencies in the production of factors involved in cell proliferation and migration, such as vascular endothelial growth factor. However, it remains unclear how the transcriptional regulation of the genes encoding these factors is affected by the diabetic environment. Hypoxia‐inducible factor‐1α (Hif‐1α), the regulatory subunit of the Hif‐1 transcription factor, plays an important role in activating many of these genes. Therefore, we tested whether Hif‐1α function is impaired in the diabetic wound environment and whether restoring Hif‐1 function improves wound healing. Here, we show that Hif‐1α protein levels are dramatically reduced in wounds of leptin receptor‐deficient diabetic mice compared with nondiabetic littermates. Reduction in Hif‐1α levels results in decreased DNA‐binding activity and in decreased expression of several Hif‐1 target genes, including vascular endothelial growth factor, heme oxygenase‐1, and inducible nitric oxide synthase. Furthermore, we demonstrate that sustained expression of Hif‐1α in leptin receptor‐deficient diabetic wounds restores expression of these factors, enhances angiogenesis, and significantly accelerates wound healing. Taken together, these results suggest that Hif‐1α function plays a significant role in wound healing and reduced levels of Hif‐1α may contribute to impaired healing.
Influence of papain urea copper chlorophyllin on wound matrix remodeling
Authors: Telgenhoff Dale , Lam Kan , Ramsay Sarah , Vasquez Valerie , Villareal Kristine , Slusarewicz Paul , Attar Paul , Shroot Braham
Published: September 2007

The purpose of this study was to examine the dermal and epidermal alterations associated with wound healing in wounds treated with papain urea copper chlorophyllin (PUC), papain‐urea, copper chlorophyllin, or urea base ointment and compare these with moist wound care using a porcine full‐thickness infected wound model. All the wounds were evaluated postsurgery for erythema, transepidermal water loss, microscopic morphology, and changes in protein expression. Examination of stained paraffin sections revealed an increase in the number of keratinocytes present in the epidermis of the PUC and papain‐treated pigs, relative to moist control. This increase in keratinocyte number corresponded to an increase in the movement of the keratinocytes into the underlying dermis in the form of rete pegs. In the dermis, there appeared to be an increase in blood vessel formation, collagen I deposition, and mature collagen in the papain and PUC treated tissues. The quality of healing appears to be enhanced based on the number of keratinocytes present in the epidermis, the extensive rete peg formation, the increase in vasculature, and the increase in collagen birefringence.
Wound‐healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes
Authors: Spiekstra Sander W. , Breetveld Melanie , Rustemeyer Thomas , Scheper Rik J. , Gibbs Susan
Published: September 2007

Full‐skin substitutes, epidermal substitutes, and dermal substitutes are currently being used to heal deep burns and chronic ulcers. In this study, we investigated which wound‐healing mediators are released from these constructs and whether keratinocyte–fibroblast interactions are involved. Autologous skin substitutes were constructed from human keratinocytes, fibroblasts, and acellular donor dermis. Full‐thickness skin was used to represent an autograft. Secretion of wound‐healing mediators was investigated by means of protein array, enzyme‐linked immunosorbent assay, neutralizing antibodies, and conditioned culture supernatants. Full‐skin substitutes and autografts produce high amounts of inflammatory/angiogenic mediators (IL‐6, CCL2, CXCL1, CXCL8, and sST2). Epidermal and dermal substitutes produced less of these proteins. Epidermal‐derived proinflammatory cytokines interleukin‐1α (IL‐1α) and tumor necrosis factor‐α (TNF‐α) were found to mediate synergistically the secretion of these wound‐healing mediators (with the exception of sST2) from fibroblasts in dermal substitutes. The secretion of proinflammatory cytokines (IL‐1α, TNF‐α), chemokine/mitogen (CCL5) and angiogenic factor (vascular endothelial growth factor) by epidermal substitutes and tissue remodeling factors (tissue inhibitor of metalloproteinase‐2, hepatocyte growth factor) by dermal substitutes was not influenced by keratinocyte–fibroblast interactions. The full‐skin substitute has a greater potential to stimulate wound healing than epidermal or dermal substitutes. Both epidermal‐derived IL‐1α and TNF‐α are required to trigger the release of dermal‐derived inflammatory/angiogenic mediators from skin substitutes.
Keratinocyte regulation of TGF‐β and connective tissue growth factor expression: A role in suppression of scar tissue formation
Authors: Amjad Syed Basith , Carachi Robert , Edward Michael
Published: September 2007

Allogeneic keratinocytes applied to large full‐thickness wounds promote healing while suppressing scar tissue formation. This effect may be mediated in part by their effect on the levels of transforming growth factor‐βs (TGF‐βs) and connective tissue growth factor (CTGF) in the wound and subsequent modulation of fibroblast activity. We have examined the levels of TGF‐β and CTGF produced by keratinocytes and fibroblasts, and the effect of keratinocyte‐conditioned medium using monolayer and living skin‐equivalent cultures. Keratinocyte monolayers did not release any detectable TGF‐β1, but released moderate levels of TGF‐β2 into culture medium, and stained strongly for TGF‐β1, but only weakly for TGF‐β2. Fibroblasts released large amounts of TGF‐β1, no TGF‐β2, and stained strongly for TGF‐β1. Neither cell type released TGF‐β3, but both stained strongly for TGF‐β3. Keratinocyte‐conditioned medium suppressed the levels of TGF‐βs and CTGF associated with the fibroblasts compared with fibroblasts incubated in Dulbecco's minimal essential medium and fibroblast‐conditioned medium. In living skin equivalents, keratinocytes stained very strongly for TGF‐β1 and CTGF, moderately strongly for TGF‐β3, and only weakly for TGF‐β2. Fibroblasts stained strongly for TGF‐β1 and 3 and CTGF. These observations suggest that keratinocytes may affect the TGF‐β profile in such a way as to suppress the formation of scar tissue.
Formation of eclogite, and reaction during exhumation to mid‐crustal levels, Snowbird tectonic zone, western Canadian Shield
Authors: BALDWIN J. A. , POWELL R. , WILLIAMS M. L. , GONCALVES P.
Published: September 2007

A re‐evaluation of the P–T history of eclogite within the East Athabasca granulite terrane of the Snowbird tectonic zone, northern Saskatchewan, Canada was undertaken. Using calculated pseudosections in combination with new garnet–clinopyroxene and zircon and rutile trace element thermometry, peak metamorphic conditions are constrained to ∼16 kbar and 750 °C, followed by near‐isothermal decompression to ∼10 kbar. Associated with the eclogite are two types of occurrences of sapphirine‐bearing rocks preserving a rich variety of reaction textures that allow examination of the retrograde history below 10 kbar. The first occurs as a 1–2 m zone adjacent to the eclogite body with a peak assemblage of garnet–kyanite–quartz interpreted to have formed during the eclogite facies metamorphism. Rims of orthopyroxene and plagioclase developed around garnet, and sapphirine–plagioclase and spinel–plagioclase symplectites developed around kyanite. The second variety of sapphirine‐bearing rocks occurs in kyanite veins within the eclogite. The veins involve orthopyroxene, garnet and plagioclase layers spatially organized around a central kyanite layer that are interpreted to have formed following the eclogite facies metamorphism. The layering has itself been modified, with, in particular, kyanite being replaced by sapphirine–plagioclase, spinel–plagioclase and corundum–plagioclase symplectites, as well as the kyanite being replaced by sillimanite. Petrological modelling in the CFMAS system examining chemical potential gradients between kyanite and surrounding quartz indicates that these vein textures probably formed during further essentially isothermal decompression, ultimately reaching ∼7 kbar and 750 °C. These results indicate that the final reaction in these rocks occurred at mid‐crustal levels at upper amphibolite facies conditions. Previous geochronological and thermochronological constraints bracket the time interval of decompression to <5–10 Myr, indicating that ∼25 km of exhumation took place during this interval. This corresponds to minimum unroofing rates of ∼2–5 mm year−1 following eclogite facies metamorphism, after which the rocks resided at mid‐crustal levels for 80–100 Myr.
Ultrahigh‐pressure eclogite transformed from mafic granulite in the Dabie orogen, east‐central China
Authors: LIU Y.‐C. , LI S.‐G. , GU X.‐F. , XU S.‐T. , CHEN G.‐B.
Published: September 2007

Although ultrahigh‐pressure (UHP) metamorphic rocks are present in many collisional orogenic belts, almost all exposed UHP metamorphic rocks are subducted upper or felsic lower continental crust with minor mafic boudins. Eclogites formed by subduction of mafic lower continental crust have not been identified yet. Here an eclogite occurrence that formed during subduction of the mafic lower continental crust in the Dabie orogen, east‐central China is reported. At least four generations of metamorphic mineral assemblages can be discerned: (i) hypersthene + plagioclase ± garnet; (ii) omphacite + garnet + rutile + quartz; (iii) symplectite stage of garnet + diopside + hypersthene + ilmenite + plagioclase; (iv) amphibole + plagioclase + magnetite, which correspond to four metamorphic stages: (a) an early granulite facies, (b) eclogite facies, (c) retrograde metamorphism of high‐pressure granulite facies and (d) retrograde metamorphism of amphibolite facies. Mineral inclusion assemblages and cathodoluminescence images show that zircon is characterized by distinctive domains of core and a thin overgrowth rim. The zircon core domains are classified into two types: the first is igneous with clear oscillatory zonation ± apatite and quartz inclusions; and the second is metamorphic containing a granulite facies mineral assemblage of garnet, hypersthene and plagioclase (andesine). The zircon rims contain garnet, omphacite and rutile inclusions, indicating a metamorphic overgrowth at eclogite facies. The almost identical ages of the two types of core domains (magmatic = 791 ± 9 Ma and granulite facies metamorphic zircon = 794 ± 10 Ma), and the Triassic age (212 ± 10 Ma) of eclogitic facies metamorphic overgrowth zircon rim are interpreted as indicating that the protolith of the eclogite is mafic granulite that originated from underplating of mantle‐derived magma onto the base of continental crust during the Neoproterozoic (c. 800 Ma) and then subducted during the Triassic, experiencing UHP eclogite facies metamorphism at mantle depths. The new finding has two‐fold significance: (i) voluminous mafic lower continental crust can increase the average density of subducted continental lithosphere, thus promoting its deep subduction; (ii) because of the current absence of mafic lower continental crust in the Dabie orogen, delamination or recycling of subducted mafic lower continental crust can be inferred as the geochemical cause for the mantle heterogeneity and the unusually evolved crustal composition.
Morbidity associated with the use of foramen ovale electrodes
Authors: Pastor Jesús , Sola Rafael G. , Hernando‐Requejo Virgilio , Navarrete Eduardo G. , Pulido Paloma
Published: September 2007

Summary

Purpose: The identification of the epileptic zone in patients with mesial temporal lobe epilepsy sometimes requires intracranial recordings, for example, with foramen ovale electrodes (FOE). This paper reviews and analyzes the resulting complications in a series of patients studied with bilateral FOE for presurgical evaluation.

Methods: The clinical records of 331 consecutive FOE implantations in 329 patients were reviewed. Complications related to FOE were divided into two groups: those that were non–life‐threatening or not directly attributable to FOE, or life‐threatening complications and those clearly related to FOE.

Results: The mean length of hospital stay in the v‐EEG unit with FOE was 5.8 ± 0.2 days (range 1–19) following a bimodal distribution (peaks at 4 and 8 days). Complications were observed in 6.64% of patients, but in 4.83% of cases, complications were non–life‐threatening (moderate disaesthesia, cheek bleeding, FOE expulsion). Complications were only severe in 1.81% of patients (clotting or intracranial hemorrhage). One patient died more than 20 days after FOE removal and after several episodes of status epilepticus. Patients suffering from life‐threatening complications were more likely to be female (83.3%) than patients experiencing no complications or non–life‐threatening complications. Patients with life‐threatening complications had a more prolonged stay in the v‐EEG unit during monitoring with FOE (8.2 ± 0.7; n = 6) than the group without complications (5.7 ± 0.2; n = 309; p < 0.01; Kruskal–Wallis test).

Discussion: FOE is a reasonably safe intracranial technique for v‐EEG monitoring with low rates of potentially severe complications, but its indication should be carefully evaluated, especially if monitoring for more than 8 days is expected.
Intravenous lacosamide as replacement for oral lacosamide in patients with partial‐onset seizures
Authors: Biton Victor , Rosenfeld William E. , Whitesides John , Fountain Nathan B. , Vaiciene Nerija , Rudd G. David
Published: September 2007

Summary

Purpose: This multicenter, double‐blind, double‐dummy, randomized, inpatient trial evaluated the safety, tolerability, and pharmacokinetics of intravenous lacosamide as replacement for oral lacosamide in patients with partial‐onset seizures.

Methods: Patients were enrolled from an ongoing open‐label extension trial of oral lacosamide and randomized (2:1) to either intravenous lacosamide and oral placebo or intravenous placebo and oral lacosamide. During the 2‐day inpatient treatment period, patients received twice‐daily doses of lacosamide equivalent to their current daily dose of oral lacosamide. The first 30 patients enrolled received infusions with 60‐min durations and the next 30 received infusions with 30‐min durations.

Results: Of 60 patients randomized, 59 completed the trial. Treatment‐emergent adverse events (AEs) were reported by 16 patients and included dizziness, headache, back pain, somnolence, and injection site pain. The tolerability profile of intravenous lacosamide was consistent with that of oral lacosamide. All AEs were considered mild or moderate in intensity, and no serious AEs or AEs leading to withdrawal were reported.

Conclusions: Intravenous lacosamide, administered as 60‐ or 30‐min twice‐daily infusions, showed a similar safety and tolerability profile to oral lacosamide when used as replacement therapy. Results from this trial support further investigation of intravenous lacosamide at shorter infusion durations.
Ictal scalp EEG recording during sleep and wakefulness: Diagnostic implications for seizure localization and lateralization
Authors: Buechler Robbie D. , Rodriguez Alcibiades J. , Lahr Brian D. , So Elson L.
Published: September 2007

Summary

To determine the localizing value of electroencephalography (EEG) for seizures during sleep versus seizures during wakefulness, we compared scalp EEG for 58 seizures that occurred during sleep with 76 seizures during wake in 28 consecutive patients with temporal lobe epilepsy. Regression analysis showed that seizures during sleep are 2.5 times more likely to have focal EEG onset (p = 0.01) and 4 times more likely to correctly localize seizure onset (p = 0.04) than seizures during wake. EEG seizure onset preceded clinical onset by a longer duration in sleep seizures (mean, 4.69 s) than in wake seizures (mean, 1.23 s; p < 0.01). Sleep seizures showed fewer artifacts, but the difference was not significant (p = 0.07). For temporal lobectomy candidates undergoing video‐EEG monitoring, the recording of seizures during sleep may be favored.
From lateral to mesial: The quest for a surgical cure for temporal lobe epilepsy
Authors: De Almeida Antonio Nogueira , Teixeira Manoel Jacoben , Feindel William Howard
Published: September 2007

Summary

Purpose: A gap of more than a hundred years occurred between the first accounts of mesial temporal sclerosis and recognition of its role in the pathogenesis of psychomotor seizures. This paper reviews how the understanding and surgical treatment of temporal lobe epilepsy developed, particularly from the work of Penfield, Jasper, and their associates at the Montreal Neurological Institute (MNI).

Methods: Publications on EEG and surgery for temporal lobe seizures from 1935 to 1953 were reviewed and charts of selected patients operated on at the MNI in the same period were examined. Attention was focused on the evolution of surgical techniques for temporal lobe epilepsy.

Results: In the late 1930s, some EEG findings suggested deep‐lying disturbances originating in the temporal lobe. However, it took another two decades before the correlation of clinical, neurophysiological, and anatomical findings provided evidence for the involvement of the mesial structures in psychomotor or temporal lobe seizures. From 1949 and onward, Penfield and his associates applied this evidence to extend the surgical resections to include the uncus and the hippocampus.

Conclusion: The collaborative work of a team led by Penfield and Jasper at the MNI helped to define the role of neurophysiological studies in epilepsy surgery. As a result, the importance of removing the mesial structures in order to obtain better seizure control in patients with temporal lobe epilepsy became firmly established.
Childhood occipital epilepsy of Gastaut: A study of 33 patients
Authors: Caraballo Roberto Horacio , Cersósimo Ricardo Oscar , Fejerman Natalio
Published: September 2007

Summary

Purpose:To characterize the electroclinical features and evolution of childhood occipital epilepsy of Gastaut (COE‐G).

Methods:Children with electroclinical criteria of COE‐G were retrospectively identified and followed‐up clinically, and with sleep and awake EEGs between 1990 and 2007.

Results:We identified 33 patients with COE‐G. In the same length of time, 201 children with Panayiotopoulos syndrome and 410 children with benign childhood epilepsy with centrotemporal spikes were registered. COE‐G had a peak age at onset of 8.5 years. Visual manifestations were the most common ictal event. Ictal deviation of the eyes was frequent. Approximately half of the patients had migraine‐like symptoms. In all patients the seizures occurred while awake, and 11 also had seizures during sleep. The majority of the patients had occipital spike‐wave discharges when the eyes were closed that disappeared or attenuated when the eyes were opened. Prognosis was excellent in 80% of the cases.

Conclusion:This study confirms the existence of COE‐G, a rare but well‐defined syndrome within the group of idiopathic focal epilepsies in childhood.
Consequences of antiepileptic drug withdrawal: A randomized, double‐blind study (Akershus Study)
Authors: Lossius Morten Ingvar , Hessen Erik , Mowinckel Petter , Stavem Knut , Erikssen Jan , Gulbrandsen Paal , Gjerstad Leif
Published: September 2007

Summary

Objective: Despite side effects associated with the use of antiepileptic drugs (AEDs), withdrawal of AEDs remains controversial, even after prolonged seizure freedom. The main objective of this study was to assess the effects of AED withdrawal on cognitive functions, seizure relapse, health‐related quality of life (HRQOL), and EEG results. Additionally, potential predictors for freedom from seizures after AED withdrawal were studied.

Methods: Patients, seizure‐free for more than 2 years on AED monotherapy, were recruited for a controlled, prospective, randomized, double‐blinded withdrawal study lasting for 12 months, or until seizure relapse. Patients were randomized to AED withdrawal (n = 79) and nonwithdrawal (n = 81) groups. The examination program included clinical neurological examinations, neuropsychological testing, EEG‐recordings, cerebral MRI, and assessments of HRQOL.

Follow‐up data on seizure relapse were also collected beyond the 12‐month study period (median 47 months).

Results: Seizure relapse at 12 months occurred in 15% of the withdrawal group and 7% of the nonwithdrawal group (RR 2.46; 95% CI: 0.85–7.08; p = 0.095). After withdrawal, seizure relapse rates were 27% after a median of 41 months off medication. A normal result to all 15 neuropsychological tests increased significantly from 11% to 28% postwithdrawal. We found no significant effects of withdrawal on quality of life and EEG. Predictors for remaining seizure‐free after AED‐withdrawal over 1 year were normal neurological examination and use of carbamazepine prior to withdrawal.

Conclusion: Seizure‐free epilepsy patients on AED monotherapy who taper their medication may improve neuropsychological performance with a relative risk of seizure relapse of 2.46, compared to those continuing therapy.
Evaluation of an algorithm based on peripheral blood hematopoietic progenitor cell and CD34+ cell concentrations to optimize peripheral blood progenitor cell collection by apheresis
Authors: Lefrère François , Zohar Sarah , Beaudier Sandrine , Audat Françoise , Ribeil Jean‐Antoine , Ghez David , Varet Bruno , Cavazzana‐Calvo Marina , Cortivo Liliane Dal , Letestu Rémi , McIntyre Elizabeth , Brouzes Chantal
Published: September 2007

BACKGROUND: Quantification of peripheral blood (PB) CD34+ cells is commonly used to plan peripheral blood progenitor cell (PBPC) collection but is time‐consuming. Sysmex has developed a hematology analyzer that can quickly identify a population of immature hematopoietic cells (HPCs) according to cell size, cell density, and differential lysis resistance, which may indicate the presence of PBPCs in PB. This prospective study has evaluated the potential of such method to predict the PBPC mobilization.

STUDY DESIGN AND METHODS: A total of 141 patients underwent PBPC mobilization. PB HPCs and PB CD34+ cells were simultaneously quantified with a hematology analyzer (SE2100, Sysmex) and flow cytometry, respectively. The number of blood volumes processed was then based on PB CD34+ cell concentration.

RESULTS: The optimal PB HPC level able to predict a minimal level of 10 × 106 PB CD34+ cells per L was 5 × 106 per L with positive and negative predictive values of 0.93 and 0.36 percent, respectively. For this cutoff point, sensitivity and specificity were 0.81 and 0.65, respectively. The median number of blood volumes processed according to the PB CD34+ cell count allowed us to perform only one apheresis procedure for a majority of patients.

CONCLUSION: PB HPC quantification is very useful to quickly determine the initiation of PBPC apheresis especially for patients with higher concentrations. For patients exhibiting a lower HPC count (<5 × 106/L), other parameters such as a CD34 test may be needed. Such a policy associated with a length of apheresis adapted to the richness in the PB CD34+ cells allows for optimizing the organization of centers with an improvement in patient comfort and economical savings.
Evaluation of bacterial inactivation in prestorage pooled, leukoreduced, whole blood–derived platelet concentrates suspended in plasma prepared with photochemical treatment
Authors: Brecher Mark E. , Hay Shauna , Corash Laurence , Hsu Jocelyn , Lin Lily
Published: September 2007

BACKGROUND: Photochemical treatment (PCT) with amotosalen and ultraviolet light was developed to inactivate pathogens in platelet (PLT) components suspended in 35 percent plasma and 65 percent additive solution (AS). Because PLT additive solutions (ASs) are not used in the United States, this study evaluated the ability of the PCT process to inactivate low levels of bacteria in pooled whole blood–derived PLTs (RDP) suspended in 100 percent plasma.

STUDY DESIGN AND METHODS: Four replicate experiments were performed with two Gram‐positive organisms, Staphylococcus epidermidis and Staphylococcus aureus, and two Gram‐negative organisms, Klebsiella pneumoniae and Escherichia coli. For each experiment, 6 ABO‐identical RDP units were pooled, leukoreduced before or after pooling, inoculated to approximately 1 to 10 colony‐forming units per mL with plasma‐resistant bacteria, and treated with the PCT process. Residual viable bacterial levels were measured before and after each step and 4 and 6 days after inoculation. For each bacterium studied, a fifth RDP pool was prepared and contaminated, but not treated. These units served as controls for bacterial growth.

RESULTS: Growth of S. epidermidis, S. aureus, and K. pneumoniae was eliminated in all four treated pools while growth continued in the control pools. There was no growth of E. coli in the treated pools and the control pool.

CONCLUSION: These pilot experiments demonstrate inactivation of bacteria in PLTs suspended in plasma, suggesting that the PCT process may address contamination in conventional RDPs. Additional experiments with a wider range of bacteria and evaluation of PLT function in 100 percent plasma will be needed before implementation.
Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria
Authors: Koppel Ahrin , Lim Stephen , Osby Melanie , Garratty George , Goldfinger Dennis
Published: September 2007

BACKGROUND: Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) attributed to a biphasic hemolysin known as the Donath‐Landsteiner (DL) antibody. It is most commonly encountered as an acute transient AIHA after a viral infection in children; the disease resolves after cessation of the infection. The rarest form of PCH is a chronic form in adults that is not (nowadays) associated with infection and is not responsive to conventional therapies. Rituximab has been found to be effective therapy in other forms of AIHA, such as cold agglutinin syndrome, that are refractory to conventional therapies. We describe a case of PCH refractory to steroids that responded to rituximab therapy on two separate occasions.

CASE REPORT: A 64‐year‐old woman with fatigue was found to be profoundly anemic with laboratory findings consistent with AIHA. She was admitted for the workup and management of her disease after she failed to respond to a course of oral steroids. Laboratory evaluation demonstrated a positive DL test suggesting PCH. She was given a course of rituximab that resulted in normalization of her hemoglobin concentration. She presented 9 months later with recurrent hemolysis. She was given another course of rituximab that again resulted in termination of hemolysis. The patient remained in remission since her last dose of rituximab 19 months previously.

CONCLUSION: To our knowledge, this is the first report of an adult case of refractory PCH successfully treated with rituximab.
Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion‐dependent thalassemia: a literature review
Authors: Delea Thomas E. , Edelsberg John , Sofrygin Oleg , Thomas Simu K. , Baladi Jean‐Francois , Phatak Pradyumna D. , Coates Thomas D.
Published: September 2007

BACKGROUND: Patients with thalassemia major require iron chelation therapy (ICT) to prevent complications from transfusional iron overload. Deferoxamine is effective, but requires administration as a slow continuous subcutaneous or intravenous infusion five to seven times per week. Deferiprone is a three‐times‐daily oral iron chelator, but has limited availability in the United States. Deferasirox is a once‐daily oral iron chelator that was approved in the United States in 2005 for patients older than 2 years of age with transfusional iron overload.

STUDY DESIGN AND METHODS: Published evidence on rates of compliance with ICT and the association between compliance, and the incidence and costs of complications of iron overload, in patients with thalassemia major was reviewed.

RESULTS: A total of 18 studies were identified reporting data on compliance with ICT, including 7 that examined deferoxamine only, 6 that examined deferiprone only, and 5 that compared deferoxamine and deferiprone; no studies reporting compliance with deferasirox were identified. In studies of deferoxamine only, estimated mean compliance ranged from 59 to 78 percent. Studies of deferiprone generally reported better compliance, ranging from 79 to 98 percent. Results of comparative studies of deferoxamine and deferiprone suggest that compliance may be better with oral therapy. Numerous studies demonstrate that that poor compliance with ICT results in increased risk of cardiac disease and endocrinopathies, as well as lower survival. Although data on the costs of noncompliance are limited, a recent model‐based study estimated the lifetime costs of inadequate compliance with deferoxamine to be $33,142.

CONCLUSIONS: Inadequate compliance with ICT in thalassemia major is common and results in substantial morbidity and mortality, as well as increased costs.
Empirical Analysis of a Travel‐Time Forecasting Model
Authors: You Jinsoo , Kim Tschangho John
Published: September 2007

The purpose of this article is to analyze empirically a travel‐time forecasting model that estimates link travel times on congested road networks. In separate studies by You and Kim, a nonparametric regression model has been developed as a core forecasting algorithm to reduce computation time and increase forecasting accuracy. In this article, the sensitivity of model parameters is evaluated so that the proposed travel‐time forecasting model could be utilized in transportation information and management systems such as location‐based services and intelligent transportation systems applications.
Does Frederick Taylor’s Ghost Still Haunt the Halls of Government? A Look at the Concept of Governmental Efficiency in Our Time
Authors: Schachter Hindy Lauer
Published: September 2007

Since the Progressive Era, efficiency has been a cherished administrative value and a key concept in the study of public administration. Despite contemporary attention to other criteria, such as responsiveness and equity, efficiency remains a guiding governmental value and a focus of scholarly writing. Although efficiency is often considered an apolitical value, this article argues that public sector efficiency receives meaning through a political framework. The analysis explores changing definitions of transit efficiency to propose a revitalized, politically attuned concept.
William Robertson: Exemplar of Politics and Public Management Rightly Understood
Authors: Cooper Terry L. , Bryer Thomas A
Published: September 2007

William Robertson, director of the City of Los Angeles’ Bureau of Street Services, is profiled here as an exemplary public administrator. The authors suggest that Robertson practices politics appropriately in his role in order to achieve great outcomes for his bureau, the citizens with whom he works, and the city as a whole. To adequately define the ways in which Robertson uses politics, Sherry Arnstein’s “ladder of participation” is reconceptualized as a circle of participation in which Robertson uses multiple strategies of interaction with citizens, elected officials, employees, and peers. Lessons for public administrators are offered based on Robertson’s example.
Betting on the Future with a Cloudy Crystal Ball? How Financial Theory Can Improve Revenue Forecasting and Budgets in the States
Authors: Thompson Fred , Gates Bruce L.
Published: September 2007

Accurately predicting revenue growth is nearly impossible. Predicting the peaks and valleys of the business cycle is even more hopeless. This matters because tax revenues are largely driven by economic growth. Volatile, unpredictable revenue growth causes all sorts of unpleasant responses on the part of governments, most commonly manic‐depressive patterns of spending and taxing. Fortunately, modern financial economics gives us a set of tools that can be used to manage volatility. This article shows how such tools can be used to inform fiscal decision making. The focus here is state governments, but the analysis applies to all jurisdictions that face hard budget constraints and therefore must balance spending increases against revenue growth.
The Life Cycle of the Government‐Sponsored Enterprise: Lessons for Design and Accountability
Authors: Stanton Thomas H.
Published: September 2007

The federal government uses government‐sponsored enterprises (GSEs) to allocate credit to sectors such as housing and agriculture that are considered to deserve special support. The GSEs illustrate the importance of life cycle in the design and accountability of federal agencies and instrumentalities. Four case studies are presented here. In general, market and political dominance and rapid growth are inherent in GSE design. Dominance means inadequate feedback, which can foster poor management and financial risk. Government lacks an exit strategy for GSEs that have outlived their usefulness. Government should systematically review the organizational structure, accountability, and design of all agencies and instrumentalities, both at inception and over their life cycles.
Beyond Engagement and Participation: User and Community Coproduction of Public Services
Authors: Bovaird Tony
Published: September 2007

In recent years, there has been a radical reinterpretation of the role of policy making and service delivery in the public domain. Policy making is no longer seen as a purely top‐down process but rather as a negotiation among many interacting policy systems. Similarly, services are no longer simply delivered by professional and managerial staff in public agencies but are coproduced by users and their communities. This article presents a conceptual framework for understanding the emerging role of user and community coproduction and presents several case studies that illustrate how different forms of coproduction have played out in practice. Traditional conceptions of service planning and management are now outdated and need to be revised to account for coproduction as an integrating mechanism and an incentive for resource mobilization—a potential that is still greatly underestimated. However, coproduction in the context of multipurpose, multistakeholder networks raises important public governance issues that have implications for public services reform.
Managerial Effectiveness of Government Performance Measurement: Testing a Middle‐Range Model
Authors: Yang Kaifeng , Hsieh Jun Yi
Published: September 2007

The research on government performance measurement has been largely descriptive and prescriptive, with only limited attention paid to hypothesis testing and middle‐range theory construction. Although researchers have made prescriptions about how to make performance management work, the validity of those prescriptions has not been systematically examined. In particular, the role of the external political environment and stakeholder participation, two important factors for public sector management, remains unclear. Based on survey data, this article uses structural equation modeling to test a model that assesses how political environment, stakeholder participation, organizational support, and training affect the adoption and managerial effectiveness of performance management.