bluuebunny/crossref_metadata_2025 huggingface dataset:
Small rat islets are superior to large islets in in vitro function and in transplantation outcomes
Authors: MacGregor R. R. , Williams S. J. , Tong P. Y. , Kover K. , Moore W. V. , Stehno-Bittel L.
Published: November 2005

Barriers to the use of islet transplantation as a practical treatment for diabetes include the limited number of available donor pancreata. This project was designed to determine whether the size of the islet could influence the success rate of islet transplantations in rats. Islets from adult rats were divided into two groups containing small (diameter <125 μm) or large (diameter >150 μm) islets. An average pancreas yielded three times more small islets than large. Smaller islets were ∼20% more viable, with large islets containing a scattered pattern of necrotic and apoptotic cells or central core cell death. Small islets in culture consumed twice as much oxygen as large islets when normalized for the same islet equivalents. In static incubation, small islets released three times more insulin under basal conditions than did large islets. During exposure to high glucose conditions, the small islets released four times more insulin than the same islet equivalencies of large islets, and five times more insulin was released by the small islets in response to glucose and depolarization with K+. Most importantly, the small islets were far superior to large islets when transplanted into diabetic animals. When marginal islet equivalencies were used for renal subcapsular transplantation, large islets failed to produce euglycemia in any recipient rats, whereas small islets were successful 80% of the time. The results indicate that small islets are superior to large islets in in vitro testing and for transplantation into the kidney capsule of diabetic rats.
Regulation of blood pressure, the epithelial sodium channel (ENaC), and other key renal sodium transporters by chronic insulin infusion in rats
Authors: Song Jian , Hu Xinqun , Riazi Shahla , Tiwari Swasti , Wade James B. , Ecelbarger Carolyn A.
Published: November 2005

Hyperinsulinemia is associated with hypertension. Dysregulation of renal distal tubule sodium reabsorption may play a role. We evaluated the regulation of the epithelial sodium channel (ENaC) and the thiazide-sensitive Na-Cl cotransporter (NCC) during chronic hyperinsulinemia in rats and correlated these changes to blood pressure as determined by radiotelemetry. Male Sprague-Dawley rats (∼270 g) underwent one of the following three treatments for 4 wk ( n = 6/group): 1) control; 2) insulin-infused plus 20% dextrose in drinking water; or 3) glucose water-drinking (20% dextrose in water). Mean arterial pressures were increased by insulin and glucose (mmHg at 3 wk): 98 ± 1 (control), 107 ± 2 (insulin), and 109 ± 3 (glucose), P < 0.01. Insulin (but not glucose) increased natriuretic response to benzamil (ENaC inhibitor) and hydrochlorothiazide (NCC inhibitor) on average by 125 and 60%, respectively, relative to control rats, suggesting increased activity of these reabsorptive pathways. Neither insulin nor glucose affected the renal protein abundances of NCC or the ENaC subunits (α, β, and γ) in kidney cortex, outer medulla, or inner medulla in a major way, as determined by immunoblotting. However, insulin and to some extent glucose increased apical localization of these subunits in cortical collecting duct principal cells, as determined by immunoperoxidase labeling. In addition, insulin decreased cortical “with no lysine” kinase (WNK4) abundance (by 16% relative to control), which may have increased NCC activity. Overall, insulin infusion increased blood pressure, and NCC and ENaC activity in rats. Increased apical targeting of ENaC and decreased WNK4 expression may be involved.
Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP
Authors: Zhou Xiaoming , Ferraris Joan D. , Burg Maurice B.
Published: November 2005

Hypertonicity activates the transcription factor tonicity-responsive enhancer/osmotic response element binding protein (TonEBP/OREBP), resulting in increased expression of genes involved in osmoprotective accumulation of organic osmolytes, including glycine betaine, and in increased expression of osmoprotective heat shock proteins. Our previous studies showed that high NaCl increases reactive oxygen species (ROS), which contribute to activation of TonEBP/OREBP. Mitochondria are a major source of ROS. The purpose of the present study was to examine whether mitochondria produce the ROS that contribute to activation of TonEBP/OREBP. We inhibited mitochondrial ROS production in HEK293 cells with rotenone and myxothiazol, which inhibit mitochondrial complexes I and III, respectively. Rotenone (250 nM) and myxothiazol (12 nM) reduce high NaCl-induced ROS over 40%, whereas apocynin (100 μM), an inhibitor of NADPH oxidase, and allopurinol (100 μM), an inhibitor of xanthine oxidase, have no significant effect. Rotenone and myxothiazol reduce high NaCl-induced increases in TonEBP/OREBP transcriptional activity (ORE/TonE reporter assay) and BGT1 (betaine transporter) mRNA abundance ranging from 53 to 69%. They inhibit high NaCl-induced TonEBP/OREBP transactivating activity, but not its nuclear translocation. Release of ATP into the medium on hypertonic stress has been proposed to be a signal that triggers cellular osmotic responses. However, we do not detect release of ATP into the medium or inhibition of high NaCl-induced ORE/TonE reporter activity by an ATPase, apyrase (20 U/ml), indicating that high NaCl-induced activation of TonEBP/OREBP is not mediated by release of ATP. We conclude that high NaCl increases mitochondrial ROS production, which contributes to the activation of TonEBP/OREBP by increasing its transactivating activity.
Lack of the Kir4.1 Channel Subunit Abolishes K+ Buffering Properties of Astrocytes in the Ventral Respiratory Group: Impact on Extracellular K+ Regulation
Authors: Neusch Clemens , Papadopoulos Nestoras , Müller Michael , Maletzki Iris , Winter Stefan M. , Hirrlinger Johannes , Handschuh Melanie , Bähr Mathias , Richter Diethelm W. , Kirchhoff Frank , Hülsmann Swen
Published: November 2005

Ongoing rhythmic neuronal activity in the ventral respiratory group (VRG) of the brain stem results in periodic changes of extracellular K+. To estimate the involvement of the weakly inwardly rectifying K+ channel Kir4.1 (KCNJ10) in extracellular K+ clearance, we examined its functional expression in astrocytes of the respiratory network. Kir4.1 was expressed in astroglial cells of the VRG, predominantly in fine astrocytic processes surrounding capillaries and in close proximity to VRG neurons. Kir4.1 expression was up-regulated during early postnatal development. The physiological role of astrocytic Kir4.1 was studied using mice with a null mutation in the Kir4.1 channel gene that were interbred with transgenic mice expressing the enhanced green fluorescent protein in their astrocytes. The membrane potential was depolarized in astrocytes of Kir4.1−/− mice, and Ba2+-sensitive inward K+ currents were diminished. Brain slices from Kir4.1−/− mice, containing the pre-Bötzinger complex, which generates a respiratory rhythm, did not show any obvious differences in rhythmic bursting activity compared with wild-type controls, indicating that the lack of Kir4.1 channels alone does not impair respiratory network activity. Extracellular K+ measurements revealed that Kir4.1 channels contribute to extracellular K+ regulation. Kir4.1 channels reduce baseline K+ levels, and they compensate for the K+ undershoot. Our data indicate that Kir4.1 channels 1) are expressed in perineuronal processes of astrocytes, 2) constitute the major part of the astrocytic Kir conductance, and 3) contribute to regulation of extracellular K+ in the respiratory network.
Molecular profiling of murine sensory neurons in the nodose and dorsal root ganglia labeled from the peritoneal cavity
Authors: Peeters Pieter J. , Aerssens Jeroen , de Hoogt Ronald , Stanisz Andrzej , Göhlmann Hinrich W. , Hillsley Kirk , Meulemans Ann , Grundy David , Stead Ronald H. , Coulie Bernard
Published: November 2005

Vagal afferent neurons are thought to convey primarily physiological information, whereas spinal afferents transmit noxious signals from the viscera to the central nervous system. To elucidate molecular identities for these different properties, we compared gene expression profiles of neurons located in nodose ganglia (NG) and dorsal root ganglia (DRG) in mice. Intraperitoneal administration of Alexa Fluor-488-conjugated cholera toxin B allowed enrichment for neurons projecting to the viscera. Fluorescent neurons in DRG (from T10 to T13) and NG were isolated using laser-capture microdissection. Gene expression profiles of these afferent neurons, obtained by microarray hybridization, were analyzed using multivariate spectral map analysis, significance analysis of microarrays (SAM) algorithm, and fold-difference filtering. A total of 1,996 genes were differentially expressed in DRG vs. NG, including 41 G protein-coupled receptors and 60 ion channels. Expression profiles obtained on laser-captured neurons were contrasted to those obtained on whole ganglia, demonstrating striking differences and the need for microdissection when studying visceral sensory neurons because of dilution of the signal by somatic sensory neurons. Furthermore, we provide a detailed catalog of all adrenergic and cholinergic, GABA, glutamate, serotonin, and dopamine receptors; voltage-gated potassium, sodium, and calcium channels; and transient receptor potential cation channels present in afferents projecting to the peritoneal cavity. Our genome-wide expression profiling data provide novel insight into molecular signatures that underlie both functional differences and similarities between NG and DRG sensory neurons. Moreover, these findings will offer novel insight into mode of action of pharmacological agents modulating visceral sensation.
Umbilical Cord Levels of Interleukin-1 Receptor Antagonist and Neonatal Outcome
Authors: Elsmén Emma , Ley David , Cilio Corrado M. , Hansen-Pupp Ingrid , Hellström-Westas Lena
Published: November 2005

Background: Previous studies indicate that there may be infant gender differences in cytokine expression associated with differences in neonatal morbidity. Objective: We tested the hypothesis that umbilical cord interleukin-1 receptor antagonist (IL-1ra) correlates with infant gender and neonatal outcome in preterm infants. Study Design: IL-1ra was measured in cord blood taken from 58 preterm infants (33 males, 25 females) with gestational age less than 32 weeks. Receiver operating characteristics (ROC) curve were used for identifying IL-1ra values with high sensitivity and specificity for neonatal morbidity and adverse outcome, i.e., death or survival with severe intraventricular hemorrhage or periventricular leukomalacia. Results: In the female infants, but not the male infants, cord IL-1ra values correlated with postnatal depression, expressed as Apgar scores at 1 min (correlation coefficient, rs; p value: –0.542; 0.005), 5 min (–0.571; 0.018), and 10 min (–0.442; 0.035); and postnatal age at intubation (–0.799; 0.001). The ROC area under the curve (AUC) was 0.735 for adverse outcome (p = 0.013), and 0.683 for bronchopulmonary dysplasia (p = 0.021) when all infants were included. However, there was a significant gender difference in the ROC curve for adverse outcome (p = 0.026), with AUC 0.640 (p = 0.240) in males and AUC 0.929 (p = 0.008) in females. Above a chosen cutoff at 13,500 ng/l for IL-1ra cord the sensitivity and specificity for predicting adverse outcome was 100 and 81%, respectively in females versus 50 and 84% in males. Conclusion: Increased levels of cord IL-1ra levels are associated with neonatal morbidity and adverse outcome in preterm infants. Comparable levels of IL-1ra have different predictive value depending on infant gender.
Inhibitory Effect of Pravastatin on Transforming Growth Factor β1-Inducible Gene h3 Expression in a Rat Model of Chronic Cyclosporine Nephropathy
Authors: Li Can , Lim Sun Woo , Choi Bum Soon , Lee Suk Hee , Cha Jung Ho , Kim In San , Kim Jin , Yang Chul Woo
Published: November 2005

Background/Aims: Overexpression of transforming growth factor β1-inducible gene h3 (βig-h3) is associated with renal scarring in several models of renal disease. We investigated the inhibitory effect of pravastatin on βig-h3 expression in a rat model of chronic cyclosporin A (CsA)-induced nephropathy. Methods: Adult Sprague Dawley rats kept on a low salt diet (0.05% sodium) were treated daily for 4 weeks with vehicle (olive oil, 1 ml/kg), CsA (15 mg/kg) or both CsA and pravastatin (20 mg/kg in drinking water). The effect of pravastatin on βig-h3 expression was evaluated using in situ hybridization, immunohistochemistry, and immunoblotting. Functional parameters, histopathology (tubulointerstitial fibrosis, TIF, and arteriolopathy), and levels of transforming growth factor β1 (TGF-β1) and endothelial nitric oxide synthase were compared for the different treatment groups. Results: Co-administration of pravastatin significantly inhibited βig-h3 mRNA production and gene expression within the tubulointerstitium of the CsA-treated kidneys, and this paralleled an attenuation of TIF (12.7 ± 2.2 vs. 35.9 ± 5.4%, p < 0.01 vs. CsA) and the expression of TGF-β1 mRNA (279 ± 40 vs. 719 ± 85%, p < 0.01 vs. CsA). Pravastatin treatment reduced endothelial nitric oxide synthase protein levels and reversed the renal dysfunction caused by CsA. Neither CsA nor pravastatin affected total serum cholesterol or triglyceride levels in the treatment groups. Conclusion: Pravastatin thus effectively abrogated the upregulation of βig-h3 gene expression and associated TGF-β1 production, and this was associated with attenuated TIF in this model of chronic CsA-induced nephropathy.
Endothelial Extracellular Matrix
Authors: Davis George E. , Senger Donald R.
Published: November 2005

The extracellular matrix (ECM) is critical for all aspects of vascular biology. In concert with supporting cells, endothelial cells (ECs) assemble a laminin-rich basement membrane matrix that provides structural and organizational stability. During the onset of angiogenesis, this basement membrane matrix is degraded by proteinases, among which membrane-type matrix metalloproteinases (MT-MMPs) are particularly significant. As angiogenesis proceeds, ECM serves essential functions in supporting key signaling events involved in regulating EC migration, invasion, proliferation, and survival. Moreover, the provisional ECM serves as a pliable scaffold wherein mechanical guidance forces are established among distal ECs, thereby providing organizational cues in the absence of cell–cell contact. Finally, through specific integrin-dependent signal transduction pathways, ECM controls the EC cytoskeleton to orchestrate the complex process of vascular morphogenesis by which proliferating ECs organize into multicellular tubes with functional lumens. Thus, the composition of ECM and therefore the regulation of ECM degradation and remodeling serves pivotally in the control of lumen and tube formation and, finally, neovessel stability and maturation.
Application of Adjoint-Derived Forecast Sensitivities to the 24–25 January 2000 U.S. East Coast Snowstorm
Authors: Kleist Daryl T. , Morgan Michael C.
Published: November 2005

The 24–25 January 2000 eastern United States snowstorm was noteworthy as operational numerical weather prediction (NWP) guidance was poor for lead times as short as 36 h. Despite improvements in the forecast of the surface cyclone position and intensity at 1200 UTC 25 January 2000 with decreasing lead time, NWP guidance placed the westward extent of the midtropospheric, frontogenetically forced precipitation shield too far to the east.

To assess the influence of initial condition uncertainties on the forecast of this event, an adjoint model is used to evaluate forecast sensitivities for 36- and 48-h forecasts valid at 1200 UTC 25 January 2000 using as response functions the energy-weighted forecast error, lower-tropospheric circulation about a box surrounding the surface cyclone, 750-hPa frontogenesis, and vertical motion. The sensitivities with respect to the initial conditions for these response functions are in general very similar: geographically isolated, maximized in the middle and lower troposphere, and possessing an upshear vertical tilt. The sensitivities are maximized in a region of enhanced low-level baroclinicity in the vicinity of the surface cyclone’s precursor upper trough. However, differences in the phase and structure of the gradients for the four response functions are evident, which suggests that perturbations could be constructed to alter one response function but not necessarily the others.

Gradients of the forecast error response function with respect to the initial conditions are used in an iterative procedure to construct initial condition perturbations that reduce the forecast error. These initial condition perturbations were small in terms of both spatial scale and magnitude. Those initial condition perturbations that were confined primarily to the midtroposphere grew rapidly into much larger amplitude upper-and-lower tropospheric perturbations. The perturbed forecasts were not only characterized by reduced final time forecast error, but also had a synoptic evolution that more closely followed analyses and observations.
U.S. West Coast Surface Heat Fluxes, Wind Stress, and Wind Stress Curl from a Mesoscale Model
Authors: Haack T. , Burk S. D. , Hodur R. M.
Published: November 2005

Monthly averages of numerical model fields are beneficial for depicting patterns in surface forcing such as sensible and latent heat fluxes, wind stress, and wind stress curl over data-sparse ocean regions. Grid resolutions less than 10 km provide the necessary mesoscale detail to characterize the impact of a complex coastline and coastal topography. In the present study a high-resolution mesoscale model is employed to reveal patterns in low-level winds, temperature, relative humidity, sea surface temperature as well as surface fluxes, over the eastern Pacific and along the U.S. west coast. Hourly output from successive 12-h forecasts are averaged to obtain monthly mean patterns from each season of 1999. The averages yield information on interactions between the ocean and the overlying atmosphere and on the influence of coastal terrain forcing in addition to their month-to-month variability.

The spring to summer transition is characterized by a dramatic shift in near-surface winds, temperature, and relative humidity as offshore regions of large upward surface fluxes diminish and an alongshore coastal flux gradient forms. Embedded within this gradient, and the imprint of strong summertime topographic forcing, are small-scale fluctuations that vary in concert with local changes in sea surface temperature. Potential feedbacks between the low-level wind, sea surface temperature, and the wind stress curl are explored in the coastal regime and offshore waters. In all seasons, offshore extensions of colder coastal waters impose a marked influence on low-level conditions by locally enhancing stability and reducing the wind speed, while buoy measurements along the coast indicate that sea surface temperatures and wind speeds tend to be negatively correlated.
Low-Level Kinematic, Thermodynamic, and Reflectivity Fields Associated with Hurricane Bonnie (1998) at Landfall
Authors: Schneider Rebecca , Barnes Gary M.
Published: November 2005

During 11 h on 26 August 1998, two NOAA WP-3D aircraft deployed 85 Global Positioning System (GPS) dropwindsondes within 2° of latitude of the circulation center of Hurricane Bonnie as it made landfall in North Carolina. About 75% of the sondes successfully collected data, which were used to create a series of storm-relative horizontal maps of kinematic and thermodynamic variables from 10 m to 2 km. Reflectivity fields were analyzed from the Weather Surveillance Radar-1988 Dopplers (WSR-88Ds) located at Wilmington and Morehead City, North Carolina, and the tail and lower fuselage radars aboard the WP-3Ds.

GPS sonde performance and deployment spacing is adequate to identify several aspects of the vortex. These include 1) warm, dry, stable air in the offshore flow that results in reduced equivalent potential temperatures entering the southern portion of the eyewall, 2) cooler air collocated with the upwelled water in the right-rear quadrant and under the eyewall, and 3) an atypical radial wind pattern with strong inflow southwest of the circulation center and outflow northeast of the center. The strongly asymmetric structure found at 10 m becomes much more homogeneous by 2-km altitude.

No intense rainbands developed over land in the onshore flow nor did the bands in the onshore flow undergo any significant changes once they made landfall. Beyond the eyewall the offshore flow contained much less precipitation than the onshore portion of the storm.

Characteristics beyond the eyewall appear to have been modulated by the proximity to land but hurricane intensity did not vary. The authors infer that the lower energy content of the inflow was offset by the contraction of the eyewall.
Thirteen Years After Rio: The State of Energy Efficiency and Renewable Energy in Canada
Authors: Karimi Shahram
Published: November 2005

Greenhouse gas emissions are adversely affecting the earth’s climate, a global common and a public good. The contribution of individual countries has a limited effect on the biosphere, implying that only globally coordinated efforts may result in significant climate improvements. The Rio Earth Summit (1992) and Kyoto Protocol (1997) are manifestations of international efforts to achieve sustainable development through efficient use of energy and incorporating more renewable sources in global economy. In this article, the author examines the energy-related emissions of greenhouse gases and the utilization of renewable energy sources in Canada with respect to Agenda 21 commitments. An overview of the results of Canada’s policies on climate change since Rio in terms of energy consumption, various sources of energy, and emission rates of greenhouse gases is also presented. It is concluded that the current plans of the Canadian government to deal with greenhouse gas emissions have not been effective.
Arthroscopic Transtibial Posterior Cruciate Ligament Reconstruction with Preservation of Posterior Cruciate Ligament Fibers
Authors: Ahn Jin Hwan , Yang Hyoung Seop , Jeong Woong Kyo , Koh Kyoung Hwan
Published: November 2005

Background

The transtibial technique for posterior cruciate ligament reconstructions can potentially lead to poor clinical outcomes due to the “killer turn” effect.

Hypothesis

Preserving the original posterior cruciate ligament fibers in the reconstruction will contribute significantly to the posterior stability of the knee joint, healing of the graft, and prevention of graft failure.

Study Design

Case series; Level of evidence, 4.

Methods

Sixty-one patients (45 men and 16 women; mean age, 30.4 years) underwent transtibial posterior cruciate ligament reconstruction with preservation of the cruciate ligament fibers; they were reviewed at a mean period of 40.8 months. All patients were assessed with the Lysholm knee score, International Knee Documentation Committee subjective and objective evaluations, and KT-2000 arthrometry. Follow-up magnetic resonance imaging was performed in 40 patients; images were assessed for graft continuity, thickness, and signal intensity. Second-look arthroscopy was performed in 42 patients.

Results

The mean Lysholm score improved from 65.8 to 92.9. The final International Knee Documentation Committee subjective evaluation rated all patients as normal or nearly normal, and the objective evaluation showed normal or nearly normal in 59 patients (97%) and abnormal in 2 patients (3%). The mean side-to-side difference on the KT-2000 arthrometer was 2.79 mm. All patients showed well-preserved graft continuity on magnetic resonance images. Mean graft thickness was 9.9 mm in the sagittal plane and 12.3 mm in the coronal oblique plane. Images for all patients revealed homogeneously low signal intensity in the distal portion of the graft, with complete healing of the graft and original posterior cruciate ligament fibers as one ligament. Graft loosening or graft tear by the killer turn effect was not detected in any patients. Second-look arthroscopy revealed complete healing and graft integration, with the original posterior cruciate ligament fibers in all patients.

Conclusion

In transtibial posterior cruciate ligament reconstructions, poor outcomes from the killer turn effect may be reduced by preserving the original posterior cruciate ligament fibers.
Apolipoprotein E ε4 and Change in Cognitive Functioning in Community-Dwelling Older Adults
Authors: Swan Gary E. , Lessov-Schlaggar Christina N. , Carmelli Dorit , Schellenberg Gerard D. , La Rue Asenath
Published: November 2005

The relationship between apolipoprotein E ( APOE) ε 4 and change in cognition was examined in older men (n = 247; age = 75.0 ± 3.5 years) and women (n = 79; age = 70.8 ± 4.9 years) free of history of stroke. Participants were examined again 4.0 ± 0.5 years later. Exclusion criteria were (1) initial scores on the Mini-Mental State Examination of 23 or less or (2) the presence of the APOE 2/4genotype. Men with ε 4showed greater decline in some measures of executive function and verbal memory compared to those without ε 4; women with ε 4showed greater decline in Trail Making test performance relative to women without the allele. A significant gender × APOEε 4interaction was seen for change in performance on short delay cued recall. These results suggest that APOEε 4is associated with cognitive decline differently in older adult men and women.
Similar Neurocognitive Performance of Adults With and Without a History of Parental Alzheimer’s Disease: A Pilot Study
Authors: Ercoli Linda , Siddarth Prabha , Harrison Tracy , Jimenez Elvira , Jarvik Lissy F.
Published: November 2005

The first reported 20-year prospective follow-up of middle-aged children of Alzheimer patients failed to find statistically significant neurocognitive decline. Because that report did not include a comparison group, the current study compared the 20-year follow-up scores with scores obtained on the same 8 measures by an age-comparable sample of healthy adults without a family history of Alzheimer’s disease. Both were convenience samples (n = 24). Statistical analyses (correcting for age) yielded no significant group differences in neurocognitive scores but did show a significantly higher mean score for the comparison group on the Mini-Mental State Examination (29.5 vs 28.8, P = .003, controlling for age). Even though this finding suggests that adult children of a parent with Alzheimer’s disease performed well on a limited neurocognitive battery and on the Mini-Mental State Examination, the findings are preliminary and require confirmation on large representative samples with appropriate controls and long-term follow-up.
What the Study of Persons At Risk for Familial Alzheimer's Disease Can Tell Us About the Earliest Stages of the Disorder: A Review
Authors: Ringman John M.
Published: November 2005

As the proportion of elderly persons continues to expand, understanding the pathobiology of Alzheimer's disease and being able to diagnose it at an early stage become more critical. A minority of Alzheimer's disease cases are inherited as a fully-penetrant, autosomal dominant trait with a young age of onset. The molecular study of the pathogenic mutations has led to insights regarding the etiology of sporadic Alzheimer's disease. Clinical studies in persons at risk for these mutations have confirmed early episodic memory and executive deficits in Alzheimer's disease and suggested that dysphoria may precede the cognitive changes of Alzheimer's disease. Imaging studies have indicated that medial temporal lobe atrophy begins 3 to 4 years before cognitive symptoms, and quantitative cerebral metabolic changes are also present from early on. Studies of biochemical markers suggest that elevations of plasma A 1-42 occur early in familial Alzheimer's disease but that tau may not be elevated in cerebrospinal fluid until the disease is more advanced.
Inflation, Extension, Torsion and Shearing of an Inhomogeneous Compressible Elastic Right Circular Annular Cylinder
Authors: Saravanan U. , Rajagopal K. R.
Published: November 2005

We study the inflation, extension, torsion and shearing of an isotropic inhomogeneous compressible annular right circular cylinder. Current approaches to homogenization that appeal to an equivalence in the stored energies could lead to serious errors in the estimate for stresses in a inhomogeneous body as stresses depend on the derivatives of the stored energy with respect to the deformation gradient. This is a serious drawback as many a time failures are determined by the stresses. The study demonstrates that, in particular, great caution should be exercised in homogenization, especially if an inhomogeneous body is to be approximated by a homogeneous body belonging to the same class. Comparison of local measures, such as stresses, reveal that their values in the case of the inhomogeneous body and its homogeneous counterpart can be both qualitatively and quantitatively far apart. Even the differences in global measures like the axial load, torque, etc., are found to be significant between the inhomogeneous body and its homogeneous counterpart. It is also shown that the material parameters characterizing the homogenous approximation gleaned from correlations from different experiments, performed on the same inhomogeneous body, can be quite different.
Some Comments on the Mechanical Response of Elastomers Undergoing Scission and Healing at Elevated Temperatures
Authors: Wineman Alan
Published: November 2005

When the temperature of an elastomer exceeds a critical value, there can be scission and recrosslinking of molecular chains and the formation of new molecular networks. These events are time and temperature dependent. When this happens in a deforming elastomer, there can be permanent set and modified mechanical properties. A constitutive theory has recently been proposed that accounts for these continuous changes in microstructure. Several analytical results are presented in this paper for materials that are described by this theory. First, several motions and associated temperature distributions are presented that are possible in every material described by the constitutive theory, independent of material properties. Second, when the temperature of an elastomer increases beyond the critical value and then decreases below it, scission and re-crosslinking stops and the resulting material exhibits modified elastic response. The constitutive equation for the modified elastic response is developed from the underlying constitutive theory, and the associated material anisotropy is discussed. Lastly, special results are obtained when the original and newly formed networks can be described as neo-Hookean.
Why is “Bad” Parenting Criminogenic? Implications From Rival Theories
Authors: Unnever James D. , Cullen Francis T. , Agnew Robert
Published: November 2005

This article tests two rival theories: low self-control and differential association and social learning and their competing accounts of why bad parenting matters. The analysis revealed that several dimensions of parenting (including monitoring and caring and parental reinforcement of aggression) affected both low self-control and aggressive attitudes. Both low self-control and aggressive attitudes predicted delinquent involvement and were found to partially mediate the effect of parenting measures on delinquency. The influence of self-control on delinquent involvement was found to vary across levels of aggressive attitudes—adolescents who had aggressive attitudes and little self-control were especially likely to engage in criminal behavior. The results indicate that ineffective parenting is likely to produce low self-control and aggressive attitudes through not only direct control (e.g., monitoring and punishment) but also through modeling. Thus, the findings question the claim by Gottfredson and Hirschi and Akers that they have set forth truly general theories of crime.
Aplastic Anemia: Management of Pediatric Patients
Authors: Guinan Eva C.
Published: November 2005

Aplastic anemia is a term describing the common findings of pancytopenia and marrow hypoplasia arising from a variety of disease states, including acquired aplastic anemia and a variety of congenital marrow failure states. The management of children with these disorders has been confounded by difficulties of diagnosis. The availability of molecular testing has assisted in partial resolution of this problem but has raised new issues, such as the potential of genetic predisposition and the management of asymptomatic individuals with molecular markers. Longitudinal data from large cohort studies and disease registries are providing a rational basis for making more informed treatment decisions for children with these disorders. In particular, the ability to subset patients more accurately has improved triage of treatments. Approaches to hematopoietic stem cell transplantation (SCT), using both conventional and alternative donors, are changing rapidly, and the long-term sequelae of newer approaches are not entirely clear. Improved diagnosis and longer survival have fostered an understanding of the multidisciplinary approach necessary to manage both the underlying problems and the significant sequelae of treatment in both acquired and congenital disease.
Red Cell Membrane Disorders
Authors: Gallagher Patrick G.
Published: November 2005

Disorders of the erythrocyte membrane, including hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, and hereditary stomatocytosis, comprise an important group of inherited hemolytic anemias. These syndromes are characterized by marked clinical and laboratory heterogeneity. Recent molecular studies have revealed that there is also significant genetic heterogeneity in these disorders. This is particularly true for the spherocytosis syndromes where each kindred has a private mutation in one of the spherocytosis genes.

Treatment with splenectomy is curative in most patients. Splenectomy via a laparoscopic approach has become the surgical method of choice. Growing recognition and understanding of the long-term risks and complications of splenectomy, including cardiovascular disease, thrombotic disorders, and pulmonary hypertension, and the emergence of penicillin-resistant pneumococci, a concern for infection in overwhelming postsplenectomy infection, have led to reevaluation of the role of splenectomy. Recent management guidelines acknowledge these important considerations when entertaining splenectomy and recommend detailed discussion between health care providers, patient, and family.
The Molecular Pathology of Acute Myeloid Leukemia
Authors: Licht Jonathan D. , Sternberg David W.
Published: November 2005

The pathogenesis of acute myelogenous leukemia (AML) involves an array of molecular alterations that disrupt almost every facet of cell transformation. These processes include the regulation of cell proliferation, differentiation, self-renewal, survival, cell cycle checkpoint control, DNA repair and chromatin stability, and cell dissemination. Normal regulatory networks are disrupted or usurped by these leukemogenic insults, and the understanding of these alterations is guiding the design of new therapeutic strategies. This overview describes some of the critical molecular alterations and implicates the rogue leukemogenic proteins in the onset and progression of AML.
Role of Allogeneic Stem Cell Transplantation in Current Treatment of Acute Myeloid Leukemia
Authors: Cornelissen Jan J. , Löwenberg Bob
Published: November 2005

Allogeneic hematopoietic stem cell transplantation (alloSCT) has been established as an effective consolidation therapy in acute myeloid leukemia (AML) in first or subsequent remission. Although it effectively prevents relapse, treatment-related mortality (TRM) associated with alloSCT may compromise that beneficial effect. As a result, alloSCT may be restricted to patients with a relatively high risk of relapse. Here, we review studies that identify categories of AML patients who may specifically benefit from alloSCT. In addition, we discuss recent developments with respect to alternative donors, stem cell sources, and supportive care. Finally, we highlight recent results obtained with reduced-intensity alloSCT, which already significantly influence our therapeutic strategy in elderly patients with AML.
Management of Early Stage Disease
Authors: Deininger Michael W.N.
Published: November 2005

More than 80% of newly diagnosed patients with chronic myeloid leukemia in chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg imatinib daily. The probability of progression free survival is tightly correlated with the level of response, approaching 100% in those patients who achieve a reduction of BCR-ABL mRNA by at least 3-log at 12 months. High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Standard disease monitoring includes full blood counts, cytogenetics and quantitative RT-PCR for BCR-ABL mRNA but must be tailored to the level of response attained by a given patient. Conservative therapeutic milestones include a complete hematologic response at 3 months, a minor cytogenetic response at 6, a major cytogenetic response at 12 and CCR at 18, but a more aggressive approach may be justified in specific circumstances. Failure to achieve any of these milestones should trigger a re-assessment of the therapeutic strategy. Most patients with CCR remain positive by RT-PCR, and discontinuation of drug is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells. The mechanisms underlying disease persistence are not well understood. Evidence is accumulating that early therapy intensification using high doses of imatinib (800 mg daily) or imatinib in combination with cytarabine or interferon-alpha may induce higher rates of RT-PCR negativity. Large studies will be required to determine whether this translates into improved progression free and overall survival.
Neurovisceral Porphyrias: What a Hematologist Needs to Know
Authors: Bonkovsky Herbert L.
Published: November 2005

The acute or inducible hepatic porphyrias comprise four inherited disorders of heme biosynthesis. They usually remain asymptomatic for most of the lifespan of individuals who inherit the specific enzyme deficiencies but may cause life-threatening attacks of neurovisceral symptoms. Failure to consider the diagnosis frequently delays effective treatment, and inappropriate diagnostic tests and/or mistaken interpretation of results may lead to misdiagnosis and inappropriate treatment. The four disorders are ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Other conditions that clinically and biochemically may mimic acute porphyria include lead poisoning and hereditary tyrosinemia type I. The diagnosis of one of these acute porphyric syndromes should be considered in many patients with otherwise unexplained abdominal pain, severe constipation, systemic arterial hypertension, or other characteristic symptoms. Critical to the rapid diagnosis of the three most common of these disorders is demonstration of markedly increased urinary porphobilinogen (PBG) in a single-void urine specimen. The treatment of choice for all but mild attacks of the acute porphyrias is intravenous hemin therapy, which should be started as soon as possible. Intravenous glucose alone is recommended only for mild attacks (no weakness or hyponatremia) or until hemin is available.
Aggressive Peripheral T-Cell Lymphomas (Specified and Unspecified Types)
Authors: Savage Kerry J.
Published: November 2005

Peripheral T-cell lymphomas (PTCLs) are a biologically diverse and uncommon group of diseases. Compared to their B-cell counterparts, PTCLs remain largely unexplored and the optimal treatment ill-defined due to disease rarity and biological heterogeneity. For the majority of PTCL subtypes, prognosis is poor with a 5-year overall survival of approximately 30% in most series.

The notable exception is ALK-positive anaplastic large-cell lymphoma (ALK-pos ALCL), which has a superior outcome. The international prognostic index can be used to some extent to define risk groups within some PTCL subtypes, including PTCL unspecified (PTCLUS). It is likely that the observed clinical heterogeneity reflects differences at the molecular level. With the more widespread availability of gene expression profiling, it may be possible in the future to further refine the classification of PTCLs and elucidate novel therapeutic targets. Future clinical trials are needed that focus specifically on PTCL to advance our understanding and define the optimal management in this disease.
Clinical Presentation and Management of Marginal Zone Lymphomas
Authors: Thieblemont Catherine
Published: November 2005

Marginal-zone lymphoma (MZL) includes three subtypes depending on the site of lymphoma involvement: extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma); splenic MZL; and nodal MZL. Beside a common cell-of-origin and similarities concerning a possible chronic antigenic stimulation by microbial pathogens and/or autoantigens, the clinical presentation is very different with symptoms related to lymphoma location. MALT and splenic MZL present with an indolent disease with good performance status, no B symptoms, and no adverse prognostic factors and are associated with long survival. Patients with nodal MZL present with a more aggressive disease and have a shorter failure-free survival. Clinical and biological prognostic factors identified in reported series are heterogeneous. The optimal treatment has yet to be defined for the three subtypes, and current strategies will be described in this review.
Acquired Disorders of Platelet Function
Authors: Hassan Amy A. , Kroll Michael H.
Published: November 2005

A qualitative abnormality of platelet function should be considered in patients with mucocutaneous bleeding in the absence of thrombocytopenia or von Willebrand disease. Antiplatelet drugs are the most common cause of acquired platelet disorders leading to bleeding. Uremia, hepatic cirrhosis, myeloma and related disorders, polycythemia vera, essential thrombocythemia, and cardiopulmonary bypass have long been recognized as clinical situations in which platelet dysfunction may contribute to bleeding. When an acquired platelet disorder is suspected, it is useful to examine platelet function by measuring the bleeding time, examining platelet-dependent closure time in a platelet function analyzer and performing platelet aggregometry. When a specific acquired platelet disorder is diagnosed, many treatment options are available including controlling the underlying disease, giving platelet transfusions and administering a hemostatic drug.
Genetic Risk Factors for Arterial Thrombosis and Inflammation
Authors: Ginsburg David
Published: November 2005

Arterial thrombosis is a central pathologic mechanism contributing to myocardial infarction and stroke, together the leading causes of death in developed countries. This article reviews the current state of knowledge concerning the role of inherited variation in hemostatic and inflammatory factor genes in determining the risk of arterial thrombosis/ischemic heart disease. Despite considerable progress in identifying important genetic risk factors underlying predisposition to venous thrombosis, the genetic factors contributing to the risk for arterial thrombosis remain largely unknown. However, the rapid development of powerful new genomic resources should facilitate considerably more sophisticated analyses, leading to novel insight into the molecular pathophysiology of this important set of human diseases.
The Transfusion Services Committee—Responsibilities and Response to Adverse Transfusion Events
Authors: Shulman Ira A. , Saxena Sunita
Published: November 2005

Healthcare institutions in the United States must review blood transfusion practices and adverse outcomes in order to receive payments from the Centers for Medicare/Medicaid program, but it is not required for a specific committee to be assigned to oversee the review process. Regardless of the group or individuals responsible, the review process must include a program of quality assessment and performance improvement that is ongoing, hospital-wide, and data-driven, reflects the complexity of the hospital’s organization and services, and involves all hospital departments and services (including those contracted). To be most effective, the performance improvement activity should be prioritized around high-risk, high-volume activities and/or in problem-prone areas. Even if a hospital elects not to receive payments from Medicare, it must still comply with applicable sections of the Code of Federal Regulations pertaining to transfusion services such as the follow up of adverse outcomes of transfusion.
Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia
Authors: Gladwin Mark T. , Kato Gregory J.
Published: November 2005

Medical advances in the management of patients with sickle cell disease, thalassemia, and other hemolytic anemias have led to significant increases in life expectancy. Improved public health, neonatal screening, parental and patient education, advances in red cell transfusion medicine, iron chelation therapy, penicillin prophylaxis for children, pneumococcal immunization, and hydroxyurea therapy have all likely contributed to this effect on longevity.1,2 Importantly, as a generation of patients with sickle cell disease and thalassemia ages, new chronic complications of these hemoglobinopathies develop. In this context, pulmonary hypertension is emerging as one of the leading causes of morbidity and mortality in adult sickle cell and thalassemia patients, and likely in patients with other hemolytic anemias. A common feature of both sickle cell disease and thalassemia is intravascular hemolysis and chronic anemia. Recent data suggest that chronic intravascular hemolysis is associated with a state of endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability, pro-oxidant and pro-inflammatory stress and coagulopathy, leading to vasomotor instability and ultimately producing a proliferative vasculopathy, a hallmark of which is the development of pulmonary hypertension in adulthood.3–5 In conclusion, pulmonary hypertension is common in patients with hereditary hemolytic anemias and is associated with a high risk of death in patients with sickle cell disease. New therapies targeting this vasculopathy and aimed at normalizing the vasodilator:vasoconstrictor balance are discussed.
Hematology Grants K08 and K23
Authors: Bodine David M.
Published: November 2005

The first National Institutes of Health (NIH) grant awarded to physician scientists is often a K08 or K23 award. This chapter is designed for the Hematology Fellow who is preparing for an independent faculty position in 3–5 years. The topics covered include deciding which award to apply for, advice about planning and writing the application, as well as a description of the review process and how candidates can make their application stand out.