bluuebunny/crossref_metadata_2025 huggingface dataset:
Healthcare Outcomes Associated with Beers' Criteria: A Systematic Review
Authors: Jano Elda , Aparasu Rajender R
Published: February 2007

Objective:

To examine healthcare outcomes associated with Beers' criteria of inappropriate medication use based on a literature review.

Data Sources:

A search of MEDLINE, International Pharmaceutical Abstracts, and Cumulative Index to Nursing and Allied Health Literature was conducted to identify articles published from October 1991 to October 2006. The following key words were used: Beers, inappropriate, medication, drug, use, prescribing, and elderly. A manual search was also conducted using the references listed in the articles identified through the database search.

Study Selection And Data Extraction:

Studies that examined the impact or outcomes of Beers' criteria of inappropriate medication use (1991, 1997, and 2003 critera) were selected. Each article was examined for study setting, data source, study sample, study design, criteria, analysis and covariates, type of healthcare outcome, and study findings. Of 235 articles retrieved, 18 presented studies that examined healthcare outcomes associated with inappropriate medication use based on Beers' criteria. Specifically, setting-specific evidence as well as overall evidence was examined from the selected studies. The review considered evidence of association if more than 50% of the findings were statistically significant.

Data Synthesis:

Most of the 18 studies evaluated were retrospective cohort studies involving patients 65 years of age or older from diverse healthcare settings. In community settings, there was no evidence of association with respect to mortality and other healthcare use, and evidence regarding quality of life and costs was inconclusive. However, inappropriate medication use was associated with hospitalization measures in community elderly. In nursing homes, there was no evidence of association with mortality and the association with hospitalization measures was inconclusive. In hospitals, there was inconclusive evidence to make any generalizations. Across healthcare settings, inappropriate medication use was associated with adverse drug reactions and costs but not with other outcome measures.

Conclusions:

There is evidence that Beers' criteria of inappropriate medication use is associated with adverse healthcare impact in the community-dwelling elderly. With increasing use of Beers' criteria as quality-of-care measures, there is a need to strengthen the predictive validity of these criteria in all healthcare settings.
Heat shock protein 70-1 gene expression in pediatric heart surgery using blood cardioplegia
Authors: Vittorini Simona , Storti Simona , Andreani Giovanna , Giusti Lauro , Murzi Bruno , Furfori Pierantonio , Baroni Alessandra , Lucia Vittoria De , Luisi Vincenzo Stefano , Clerico Aldo
Published: February 2007

Clin Chem Lab Med 2007;45:244–8.
Biochemical reference intervals for sex hormones with a new AutoDelfia method in aged men
Authors: Eskelinen Seija , Vahlberg Tero , Isoaho Raimo , Kivelä Sirkka-Liisa , Irjala Kerttu
Published: February 2007

Our aim was to establish sex hormone reference intervals measured with a new AutoDelfia immunoassay method for aged men free of medication and/or conditions known to influence sex hormone levels.

The reference population consisted of 466 individuals between 64 and 97 years (mean 72 years) and a mean body mass index (BMI) of 26.9 kg/m

Because age correlated significantly with most sex hormones studied, we calculated reference intervals for three age groups (64–69, 70–74 and ≥75 years). In clinical practice, single ranges can be used for men aged 64 years or over for testosterone, estradiol and follicle-stimulating hormone (FSH) with the AutoDelfia method. For free testosterone and luteinizing hormone (LH), separate reference intervals should be used for men aged 64–74 years and those aged 75 years or over. For sex hormone-binding globulin, two separate reference intervals by age (64–69 and ≥70 years) are also needed for aged men. LH and FSH reference ranges should be judged with caution, because they may be too high due to cases of subclinical hypogonadism included in the reference population.

Clin Chem Lab Med 2007;45:249–53.
Association of thyroid dysfunction with vitamin B12, folate and plasma homocysteine levels in the elderly: a population-based study in Sicily
Authors: Stella Giuseppe , Spada Rosario Sebastiano , Calabrese Santa , Bosco Paolo , Anello Guido , Guéant-Rodriguez Rosa-Maria , Romano Antonino , Benamghar Lahoucine , Proto Caterina , Castellano Antonino , Fajardo Adrian , Lipari Lina , Sirna Salvatore , Guéant Jean-Louis
Published: February 2007

Association of thyroid dysfunction with plasma homocysteine levels and vitamin B

Subjects (n=279) aged 60–85 years (119 males and 160 females) were examined using self-reported signs, clinical examination and laboratory tests.

Hypothyroidism and/or goiter were two characteristics that were not associated with a significant change in homocysteine when compared with euthyroidism and the absence of goiter. Vitamin B

Our results suggest that the influence of thyroid hormones on homocysteine is much weaker in elderly subjects than in selected patients with hypothyroidism.

Clin Chem Lab Med 2007;45:143–7.
Number and Density of AMPA Receptors in Individual Synapses in the Rat Cerebellum as Revealed by SDS-Digested Freeze-Fracture Replica Labeling
Authors: Masugi-Tokita Miwako , Tarusawa Etsuko , Watanabe Masahiko , Molnár Elek , Fujimoto Kazushi , Shigemoto Ryuichi
Published: February 2007

The number of AMPA receptor (AMPAR) is the major determinant of synaptic strength at glutamatergic synapses, but little is known about the absolute number and density of AMPARs in individual synapses. Using SDS-digested freeze-fracture replica labeling, which has high detection efficiency comparable with electrophysiological noise analysis for functional AMPAR, we analyzed three kinds of excitatory synapses in the molecular layer of the adult rat cerebellum. In parallel fiber (PF)–Purkinje cell (PC) synapses, we found large variability in the number (38.1 ± 34.4 particles per synapse, mean ± SD; range, 2–178 particles per synapse) and density (437 ± 277 particles/μm2; range, 48–1210 particles/μm2) of immunogold-labeled AMPARs. Two-dimensional view and high sensitivity of this method revealed irregular-shaped small AMPAR clusters within synapses. Climbing fiber (CF)–PC synapses had higher number of AMPAR labeling (68.6 ± 34.5 particles per synapse) than PF–PC and PF–interneuron synapses (36.8 ± 14.4 particles per synapse). Furthermore, AMPAR density at CF–PC and PF–interneuron synapses was approximately five times higher and more uniform than that at PF–PC synapses. These results suggest input- and target-dependent regulation of AMPAR-mediated synaptic strength.
Contribution of NMDA and AMPA Receptors to Temporal Patterning of Auditory Responses in the Inferior Colliculus
Authors: Sanchez Jason Tait , Gans Donald , Wenstrup Jeffrey J.
Published: February 2007

Although NMDA receptors (NMDARs) are associated with synaptic plasticity, they form an essential part of responses to sensory stimuli. We compared contributions of glutamatergic NMDARs and AMPA receptors (AMPARs) to auditory responses in the inferior colliculus (IC) of awake, adult mustached bats. We examined the magnitude and temporal pattern of responses to tonal signals in single units before, during, and after local micro-iontophoretic application of selective antagonists to AMPARs [NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide)] and NMDARs [CPP ((±)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid)]. Combined blockade of AMPARs and NMDARs eliminated excitatory responses in nearly all neurons, whereas separate blockade of each receptor was quantitatively similar, causing substantial (>50%) spike reductions in ∼75% of units. The major result was that effects of receptor blockade were most closely related to the first-spike latency of a unit. Thus, AMPAR blockade substantially reduced spikes in all short-latency units (<12 ms) but never in long-latency units (≥12 ms). NMDAR blockade had variable effects on short-latency units but reduced spikes substantially for all long-latency units. There were no distinct contributions of AMPARs and NMDARs to early and late elements of responses. Thus, AMPAR blockade reduced early (onset) spikes somewhat more effectively than NMDAR blockade in short-latency units, but NMDAR blockade reduced onset spikes more effectively in long-latency units. AMPAR and NMDAR blockade were equally effective in reducing later elements of sustained responses in short-latency units, whereas NMDAR blockade was much more effective in long-latency units. These results indicate that NMDARs play multiple roles for signal processing in adult IC neurons.
Kv4.3-Mediated A-Type K+Currents Underlie Rhythmic Activity in Hippocampal Interneurons
Authors: Bourdeau Mathieu L. , Morin France , Laurent Charles E. , Azzi Mounia , Lacaille Jean-Claude
Published: February 2007

Hippocampal-dependent learning and memory processes are associated with theta frequency rhythmic activity. Interneuron and pyramidal cell network interactions underlie this activity, but contributions of interneuron voltage-gated membrane conductances remain unclear. We show that interneurons at the CA1 lacunosum-moleculare (LM) and radiatum (RAD) junction (LM/RAD) display voltage-dependent subthreshold membrane potential oscillations (MPOs) generated by voltage-gated tetrodotoxin-sensitive Na+and 4-aminopyridine (4-AP)-sensitive K+currents. They also exhibit prominent 4-AP-sensitive A-type K+currents, with gating properties showing activation at subthreshold membrane potentials. We found that LM/RAD cells are part of specific interneuron subpopulations expressing the K+channel subunit Kv4.3 and their transfection with Kv4.3 small interfering RNA selectively impaired A-type K+currents and MPOs. Thus, our findings reveal a novel function of Kv4.3-mediated A-type K+currents in the generation of intrinsic MPOs in specific subpopulations of interneurons that may participate in hippocampal theta-related rhythmic activity.
Long-Term Depression of a Dopamine IPSC
Authors: Beckstead Michael J. , Williams John T.
Published: February 2007

Two determinants of dopamine release from terminals in striatal and limbic structures are the pattern and rate of dopamine neuron firing in the ventral midbrain. This activity is regulated in part by somatodendritic release of dopamine and subsequent feedback inhibition through activation of D2receptors on dopamine neuron cell bodies and dendrites. This study describes stimulus-dependent long-term depression (LTD) of IPSCs mediated by dopamine. This LTD was blocked by chelation of postsynaptic intracellular calcium, was dependent on the activation of D2receptors and was independent of glutamate-mediated transmission. Application of a high concentration of dopamine mimicked depression of the IPSC and prevented additional attempts to induce LTD, suggesting that the mechanism of the depression is agonist-dependent receptor activation. Using extracellular recording, there is an inhibition of firing that follows electrical stimulation, and after the induction of LTD the duration of that inhibition was decreased. Reduced inhibition could increase burst firing and action potential-dependent release of dopamine in terminal regionsin vivo.
Bed Nucleus of the Stria Terminalis Subregions Differentially Regulate Hypothalamic–Pituitary–Adrenal Axis Activity: Implications for the Integration of Limbic Inputs
Authors: Choi Dennis C. , Furay Amy R. , Evanson Nathan K. , Ostrander Michelle M. , Ulrich-Lai Yvonne M. , Herman James P.
Published: February 2007

Limbic and cortical neurocircuits profoundly influence hypothalamic–pituitary–adrenal (HPA) axis responses to stress yet have little or no direct projections to the hypothalamic paraventricular nucleus (PVN). Numerous lines of evidence suggest that the bed nucleus of the stria terminalis (BST) is well positioned to relay limbic information to the PVN. The BST comprises multiple anatomically distinct nuclei, of which some are known to receive direct limbic and/or cortical input and to heavily innervate the PVN. Our studies test the hypothesis that subregions of the BST differentially regulate HPA axis responses to acute stress. Male Sprague Dawley rats received bilateral ibotenate lesions, targeting either the principal nucleus in the posterior BST or the dorsomedial/fusiform nuclei in the anteroventral BST. Posterior BST lesions elevated plasma ACTH and corticosterone in response to acute restraint stress, increased stress-induced PVN c-fos mRNA, and elevated PVN corticotropin-releasing hormone (CRH) and parvocellular arginine vasopressin (AVP) mRNA expression relative to sham-lesion animals. In contrast, anterior BST lesions attenuated the plasma corticosterone response and decreased c-fos mRNA induction in the PVN but did not affect CRH and parvocellular AVP mRNA expression in the PVN. These data suggest that posterior BST nuclei are involved in inhibition of the HPA axis, whereas the anteroventral BST nuclei are involved in HPA axis excitation. The results indicate that the BST contains functional subdomains that play different roles in integrating and processing limbic information in response to stress and further suggest that excitatory as well as inhibitory limbic information is funneled through these important cell groups.
Deletion ofNf1in Neurons Induces Increased Axon Collateral Branching after Dorsal Root Injury
Authors: Romero Mario I. , Lin Lu , Lush Mark E. , Lei Lei , Parada Luis F. , Zhu Yuan
Published: February 2007

Ras-mediated signaling pathways participate in multiple aspects of neural development and function. For example, Ras signaling lies downstream of neurotrophic factors and Trk family receptor tyrosine kinases to regulate neuronal survival and morphological differentiation, including axon extension and target innervation. Neurofibromin, the protein encoded by the tumor suppressor geneNf1, is a negative regulator of Ras [Ras-GAP (GTPase-activating protein)], and we previously demonstrated thatNf1null embryonic sensory and sympathetic neurons can survive and differentiate independent of neurotrophin support. In this report, we demonstrate thatNf1loss in adult sensory neurons enhances their intrinsic capacity for neurite outgrowth and collateral branchingin vitroandin vivoafter dorsal root injury. In contrast to the permanent sensory deficits observed in control mice after dorsal rhizotomy, neuron-specificNf1mutant mice spontaneously recover proprioceptive function. This phenomenon appears to be mediated both by a cell-autonomous capacity of sparedNf1−/− DRG neurons for increased axonal sprouting, and by non-cell-autonomous contribution fromNf1−/− neurons in the denervated spinal cord.
White Matter Plasticity and Enhanced Remyelination in the Maternal CNS
Authors: Gregg Christopher , Shikar Viktor , Larsen Peter , Mak Gloria , Chojnacki Andrew , Yong V. Wee , Weiss Samuel
Published: February 2007

Myelination, the process in which oligodendrocytes coat CNS axons with a myelin sheath, represents an important but poorly understood form of neural plasticity that may be sexually dimorphic in the adult CNS. Remission of multiple sclerosis during pregnancy led us to hypothesize that remyelination is enhanced in the maternal brain. Here we report an increase in the generation of myelin-forming oligodendrocytes and in the number of myelinated axons in the maternal murine CNS. Remarkably, pregnant mice have an enhanced ability to remyelinate white matter lesions. The hormone prolactin regulates oligodendrocyte precursor proliferation and mimics the regenerative effects of pregnancy. This suggests that maternal white matter plasticity imparts a striking ability to repair demyelination and identifies prolactin as a potential therapeutic agent.
GABAergic Neurons Are Less Selective to Stimulus Orientation than Excitatory Neurons in Layer II/III of Visual Cortex, as Revealed byIn VivoFunctional Ca2+Imaging in Transgenic Mice
Authors: Sohya Kazuhiro , Kameyama Katsuro , Yanagawa Yuchio , Obata Kunihiko , Tsumoto Tadaharu
Published: February 2007

Most neurons in the visual cortex are selectively responsive to visual stimulation of a narrow range of orientations, and GABAergic neurons are considered to play a role in the formation of such orientation selectivity. This suggests that response properties of GABAergic neurons may be different from those of excitatory neurons. This view remains unproved, however. To address this issue, we appliedin vivotwo-photon functional Ca2+imaging to transgenic mice, in which GABAergic neurons express enhanced green fluorescent protein. Astroglia were stained by an astrocyte-specific dye. The three types of cells, GABAergic neurons, excitatory neurons, and astrocytes, in layer II/III of the visual cortex were differentially identified by using different wavelengths of excitation light and a dichroic mirror for emitted fluorescence, and their responses to moving visual stimuli at different orientations were measured with changes in the intensity of fluorescence of a Ca2+-sensitive dye. We found that almost all GABAergic neurons have orientation-insensitive responses, whereas most of excitatory neurons have orientation-selective responses.
Interferon-γ-Oligodendrocyte Interactions in the Regulation of Experimental Autoimmune Encephalomyelitis
Authors: Balabanov Roumen , Strand Krystle , Goswami Rajendra , McMahon Eileen , Begolka Wendy , Miller Stephen D. , Popko Brian
Published: February 2007

Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human demyelinating disorder multiple sclerosis (MS). The immune cytokine interferon-gamma (IFN-γ) is believed to participate in disease pathogenesis in both EAE and MS. In the present study, we examined the significance of IFN-γ-oligodendrocyte interactions in the course of EAE. For the purpose of our study, we used the previously described [proteolipid protein/suppressor of cytokine signaling 1 (PLP/SOCS1)] transgenic mouse line that displays suppressed oligodendrocyte responsiveness to IFN-γ.PLP/SOCS1mice developed EAE with an accelerated onset associated with enhanced early inflammation and markedly increased oligodendrocyte apoptosis. Moreover, we found that IFN-γ pretreatment of mature oligodendrocytesin vitrohad a protective effect against oxidative stress and the inhibition of proteasome activity and resulted in upregulation in expression of a number of chemokines, including CXCL10 (IP10), CCL2 (MCP-1), CCL3 (MCP-1α), and CCL5 (RANTES). These results suggest that IFN-γ-oligodendrocyte interactions are of significance to the clinical and pathological aspects of EAE. In addition, the present study suggests that oligodendrocytes are not simply targets of inflammatory injury but active participants of the neuroimmune network operating during the course of EAE.
Endosomal Accumulation of Toll-Like Receptor 4 Causes Constitutive Secretion of Cytokines and Activation of Signal Transducers and Activators of Transcription in Niemann–Pick Disease Type C (NPC) Fibroblasts: A Potential Basis for Glial Cell Activation in the NPC Brain
Authors: Suzuki Michitaka , Sugimoto Yuko , Ohsaki Yuki , Ueno Makoto , Kato Shinsuke , Kitamura Yukisato , Hosokawa Hiroshi , Davies Joanna P. , Ioannou Yiannis A. , Vanier Marie T. , Ohno Kousaku , Ninomiya Haruaki
Published: February 2007

Niemann–Pick disease type C (NPC) is an inherited lipid storage disorder caused by mutations inNPC1orNPC2genes. Loss of function of either protein results in the endosomal accumulation of cholesterol and other lipids, progressive neurodegeneration, and robust glial cell activation. Here, we report that cultured human NPC fibroblasts secrete interferon-β, interleukin-6 (IL-6), and IL-8, and contain increased levels of signal transducers and activators of transcription (STATs). These cells also contained increased levels of Toll-like receptor 4 (TLR4) that accumulated in cholesterol-enriched endosomes/lysosomes, and small interfering RNA knockdown of this receptor reduced cytokine secretion. In theNPC1−/−mouse brain, glial cells expressed TLR4 and IL-6, whereas both glial and neuronal cells expressed STATs. Genetic deletion of TLR4 inNPC1−/−mice reduced IL-6 secretion by cultured fibroblasts but failed to alter STAT levels or glial cell activation in the brain. In contrast, genetic deletion of IL-6 normalized STAT levels and suppressed glial cell activation. These findings indicate that constitutive cytokine secretion leads to activation of STATs in NPC fibroblasts and that this secretion is partly caused by an endosomal accumulation of TLR4. These results also suggest that similar signaling events may underlie glial cell activation in theNPC1−/−mouse brain.
Estrogen Mobilizes a Subset of Estrogen Receptor-α-Immunoreactive Vesicles in Inhibitory Presynaptic Boutons in Hippocampal CA1
Authors: Hart Sharron A. , Snyder Melissa A. , Smejkalova Tereza , Woolley Catherine S.
Published: February 2007

Although the classical mechanism of estrogen action involves activation of nuclear transcription factor receptors, estrogen also has acute effects on neuronal signaling that occur too rapidly to involve gene expression. These rapid effects are likely to be mediated by extranuclear estrogen receptors associated with the plasma membrane and/or cytoplasmic organelles. Here we used a combination of serial-section electron microscopic immunocytochemistry, immunofluorescence, and Western blotting to show that estrogen receptor-α is associated with clusters of vesicles in perisomatic inhibitory boutons in hippocampal CA1 and that estrogen treatment mobilizes these vesicle clusters toward synapses. Estrogen receptor-α is present in approximately one-third of perisomatic inhibitory boutons, and specifically in those that express cholecystokinin, not parvalbumin. We also found a high degree of extranuclear estrogen receptor-α colocalization with neuropeptide Y. Our results suggest a novel mode of estrogen action in which a subset of vesicles within a specific population of inhibitory boutons responds directly to estrogen by moving toward synapses. The mobilization of these vesicles may influence acute effects of estrogen mediated by estrogen receptor-α signaling at inhibitory synapses.
Representing School Success and Failure: Media Coverage of International Tests
Authors: Stack Michelle
Published: February 2007

It is through the media that audiences come to learn about the apparent successes and failure of the education system. Despite this power, the connection of the media to educational leadership and policy making is often given little attention in determining the forces at play in evaluating what happens in schools. Using a critical discourse analysis of media coverage concerning the 1999 Trends in Mathematics and Science Study (TIMSS) and the 2000 and 2003 Programme for International Student Assessment (PISA), the author argues that the media interpreted these test results in concert with business and electoral elites as a ‘failure of marginalized students,’ rather than a failure of society to address systemic discrimination. The media coverage of such failures presents solutions provided by business and government as common sense. Consequently, alternative framings, for example, as to what a successful education system would look like to people who are judged school failures based on the tests are never sought. There is also no discussion of the ways in which the PISA and TIMSS tests are constructed to favor the knowledge of dominant interests and ignore that which is outside this realm.
Prospective Evaluation of the AM-PAC-CAT in Outpatient Rehabilitation Settings
Authors: Jette Alan M , Haley Stephen M , Tao Wei , Ni Pengsheng , Moed Richard , Meyers Doug , Zurek Matthew
Published: February 2007

Background and Purpose

The purpose of this study was to prospectively evaluate the practical and psychometric adequacy of the Activity Measure for Post-Acute Care (AM-PAC) “item bank” and computerized adaptive testing (CAT) assessment platform (AM-PAC-CAT) when applied within orthopedic outpatient physical therapy settings.

Method

This was a prospective study with a convenience sample of 1,815 patients with spine, lower-extremity, or upper-extremity impairments who received outpatient physical therapy in 1 of 20 outpatient clinics across 5 states. The authors conducted an evaluation of the number of items used and amount of time needed to complete the CAT assessment; evaluation of breadth of content coverage, item exposure rate, and test precision; as well as an assessment of the validity and sensitivity to change of the score estimates.

Results

Overall, the AM-PAC-CAT's Basic Mobility scale demonstrated excellent psychometric properties while the Daily Activity scale demonstrated less adequate psychometric properties when applied in this outpatient sample. The mean length of time to complete the Basic Mobility scale was 1.9 minutes, using, on average, 6.6 items per CAT session, and the mean length of time to complete the Daily Activity scale was 1.01 minutes, using on average, 6.8 items.

Background and Conclusion

Overall, the findings are encouraging, yet they do reveal several areas where the AM-PAC-CAT scales can be improved to best suit the needs of patients who are receiving outpatient orthopedic physical therapy of the type included in this study.
Arthrokinematics in a Subgroup of Patients Likely to Benefit From a Lumbar Stabilization Exercise Program
Authors: Teyhen Deydre S , Flynn Timothy W , Childs John D , Abraham Lawrence D
Published: February 2007

Background and Purpose

A clinical prediction rule (CPR) has been reported to identify patients with low back pain who are likely to benefit from stabilization exercises. The aim of this study was to characterize the spinal motion, using digital fluoroscopic video, of a subgroup of subjects with low back pain.

Subjects

Twenty subjects who were positive on the CPR were compared with 20 control subjects who were healthy.

Methods

The magnitude and timing of lumbar sagittal-plane intersegmental angular and linear displacement were assessed. Receiver operating characteristic curves and accuracy statistics were used to develop a kinematic model.

Results

A 10-variable model was developed that could distinguish group membership. Seven of these variables described a disruption in timing of angular or linear displacement during mid-range movements. None of the variables suggested hypermobility.

Discussion and Conclusion

The findings suggest that individuals with mid-range aberrant motion without signs of hypermobility are likely to benefit from these exercises. The developed model describes altered kinematics of this subgroup of subjects and helps to provide construct validity for the developed CPR.
The SOCS‐1 gene methylation in chronic myeloid leukemia patients
Authors: Hatirnaz Ozden , Ure Umit , Ar Cem , Akyerli Cemaliye , Soysal Teoman , Ferhanoğlu Burhan , Özçelik Tayfun , Ozbek Ugur
Published: February 2007

SOCS‐1, an important protein in the JAK/STAT pathway, has a role in the down stream of BCR‐ABL protein kinase. We investigated 56 CML patients and 16 controls for the methylation status of SOCS‐1 gene promoter and Exon 2 regions. Exon 2 was found to be methylated in 58.9% of the patients and 93.8% of the controls [P = 0.020, OR = 0.121(0.015–0.957)%95CI]. The promoter region was found unmethylated in all patient samples and controls. Although previous studies revealed a relation between SOCS1 gene Exon‐2 hypermethylation and CML development or progression, the results of this study showed no such correlation. On the contrary, our results might be indicating hypomethylation in CML patients, this hypothesis need to be studied in larger study population. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.
Zinc in the treatment of homozygous sickle cell anemia: Studies in an animal model
Authors: Schoomaker Eric B. , Brewer George J. , Oelshlegel Fred J.
Published: February 2007

We have studied the effects of zinc on the 51 Cr survival of red blood cells (RBC) from patients with homozygous sickle cell anemia (SCA) using an animal model in which the RBC were transfused into specially prepared rats. The slope (λs) of a standard 51Cr RBC survival curve was used as a measure of the rate of RBC sequestration.

The effects of intravenous zinc were of considerable therapeutic interest from the standpoint of setting guidelines for effective blood levels of zinc in patients. SCA RBC were transfused into rats whose plasma zinc levels had been raised 3–6 times above normal (300–600 μg/100 ml) by prior iv injection of zinc acetate; in three experiments the mean λss in zinc‐treated animals breathing 15–16% oxygen was significantly lower (meaning lessened sequestration and greater survival) than saline‐treated controls. A possible explanation for the requirement to lower ambient oxygen tension in order to see this zinc effect is discussed.

We have further observed an increased mean λs for RBC from 10 SCA patients compared to 4 normal controls (0.134 vs 0.030; t = 2.8, p < 0.01). The λs values are quite patient specific (4 patients studied; F = 18.2, p = 0.002). In vitro pretransfusion treatment of SCA RBC with 1.5 mM zinc resulted in a significant increase in hemoglobin oxygen affinity and a marked reduction in λs (0.073 vs 0.120; t = 4.5, p < 0.01). The mean λs was not affected by in vitro 0.3 mM zinc treatment; this level did not change hemoglobin oxygen affinity.

We conclude that systemic zinc therapy in the animal model described, at plasma levels only slightly higher than those presently obtained in patients, prolongs SCA RBC survival. This animal model is a sensitive measure of the sicklability of SCA RBC and is useful in the testing of in vitro and in vivo antisickling agents.
The effect of thrombin on the uptake and transformation of arachidonic acid by human platelets
Authors: Russell Francis A. , Deykin Daniel
Published: February 2007

Washed human platelets take up arachidonic acid from plasma and incorporate the fatty acid into the major classes of complex lipids. Thrombin impairs net incorporation. It activates endogenous phospholipases which liberate arachidonic acid from phospholipids. As a consequence of thrombin induced aggregation platelets release arachidonic acid intermediates formed by the action of platelet fatty acid cyclooxygenase and by platelet fatty acid lipoxygenase. Cyclooxygenase, but not lipoxygenase, is inhibited by aspirin and indomethicin. Analysis of the pathways of arachidonic acid metabolism may furnish new insight into platelet function and into disorders of primary hemostasis.
Effects of single and combined chemotherapeutic agents on hemopoietic stem cells in mice
Authors: Jenkins V. K. , Costanzi J. J. , Ellis H. N.
Published: February 2007

Bone marrow cell responses to injections of nitrogen mustard, oncovin, procarbazine, hydrocortisone, and a regimen of all four drugs (MOPH) were evaluated in CRF1 and C57B 1/6 mice by determining bone marrow cellularity and content of transplantable colony forming units (CFU) after treatment. The study was done to determine whether the combined regimen, which is widely used clinically in treatment of disseminated Hodgkin's disease, is more or less detrimental to the hemopoietic system than the same drugs used as single agents. Nitrogen mustard and procarbazine used clinically as single drugs are given in three and two times, respectively, greater doses than in the combined regimen. Hydrocortisone, given singly, was least toxic of the drugs, reducing the CFU/femur to 63% and 71% of control values. MOPH appeared slightly more toxic than hydrocortisone, resulting in 41% and 52% of the CFU/femur surviving, and was about equally as toxic as oncovin alone. Nitrogen mustard and procarbazine, administered as single drugs in high doses, were highly suppressive, resulting in only 10–19% survival of CFU/femur, whereas, reduced doses of the two drugs as used in the MOPH regimen spared 30–45% of the CFU/femur. Survival of CFU after MOPH treatment was three to four times greater than after high doses of nitrogen mustard or procarbazine alone. The component drugs of the combined regimen did not act on separate populations of stem cells to produce an additive effect but appeared to inactivate the same population of cells.
IMFRA (Intermittent Intrathecal Methotrexate and Fractional Radiation) plus chemotherapy in childhood leukemia
Authors: Zuelzer W. W. , Ravindranath Y. , Lusher J. M. , Sarnaik Sharada , Considine Basil
Published: February 2007

A protocol for the prophylaxis of CNS leukemia was devised involving intermittent low‐dosage radiation of the craniospinal axis combined with single intrathecal injections of MTX. The retionale for this protocol was the timing of first CNS relapses in patients not receiving prophylaxis which suggests that leukemic colonization of the CNS is not restricted to the initial stage of the disease and that periodic measures might be advantageous. The low dosage of radiation was chosen because it is well tolerated and has been found temporarily effective in overt CNS relapse. The two series of patients were comparable as to various parameters. Results after three years of observation were comparable to those obtained by others with a single initial course of high‐dose radiation, with an expected 50% uninterrupted complete 5‐year remission. On the basis of 30 months follow up in 26 patients, the therapy is well tolerated. An increase in morbidity due to infections in remission was not associated with a higher mortality.
Chemotherapy of acute lymphoblastic leukemia in children
Authors: Haghbin Mahroo
Published: February 2007

Between 1969‐1973, 75 consecutive children under the age of 15 years with acute lymphoblastic leukemia were treated with a multiple‐drug regimen (L‐2). Prophylaxis for meningeal leukemia was limited to the repeated intrathecal injections of methotrexate. Seventy‐four patients achieved remission; the duration of remissions could be evaluated only for 70. Relapse terminated complete remission within 1‐54 months in 21 children. Four of these relapses were confined to the central nervous system. Forty‐nine patients continue in complete remission from 23 to 63 months. Chemotherapy has been discontinued in 29 children, and 25 of these remain without evidence of recurrence for 2‐27 months posttreatment.
Thalassemia intermedia caused by heterozygosity for both β‐thalassemia and hemoglobin saki [β14 (a11) leu→pro]
Authors: Milnera Paul F. , Corley Charles C. , Pomeroy William L. , Wilson Jerry B. , Gravely Marsha , Huisman Titus H. J.
Published: February 2007

The syndrome thalassemia intermedia can be the clinical expression of heterozygosity for different types of thalassemia, β‐thalassemia and hereditary persistence of fetal hemoglobin, β‐thalassemia and Hb‐Lepore, and in blacks it may even represent a true β‐thalassemia homozygote. This report describes thalassemia intermedia in a white male due to β‐thalassemia and an unstable hemoglobin. Chain‐synthesis studies showed an excess of β‐chain production over β‐chain production in the propositus and his mother but balanced chain synthesis in the clinically normal father, who is heterozygous for the unstable hemoglobin. The unstable hemoglobin was found to be β14 (A11) Leu→Pro, which has previously been described in a clinically normal African woman, and named Hb‐Saki. This hemoglobin is not distinguishable from Hb‐A on routine electrophoresis at alkaline or acid pH and tests for unstable hemoglobins are necessary for its detection. The increasing list of such hemoglobin variants and previous cases of heterozygosity for β‐thalassemia and unstable hemoglobins are reviewed.
Quantitative microchromatographic determination of hemoglobin f in patients with hemoglobins s and/or c
Authors: Schroeder W. A. , Evans Leslie , Grussing Lana , Abraham E. C. , Huisman T. H. J. , Lam H. , Shelton Joan B.
Published: February 2007

The improved microchromatographic procedure for the detection of Hb‐S and/or Hb‐C in cord blood at birth (Schroeder et al.: J. Lab Clin Med 86:528‐532, 1975) as well as a modification thereof may also be used for the quantitative determination of Hb‐F in the presence of Hb‐S and/or Hb‐C. However, Hb‐A interferes and must be absent. The methods use 0.5 × 6 cm columns of CM‐cellulose with Tris or Bis‐tris developers and require 2‐4 hr to complete. At low percentages of Hb‐F, the sharper zone of the Tris method is more easily visible than that of the Bis‐tris method, but the latter is a somewhat more rapid procedure.

About 300 cases with Hb‐S and/or Hb‐C have been examined by the micro‐ chromatographic procedure. Most of these results (Fmicro) have been compared with data from the determination of Hb‐F by one or more of the following methods: alkali denaturation (FAD), conventional DEAE‐Sephadex chromatography (FDES), or isoleucine analyses of zones from DEAE‐Sephadex chromatography (FIle). The accuracy and precision of the microchromatographic method is estimated to be 5‐10%.

The microchromatographic methods require much less time than conventional chromatography but more time than alkali denaturation procedures. Compared to the latter, the new methods use whole blood and less blood and permit the physical separation of Hb‐F.
Pathogenesis of polycythemia vera—new concepts
Authors: Golde David W. , Cline Martin J.
Published: February 2007

Data presently available suggest that polycythemia vera is an acquired clonal disorder of the pluripotent stem cell resulting in expansion of committed stem cell pools, most prominently in the erythroid line. In vitro and in vivo studies suggest that erythropoiesis in polycythemia vera is at least partially modulated by erythropoietin.
Staging laparotomy and splenectomy: Treatment and complications of hodgkin's disease in children
Authors: Lanzkowsky P. , Shende A. , Karayalcin G. , Aral I.
Published: February 2007

Twenty‐five cases of Hodgkin's Disease (15 males and 10 females) aged 5 to 17 years were studied from April 1970 to July 1976 (75 month period). Histology revealed that 2 had lymphocytic predominance, 12 had nodular sclerosis, and 11 had mixed cellularity. Pathologic staging revealed that 3 were IA, 1 IB, 5 IIA, 4 IIB, 6 IIIA, and 6 IIIB. Laparotomy altered the staging in 12 patients (9 were staged up and 3 down). All but 2 patients received extended field radiation, and 5 had recurrence of disease and were treated with combination chemotherapy. Twenty‐three are alive without evidence of disease (21–75 months), and the 2 deaths were not due to Hodgkin's Disease but to hemobilia (postliver biopsy) and penumococcal septicemia, purpura fulminans, and disseminated intravascular coagulation (14 months postsplenectomy). Other complications included 2 patients with intestinal obstruction, 1 with postoperative subphrenic abscess, and 1 with streptococcal septicemia and polyarthritis. Nineteen patients received continuous penicillin prophylaxis postoperatively and the 2 with serious infections were amongst the 6 who had not received penicillin or whose penicillin had been discontinued at the time of infection. It is concluded that laparotomy and splenectomy in children is essential for accurate staging but carries significant risk, and continuous penicillin prophylaxis is recommended.
Prognostic significance of surface marker analysis in childhood non‐hodgkin's lymphoproliferative malignancies
Authors: Coccia Peter F. , Kersey John H. , Gajl‐Peczalska Katamiera J. , Krivit William , Nesbit Mark E.
Published: February 2007

Blast cell surface markers for T‐ and B‐lymphocyte characteristics were studied at diagnosis in 73 children with non‐Hodgkin's lymphoproliferative malignancies. Three distinctive groups of patients were identified on the basis of the analysis of blast cells for surface immunoglobulin (SIg), sheep erythrocyte (sE) rosette formation, and complement receptors. The seven group I patients had monoclonal IgM on their blast cells, morphologic features of Burkitt's lymphoma, abdominal masses, and very short survival. The 13 group II patients had receptors for sE, complement, or both on their blast cells, mediastinal or nodal masses, and short survival. The distinction between leukemia and lymphoma based on the presence of bone marrow involvement at diagnosis is not prognostically useful in this group of patients. The blast cells of group II patients could not be morphologically distinguished from those of the group III patients. The 53 group III patients had SIg, sE, and complement negative blast cells and could be further subdivided on the basis of white blood cell count. The nine group IIIA patients (> 100.0 × 109/liter) had in general short survival, while most of the 44 group IIIB patients (< 100.0 × 109/liter) have remained in complete remission. Positive surface markers, mass lesions, male sex, and age of diagnosis < 2 years or ≧ 10 years appear to be interrelated factors indicating poor prognosis. Elevated white blood cell count is a prognostic indicator independent of surface marker analysis or presence of mass lesions.
In vivo and in vitro effects of thrombin and plasmin on human factor VIII (ahf)
Authors: Lian Eric Chun‐Yet , Nunez Roger L. , Harkness Donald R.
Published: February 2007

The relationship between factor VIII (AHF) procoagulant activity and factor VIII‐related antigen were examined in patients with disseminated intravascular coagulation (DIC), pulmonary embolism (PE), and coronary artery disease with or without myocardial infarction (MI). It was found that 13 of 13 patients with DIC, 17 of 17 patients with PE, and 10 of 12 patients with MI possessed a significantly elevated factor VIII‐related antigen to factor VIII activity ratio (VIII‐ratio). The VIII‐ratio returned to normal in each of 2 patients with DIC and 1 patient with PE after treatment with heparin, heparin and α‐amino‐caproic acid, and heparin and coumadin respectively. In contrast, the VIII‐ratio was slightly elevated only in 1 of 15 patients with coronary artery insufficiency without MI. In in vitro studies, after treatment of plasma with thrombin or plasmin, factor VIII activity was lost, whereas the amount of factor VIII‐related antigen remained the same or was even increased when measured by agarose quantitative immunoelectrophoresis. These observations have led us to conclude that an elevated VIII‐ratio is a very sensitive indicator of intravascular coagulation.
α‐Thalassemia and β‐thalassemia in a turkish family
Authors: Altay C. , Say B. , Yetgin S. , Huisman Titus H. J.
Published: February 2007

A Turkish family is described in which three children have a clinical picture similar to that of thalassemia major, with typical red cell morphology and indices, and with about 10% Hb Bart's but without measurable amounts of Hb H. Hematological evaluation of six members of this family that included in vitro hemoglobin synthesis suggests that β‐ (or δβ‐) thalassemia, β‐silent thalassemia, and mild and severe α‐thalassemia genes are present in different combinations. The data indicate that β/α chain ratios in patients with more than one type of thalassemia should be evaluated in relationship to values obtained for several relatives even though some of the thalassemia determinants may be silent in the parents.
Sv40 t‐antigen expression in skin fibroblasts from clinically normal individuals and from ten cases of fanconi anemia
Authors: Lubiniecki A. S. , Blattner W. A. , Dosik H. , Sun C. , Fraumeni J. F.
Published: February 2007

Previous studies of the expression of SV40 genetic information by skin fibroblasts included limited numbers of cell donors and failed to adequately consider possible effects of age, sex, and ethnic origin on assay results. A population of 76 healthy subjects were selected for study following determination of personal and family disease history and karyological analysis. Skin fibroblasts from these individuals were tested for expression of SV40 T‐antigen by indirect immunofluorescent assay. The data were normally distributed and showed no significant differences between the age, sex, or ethnic groups tested. The occurrence of rare karyological anomalies in this control population had no effect on T‐antigen expression. Fibroblasts from 10 Fanconi anemia patients demonstrated significantly elevated expression of T‐antigen compared to the well‐defined control population, based on simple statistical criteria. T‐antigen expression was elevated in two young patients prior to the onset of anemia and did not appear to correlate with the incidence or severity of other specific symptoms. Thus, elevated T‐antigen expression in Fanconi anemia fibroblasts reflects an actual defect at the cellular level, rather than clinical, age, sex, or ethnic factors not previously considered.
Hydrogen peroxide, an inhibitor of platelet function: Effect on adenine nucleotide metabolism, and the release reaction
Authors: Stuart Marie J. , Holmsen Holm
Published: February 2007

The in vitro effects of H2O2 on platelet adenine nucleotide metabolism and on the ADP‐induced platelet release reaction were examined. All studies were performed on human platelet‐rich plasma (PRP) preincubated with (3 H)‐adenine. Within 3 min of incubation with PRP, H2O2 (100–500 μM) caused an irreversible reduction in the (3 H)‐ATP level with a concomitant increase in (3 H)‐IMP and (3 H)‐inosine and hypoxanthine levels. The adenylate energy charge (AEC) initially decreased while the ATP level fell. The AEC, however, returned to levels slightly lower than the control during further incubation. No leakage of ATP and ADP to plasma was observed. The fall in the steady‐state levels of (3 H)‐ATP increased with increase of the H2O2 concentration (decrease of 8.7–40% at H2O2 concentrations from 5 to 600 μM). H2O2 pretreatment of PRP caused absence of ADP‐induced biphasic aggregation, partial inhibition of the primary wave, and complete inhibition of release of platelet nonmetabolic ATP and ADP.

Our in vitro findings support the view that part of the inhibitory effect of H2O2 may be related to the lowering of metabolic ATP levels in platelets.
Prostaglandin e2‐hemoglobin AA and SS erythrocyte interaction (prostaglandin‐erythrocyte interaction)
Authors: Sobota Joseph T. , Gruber Carolyn A. , Gilbertson Terry J. , Wilson Jerome
Published: February 2007

Prostaglandin E2 (PGE2), at concentrations ≥ 5 × 104 ng/ml, induced discocyte → echinocyte transformation of saline‐suspended hemoglobin (Hb) AA and SS erythrocytes. This erythrocyte transformation is concentration‐dependent and is reversible at room temperature after 90–120 min. The Hb SS erythrocytes treated with PGE2 did not exhibit accelerated sickling or increased formation of sickled echinocvtes. Erythrocytes suspended in autologous plasma treated with PGE2, 2 × 106 ng/ml, did not exhibit echinocytic transformation probably because of drug binding to the plasma proteins. Other in vitro studies showed that PGE2 of concentrations of 10–500 ng/ml had no adverse effects on intact, plasma‐suspended Hb SS erythrocytes. These Hb SS erythrocytes were examined for changes in morphology, potassium and calcium flux, and blood viscosity under oxygenated and hypoxic conditions.