bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasminogen Activator Inhibitor-1 Gene
Authors: Su Shaoyong , Chen Shufeng , Zhao Jiangong , Huang Jianfeng , Wang Xiaoling , Chen Runsheng , Gu Dongfeng
Published: January 2006

Objective—

To explore the effect of plasminogen activator inhibitor-1 (
PAI-1
) gene variations on the risk of coronary heart disease (CHD) in Chinese Han population.

Methods and Results—

We screened all exons and the promoter region of
PAI-1
gene in 48 patients and identified 17 polymorphisms. Five tagging single nucleotide polymorphisms were selected and genotyped in 816 patients with CHD and 937 controls. In the total sample, no main effects of the loci or haplotypes reached statistical significance after adjusting environmental covariates. However, a strongly significant gene–smoking interaction was observed. Among nonsmokers, 2 polymorphisms located at promoter region (rs2227631 and rs1799889) showed significant association with CHD. The cases had higher frequency of rs2227631 A allele and rs1799889 4G allele than the controls (0.42 versus 0.33,
P
=0.001; 0.60 versus 0.52,
P
=0.002). Haplotype analyses confirmed the effects of the
PAI-1
gene–smoking interaction on CHD risk. Compared with the most common haplotype G-5G-A-A-T (35.1%), the haplotype A-4G-A-A-C (32.7%) significantly increased the risk of CHD with adjusted odds ratio of 1.51 (95% CI, 1.12 to 2.05;
P
=0.008) in nonsmokers.

Conclusion—

This study identified a significant interaction between
PAI-1
gene and smoking status. Both single locus and haplotype analyses indicated that rs2227631 A allele and rs1799889 4G allele increased the risk of CHD among nonsmokers in Chinese.
Neurogenic Mechanisms Contribute to Hypertension in Mice With Disruption of the K-Cl Cotransporter KCC3
Authors: Rust Marco B. , Faulhaber Jörg , Budack Mareike K. , Pfeffer Carsten , Maritzen Tanja , Didié Michael , Beck Franz-Xaver , Boettger Thomas , Schubert Rudolf , Ehmke Heimo , Jentsch Thomas J. , Hübner Christian A.
Published: January 2006

The neurodegenerative disorder Andermann syndrome is caused by mutations of the K-Cl cotransporter KCC3. Mice with a targeted disruption of the corresponding gene,
Slc12a6
, reproduce neurodegeneration of the peripheral and central nervous system (CNS) and display arterial hypertension.
Kcc3
is expressed in numerous tissues, including the CNS and vascular smooth muscle cells. As the intracellular chloride concentration may influence myogenic tone and hence blood pressure, we measured the chloride concentration in vascular smooth muscle cells. It was indeed increased in superficial brain arteries and saphenous arteries of
Kcc3
−/−
mice. Isolated saphenous arteries and their third-order branches, however, reacted indistinguishably to changes in intravascular pressure, stimulation of α
1
-adrenoreceptors, exogenous nitric oxide, or blockade of calcium-activated chloride channels. Likewise, the responses to α
1
-adrenergic stimulation or exogenous nitric oxide in vivo were identical in both genotypes. These results argue against a major vascular-intrinsic component of arterial hypertension in
Kcc3
−/−
mice. In contrast, either α
1
-adrenergic blockade or inhibition of ganglionic transmission abolished the difference in arterial blood pressure between both genotypes. This demonstrates a neurogenic component in the maintenance of this phenotype, which is further supported by an increase of urinary norepinephrine and epinephrine excretion in
Kcc3
−/−
mice. Our data indicate that local control of myogenic tone does not require KCC3 and that hypertension in
Kcc3
−/−
mice depends on an elevated sympathetic tone.
Interleukin 12 Induces T-Cell Recruitment Into the Atherosclerotic Plaque
Authors: Zhang Xiaoyu , Niessner Alexander , Nakajima Takako , Ma-Krupa Wei , Kopecky Stephen L. , Frye Robert L. , Goronzy Jörg J. , Weyand Cornelia M.
Published: January 2006

CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of CD4
+
CD28
−
T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that CD4
+
CD28
−
T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. CD4
+
CD28
−
IL-12R
+
cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of CD4
+
CD28
−
T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of CD4
+
CD28
−
T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated CD4
+
CD28
−
T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, CD4
+
CD28
−
T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12–inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions.
High Basal Protein Kinase A–Dependent Phosphorylation Drives Rhythmic Internal Ca
2+
Store Oscillations and Spontaneous Beating of Cardiac Pacemaker Cells
Authors: Vinogradova Tatiana M. , Lyashkov Alexey E. , Zhu Weizhong , Ruknudin Abdul M. , Sirenko Syevda , Yang Dongmei , Deo Shekhar , Barlow Matthew , Johnson Shavsha , Caffrey James L. , Zhou Ying-Ying , Xiao Rui-Ping , Cheng Heping , Stern Michael D. , Maltsev Victor A. , Lakatta Edward G.
Published: January 2006

Local, rhythmic, subsarcolemmal Ca
2+
releases (LCRs) from the sarcoplasmic reticulum (SR) during diastolic depolarization in sinoatrial nodal cells (SANC) occur even in the basal state and activate an inward Na
+
-Ca
2+
exchanger current that affects spontaneous beating. Why SANC can generate spontaneous LCRs under basal conditions, whereas ventricular cells cannot, has not previously been explained. Here we show that a high basal cAMP level of isolated rabbit SANC and its attendant increase in protein kinase A (PKA)-dependent phosphorylation are obligatory for the occurrence of spontaneous, basal LCRs and for spontaneous beating. Gradations in basal PKA activity, indexed by gradations in phospholamban phosphorylation effected by a specific PKA inhibitory peptide were highly correlated with concomitant gradations in LCR spatiotemporal synchronization and phase, as well as beating rate. Higher levels of basal PKA inhibition abolish LCRs and spontaneous beating ceases. Stimulation of β-adrenergic receptors extends the range of PKA-dependent control of LCRs and beating rate beyond that in the basal state. The link between SR Ca
2+
cycling and beating rate is also present in vivo, as the regulation of beating rate by local β-adrenergic receptor stimulation of the sinoatrial node in intact dogs is markedly blunted when SR Ca
2+
cycling is disrupted by ryanodine. Thus, PKA-dependent phosphorylation of proteins that regulate cell Ca
2+
balance and spontaneous SR Ca
2+
cycling, ie, phospholamban and L-type Ca
2+
channels (and likely others not measured in this study), controls the phase and size of LCRs and the resultant Na
+
-Ca
2+
exchanger current and is crucial for both basal and reserve cardiac pacemaker function.
Stroke Onset Time Using Sodium MRI in Rat Focal Cerebral Ischemia
Authors: Jones Stephen C. , Kharlamov Alexander , Yanovski Boris , Kim D. Kyle , Easley Kirk A. , Yushmanov Victor E. , Ziolko Scott K. , Boada Fernando E.
Published: January 2006

Background and Purpose—

Thrombolytic therapy with intravenous tPA must be administered within 3 hours after stroke onset. However, stroke onset time cannot be established in 20% to 45% of potential patients. We propose that the rate of increase of the brain concentration of sodium ([Na
+
]
br
) after stroke, monitored using sodium MRI in a rat model of cortical ischemia, is linear in each individual animal, can locate the ischemic region, and can be used to estimate onset time.

Methods—

After induction of focal cortical ischemia in rats under isoflurane anesthesia, [Na
+
]
br
time course maps were acquired continuously on a 3 T whole body scanner from 2 to 7 hours after occlusion followed by T2-weighted proton images. Microtubule-associated protein-2 immunostained brain sections were used to verify the location of the infarct.

Results—

The ischemic region identified with microtubule-associated protein-2 corresponded to the region of maximum [Na
+
]
br
increase (
P
<0.001; n=5), and all of the animals demonstrated high linearity. [Na
+
]
br
increased at a mean rate of 25±4.7%/h in ischemic tissue (
P
=0.013) but not in normal cortex (1.0±1.1%/h;
P
=0.42). The mean onset time error was 1±4 minutes (n=4).

Conclusions—

These results of sodium MRI show that the region of maximum [Na
+
]
br
increase corresponds to the ischemic region. Although [Na
+
]
br
increases at a different rate in each animal, the increase is linear, and, therefore, onset time can be estimated. These findings suggest that this method can be used as a ticking clock to estimate time elapsed after vascular occlusion.
Greater Incidence of Both Fatal and Nonfatal Strokes in Disadvantaged Areas
Authors: Thrift Amanda G. , Dewey Helen M. , Sturm Jonathan W. , Paul Seana L. , Gilligan Amanda K. , Srikanth Velandai K. , Macdonell Richard A.L. , McNeil John J. , Macleod Malcolm R. , Donnan Geoffrey A.
Published: January 2006

Background and Purpose—

Greater stroke mortality has been reported among lower socioeconomic groups. We aimed to determine whether fatal, nonfatal, and overall stroke incidence varied by socioeconomic status.

Methods—

All suspected strokes occurring in 22 postcodes (population of 306 631) of Melbourne, Australia, during a 24-month period between 1997 and 1999 were found and assessed. Multiple overlapping sources were used to ascertain cases with standard clinical definitions for stroke. Socioeconomic disadvantage was assigned in 4 bands from least to greatest using an area-based measure developed by the Australian Bureau of Statistics.

Results—

Overall stroke incidence (number per 100 000 population per year), adjusted to the European population 45 to 84 years of age, increased with increasing socioeconomic disadvantage: 200 (95% CI, 173 to 228); 251 (95% CI, 220 to 282); 309 (95% CI, 274 to 343); and 366 (95% CI, 329 to 403; χ
2
for ranks;
P
<0.0001). Similar incidence patterns were observed for both fatal and nonfatal stroke. Nonfatal stroke contributed most to this incidence pattern: 146 (95% CI, 122 to 169); 181 (95% CI, 155 to 207); 223 (95% CI, 194 to 252); and 280 (95% CI, 247 to 313; χ
2
for ranks;
P
<0.0001).

Conclusions—

In this population-based study, both fatal and nonfatal stroke incidence increased with increasing socioeconomic disadvantage. The greater contributor to this incidence pattern was nonfatal stroke incidence. This may have implications for service provision to those least able to afford it. Area-based identification of those most disadvantaged may provide a simple and effective way of targeting regions for stroke prevention strategies.
A Pilot Study of a New Thrombolytic Agent for Acute Ischemic Stroke in Taiwan Within A Five-Hour Window
Authors: Hu Han-Hwa , Teng Michael Mu-Huo , Hsu Li-Chi , Wong Wen-Jang , Wang Lee-Min , Luk Yun-On , Chern Chang-Ming , Soong Bing-Wen , Sheng Wen-Yung
Published: January 2006

Background and Purpose—

This study was the first clinical trial in Taiwan of a new thrombolytic agent human tissue urokinase type plasminogen activator (HTUPA) in patients with acute ischemic stroke.

Methods—

Patients were treated with a single bolus intravenous HTUPA under an open-label dose escalation design within 5 hours after symptom onset. Safety outcomes were assessed by symptomatic and asymptomatic intracerebral hemorrhage (ICH) as well as other bleeding episodes. Preliminary efficacy was measured by National Institutes of Health Stroke Scale (NIHSS).

Results—

Three doses of HTUPA (0.3 mg/kg, 0.35 mg/kg, and 0.4 mg/kg) were administered to 33 patients, with the majority of patients (n=29) receiving 0.3 mg/kg. Two cases of fatal ICH occurred: 1 in the patient who received 0.4 mg/kg and the other in the 0.3 mg/kg group. Asymptomatic ICH occurred in 6 patients. Other treatment-related serious adverse events were ecchymosis, hematuria, and upper gastrointestinal bleeding, which were completely recovered. At day 90, in patients treated with 0.3 mg/kg within a 0- to 5-hour window, 34% reached NIHSS scores 0 to 1, whereas of those treated within 0 to 3 hours, 86% reached this score.

Conclusion—

Intravenous HTUPA, given at 0.3 mg/kg as a bolus injection within 5 hours after symptom onset, had an acceptable safety and efficacious profile in patients with acute ischemic stroke.
SERPINA3
Polymorphism Is Not Associated With Primary Intracerebral Hemorrhage in a Polish Population
Authors: Pera Joanna , Slowik Agnieszka , Dziedzic Tomasz , Szczudlik Andrzej
Published: January 2006

Background and Purpose—

Genetic factors involved in the pathogenesis of primary intracerebral hemorrhage (PICH) remain unknown. One of the candidate genes is
SERPINA3
. Results of a Spanish study suggested that TT genotype of the A/T
SERPINA3
polymorphism in the signal peptide sequence was a risk factor for PICH in normotensive subjects. The aim of the present study was to investigate whether
SERPINA3
A/T polymorphism is associated with PICH in a Polish population.

Methods—

We analyzed 95 PICH patients and 190 unrelated healthy controls matched for age and sex. A/T polymorphism of the
SERPINA3
gene was investigated using polymerase chain reaction restriction fragment length polymorphism method.

Results—

The distribution of
SERPINA3
genotypes was similar among PICH patients (AA 27.4%; AT 46.3%; TT 26.3%) and controls (AA 23.7%; AT 50.5%; TT 25.8%;
P
=NS). There were also no significant differences in genotype distribution when analyzing separately hypertensive and normotensive PICH patients as well as patients with lobar and deeply located hemorrhage.

Conclusions—

We failed to find an association between
SERPINA3
A/T polymorphism and PICH in a Polish population.
Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis
Authors: Schranzhofer Matthias , Schifrer Manfred , Cabrera Javier Antonio , Kopp Stephan , Chiba Peter , Beug Hartmut , Müllner Ernst W.
Published: January 2006

Terminal erythropoiesis is accompanied by extreme demand for iron to ensure proper hemoglobinization. Thus, erythroblasts must modify the “standard” post-transcriptional feedback regulation, balancing expression of ferritin (Fer; iron storage) versus transferrin receptor (TfR1; iron uptake) via specific mRNA binding of iron regulatory proteins (IRPs). Although erythroid differentiation involves high levels of incoming iron, TfR1 mRNA stability must be sustained and Fer mRNA translation must not be activated because iron storage would counteract hemoglobinization. Furthermore, translation of the erythroid-specific form of aminolevulinic acid synthase (ALAS-E) mRNA, catalyzing the first step of heme biosynthesis and regulated similarly as Fer mRNA by IRPs, must be ensured. We addressed these questions using mass cultures of primary murine erythroid progenitors from fetal liver, either undergoing sustained proliferation or highly synchronous differentiation. We indeed observed strong inhibition of Fer mRNA translation and efficient ALAS-E mRNA translation in differentiating erythroblasts. Moreover, in contrast to self-renewing cells, TfR1 stability and IRP mRNA binding were no longer modulated by iron supply. These and additional data stemming from inhibition of heme synthesis with succinylacetone or from iron overload suggest that highly efficient utilization of iron in mitochondrial heme synthesis during normal erythropoiesis alters the regulation of iron metabolism via the IRE/IRP system.
Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas
Authors: Tam Wayne , Gomez Mario , Chadburn Amy , Lee Joong W. , Chan Wing C. , Knowles Daniel M.
Published: January 2006

The PR (PRDI-BF1-RIZ) domain zinc finger protein 1 (PRDM1) is a transcription repressor with a pivotal role in plasma-cell differentiation. We identified clonal inactivating mutations in PRDM1 in the diffuse large B-cell lymphoma (DLBCL) cell line OCI-Ly3 and in 8 of 35 de novo clinical DLBCL samples. The mutational spectrum consists predominantly (7 cases) of single-nucleotide mutations affecting consensus splice donor sites, some of which are recurrent, that lead to splicing aberrations and premature translation termination. In 2 of these cases, point mutations appear to be caused by RNA editing with G-to-A and U-to-G conversions. Other mutations include frame-shift deletion and chromosomal inversion. Except for one mutant, which may act as a dominant-negative, all mutations are associated with either deletion or silencing of the paired PRDM1 allele. This study identifies PRDM1 inactivation as a recurrent genetic defect in DLBCL cells and establishes PRDM1 as a potential tumor suppressor gene in DLBCL. Moreover, it implies inhibition of terminal differentiation as a pathogenetic pathway in DLBCL, particularly for the activated B-cell–like DLBCL. It also demonstrates for the first time the potential role of RNA editing in lymphomagenesis.
Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma
Authors: Goel Apollina , Dispenzieri Angela , Geyer Susan M. , Greiner Suzanne , Peng Kah-Whye , Russell Stephen J.
Published: January 2006

Multiple myeloma is a highly radiosensitive skeletal malignancy, but bone-seeking radionuclides have not yet found their place in disease management. We previously reported that the proteasome inhibitor PS-341 selectively sensitizes myeloma cells to the lethal effects of ionizing radiation. To extend these observations to an in vivo model, we combined PS-341 with the bone-seeking radionuclide 153-Sm-EDTMP. In vitro clonogenic assays demonstrated synergistic killing of myeloma cells exposed to both PS-341 and 153-Sm-EDTMP. Using the orthotopic, syngeneic 5TGM1 myeloma model, the median survivals of mice treated with saline, 2 doses of PS-341 (0.5 mg/kg), or a single nonmyeloablative dose of 153-Sm-EDTMP (22.5 MBq) were 21, 22, and 28 days, respectively. In contrast, mice treated with combination therapy comprising 2 doses of PS-341 (0.5 mg/kg), 1 day prior to and 1 day following 153-Sm-EDTMP (22.5 MBq) showed a significantly prolonged median survival of 49 days (P < .001). In addition to prolonged survival, this treatment combination yielded reduced clonogenicity of bone marrow–resident 5TGM1 cells, reduced serum myeloma–associated paraprotein levels, and better preservation of bone mineral density. Myelosuppression, determined by peripheral blood cell counts and clonogenicity assays of hematopoietic progenitors, did not differ between animals treated with 153-Sm-EDTMP alone versus those treated with the combination of PS-341 plus 153-Sm-EDTMP. PS-341 is a potent, selective in vivo radiosensitizer that may substantially affect the efficacy of skeletal-targeted radiotherapy in multiple myeloma.
Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Münster) Multicenter Trial
Authors: Oschlies Ilske , Klapper Wolfram , Zimmermann Martin , Krams Matthias , Wacker Hans-Heinrich , Burkhardt Birgit , Harder Lana , Siebert Reiner , Reiter Alfred , Parwaresch Reza
Published: January 2006

Diffuse large B-cell lymphoma (DLBCL) in adults is a heterogeneous disease. Biologic subgroups of DLBCL with a favorable prognosis (germinal center B-cell–like, GCB) and with a poor prognosis (activated B-cell–like, ABC) have been defined by gene expression profiling and can be distinguished by immunohistochemistry. In contrast to their adult counterparts, children with DLBCL have an excellent prognosis. We analyzed 63 cases of DLBCL in pediatric patients by immunohistochemistry and fluorescence in situ hybridization (FISH) and found a striking predominance of a GCB subtype, which might explain the good clinical outcome in these lymphomas. Interestingly, FISH applied to 50 of these cases, as well as conventional cytogenetics available in 3 cases, revealed absence of the translocation t(14;18) involving the BCL2 gene, which is present in about 15% of adult GCB subtype DLBCL. Our data indicate that pediatric DLBCL differs from adult DLBCL and might comprise a biologically unique subgroup of DLBCL from which important insights into the pathogenesis and biology of this disease might be gained.
A Multistep Kinase-Based Sertoli Cell Autocrine-Amplifying Loop Regulates Prostaglandins, Their Receptors, and Cytokines
Authors: Ishikawa Tomomoto , Morris Patricia L.
Published: January 2006

In Sertoli epithelial cells, the IL-1β induces prostaglandins (PG) PGE2, PGF2α and PGI2 (7-, 11-, and 2-fold, respectively), but not PGD2, production. Cyclohexamide pretreatment inhibiting protein synthesis prevents IL-1β increases in PG levels, indicating that induction requires de novo protein synthesis. IL-1β-regulated PGE2 and PGF2α production and cytokine expression require activation of cyclooxygenase-2 (COX-2) and c-Jun NH2-terminal kinase, as shown using specific enzyme inhibition. PGE2 and PGF2α stimulate expression of IL-1α, -1β, and -6, findings consistent with PG involvement in IL signaling within the seminiferous tubule. PGE2 and PGF2α reverse COX-2-mediated inhibition of IL-1β induction of cytokine expression and PG production. Sertoli PG receptor expression was determined; four known E-prostanoid receptor (EP) subtypes (1–4) and the F-prostanoid and prostacyclin prostanoid receptors were demonstrated using RNA and protein analyses. Pharmacological characterization of Sertoli PG receptors associated with cytokine regulation was ascertained by quantitative real-time RT-PCR analyses. IL-1β regulates both EP2 mRNA and protein levels, data consistent with a regulatory feedback loop. Butaprost (EP2 agonist) and 11-deoxy PGE1 (EP2 and EP4 agonist) treatments show that EP2 receptor activation stimulates Sertoli cytokine expression. Consistent with EP2-cAMP signaling, protein kinase A inhibition blocks both IL-1β- and PGE2-induced cytokines. Together, the data indicate an autocrine-amplifying loop involving IL-1β-regulated Sertoli function mediated by COX-2-induced PGE2 and PGF2α production. PGE2 activates EP2 and/or EP4 receptor(s) and the protein kinase A-cAMP pathway; PGF2α activates F-prostanoid receptor-protein kinase C signaling. Further identification of the molecular mechanisms subserving these mediators may offer new insights into physiological events as well as proinflammatory-mediated pathogenesis in the testis.
Ramifications of the 1918 Turkana Patrol: Narratives by Ngturkana
Authors: Lokuruka Michael N. I. , Lokuruka Pauline A.
Published: January 2006

The original wave of Turkana immigrants from southwestern Sudan coalesced over time—through intermarriage with earlier inhabitants of Turkan (Turkana country) and with other nomadic pastoralists in Kenya, Ethiopia, Uganda, and Sudan—to grow into Ngturkana (the Turkana community). Competition over resources for livestock husbandry contributed to cattle rustling between Ngturkana and their nomadic pastoralist neighbors. The punitive raids of 1901, 1913, 1915, and 1917-18 by the British led to the exodus of Ngturkana to other districts of Kenya and to Karimojong in Uganda. Currently, more than 60 percent of Ngturkana in Kenya live outside Turkan, while increasing numbers of other migrants enter the district, with the latest entrants being refugees from more than eight other African countries. The immigration is beginning to disastrously alter the arid environment and the sociopolitical life of the Turkana nomads. This is likely to reduce the Ngturkana's capacity to survive in their homeland and/or introduce and hasten their embrace of other survival strategies, similar to the situation exacerbated by the British raids in the early twentieth century.
The People of the Five “Drums”: Gabra Ethnohistorical Origins
Authors: Kassam Aneesa
Published: January 2006

The “ethnic” origins of the Gabra camel pastoralists who live on the Kenyan-Ethiopian border and their relationship to the territorially adjacent Borana cattle pastoralists are matters of ongoing academic debate. This article, which is based on Gabra clan traditions, suggests that the five phratries are an aggregate of some of the communities that live in the Lake Turkana region and beyond it. It describes the precolonial relationship of the Gabra and Borana, which is expressed by the latter in the idiom of kinship as a territorial one.
A Brief History of Research at Koobi Fora, Northern Kenya
Authors: Harris John M. , Leakey Meave G. , Brown Francis H.
Published: January 2006

Lake Turkana itself is a geologically recent phenomenon, but what is now the Lake Turkana basin has an archaeological record that stretches back 2.5 million years and a paleontological record that extends back to the Cretaceous Period. Vertebrate fossils were first discovered in the lower Omo Valley at the beginning of the twentieth century, but the first multidisciplinary international expedition to investigate the region was that of the International Omo Research Expedition in 1967. The National Museums of Kenya participated in the first IORE but thereafter mounted their own multinational and multidisciplinary expeditions to the Kenyan part of the Lake Turkana basin. The Koobi Fora sand spit on the east side of the lake served as the National Museums' field headquarters for the Koobi Fora Research Project on that side of the lake, the subsequent West Turkana Project, more recent fieldwork at Lothagam and Kanapoi, and ongoing field research today. The fossils and artifacts recovered from the Lake Turkana basin have contributed much to our current understanding of early human origins.
Lake Turkana Archaeology: The Holocene
Authors: Robbins Lawrence H.
Published: January 2006

Pioneering research in the Holocene archaeology of Lake Turkana contributed significantly to the development of broader issues in the prehistory of Africa, including the aquatic civilization model and the initial spread of domesticated livestock in East Africa. These topics are reviewed following retrospective discussion of the nature of pioneering fieldwork carried out in the area in the 1960s. The early research at Lake Turkana uncovered the oldest pottery in East Africa as well as large numbers of bone harpoons similar to those found along the Nile Valley and elsewhere in Africa. The Lake Turkana area remains one of the major building blocks in the interpretation of the later prehistory of Africa as a whole, just as it is a key area for understanding the early phases of human evolution.
Poetics and Politics of Estrangement: Victor Shklovsky and Hannah Arendt
Authors: Boym Svetlana
Published: January 2006

This essay proposes to place the poetics of Russian Formalism within a broader European context of literary, philosophical, and political reflection on modernity. The historical metamorphosis of estrangement from a technique of art to an existential art of survival and a practice of freedom and dissent is traced here through Victor Shklovsky's experimental autobiographical texts of the 1920s and their critical reception. In this analysis, estrangement is not regarded as an escape from the political; instead, it helps us think anew the relationship between aesthetic and political practices in Stalin's time. Shklovsky's writing on estrangement and freedom is read together with Hannah Arendt's reflections on distance, freedom, and the banality of evil.
Minding the Gap: Toward a Historical Poetics of Estrangement
Authors: Holquist Michael , Kliger Ilya
Published: January 2006

Under different names, alienation has been around for a long time. However, Immanuel Kant's Copernican revolution marks a new and deeper degree of alienation. Kant's definition of the subject—denied contact with the world as such and forced constantly to synthesize the immediacy of intuitions with the lawfulness of concepts—is a hopelessly riven “I-think.” Reading Kant was a traumatic event for contemporaries, especially for philosophers, who attempted to make the world whole again by formulating new versions of absolute unity. It was Wilhelm von Humboldt who theorized a way both to accept the gap in Kantian epistemology and, at least partially—through language understood as inner speech—to overcome the gap. Reacting to later appropriations of von Humboldt, Russian linguists and such literary theorists as Victor Shklovsky, Roman Jakobson, Sergej Karcevskij, and Mikhail Bakhtin explored the complexity of alienation in language and offered proposals for negotiating it in different versions of literariness.
Shklovsky'sostranenie, Bakhtin'svnenakhodimost'(How Distance Serves an Aesthetics of Arousal Differently from an Aesthetics Based on Pain)
Authors: Emerson Caryl
Published: January 2006

As literary critics and language theorists, Viktor Shklovsky and Mikhail Bakhtin each utilize “aesthetic distance” in an unconventional way—unrelated, it would seem, to the usual aesthetic criteria of beauty, goodness, or truth. For the Formalist Shklovsky, the distancing or estrangement of an object sharpens our perception and stimulates our senses, thereby arousing us to artistic (as opposed to drably everyday) experience. For the dialogic Bakhtin, the mandate to “be outside” that which you create is a matter of subject-subject relations, not subject-object. This essay considers only one aspect of this intersection: the role of pain (the hurting body as the norm) in these two aesthetic economies, Shklovsky's and Bakhtin's.
The Politics of Estrangement: The Case of the Early Shklovsky
Authors: Tihanov Galin
Published: January 2006

I discuss here Shklovsky's theory of estrangement as formulated in a number of texts written before the October revolution of 1917. The concept of estrangement can only be properly grasped if the early Shklovsky is placed in the context of World War I; we need to begin to see him as an author shaped by that war and as a participant in the larger constellation of brilliant European essayists who responded to this momentous event. To this end, the article draws parallels between his writings and those of Ernst Jünger and Georg Simmel. More importantly, it uncovers the conservative aspects of Shklovsky's theory of estrangement and analyzes his contradictory attitudes toward democracy and modernization. The final section traces the fortunes of Shklovsky's concept of estrangement at the hands of its most significant critics, Bertolt Brecht and Herbert Marcuse.
Why the First-Wave Russian Literary Diaspora Embraced Shklovskian Estrangement
Authors: Slobin Greta N.
Published: January 2006

This essay explores the implications of Victor Shklovsky's concept of estrangement as it extends to the experience of Russian writers in exile, following the October revolution. The discussion, informed by diaspora theory, begins with Shklovsky's stay in Berlin in 1922–23, when border crossings were still possible. He argued for literature's independence from politics. The dynamics of diasporic literary life and its evolving “articulations of identity” are considered in the context of Soviet literary politics. The semantic unfolding of estrangement and its “historical metamorphoses” emerge in the work of two émigré writers. Aleksei Remizov relied on estrangement in linguistic and genre experiments in exile that encompass historical changes in the Russian language at home and abroad. The poet Vladislav Khodasevich argued for the creative continuity of Russian literature in exile, citing past models, from Dante to the Hebrew Poetic Renaissance in the Russian empire at the turn of the twentieth century.
Dostoevsky's Estrangement
Authors: Ruttenburg Nancy
Published: January 2006

During the transitional period between the early works of the late 1840s and production of the “great novels” in the mid-1860s, Dostoevsky confronted the problem of the Russian common people with particular urgency and immediacy. The consolations of the social theories which underlay his earlier political activism—and for which he suffered a decade of Siberian exile, spent partly in a hard-labor camp— withered in the face of actual, enforced contact with the common class. Upon his return to the capital on the eve of peasant emancipation in 1861, Dostoevsky staked the resurrection of his authorial career on his insistence that an abyss divided common and elite cultures which would bedevil elite attempts to represent the Russian common people as objects of literary and journalistic inquiry. At a moment when intellectuals and other urban elites struggled to prepare bureaucratically and imaginatively for a liberated peasantry, estrangement became the cornerstone of Dostoevsky's aesthetic practice. Instead of rendering a naturalistic portrait of the common people enhanced by the pathos of a firsthand knowledge bought dear, Dostoevsky traces in his fictionalized account of his prison experience, Notes from the House of the Dead, a peculiar disintegration of the narrating consciousness for whom estrangement emerges as the condition by which the peasant-other can be known and the limitations of knowing acknowledged and suffered. This article explores the genesis in fictionalized autobiography of the Dostoevskian narrator familiar to readers of thegreat novels, a narrator who dismantles the very structure of knowing and telling, a would-be guide to the text's action who becomes mired in a confession of what he does not understand.
The Changing Process and Politics of Health Policy in Korea
Authors: Kwon Soonman , Reich Michael R.
Published: January 2006

Korea recently introduced three major health care reforms: in financing (1999), pharmaceuticals (2000), and provider payment (2001). In these three reforms, new government policies merged more than 350 health insurance societies into a single payer, separated drug prescribing by physicians from dispensing by pharmacists, and attempted to introduce a new prospective payment system. This essay compares the three reforms in Korea and draws important lessons about the country's changing process and politics of health care policy. The change of government, the president's keen interest in health policy, and democratization in the public policy process toward a more pluralist context opened a policy window for reform. Civic groups played an active role in the policy process by shaping the proposals for reform—a major change from the previous policy process that was dominated by government bureaucrats. The three reforms also showed important differences in the role of interest groups. Strong support by the rural population and labor unions contributed to the financing reform. In the pharmaceutical reform, which was a big threat to physician income, the president and civic groups succeeded in quickly setting the reform agenda; the medical profession was unable to block the adoption of the reform but their strikes infl uenced the content of the reform during implementation. Physician strikes also helped block the implementation of the payment reform. Future reform efforts in Korea will need to consider the political management of vested interest groups and the design of strategies for both scope and sequencing of policy reforms.
The Norwegian Hospital Reform: Balancing Political Control and Enterprise Autonomy
Authors: Lægreid Per , Opedal Ståle , Stigen Inger Marie
Published: January 2006

This essay focuses on the balance between governmental control and enterprise autonomy by examining the Norwegian hospital reform. We describe the enterprise model and give a description of the policy instruments that the government, as owner, has for exercising power and control vis-à-vis the health enterprises. How the trade-off between autonomy and control is experienced and practiced is analyzed from an instrumental, an institutional, and an environmental perspective. The database comprises a survey collected from health enterprise executives and illustrative cases. The trade-off can be characterized as ambiguous and unstable and we ask whether it is possible to achieve a strategy to more appropriately balance the goals of control and autonomy.
Why Some Market Reforms Lack Legitimacy in Health Care
Authors: Laugesen Miriam
Published: January 2006

Market-oriented health policy reforms in the 1980s and 1990s generally included five kinds of proposals: increased cost sharing for patients through user fees, the separation of purchaser-provider functions, management reforms of hospitals, provider competition, and vouchers for purchasing health insurance. These policies are partly derived from agency theory and a model of managed competition in health insurance. The essay reviews the course of reform in five countries that had a national health service model in place in the late 1980s: Italy, New Zealand, Spain, Sweden, and the United Kingdom. Special consideration is given to New Zealand, where the market model was extensively adopted but short lived. In New Zealand, surveys and polls are compared to archival records of reformers' deliberations. Voters saw health care differently from elites, and voters particularly felt that health care was ill suited to commercialization. There are similarities across all five countries in what has been adopted and rejected. Some market reforms are more legitimate than others. Reforms based on resolving principal-agent problems, including purchaser-provider splits and managerial reforms, have been more successful, although cost sharing has not. Competition-based reforms in financing and to a lesser extent in provision have not gained legitimacy. Most voters in these countries see health care as different from other parts of the economy and view managerial reforms differently from policies that try to make health care more like other sectors.
State Social Capital and Individual Health Status
Authors: Mellor Jennifer M. , Milyo Jeffrey
Published: January 2006

Recent studies have found that two state-level measures of social capital, average levels of civic participation and trust, are associated with improvements in individual health status. In this study we employ these measures, together with the Putnam index of state social capital, to examine several key aspects of the relationship between state social capital and individual health. We find that for all three measures, the association with health status persists after carefully adjusting for household income and that for two measures, mistrust and the Putnam index, the size of this association warrants further attention. Using the Putnam index, we find particular support for the hypothesis that social capital has a more pronounced salutary effect for the poor. Our findings generate both support for the social capital and health hypothesis and a number of implications for future research.
Can Education Policy Be Health Policy? Implications of Research on the Social Determinants of Health
Authors: Low M. David , Low Barbara J. , Baumler Elizabeth R. , Huynh Phuong T.
Published: January 2006

Research on the social determinants of health has demonstrated robust correlations between several social factors, health status, and life expectancy. Some of these factors could be modified through policy intervention. National-level public policies explicitly based on population health research are in various stages of development in many Western countries, but in spite of evident need, seemingly not at all in the United States. Because research shows such a strong association between education and good health, we offer evidence to show that at least two pressing problems in American society, namely the uneven distribution of educational attainment and health disparities linked to socioeconomic position, may be ameliorated through policy initiatives that link quality early childhood care, child development programs, and parental training in a seamless continuum with strengthened K–12 education.
Structure of a self-splicing group II intron catalytic effector domain 5: Parallels with spliceosomal U6 RNA
Authors: SEETHARAMAN MAHADEVAN , ELDHO NADUKKUDY V. , PADGETT RICHARD A. , DAYIE KWAKU T.
Published: January 2006

Domain 5 (D5) is absolutely required for all catalytic functions of group II introns. Here we describe the solution NMR structure, electrostatic calculations, and detailed magnesium ion-binding surface of D5 RNA from the Pylaiella littoralis large ribosomal RNA intron (D5-PL). The overall structure consists of a hairpin capped by a GNRA tetraloop. The stem is divided into lower and upper helices of 8 and 5 bp, respectively, separated by an internal bulge. The D5-PL internal bulge nucleotides stack into the helical junction, resulting in a coupling between the bulge A25 and the closing base pair (G8–C27) of the lower helix. Comparison of the D5-PL structure to previously reported related structures indicates that our structure is most similar, in the helical regions, to the crystal structure of D5 from yeast Ai5γ (D5-Ai5γ) and the NMR structure of the U6 snRNA stem–loop region. Our structure differs in many respects from both the NMR and X-ray structures of D5-Ai5γ in the bulge region. Electrostatic calculations and NMR chemical shift perturbation analyses reveal magnesium ion-binding sites in the tetraloop, internal bulge, and the AGC triad in the lower stem. Our results suggest that the structure, electrostatic environment, and the magnesium ion-binding sites within the tetraloop, bulge, and triad regions are conserved features of the splicing machinery of both the group II introns and the spliceosome that are likely key for catalytic function.
Biological Determinants of and Reference Values for Plasma Interleukin-8, Monocyte Chemoattractant Protein-1, Epidermal Growth Factor, and Vascular Endothelial Growth Factor: Results from the STANISLAS Cohort
Authors: Berrahmoune Hind , Lamont John V , Herbeth Bernard , FitzGerald Peter S , Visvikis-Siest Sophie
Published: January 2006

Background: Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) are known to be involved in various diseases related to inflammation, vascular remodeling, or growth deregulation. In addition, increases in plasma concentrations of these cytokines appear to provide useful diagnostic and prognostic information. We therefore investigated which factors most strongly influence the biological variations of plasma IL-8, MCP-1, EGF, and VEGF concentrations.

Methods: We used the Evidence® biochip array analyzer to quantify plasma IL-8, MCP-1, EGF, and VEGF concentrations in a subsample of 304 children (age range, 4–17 years) and 540 adults (age range, 18–55 years) from the STANISLAS family study. We also calculated reference intervals for the 4 cytokines.

Results: We found the following associations with plasma marker concentrations: Age, neutrophil count, and glucose concentration were positively associated with IL-8 concentrations in children and adults, as were smoking and platelet count in adults. MCP-1 concentrations were associated with age and smoking in both children and adults, monocyte count in children, and sex and hematocrit in adults. EGF concentrations were associated with platelet count in children and monocyte count and glucose in adults. VEGF concentrations were associated with age in children and adults and platelet count and alanine aminotransferase activity in adults.

Conclusion: Our results for IL-8, MCP-1, EGF, and VEGF may be useful for interpretation of patients’ laboratory results and for understanding the regulation of concentrations of these cytokines in physiologic conditions.
Adipocyte Fatty Acid–Binding Protein Is a Plasma Biomarker Closely Associated with Obesity and Metabolic Syndrome
Authors: Xu Aimin , Wang Yu , Xu Jian Yu , Stejskal David , Tam Sidney , Zhang Jialiang , Wat Nelson MS , Wong Wai Keung , Lam Karen SL
Published: January 2006

Background: Adipocyte fatty acid–binding protein (A-FABP) is traditionally thought to be a cytosolic fatty acid chaperone expressed in adipocytes. Mice with targeted disruption of the A-FABP gene exhibit a striking phenotype with strong protection from insulin resistance, hyperglycemia, and atherosclerosis. The clinical relevance of these findings remains to be confirmed.

Methods: We used tandem mass spectrometry–based proteomic analysis to identify proteins secreted from adipocytes and present in human serum. We measured serum A-FABP concentrations in 229 persons (121 men and 108 women; age range, 33–72 years), including 100 lean [body mass index (BMI) <25 kg/m2] and 129 overweight/obese individuals (BMI >25 kg/m2) selected from a previous cross-sectional study.

Results: A-FABP was released from adipocytes and was abundantly present in human serum. Mean (SD) circulating concentrations of A-FABP were significantly higher in overweight/obese than in lean persons [32.3 (14.8) vs 20.0 (9.8) μg/L; P <0.001]. Age- and sex-adjusted serum A-FABP concentrations correlated positively (P <0.005) with waist circumference, blood pressure, dyslipidemia, fasting insulin, and the homeostasis model assessment insulin resistance index. Moreover, we observed a significant increase in A-FABP concentrations corresponding with increases in the number of components of the metabolic syndrome (P <0.05).

Conclusions: A-FABP is a circulating biomarker closely associated with obesity and components of the metabolic syndrome, and measurement of serum concentrations of A-FABP might be useful for clinical diagnosis of obesity-related metabolic and cardiovascular disorders.
Photobleaching of Reduced Nicotinamide Adenine Dinucleotide and the Development of Highly Fluorescent Lesions in Rat Basophilic Leukemia Cells During Multiphoton Microscopy
Authors: Tiede LeAnn M. , Nichols Michael G.
Published: January 2006

Endogenous reduced nicotinamide adenine dinucleotide (NADH) fluorescence provides an intrinsic indicator of the cellular metabolic state, but prolonged monitoring is limited by photobleaching and/or phototoxicity. Multiphoton excitation of NADH by ultrashort, 740‐nm laser pulses provides a significant improvement over UV excitation by eliminating peripheral photobleaching; however, molecules within the subfemtoliter excitation volume remain susceptible. We have investigated the photophysical mechanisms responsible for multiphoton photobleaching of NADH in living cells to permit the imaging technique to be optimized. The loss of fluorescence because of multiphoton photobleaching was measured by repetitively imaging individual planes within rat basophilic leukemia cells. The photobleaching rate was proportional to the fourth power of the laser intensity. Based on these measurements, we propose a double‐biphotonic, four‐photon photobleaching mechanism and estimate the quantum yield of photobleaching of intracellular NADH to be 0.0073 ± 0.0002 by this mechanism. In addition to photobleaching, the development of bright, punctate fluorescent lesions can also be observed. The frequency of lesion formation also increased approximately as the fourth power of the laser intensity after an intensity‐dependent threshold number of images had been exceeded. The consequences for two‐photon metabolic imaging are discussed.