bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retinal Peripapillary Blood Flow before and after Topical Brinzolamide
Authors: Iester Michele , Altieri Michele , Michelson Georg , Vittone Paolo , Traverso Carlo E. , Calabria Giovanni 
Published: December 2004

<i>Purpose:</i> To study the effect of topical brinzolamide on retinal capillary blood flow by the Heidelberg Retina Flowmeter (HRF) in patients with glaucoma. <i>Methods:</i> Twenty patients with glaucoma were consecutively recruited. One eye for each patient was randomly selected. Patients were classified as glaucomatous if they had an abnormal visual field and/or an abnormal optic nerve head with an intraocular pressure (IOP) greater than 21 mm Hg without any treatment. After an eye examination, baseline retinal blood flow measurements were made with confocal scanning laser Doppler flowmetry. Blood flow and IOP measurements were then repeated after 1 month of treatment. Blood flow measurements were analyzed by using an automatic full-field perfusion image analysis (AFFPIA) program. The blood flow was calculated in the superior and inferior part of the optic disk. In each area, the blood flow was calculated as temporal area, the nasal area and the rim area as for software AFFPIA. <i>Results:</i> The mean age of the patients was 56 ± 7 (mean ± standard deviation) years. The mean IOP before treatment was 23.7 ± 1.5 mm Hg while the mean IOP after 4 weeks of treatment was 19.1 ± 2.2 mm Hg. This difference was statistically significant (p < 0.01). Significant (p < 0.05) increases in retinal blood flow were found for the temporal and nasal areas between baseline and 1 month after the treatment. No difference was found between superior and inferior sectors. <i>Conclusion:</i> Topical brinzolamide reduced the IOP significantly and apparently improved retinal blood flow as measured by the HRF.
The Effect of Posterior Cruciate Ligament Deficiency on Knee Kinematics
Authors: Logan Martin , Williams Andrew , Lavelle Jonathon , Gedroyc Wady , Freeman Michael 
Published: December 2004

Background Alteration of the kinematics of the PCL-deficient knee might be a factor in producing the articular damage. Very little is known about the in vivo weightbearing kinematics of the PCL-deficient knee. Hypothesis Isolated rupture of the posterior cruciate ligament alters knee kinematics, predisposing the patient to development of early osteoarthritis. Study Design Case series. Methods Tibiofemoral motion was assessed using open-access magnetic resonance imaging, weightbearing in a squat, through the arc of flexion from 0° to 90° in 6 patients with isolated rupture of the posterior cruciate ligament in one knee and a normal contralateral knee. Passive sagittal laxity was assessed by performing the posterior and anterior drawer tests while the knees were scanned, again using the same magnetic resonance imaging scanner. The tibiofemoral positions during this stress magnetic resonance imaging examination were measured from midmedial and midlateral sagittal images of the knees. Results Rupture of the posterior cruciate ligament leads to an increase in passive sagittal laxity in the medial compartment of the knee (P < .006). In the weightbearing scans, posterior cruciate ligament rupture alters the kinematics of the knee with persistent posterior subluxation of the medial tibia so that the femoral condyle rides up the anterior upslope of the medial tibial plateau. This fixed subluxation was observed throughout the extension-flexion arc and was statistically significant at all flexion angles (P < .018 at 0°, P < .013 at 20°, P < .014 at 45°, P < .004 at 90°). The kinematics of the lateral compartment were not altered by posterior cruciate ligament rupture. The posterior drawer test showed increased laxity in the medial compartment. Conclusion Posterior cruciate ligament rupture alters the kinematics of the medial compartment of the knee, resulting in “fixed” anterior subluxation of the medial femoral condyle (posterior subluxation of the medial tibial plateau). This study helps to explain the observation of increased incidence of osteoarthritis in the medial compartment, and specifically the femoral condyle, in posterior cruciate ligament-deficient knees.
Leydig cell injury as a consequence of an acute graft-versus-host reaction
Authors: Wagner Anna-Margaretha , Beier Konstantin , Christen Elli , Holländer Georg A. , Krenger Werner 
Published: December 2004

AbstractHematopoietic stem cell transplantation (HSCT) is associated with significant posttransplantation gonadotoxicity. This deficit has been mainly attributed to pretransplantation conditioning, but lower sperm counts in humans also appear to be associated with graft-versus-host disease (GVHD) following allogeneic HSCT. However, the mechanisms leading to diminished spermatocyte levels during GVHD remain unknown. Here we demonstrate that injury to intratesticular cells occurs in unconditioned F1 mice following the infiltration of donor alloreactive T cells during an acute graft-versus-host reaction (GVHR). Using computer-aided quantitative microscopic morphometry we demonstrate that the nadir of Leydig cell volume density coincides with the peak of intratesticular infiltration by donor T cells. Injury to Leydig cells correlates with an intratesticular inflammatory response characterized by interferon-γ and tumor necrosis factor-α production. These results demonstrate impairment of testosterone-producing Leydig cells during a local alloresponse, thus representing a mechanism that contributes to gonadal insufficiency following allogeneic HSCT.
Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas
Authors: Muris Jettie J. F. , Cillessen Saskia A. G. M. , Vos Wim , van Houdt Inge S. , Kummer J. Alain , van Krieken Johan H. J. M. , Jiwa N. Mehdi , Jansen Patty M. , Kluin-Nelemans Hanneke C. , Ossenkoppele Gert J. , Gundy Chad , Meijer Chris J. L. M. , Oudejans Joost J. 
Published: December 2004

AbstractWe used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL.
CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells
Authors: Wang Tao , Ward Yvona , Tian Linhua , Lake Ross , Guedez Liliana , Stetler-Stevenson William G. , Kelly Kathleen 
Published: December 2004

AbstractCD97, a membrane protein expressed at high levels on inflammatory cells and some carcinomas, is a member of the adhesion G protein–coupled receptor family, whose members have bipartite structures consisting of an extracellular peptide containing adhesion motifs noncovalently coupled to a class B 7-transmembrane domain. CD97α, the extracellular domain of CD97, contains 3 to 5 fibrillin class 1 epidermal growth factor (EGF)–like repeats, an Arg-Gly-Asp (RGD) tripeptide, and a mucin stalk. We show here that CD97α promotes angiogenesis in vivo as demonstrated with purified protein in a directed in vivo angiogenesis assay (DIVAA) and by enhanced vascularization of developing tumors expressing CD97. These data suggest that CD97 can contribute to angiogenesis associated with inflammation and tumor progression. Strong integrin α5β1 interactions with CD97 have been identified, but αvβ3 also contributes to cell attachment. Furthermore, soluble CD97 acts as a potent chemoattractant for migration and invasion of human umbilical vein endothelial cells (HUVECs), and this function is integrin dependent. CD97 EGF-like repeat 4 is known to bind chondroitin sulfate. It was found that coengagement of α5β1 and chondroitotin sulfate proteoglycan by CD97 synergistically initiates endothelial cell invasion. Integrin α5β1 is the first high-affinity cellular counterreceptor that has been identified for a member within this family of adhesion receptors.
Prevalence and Incidence of Androgen Deficiency in Middle-Aged and Older Men: Estimates from the Massachusetts Male Aging Study
Authors: Araujo Andre B. , O’Donnell Amy B. , Brambilla Donald J. , Simpson William B. , Longcope Christopher , Matsumoto Alvin M. , McKinlay John B. 
Published: December 2004

Abstract
Little is known about the descriptive epidemiology of androgen deficiency. In this study, we sought to address this issue by providing estimates of the crude and age-specific prevalence and incidence rates of androgen deficiency in a randomly sampled population-based cohort of middle-aged and older men. Data on androgen deficiency (defined using both signs/symptoms plus total and calculated free testosterone) were available for n = 1691 (baseline) and n = 1087 (follow-up) men from the Massachusetts Male Aging Study. Crude and age-specific prevalence and incidence rates were calculated. Based on these estimates, projections for the number of cases of androgen deficiency in the 40- to 69-yr-old U.S. male population were computed. Estimates of the crude prevalence of androgen deficiency at baseline and follow-up were 6.0 and 12.3%, respectively. Prevalence increased significantly with age. From baseline age-specific prevalence data, it is estimated that there are approximately 2.4 million 40- to 69-yr-old U.S. males with androgen deficiency. The crude incidence rate of androgen deficiency was 12.3 per 1,000 person-years, and the rate increased significantly (P &lt; 0.0001) with age. Based on these incidence data, we can expect approximately 481,000 new cases of androgen deficiency per year in U.S. men 40–69 yr old.
A Germline Variation in the Progesterone Receptor Gene Increases Transcriptional Activity and May Modify Ovarian Cancer Risk
Authors: Agoulnik Irina U. , Tong Xiao-Wen , Fischer Dagmar-C. , Körner Klaus , Atkinson Neely E. , Edwards Dean P. , Headon Denis R. , Weigel Nancy L. , Kieback Dirk G. 
Published: December 2004

AbstractRecently, we and others have detected a haplotype of the human progesterone receptor gene (PR). This haplotype consists of a 320-bp insertion in intron G together with point mutations in exons 4 and 5 and was named PROGINS. Whereas the exon 5 mutation is silent, the mutation in exon 4 results in a V660L substitution. Interestingly, this genetic polymorphism was seen to cosegregate with an increased risk of sporadic ovarian cancer in different ethnic groups. Our data provide evidence for the existence of an epidemiological link between a mutated progesterone receptor allele and ovarian cancer (odds ratio, 3.02; 95% confidence interval, 1.86–4.91). Functional characterization of the mutated receptor protein revealed a greater transcriptional activity compared with the wild-type receptor. By contrast, hormone binding and hormone dissociation rates were similar in both receptor proteins. We found that the increased transcriptional activity was due to increased stability resulting in higher expression of the mutant protein. Thus, the long-lasting hyperactivation of progesterone receptor-driven genes secondary to the increased transcriptional activity of the mutated progesterone receptor may participate in ovarian carcinogenesis. This is of special interest, because only a few genetic markers are available for the majority of women diagnosed with sporadic ovarian cancer.
Phenotypic and Molecular Genetic Aspects of Pseudohypoparathyroidism Type Ib in a Greek Kindred: Evidence for Enhanced Uric Acid Excretion Due to Parathyroid Hormone Resistance
Authors: Laspa Elena , Bastepe Murat , Jüppner Harald , Tsatsoulis Agathocles 
Published: December 2004

Abstract
The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the α-subunit of the stimulatory G protein (Gsα). Besides PTH resistance, PHP-Ia patients have Albright’s hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright’s hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.
Rosiglitazone, But Not Glyburide, Reduces Circulating Proinsulin and the Proinsulin:Insulin Ratio in Type 2 Diabetes
Authors: Smith Stephen A. , Porter Lisa E. , Biswas Nandita , Freed Martin I. 
Published: December 2004

AbstractAn elevation in the ratio of proinsulin (PI) to immunoreactive insulin (IRI) is inversely related to β-cell function in type 2 diabetes, and increased PI is an independent risk factor for coronary heart disease. An objective of the present studies was to assess the effects of the thiazolidinedione insulin sensitizer, rosiglitazone, on indirect markers of β-cell function and cardiovascular risk in people with type 2 diabetes by measuring plasma PI and the PI:IRI ratio. Parameters of insulin processing, including plasma PI and PI:IRI ratios, were determined in type 2 diabetes patients enrolled in two randomized double-blind studies comparing the effects of rosiglitazone (4 or 8 mg/d) with placebo (study 1, 26-wk treatment) or the sulfonylurea glyburide (study 2, 52-wk treatment). Treatment with rosiglitazone for 26 wk (study 1) produced significant dose-dependent decreases in both plasma PI concentrations (18–29%) and the PI:IRI ratio compared with baseline (7–14%) and placebo (19–29%) (P &lt; 0.001). A significant increase in the PI:IRI ratio in placebo-treated patients occurred (P &lt; 0.001). In study 2, rosiglitazone also significantly reduced both plasma PI and the PI:IRI ratio compared with baseline (P &lt; 0.001). In contrast, glyburide significantly increased both plasma PI (45%; P &lt; 0.001) and the PI:IRI ratio (10%) (P &lt; 0.05 vs. baseline). These results show that rosiglitazone and glyburide have differential effects on absolute PI levels and the PI:IRI ratio in people with type 2 diabetes.
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity
Authors: Tornovsky Sharona , Crane Ana , Cosgrove Karen E. , Hussain Khalid , Lavie Judith , Heyman Ma’ayan , Nesher Yaron , Kuchinski Na’ama , Ben-Shushan Etti , Shatz Olga , Nahari Efrat , Potikha Tamara , Zangen David , Tenenbaum-Rakover Yardena , de Vries Liat , Argente Jesús , Gracia Ricardo , Landau Heddy , Eliakim Alon , Lindley Keith , Dunne Mark J. , Aguilar-Bryan Lydia , Glaser Benjamin 
Published: December 2004

Abstract
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (KIR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
Structural and Functional Characteristics of the Val44Met Insulin-Like Growth Factor I Missense Mutation: Correlation with Effects on Growth and Development
Authors: Denley Adam , Wang Chunxiao C. , McNeil Kerrie A. , Walenkamp Marie J. E. , van Duyvenvoorde Hermine , Wit Jan M. , Wallace John C. , Norton Raymond S. , Karperien Marcel , Forbes Briony E. 
Published: December 2004

AbstractWe have previously described the phenotype resulting from a missense mutation in the IGF-I gene, which leads to expression of IGF-I with a methionine instead of a valine at position 44 (Val44Met IGF-I). This mutation caused severe growth and mental retardation as well as deafness evident at birth and growth retardation in childhood, but is relatively well tolerated in adulthood. We have conducted a biochemical and structural analysis of Val44Met IGF-I to provide a molecular basis for the phenotype observed. Val44Met IGF-I exhibits a 90-fold decrease in type 1 IGF receptor (IGF-1R) binding compared with wild-type human IGF-I and only poorly stimulates autophosphorylation of the IGF-1R. The ability of Val44Met IGF-I to signal via the extracellular signal-regulated kinase 1/2 and Akt/protein kinase B pathways and to stimulate DNA synthesis is correspondingly poorer. Binding or activation of both insulin receptor isoforms is not detectable even at micromolar concentrations. However, Val44Met IGF-I binds IGF-binding protein-2 (IGFBP-2), IGFBP-3, and IGFBP-6 with equal affinity to IGF-I, suggesting the maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by nuclear magnetic resonance confirms retention of near-native structure with only local side-chain disruptions despite the significant loss of function. To our knowledge, our results provide the first structural study of a naturally occurring mutant human IGF-I associated with growth and developmental abnormalities and identifies Val44 as an essential residue involved in the IGF-IGF-1R interaction.
Evolution of Brain Tissue Injury after Evacuation of Acute Traumatic Subdural Hematomas
Authors: Hlatky Roman , Valadka Alex B. , Goodman J Clay , Robertson Claudia S. 
Published: December 2004

Abstract

OBJECTIVE:
Acute traumatic subdural hematoma complicated by brain parenchymal injury is associated with a 60 to 90% mortality rate. Early surgical evacuation of the mass lesion is essential for a favorable outcome, but the severity of the underlying brain injury determines the outcome, even when surgery has been prompt. The purpose of this study was to analyze tissue biochemical patterns in the brain underlying an evacuated acute subdural hematoma to identify a characteristic pattern of changes that might indicate evolving brain injury.

METHODS:
Prospectively collected data from 33 patients after surgical evacuation of acute subdural hematoma were analyzed. Both a brain tissue oxygen tension probe and an intracerebral microdialysis probe were placed in brain tissue exposed at surgery. On the basis of the postoperative clinical course, the patients were divided into three groups: patients with early intractable intracranial hypertension, patients with evolution of delayed traumatic injury (DTI), and patients with an uncomplicated course (the no-DTI group).

RESULTS:
The overall mortality rate was 46%, with 100% mortality in the intracranial hypertension group (five patients). Mortality in the DTI group was 53% compared with only 9% in the no-DTI group (P = 0.002). There were no significant differences in the initial computed tomographic scan characteristics, such as thickness of the subdural hematoma or amount of midline shift, among the three groups. Physiological variables, as well as the microdialysate measures of brain biochemistry, were markedly different in the intracranial hypertension group compared with the other groups. Differences between the other two groups were more subtle but were significant. Significantly lower values of brain tissue oxygen tension (14 ± 8 mm Hg versus 27 ± 14 mm Hg) and higher dialysate values of lactate and pyruvate were documented in patients who developed a delayed injury compared with patients with uncomplicated courses (4.1 ± 2.3 mmol/L versus 1.7 ± 0.7 mmol/L for lactate, and 104 ± 47 μmol/L versus 73 ± 54 μmol/L for pyruvate at 24 h after injury).

CONCLUSION:
Evolution of DTI in the area of brain underlying an evacuated subdural hematoma is associated with a significant increase in mortality. Postoperatively decreasing brain tissue oxygen tension and increasing dialysate concentrations of lactate and pyruvate in this area may warn of evolving brain injury and evoke further diagnostic and therapeutic activity.