bluuebunny/crossref_metadata_2025 huggingface dataset:
Purulent Flexor Tenosynovitis: Factors Influencing the Functional Outcome
Authors: DAILIANA Z. H. , RIGOPOULOS N. , VARITIMIDIS S. , HANTES M. , BARGIOTAS K. , MALIZOS K. N.
Published: June 2008

This retrospective study aimed to evaluate the factors that influence the final outcome of treatment of purulent flexor tenosynovitis, viz. delay in treatment, severity of the condition, the infecting pathogen and the method of treatment. Of 41 patients with this condition treated by drainage and irrigation through two small incisions (16) and wide incision (25), 16 were treated after a delay. Continuous postoperative irrigation was applied in 26 patients. Re-operation was necessary in 11 patients. In most cases, Staphylococcus aureus was detected. The results were excellent in 32 cases and the mean Disabilities of the Arm, Shoulder and Hand score was 8.1. Irrigation through small incisions and continuous postoperative irrigation decreased the probability of an unfavourable outcome. Delayed treatment and infections with specific pathogens led to a worse outcome. Early diagnosis of purulent flexor tenosynovitis followed by drainage through small incisions and continuous postoperative irrigation appear, from this retrospective review, to lead to the best functional outcome.
Isolated Dorsal Fracture–Dislocation of the Scaphoid: A Case Report
Authors: WANAJO S. , SATO K. , NAKAMURA T. , IKEGAMI H. , TANINO Y. , TOYAMA Y.
Published: June 2008

This paper reports an isolated dorsal fracture–dislocation of the scaphoid at its waist with the proximal fragment dislocated dorsally. Such a fracture–dislocation is extremely rare. We believe the pathomechanics of this injury to have been a flexion and radial deviation with an axial force on the wrist.
Abductor Pollicis Longus “Hammock” Ligamentoplasty for Treatment of First Carpometacarpal Arthritis
Authors: MATHOULIN C. , MOREEL P. , COSTA R. , WILSON S. M.
Published: June 2008

The association of trapeziectomy with ligamentoplasty is a simple treatment for osteoarthritis at the base of the thumb. Here we present the long-term results of a technique that creates a “hammock” under the first metacarpal bone using the Abductor Pollicis Longus tendon. This paper reports the results of treatment by this operation of 60 thumbs in 50 patients, including 13 men and 37 women of average age 60 (46–75) years. Thirty thumbs presented with severe pain and 30 with moderate pain. At final follow-up, 47 thumbs (78%) had experienced dramatic relief of pain following the procedure, 12 (20%) thumbs still had mild pain and one (2%) thumb had severe pain. No patients needed revision.
Keeping Osteocytes Alive: A Comparison of Drilling and Hammering K-Wires into Bone
Authors: FRANSSEN B. B. G. M. , VAN DIEST P. J. , SCHUURMAN A. H. , KON M.
Published: June 2008

In this study, the insertion time and histological effects of drilling and hammering K-wires into bone are described. The insertion time was measured while drilling or hammering K-wires into the femurs and tibias of ten rabbits. Four K-wires, inserted into one hind limb, were used for histological examination directly after insertion and four K-wires inserted into the contralateral hind limb were used for the same measurements 4 weeks later. The specimens were scored for presence, or absence, of osteocytes, fragmentation of the bone edges, haemorrhage, microfractures, cortical reaction and callus formation around the pin track. The insertion time needed for drilling in K-wires was significantly longer than that of hammering. Drilling also resulted in the disappearance of the osteocytes in almost all sections while hammering did not have this effect but did result in more microfractures. Hammering K-wires may be a superior technique because it prevents osteonecrosis and requires a shorter insertion time.
The “Biro Test” for Autonomic Dysfunction in Carpal Tunnel Syndrome
Authors: KUMAR A. , BISMIL Q. , MORGAN B. , ASHBROOKE A. , DAVIES S. , SOLAN M.
Published: June 2008

The aim of this study was to assess whether autonomic dysfunction associated with carpal tunnel syndrome (CTS) can be assessed quantitatively with a (modified) biro test of finger sweating. Twenty-six hands of 16 patients with CTS were compared with 30 hands of 15 normal subjects. A device was constructed to measure the angle from the horizontal at which a biro slips from the finger (the critical angle). In the control subjects, no significant difference was found in the critical angle between the little and index fingers in either hand. By comparison, in subjects with CTS, the critical angle was significantly lower in the index finger than in the little finger, the mean difference being 8.65°, indicating a quantifiable and significant difference of sweating of the median nerve-innervated index finger.
Vascularised Joint Transfer in the Management of Recurrent Giant Cell Tumour of the Second Metacarpal
Authors: KOTWAL P. P. , NAGARAJ C. , GUPTA V.
Published: June 2008

This paper presents the medium-term follow-up results (34 and 40 months, respectively) of two cases of recurrent giant cell tumour of the head of the second metacarpal, treated by marginal excision and reconstruction with a vascularised toe joint transfer. Both patients had painless, stable joints with excellent ranges of motion at the metacarpophalangeal joint of 80° and 70°, respectively, no degenerative changes and no recurrence of the tumours.
Joseph Swan (1791–1874): Pioneer of Research on Peripheral Nerves
Authors: BARTON N. J. , SMITH B. D.
Published: June 2008

Joseph Swan was born in 1791 and appointed surgeon to Lincoln County Hospital in 1814. In addition to his clinical work, he carried out what were probably the first animal experiments on nerve injuries. These were mostly on rabbits, in which the sciatic nerves were partly or wholly divided, had a section excised, or were ligated. He found that regeneration could occur, even after neurectomy. He reported these results, together with his experience in human patients and the effects of neurectomy in a horse, in an essay of 1819, which won the Jacksonian Prize of the Royal College of Surgeons of England and is still preserved there. In 1827 he moved to London, where he devoted himself mainly to dissections of the nervous system and was active in the College. He retired to Filey in Yorkshire, where he died in 1874.
A New Method of Nerve Bridging with a Collagen Mesothelial Tube
Authors: RYOKE K. , NSHIKAWA U. , OCHI M. , UCHIO Y.
Published: June 2008

The effectiveness of a collagen mesothelial tube for nerve bridging was investigated in an experimental model of repair of rat sciatic nerves. The right sciatic nerve was cut, the two stumps were reflected and a collagen mesothelial tube was placed in the gap. The rod was removed at 4 weeks after implantation. At this point, the “bridging” was performed with a 10-mm gap (Group M). Two control groups were similarly treated but one with a collagen tube (Group C) and the other with a silicone tube (Group S). Regeneration of the sciatic nerves was assessed using a sciatic function index, by measuring blood flow and by the number of regenerated axons at 4, 8 and 12 weeks after bridging. Group M showed significantly better results with respect to all three assessments. The collagen mesothelial tube used in our study appears to be a promising tool for bridging peripheral nerve defects.
Long-term Outcome after Carpal Tunnel Decompression – A Prospective Randomised Study of the Indiana Tome and a Standard Limited Palmar Incision
Authors: CRESSWELL T. R. , HERAS-PALOU C. , BRADLEY M. J. , CHAMBERLAIN S. T. , HARTLEY R. H. , DIAS J. J. , BURKE F. D.
Published: June 2008

This randomised trial compared the results of carpal tunnel decompression using the TM Indiana Tome (Biomet, Warsaw, Indiana, USA) and a standard limited palmar open incision. Two hundred patients were randomly selected to have a carpal tunnel decompression with either the Indiana Tome or a limited palmar technique. They were assessed clinically for 3 months and using the Levine–Katz self-assessment evaluation for 7 years. After 7 years, there were 62 returned questionnaires from the open group and 53 from the Tome group. There were no significant differences in functional scores, pain, scar tenderness, pinch and grip strength at 3 months. There were two complications in the open group and nine in the Tome group, including one median nerve injury. There was both a higher rate of immediate complications, and more recurrences and persisting symptoms at 7 years in the Indiana Tome group.
Arthroscopic-Assisted Percutaneous Reduction and Screw Fixation of Displaced Scaphoid Fractures
Authors: SLADE J. F. , LOZANO-CALDERÓN S. , MERRELL G. , RING D.
Published: June 2008

Many scaphoid fractures can be treated with percutaneous screw insertion, but fracture displacement usually necessitates open reduction. Two surgeons treated 20 consecutive patients with displaced fractures of the scaphoid using arthroscopic-assisted percutaneous screw fixation. Thirteen patients had dorsal (antegrade) and seven had palmar (retrograde) percutaneous screw insertion. At an average follow-up of 18 (range 6–48) months, all of the fractures were healed and there were no implant problems. The early results of arthroscopic-assisted percutaneous screw fixation of displaced fractures of the scaphoid suggest that union can be obtained and good to excellent function achieved predictably without the need for open exposure. Avoidance of an open exposure limits wrist ligament injury and may preserve blood supply. Further evaluation of this procedure is merited.
Management of Total Paralysis of the Brachial Plexus by the Double Free-muscle Transfer Technique
Authors: DOI K.
Published: June 2008

The double free-muscle transfer technique achieved a dramatic revolution in the treatment of total paralysis of the brachial plexus by providing universal prehensile function, although several requirements such as successful free-muscle transfers, stability of the proximal joints and prolonged postoperative rehabilitation are necessary for the success of this procedure. To obtain the best outcome of double free-muscle transfer, it is imperative to understand the key factors, viz. selection of the donor muscle, meticulous microsurgical technique, importance of proximal joint stability, selection of the kind of grip and postoperative rehabilitation. Double free-muscle transfer is not a simple microsurgical muscle transfer for finger movement, but a universal reconstructive procedure for total paralysis of the upper limb.
Comparison of MRI and Wrist Arthroscopy for Assessment of Wrist Cartilage
Authors: MUTIMER J , GREEN J , FIELD J
Published: June 2008

In order to perform motion-preserving procedures for wrist arthritis rather than total joint fusion, it is important to determine the integrity of specific areas of wrist cartilage. This is generally performed using a wrist arthroscope and by directly visualising the cartilage. Twenty patients with wrist pain were investigated over a 1-year period with both MRI and wrist arthroscopy. Kappa analysis was used to compare the two methods of cartilage assessment. There is only a fair correlation ( K = 0.38) between the two methods. With only a fair correlation between arthroscopy and MRI, it cannot be concluded that the two methods are equivalent for assessing wrist cartilage and, as such, wrist arthroscopy still has an important role to play in the assessment of a painful degenerative wrist.
A Finite-Element Analysis of Kienböck’s Disease
Authors: LEDOUX P. , LAMBLIN D. , WUILBAUT A. , SCHUIND F.
Published: June 2008

A finite-element analysis model of the lunate was established using geometrical data obtained from cadaveric bones. The lunate cortex was modelled with triangular and quadrilateral elements and its intraosseous structure was represented either as a homogenous elastic structure or as an anisotropic network of cortical bone beams (trabeculae) with different orientations and thicknesses. Compressive loads applied to the metacarpus were distributed in the carpus against the fixed radius and ulna. The ulnar variance had a strong influence on the ratios radiolunate/ulnolunate total load and peak pressures. The distribution of internal stresses was markedly affected by the lunate uncovering index. The evolution of a simulated incomplete fracture was dramatically influenced by morphological parameters: with positive ulnar variance, the fracture did not progress, but in the presence of three associated conditions, negative ulnar variance, a high lunate uncovering index and angulated trabeculae, the fracture progressed and the proximal part of the lunate collapsed. This study supports the concept that some lunates are predisposed to Kienböck’s disease because their anatomy induces abnormal internal stresses, which allow an incomplete fracture to progress, under heavy loading conditions, and cause progressive collapse and localised trabecular osteonecrosis.
Single-Stage Distraction Correction for Neglected Dorsal Fracture Dislocations of the Proximal Interphalangeal Joint: A Report of Eight Cases
Authors: HOUSHIAN S. , GHANI A. , CHIKKAMUNIYAPPA C. , SAKKA S. A.
Published: June 2008

We present the outcome of treatment of eight chronic neglected dorsal fracture dislocations of the proximal interphalangeal joint treated with a single-stage ligamentous distraction using the Penning mini-external fixator and a closed reduction. The distraction correction and 2 to 3 mm over distraction was performed acutely at the time of operation in all eight cases at an average injury-to-surgery time of 6 weeks. Satisfactory results with an average range of motion of 79° were obtained at an average follow-up of 20 months. This technique is simple, effective and offers the advantage of being minimally invasive. We recommend this single-stage distraction correction technique for the treatment of chronic neglected dorsal dislocations of the proximal interphalangeal joint, which are no more than 10 weeks-old.
Evidence for infection, inflammation and shock in sudden infant death: parallels between a neonatal rat model of sudden death and infants who died of sudden infant death syndrome
Authors: Blood-Siegfried Jane , Rambaud Caroline , Nyska Abraham , Germolec Dori R.
Published: June 2008

This study compared pathological findings from a neonatal rat model of sudden death with those from 40 sudden infant death syndrome (SIDS) infants collected at autopsy. In the rat model, influenza A virus was administered intranasally on postnatal day 10, and on day 12 a sublethal, intraperitoneal dose of Escherichia coli endotoxin; mortality was 80%. Tissue samples from the animals and infants were fixed in formaldehyde, embedded in paraffin, and sections stained with hematoxylin and eosin. Tissues from the SIDS specimens were additionally cultured for bacteria and viruses; post-mortem blood samples were evaluated for signs of inflammation. All sections were examined by a pediatric forensic pathologist familiar with SIDS pathology. Comparisons between the rat model and the human SIDS cases revealed that both exhibited gross and microscopic pathology related to organ shock, possibly associated with the presence of endotoxin. Uncompensated shock appeared to be a likely factor that caused death in both infants and rat pups. Response to a shock-inducing event might have played an important role in the events leading to death. The similarities between the neonatal rats and the human cases indicate that further research with the model might elucidate additional aspects of SIDS pathology.
The effect of systemic iNOS inhibition during human endotoxemia on the development of tolerance to different TLR-stimuli
Authors: Draisma Annelies , Dorresteijn Mirrin , Pickkers Peter , van der Hoeven Hans
Published: June 2008

The phenomenon of repeated exposure to endotoxin resulting in diminished release of pro-inflammatory cytokines is called endotoxin tolerance, in which there is a putative role for nitric oxide (NO). We investigated the effect of selective inducible NO-synthase (iNOS) inhibition during experimental human endotoxemia on the development of tolerance to various Toll-like receptor (TLR) agonists ex vivo. Volunteers received 2 ng/kg Escherichia coli endotoxin in the absence ( n = 7) or presence ( n = 7) of the selective iNOS inhibitor aminoguanidine (bolus 5 mM followed by a continuous infusion of 1.5 mmol/h). At 0, 2 and 4 h, blood samples were drawn for ex vivo stimulation with different TLR agonists. Experimental endotoxemia did not induce tolerance to TLR-2 and TLR-7 stimulation. In TLR-3, TLR-4 and TLR-5 stimulated whole blood, pro- and anti-inflammatory cytokine release was attenuated at 4 h, indicating that endotoxin-induced tolerance is not confined to subsequent TLR-4 stimulation alone. Aminoguanidine-treated subjects also developed tolerance to TLR-4 stimulation. In contrast, tolerance to TLR-3 stimulation did not occur for IL-10, and tolerance in TLR-5 stimulated blood did not develop for both pro- and anti-inflammatory cytokines. The role of NO in the development of tolerance is different for the various TLRs stimulated and pro- and anti-inflammatory cytokines measured.
Expression profiling and binding properties of fibrinogen-related proteins (FREPs), plasma proteins from the schistosome snail host Biomphalaria glabrata
Authors: Zhang Si-Ming , Yong Zeng  , Loker Eric S.
Published: June 2008

A growing body of evidence suggests an important role for fibrinogen-like proteins in innate immunity in both vertebrates and invertebrates. It has been shown that fibrinogen-related proteins (FREPs), plasma proteins present in the freshwater snail Biomphalaria glabrata, the intermediate host for the human blood fluke Schistosoma mansoni, are diverse and involved in snail innate defense responses. To gain further insight into the functions of FREPs, recombinant FREP proteins (rFREPs) were produced in Escherichia coli and antibodies (Abs) were raised against the corresponding rFREPs. We first show that most FREP proteins exist in their native conformation in snail hemolymph as multimeric proteins. Western blot analyses reveal that expression of multiple FREPs including FREP4 in plasma from M line and BS-90 snails, which are susceptible and resistant to S. mansoni infection, respectively, is up-regulated significantly after infection with the trematode Echinostoma paraensei. Moreover, our assays demonstrate that FREPs are able to bind E. paraensei sporocysts and their secretory/excretory products (SEPs), and a variety of microbes (Gram-positive and Gram-negative bacteria and yeast). Furthermore, this binding capability shows evidence of specificity with respect to pathogen type; for example, 65—75-kDa FREPs (mainly FREP4) bind to E. paraensei sporocysts and their SEPs whereas 95-kDa and 125-kDa FREPs bind the microbes assayed. Our results suggest that FREPs can recognize a wide range of pathogens, from prokaryotes to eukaryotes, and different categories of FREPs seem to exhibit functional specialization with respect to the pathogen encountered.
Hydrogen peroxide induces the production of tumor necrosis factor-α in RAW 264.7 macrophage cells via activation of p38 and stress-activated protein kinase
Authors: Nakao Noiku , Kurokawa Tsuyoshi , Nonami Toshiaki , Tumurkhuu Gantsetseg , Koide Naoki , Yokochi Takashi
Published: June 2008

The effect of hydrogen peroxide (H2O2) on production of tumor necrosis factor (TNF)-α was examined in RAW 264.7 murine macrophage cells. H2O2led to production of TNF-α up to 24 h after the treatment, but not nitric oxide in RAW 264.7 cells. H2O2induced TNF-α production in mouse peritoneal macrophages as well as RAW 264.7 cells. The H2O2induced TNF-α production was prevented by inhibitors of p38 and stress-activated protein kinase (SAPK/JNK), and H2O2induced the phosphorylation of p38 and SAPK. Further, H2O2significantly augmented the AP-1 activity, but not nuclear factor (NF)-κB activity in RAW 264.7 cells. A high level of intracellular reactive oxygen radicals (ROS) was detected in H2O2-exposed RAW 264.7 cells. Ebselen, a cell permeable antioxidant, prevented the H2O2-induced TNFα production. H2O2significantly enhanced lipopolysaccharide (LPS)-induced TNF-α production. Therefore, H2O2was suggested to induce TNF-α production in macrophages via activating p38 and SAPK/JNK as oxidative stress-related signal pathways.
Review: Chemical and biological features of Burkholderia cepacia complex lipopolysaccharides
Authors: De Soyza Anthony , Silipo Alba , Lanzetta Rosa , Govan John R. , Molinaro Antonio
Published: June 2008

The Burkholderia cepacia complex comprises 10 closely related Gram-negative organisms all of which appear capable of causing disease in humans. These organisms appear of particular relevance to patients with cystic fibrosis. Lipopolysaccharide (LPS) is an important virulence determinant in Gram-negative pathogens. In this review, we highlight important data within the field commenting on LPS/lipid A structure-to-function relationships and cytokine induction capacity of Burkholderia strains studied so far.
Review: Hypertension, a health economics perspective
Authors: Alcocer Luis , Cueto Liliana
Published: June 2008

The economic aspects of hypertension are critical to modern medicine. The medical, economic, and human costs of untreated and inadequately controlled hypertension are enormous. Hypertension is distributed unequally and with iniquity in different countries and regions of the world. Treatment of hypertension requires an investment over many years to prolong disease-free quality years of life. The high prevalence and high cost of the disease impacts on the microeconomics and macroeconomics of countries and regions. The criteria used for inclusion in clinical guidelines for hypertension impact on the cost and cost/utility of diagnosis or treatment.
Review: Avoiding restenosis: is there a role for glucocorticoids in the drug-eluting stent era?
Authors: Jimenez-Valero Santiago , Moreno Raul , Sanchez-Recalde Angel , Galeote Guillermo , Calvo Luis , Viana Ana , Lopez de Sá Esteban , López-Sendón Jose
Published: June 2008

Restenosis is an important limitation of percutaneous coronary interventions (PCI). In-stent restenosis is mainly due to neointimal hyperplasia, a proliferative process modulated by inflammatory mechanisms. Numerous technical and pharmacological means have been tested to reduce restenosis rates, with frequently disappointing clinical results. Drug-eluting stents (DES) have demonstrated a high efficacy in reducing restenosis, but there are some associated problems that limit its generalized utilization. Glucocorticoids (GC), as potent anti-inflammatory agents, may exert beneficial effects on neointimal proliferation. Clinical studies with oral and intracoronary GC therapy have demonstrated reduction in restenosis rates in selected patients. Although further investigations are warranted, GC might have a potential role for restenosis prevention in selected cases.
Review: PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury
Authors: Collino Massimo , Patel Nimesh S.A. , Thiemermann Christoph
Published: June 2008

Stroke is a leading cause of death and long-term disability in industrialized countries. Despite advances in understanding its pathophysiology, little progress has been made in the treatment of stroke. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signaling proteins which could be exploited to design novel therapeutic modalities. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. PPARs regulate gene expression by binding with the retinoid X receptor (RXR) as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated α, β/ δ, and γ, have been identified. Recently, they have been found to play an important role for the pathogenesis of various disorders of the central nervous system and accumulating data suggest that PPARs may serve as potential targets for treating ischemic stroke. Activation of all PPAR isoforms, but especially of PPAR γ, was shown to prevent post-ischemic inflammation and neuronal damage in several in vitro and in vivo models, negatively regulating the expression of genes induced by ischemia/ reperfusion (I/R). This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPAR-agonists in the treatment of cerebral I/R injury.
Review: Statins and stroke
Authors: Rodríguez-Yáñez Manuel , Agulla Jesús , Rodríguez-González Raquel , Sobrino Tomás , Castillo José
Published: June 2008

Statins play an important role in brain ischemia. These drugs reduce cholesterol levels, which have been related to a reduction in vascular event risk, but they also have other functions besides cholesterol metabolism, called pleiotropic effects. Statins play an important role during the acute phase of ischemia, and might have neuroprotective effects, as they act in several mechanisms during the acute phase of stroke, such as in nitric oxide (NO) and glutamate metabolism, inflammation, platelet aggregation, immune responses and apoptosis. They also have other functions that can be related, with better long-term outcome, to neurorepair mechanisms. Statins promote angiogenesis, endogenous cell proliferation, neurogenesis and new synapse formation.
Review: Atrial fibrillation and renin-angiotensin system
Authors: Serra José Luis , Bendersky Mario
Published: June 2008

Atrial Fibrillation (AF) is one of the most frequent arrhythmias, especially in elderly patients. Cardiac overload increases the incidence of AF. Clinical presentation of atrial fibrillation can occur as nonsustained paroxysms, persistent episodes and in chronic-permanent form. The physio-pathological mechanisms are:

• Circuit of multiple and anarchic re-entries

• Atrial fibrillatory conduction

• Re-entry circuit with fibrillatory conduction.

Remodeling (electrical or structural) facilitates the appearance and persistence of AF: Neurovegetative changes and cytosolic Ca overload facilitate AF. Interstitial atrial fibrosis, in which Renin-Angiotensin System (RAS) hyperactivity is a main aspect of remodeling. There is clinical evidence that supports the antiatrial fibrillatory actions of RAS blockade. Potential mechanisms are: (a) direct modulation of ionic channels, (b) hemodynamic improvement, (c) reduction of atrial stretching, (d) antifibrotic effects. There is less clinical evidence with antialdosterone drugs, but theoretically these might also be useful.
Review: Endothelial progenitor cells: markers of vascular reparative capacity
Authors: Povsic Thomas J. , Goldschmidt-Clermont Pascal J.
Published: June 2008

Assessment of the propensity for vascular events has been based on measurement of risk factors predisposing one to vascular injury. These assessments are based on the strong associations between risk factors such as hypertension, cholesterol levels, smoking, and diabetes which were first described almost a half century ago. The more recent discovery of the relationship between ongoing inflammation and clinical outcomes has led to a variety of blood-based assays which may impart additional knowledge about an individual's propensity for future cardiovascular events. Vascular health is now better represented as a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating endothelial progenitor cells. To date, one's risk for vascular events has focused exclusively on assessing propensity for vascular damage, either by assessing conventional risk factors which were initially identified over half a century ago, or more recently by assessing markers of inflammation and other circulating factors which area related to subsequent clinical events. Circulating endothelial progenitor cells play important roles in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. To date, EPC numbers have been correlated with the numbers of cardiovascular risk factors, extent of coronary disease, and future cardiovascular events. Given that EPC enumeration and functional characterization represent the only assessment of the reparative side of the balance between damage and renovation, this technique may offer independent and different assessment of propensity to cardiovascular injury, greatly improving risk stratification of patients.
Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos
Authors: Trindade Alexandre , Ram Kumar S. , Scehnet Jeffrey S. , Lopes-da-Costa Luis , Becker Jorg , Jiang Weidong , Liu Ren , Gill Parkash S. , Duarte Antonio
Published: June 2008

The importance of Notch signaling pathway in the regulation of vascular development and angiogenesis is suggested by the expression of Notch receptors and ligands in vascular endothelial cells (ECs) and the observed vascular phenotypes in mutants of Notch receptors or ligands, especially Dll4. DLL4 is specifically expressed in arterial ECs during development, and haplo-insufficiency is embryonically lethal in mice. To address the role of Dll4 in vascular development, we produced mDll4 conditionally overexpressed transgenic mice that were crossed with constitutive recombinase cre lines. Double transgenic embryos displayed grossly enlarged dorsal aortae (DA) and died before embryonic day 10.5 (E10.5), showing a variable degree of premature arteriovenous fusion. Veins displayed ectopic expression of arterial markers. Other defects included reduced vascular sprouting, EC proliferation, and migration. mDll4 overexpression also inhibited VEGF signaling and increased fibronectin accumulation around the vessels. In vitro and in vivo studies of DLL4-FL (Dll4–full-length) in ECs recapitulate many of the mDll4 transgenics findings, including decreased tube formation, reduced vascular branching, fewer vessels, increased pericyte recruitment, and increased fibronectin expression. These results establish the role of Dll4 in arterial identity determination, and regulation of angiogenesis subject to dose and location.
Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study
Authors: Young Ken H. , Leroy Karen , Møller Michael B. , Colleoni Gisele W. B. , Sánchez-Beato Margarita , Kerbauy Fábio R. , Haioun Corinne , Eickhoff Jens C. , Young Allen H. , Gaulard Philippe , Piris Miguel A. , Oberley Terry D. , Rehrauer William M. , Kahl Brad S. , Malter James S. , Campo Elias , Delabie Jan , Gascoyne Randy D. , Rosenwald Andreas , Rimsza Lisa , Huang James , Braziel Rita M. , Jaffe Elaine S. , Wilson Wyndham H. , Staudt Louis M. , Vose Julie M. , Chan Wing C. , Weisenburger Dennis D. , Greiner Timothy C.
Published: June 2008

The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.
Crystal structures of TAFI elucidate the inactivation mechanism of activated TAFI: a novel mechanism for enzyme autoregulation
Authors: Marx Pauline F. , Brondijk T. Harma C. , Plug Tom , Romijn Roland A. , Hemrika Wieger , Meijers Joost C. M. , Huizinga Eric G.
Published: June 2008

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-metallocarboxypeptidase that can be proteolytically activated (TAFIa). TAFIa is unique among carboxypeptidases in that it spontaneously inactivates with a short half-life, a property that is crucial for its role in controlling blood clot lysis. We studied the intrinsic instability of TAFIa by solving crystal structures of TAFI, a TAFI inhibitor (GEMSA) complex and a quadruple TAFI mutant (70-fold more stable active enzyme). The crystal structures show that TAFIa stability is directly related to the dynamics of a 55-residue segment (residues 296-350) that includes residues of the active site wall. Dynamics of this flap are markedly reduced by the inhibitor GEMSA, a known stabilizer of TAFIa, and stabilizing mutations. Our data provide the structural basis for a model of TAFI auto-regulation: in zymogen TAFI the dynamic flap is stabilized by interactions with the activation peptide. Release of the activation peptide increases dynamic flap mobility and in time this leads to conformational changes that disrupt the catalytic site and expose a cryptic thrombin-cleavage site present at Arg302. This represents a novel mechanism of enzyme control that enables TAFI to regulate its activity in plasma in the absence of specific inhibitors.
A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function
Authors: Lasry Inbal , Berman Bluma , Straussberg Rachel , Sofer Yael , Bessler Hanna , Sharkia Mohamad , Glaser Fabian , Jansen Gerrit , Drori Stavit , Assaraf Yehuda G.
Published: June 2008

Hereditary folate malabsorption (HFM) patients harbor inactivating mutations including R113S in the proton-coupled folate transporter (PCFT), an intestinal folate transporter with optimal activity at acidic pH. Here we identified and characterized a novel R113C mutation residing in the highly conserved first intracellular loop of PCFT. Stable transfectants overexpressing a Myc-tagged wild-type (WT) and mutant R113C PCFT displayed similar transporter targeting to the plasma membrane. However, whereas WT PCFT transfectants showed a 22-fold increase in [3H]folic acid influx at pH 5.5, R113C or mock transfectants showed no increase. Moreover, WT PCFT transfectants displayed a 50% folic acid growth requirement concentration of 7 nM, whereas mock and R113C transfectants revealed 24- to 27-fold higher values. Consistently, upon fluorescein-methotrexate labeling, WT PCFT transfectants displayed a 50% methotrexate displacement concentration of 50 nM, whereas mock and R113C transfectants exhibited 12- to 14-fold higher values. Based on the crystal structure of the homologous Escherichia coli glycerol-3-phosphate transporter, we propose that the cationic R113 residue of PCFT is embedded in a hydrophobic pocket formed by several transmembrane helices that may be part of a folate translocation pore. These findings establish a novel loss of function mutation in HFM residing in an intracellular loop of PCFT crucial for folate transport.
Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma
Authors: Kristinsson Sigurdur Y. , Fears Thomas R. , Gridley Gloria , Turesson Ingemar , Mellqvist Ulf-Henrik , Björkholm Magnus , Landgren Ola
Published: June 2008

Patients with multiple myeloma (MM) have an increased risk of deep venous thrombosis (DVT), particularly when treated with immunomodulatory drugs. Recently, 2 small hospital-based studies observed persons with the MM precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to be at increased risk of developing DVT. Among 4 196 197 veterans hospitalized at least once at US Veterans Affairs hospitals, we identified a total of 2374 cases of MGUS, and 39 272 persons were diagnosed with DVT (crude incidence 0.9 per 1000 person-years). A total of 31 and 151 DVTs occurred among MGUS and MM patients, respectively (crude incidence 3.1 and 8.7 per 1000 person-years, respectively; P < .01). Compared with the entire study population, the relative risk (RR) of DVT after a diagnosis of MGUS and MM was 3.3 (95% confidence interval [CI], 2.3-4.7) and 9.2 (95% CI, 7.9-10.8), respectively. The most prominent excess risk of DVT was found during the first year after diagnosis of MGUS (RR = 8.4; 95% CI, 5.7-12.2) and MM (RR = 11.6; 95% CI, 9.2-14.5). Among 229 MGUS cases (9.5%) that progressed to MM, only one person had a DVT diagnosis before transformation. Our findings suggest the operation of shared underlying mechanisms causing coagulation abnormalities among patients with MGUS and MM.
Inferring modules of functionally interacting proteins using the Bond Energy Algorithm
Authors: Watanabe Ryosuke LA , Morett Enrique , Vallejo Edgar E
Published: June 2008

Background

Non-homology based methods such as phylogenetic profiles are effective for predicting functional relationships between proteins with no considerable sequence or structure similarity. Those methods rely heavily on traditional similarity metrics defined on pairs of phylogenetic patterns. Proteins do not exclusively interact in pairs as the final biological function of a protein in the cellular context is often hold by a group of proteins. In order to accurately infer modules of functionally interacting proteins, the consideration of not only direct but also indirect relationships is required.

In this paper, we used the Bond Energy Algorithm (BEA) to predict functionally related groups of proteins. With BEA we create clusters of phylogenetic profiles based on the associations of the surrounding elements of the analyzed data using a metric that considers linked relationships among elements in the data set.

Results

Using phylogenetic profiles obtained from the Cluster of Orthologous Groups of Proteins (COG) database, we conducted a series of clustering experiments using BEA to predict (upper level) relationships between profiles. We evaluated our results by comparing with COG's functional categories, And even more, with the experimentally determined functional relationships between proteins provided by the DIP and ECOCYC databases. Our results demonstrate that BEA is capable of predicting meaningful modules of functionally related proteins. BEA outperforms traditionally used clustering methods, such as k-means and hierarchical clustering by predicting functional relationships between proteins with higher accuracy.

Conclusion

This study shows that the linked relationships of phylogenetic profiles obtained by BEA is useful for detecting functional associations between profiles and extending functional modules not found by traditional methods. BEA is capable of detecting relationship among phylogenetic patterns by linking them through a common element shared in a group. Additionally, we discuss how the proposed method may become more powerful if other criteria to classify different levels of protein functional interactions, as gene neighborhood or protein fusion information, is provided.
Partial mixture model for tight clustering of gene expression time-course
Authors: Yuan Yinyin , Li Chang-Tsun , Wilson Roland
Published: June 2008

Background

Tight clustering arose recently from a desire to obtain tighter and potentially more informative clusters in gene expression studies. Scattered genes with relatively loose correlations should be excluded from the clusters. However, in the literature there is little work dedicated to this area of research. On the other hand, there has been extensive use of maximum likelihood techniques for model parameter estimation. By contrast, the minimum distance estimator has been largely ignored.

Results

In this paper we show the inherent robustness of the minimum distance estimator that makes it a powerful tool for parameter estimation in model-based time-course clustering. To apply minimum distance estimation, a partial mixture model that can naturally incorporate replicate information and allow scattered genes is formulated. We provide experimental results of simulated data fitting, where the minimum distance estimator demonstrates superior performance to the maximum likelihood estimator. Both biological and statistical validations are conducted on a simulated dataset and two real gene expression datasets. Our proposed partial regression clustering algorithm scores top in Gene Ontology driven evaluation, in comparison with four other popular clustering algorithms.

Conclusion

For the first time partial mixture model is successfully extended to time-course data analysis. The robustness of our partial regression clustering algorithm proves the suitability of the combination of both partial mixture model and minimum distance estimator in this field. We show that tight clustering not only is capable to generate more profound understanding of the dataset under study well in accordance to established biological knowledge, but also presents interesting new hypotheses during interpretation of clustering results. In particular, we provide biological evidences that scattered genes can be relevant and are interesting subjects for study, in contrast to prevailing opinion.
Genome-scale cluster analysis of replicated microarrays using shrinkage correlation coefficient
Authors: Yao Jianchao , Chang Chunqi , Salmi Mari L , Hung Yeung Sam , Loraine Ann , Roux Stanley J
Published: June 2008

Background

Currently, clustering with some form of correlation coefficient as the gene similarity metric has become a popular method for profiling genomic data. The Pearson correlation coefficient and the standard deviation (SD)-weighted correlation coefficient are the two most widely-used correlations as the similarity metrics in clustering microarray data. However, these two correlations are not optimal for analyzing replicated microarray data generated by most laboratories. An effective correlation coefficient is needed to provide statistically sufficient analysis of replicated microarray data.

Results

In this study, we describe a novel correlation coefficient, shrinkage correlation coefficient (SCC), that fully exploits the similarity between the replicated microarray experimental samples. The methodology considers both the number of replicates and the variance within each experimental group in clustering expression data, and provides a robust statistical estimation of the error of replicated microarray data. The value of SCC is revealed by its comparison with two other correlation coefficients that are currently the most widely-used (Pearson correlation coefficient and SD-weighted correlation coefficient) using statistical measures on both synthetic expression data as well as real gene expression data fromSaccharomyces cerevisiae. Two leading clustering methods, hierarchical and k-means clustering were applied for the comparison. The comparison indicated that using SCC achieves better clustering performance. Applying SCC-based hierarchical clustering to the replicated microarray data obtained from germinating spores of the fernCeratopteris richardii, we discovered two clusters of genes with shared expression patterns during spore germination. Functional analysis suggested that some of the genetic mechanisms that control germination in such diverse plant lineages as mosses and angiosperms are also conserved among ferns.

Conclusion

This study shows that SCC is an alternative to the Pearson correlation coefficient and the SD-weighted correlation coefficient, and is particularly useful for clustering replicated microarray data. This computational approach should be generally useful for proteomic data or other high-throughput analysis methodology.
Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains
Authors: Tadepally Hamsa D , Burger Gertraud , Aubry Muriel
Published: June 2008

Background

C2H2 zinc finger genes (C2H2-ZNF) constitute the largest class of transcription factors in humans and one of the largest gene families in mammals. Often arranged in clusters in the genome, these genes are thought to have undergone a massive expansion in vertebrates, primarily by tandem duplication. However, this view is based on limited datasets restricted to a single chromosome or a specific subset of genes belonging to the large KRAB domain-containing C2H2-ZNF subfamily.

Results

Here, we present the first comprehensive study of the evolution of the C2H2-ZNF family in mammals. We assembled the complete repertoire of human C2H2-ZNF genes (718 in total), about 70% of which are organized into 81 clusters across all chromosomes. Based on an analysis of their N-terminal effector domains, we identified two new C2H2-ZNF subfamilies encoding genes with a SET or a HOMEO domain. We searched for the syntenic counterparts of the human clusters in other mammals for which complete gene data are available: chimpanzee, mouse, rat and dog. Cross-species comparisons show a large variation in the numbers of C2H2-ZNF genes within homologous mammalian clusters, suggesting differential patterns of evolution. Phylogenetic analysis of selected clusters reveals that the disparity in C2H2-ZNF gene repertoires across mammals not only originates from differential gene duplication but also from gene loss. Further, we discovered variations among orthologs in the number of zinc finger motifs and association of the effector domains, the latter often undergoing sequence degeneration. Combined with phylogenetic studies, physical maps and an analysis of the exon-intron organization of genes from the SCAN and KRAB domains-containing subfamilies, this result suggests that the SCAN subfamily emerged first, followed by the SCAN-KRAB and finally by the KRAB subfamily.

Conclusion

Our results are in agreement with the "birth and death hypothesis" for the evolution of C2H2-ZNF genes, but also show that this hypothesis alone cannot explain the considerable evolutionary variation within the subfamilies of these genes in mammals. We, therefore, propose a new model involving the interdependent evolution of C2H2-ZNF gene subfamilies.