Biomedical subjects

James Song

Publications and source records attributed to James Song.

15 recordsLinked to original sources

PubMed2025

IgStrand: A universal residue numbering scheme for the immunoglobulin-fold (Ig-fold) to study Ig-proteomes and Ig-interactomes.

The Immunoglobulin fold (Ig-fold) is found in proteins from all domains of life and represents the most populous fold in the human genome, with current estimates ranging from 2 to 3% of protein coding regions. That proportion is much higher in the surfaceome where Ig and Ig-like domains orchestrate cell-cell recognition, adhesion and signaling. The ability of Ig-domains to reliably fold and self-assemble through highly specific interfaces represents a remarkable property of these domains, making them key elements of molecular interaction systems: the immune system, the nervous system, the vascular system and the muscular system. We define a universal residue numbering scheme, common to all domains sharing the Ig-fold in order to study the wide spectrum of Ig-domain variants constituting the Ig-proteome and Ig-Ig interactomes at the heart of these systems. The "IgStrand numbering scheme" enables the identification of Ig structural proteomes and interactomes in and between any species, and comparative structural, functional, and evolutionary analyses. We review how Ig-domains are classified today as topological and structural variants and highlight the "Ig-fold irreducible structural signature" shared by all of them. The IgStrand numbering scheme lays the foundation for the systematic annotation of structural proteomes by detecting and accurately labeling Ig-, Ig-like and Ig-extended domains in proteins, which are poorly annotated in current databases and opens the door to accurate machine learning. Importantly, it sheds light on the robust Ig protein folding algorithm used by nature to form beta sandwich supersecondary structures. The numbering scheme powers an algorithm implemented in the interactive structural analysis software iCn3D to systematically recognize Ig-domains, annotate them and perform detailed analyses comparing any domain sharing the Ig-fold in sequence, topology and structure, regardless of their diverse topologies or origin. The scheme provides a robust fold detection and labeling mechanism that reveals unsuspected structural homologies among protein structures beyond currently identified Ig- and Ig-like domain variants. Indeed, multiple folds classified independently contain a common structural signature, in particular jelly-rolls. Examples of folds that harbor an "Ig-extended" architecture are given. Applications in protein engineering around the Ig-architecture are straightforward based on the universal numbering.

Humans↗

PubMed2006

Randomized controlled trial of moxifloxacin compared with piperacillin-tazobactam and amoxicillin-clavulanate for the treatment of complicated intra-abdominal infections.

OBJECTIVE: To compare the safety and efficacy of sequential intravenous (IV) to oral (PO) moxifloxacin treatment against a standard antimicrobial regimen of IV piperacillin-tazobactam followed by PO amoxicillin-clavulanate for the treatment of adults with complicated intra-abdominal infection (cIAI). SUMMARY BACKGROUND DATA: cIAIs are commonly due to mixed aerobic and anaerobic bacteria and require both source control and broad-spectrum antibiotic therapy. METHODS: A prospective, double-blind, randomized, phase III comparative trial. Patients with cIAI were stratified by disease severity (APACHE II score) and randomized to either IV/PO moxifloxacin (400 mg q24 hours) or comparator (IV piperacillin-tazobactam [3.0/0.375 g q6 hours] +/- PO amoxicillin-clavulanate [800 mg/114 mg q12 hours]), each for 5 to 14 days. The primary efficacy variable was clinical cure rate at the test-of-cure visit (days 25-50). Bacteriologic outcomes were also determined. RESULTS: : Of 656 intent-to-treat patients, 379 (58%) were valid to assess efficacy (183 moxifloxacin, 196 comparator). Demographic and baseline medical characteristics were similar between the 2 groups. Clinical cure rates at test-of-cure were 80% (146 of 183) for moxifloxacin versus 78% (153 of 196) for comparator (95% confidence interval, -7.4%, 9.3%). The clinical cure rate at test-of-cure for hospital-acquired cIAI was higher with moxifloxacin (82%, 22 of 27) versus comparator (55%, 17 of 31; P = 0.05); rates were similar for community-acquired infections (80% [124 of 156] versus 82% [136 of 165], respectively). Bacterial eradication rates were 78% (117 of 150) with moxifloxacin versus 77% (126 of 163) in the comparator group (95% confidence interval, -9.9%, 8.7%). CONCLUSIONS: Once daily IV/PO moxifloxacin monotherapy was as least as effective as standard IV piperacillin-tazobactam/PO amoxicillin-clavulanate dosed multiple times daily for the treatment of cIAIs.

Abdominal Abscess↗

PubMed2005

Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia.

Phospholipid transfer protein (PLTP) participates in key processes in lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. The impact of PLTP on reverse cholesterol transport suggests that the gene may harbor sequence anomalies that contribute to disorders of HDL metabolism. The human PLTP gene was screened for sequence anomalies by DNA melting analysis in 276 subjects with hypoalphalipoproteinemia (HA) and 364 controls. The association with plasma lipid parameters was evaluated. We discovered 18 sequence variations, including four missense mutations and a novel polymorphism (c.-34G > C). In healthy controls, the c.-34G > C minor allele was associated with higher high density lipoprotein-cholesterol (HDL-C) and was depleted in subjects with HA. Linear regression models predict that possession of the rare allele decreases plasma triglyceride (TG) and TG/HDL-C and increases HDL-C independent of TG. Decreased PLTP activity was observed in one (p.R235W) of four (p.E72G, p.S119A, p.S124Y, and p.R235W) mutations in an in vitro activity assay. These findings indicate that PLTP gene variation is an important determinant of plasma lipoproteins and affects disorders of HDL metabolism.

Adult↗

PubMed2005

Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling.

BACKGROUND: Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarction (MI) contributes to adverse left ventricular (LV) remodeling; however, noninvasive methods to monitor this process serially are needed. METHODS AND RESULTS: MMP-targeted radiotracers were developed that displayed selective binding kinetics to the active MMP catalytic domain. Initial nonimaging studies were performed with a (111)In-labeled MMP-targeted radiotracer ((111)In-RP782) and negative control compound ((111)In-RP788) in control mice (Ctrl) and in mice 1 week after surgically induced MI. Localization of (111)In-RP782 was demonstrated within the MI by microautoradiography. A 334+/-44% increase (P<0.001 versus Ctrl) in relative retention of (111)In-RP782 was confirmed by gamma well counting of myocardium. Subsequent high-resolution dual-isotope planar and hybrid micro-single-photon emission computed tomography/CT imaging studies with an analogous 99mTc-labeled MMP-targeted radiotracer (99mTc-RP805) and 201Tl demonstrated favorable biodistribution and clearance kinetics of 99mTc-RP805 for in vivo cardiac imaging, with robust retention 1 to 3 weeks after MI in regions of decreased 201Tl perfusion. Gamma well counting yielded a similar approximately 300% increase in relative myocardial retention of 99mTc-RP805 in MI regions (Ctrl, 102+/-9%; 1 week, 351+/-77%; 2 weeks, 291+/-45%; 3 weeks, 292+/-41%; P<0.05 versus Ctrl). Myocardial uptake in the MI region was also significantly increased approximately 5-fold when expressed as percentage injected dose per gram tissue. There was also a significant 2-fold increase in myocardial activity in remote regions relative to control mice, suggesting activation of MMPs in regions remote from the MI. CONCLUSIONS: This novel noninvasive targeted MMP radiotracer imaging approach holds significant diagnostic potential for in vivo localization of MMP activation and tracking of MMP-mediated post-MI remodeling.

Animals↗

PubMed2005

Sequential intravenous/oral moxifloxacin versus intravenous piperacillin-tazobactam followed by oral amoxicillin-clavulanate for the treatment of complicated skin and skin structure infection.

In this prospective, double-blind, multicentre trial, adult patients with complicated skin and skin structure infection (cSSSI) randomly received sequential intravenous (i.v.)/oral (p.o.) moxifloxacin (400 mg once a day) or a control regimen of i.v. piperacillin-tazobactam (3.0/0.375 g every 6 h) followed by p.o. amoxicillin-clavulanate (800 mg every 12 h), each for 7-14 days. Clinical cure rates at the test-of-cure visit (10-42 days post therapy) for the efficacy-valid population were 79% (143/180) for the moxifloxacin-treated group and 82% (153/187) for the control group (95% confidence interval, -12.04, 3.29). Bacteriological eradication rates for Staphylococcus aureus, the most prevalent organism, were 78% and 80%, respectively. The incidence of drug-related adverse events was similar for both groups (31% moxifloxacin, 30% control). Sequential i.v./p.o. moxifloxacin was as effective and well tolerated as i.v. piperacillin-tazobactam followed by p.o. amoxicillin-clavulanate in treating patients with cSSSI.

Administration, Oral↗

PubMed2005

Noninvasive imaging of angiogenesis with a 99mTc-labeled peptide targeted at alphavbeta3 integrin after murine hindlimb ischemia.

BACKGROUND: Noninvasive imaging strategies play a critical role in assessment of the efficacy of angiogenesis therapies. The alpha(v)beta3 integrin is activated in angiogenic vessels and represents a potential target for noninvasive imaging of angiogenesis. METHODS AND RESULTS: We evaluated a 99mTc-labeled peptide (NC100692) targeted at alpha(v)beta3 integrin for imaging in an established murine model of angiogenesis induced by hindlimb ischemia. Control mice (n=9) or mice with surgical right femoral artery occlusion (n=29) were injected with NC100692 (1.5+/-0.2 mCi IV) at different times after femoral occlusion (1, 3, 7, and 14 days) for in vivo pinhole planar gamma camera imaging. Tissue from hindlimb proximal and distal to occlusion was excised for gamma well counting and for immunostaining. On in vivo pinhole images, increased focal NC100692 activity was seen distal to the occlusion at days 3 and 7. This increase in relative NC100692 activity was confirmed by gamma well counting. Lectin staining confirmed increased angiogenesis in the ischemic hindlimb at these time points. A fluorescent analogue of NC100692 was used to confirm specificity and localization of the targeted tracer in cultured endothelial cells. In addition, endothelial cell specificity was confirmed on tissue sections with the use of dual immunofluorescent staining of endothelium and the fluorescent analogue targeted at the alpha(v)beta3 integrin. CONCLUSIONS: A 99mTc-labeled peptide (NC100692) targeted at alpha(v)beta3 integrin selectively localized to endothelial cells in regions of increased angiogenesis and could be used for noninvasive serial "hot spot" imaging of angiogenesis. This targeted radiotracer imaging approach is a major advance in tracking therapeutic myocardial angiogenesis and has an important clinical potential.

Animals↗

PubMed2005

Time to symptom relief for uncomplicated urinary tract infection treated with extended-release ciprofloxacin: a prospective, open-label, uncontrolled primary care study.

OBJECTIVE: Few studies have investigated symptom relief in urinary tract infections. This innovative exploratory trial aimed to measure the time to improvement of the signs and symptoms of uncomplicated urinary tract infection (UTI) in women receiving extended-release ciprofloxacin. Time to return to normal daily activities was also evaluated. RESEARCH DESIGN AND METHODS: An open-label, multicenter US study in adult female outpatients with uncomplicated UTI. Patients completed serial questionnaires: the Urinary tract infection Symptom Assessment [USA], tracking time to symptom improvement, and the Activity Impairment Assessment [AIA], measuring the time to return to normal daily activities, using hand-held electronic diaries. Severity on the USA questionnaire was categorized using a 4-point Likert-type scale, with improvement defined as a reduction of at least one degree of symptom severity. All patients received once-daily extended-release ciprofloxacin 500 mg tablets for 3 days. RESULTS: Of 276 female patients aged 18-78 years who enrolled at 28 sites, 273 (99%) were safety-valid, 264 (96%) completed at least 24 h of questionnaires and were valid for symptom relief analysis, and 170 (62%) had pre-therapy pathogen(s) > or = 10(3) CFU/mL and were valid for efficacy analysis. Six hours after the first dose of study drug, 50% of patients reported symptom improvement; 87% by 24 h and 91% by 48 h. At study entry, 54% of patients reported considerably decreased time at work or other activities; reduced to 23% by Day 2 and 10% by Day 3. At the test-of-cure visit (5-11 days post-therapy), 96% (163/170) of patients were clinical cures. Drug-related adverse events were reported by 18 (7%) patients and were consistent with previous extended-release ciprofloxacin studies (e.g., gastrointestinal disturbance, fungal superinfections). There were no serious adverse events or discontinuations due to adverse events. CONCLUSION: This open-label, non-comparative trial in adult women demonstrated a rapid improvement in uncomplicated UTI symptom severity (6-24 h) and the ability to return to work within 24 h following extended-release ciprofloxacin treatment. Clinical cure rate and tolerability profile were similar to results of previous extended-release ciprofloxacin studies.

Acute Disease↗

PubMed2004

Safety and efficacy of sequential i.v. to p.o. moxifloxacin versus conventional combination therapies for the treatment of community-acquired pneumonia in patients requiring initial i.v. therapy.

To compare the efficacy of sequential i.v. to p.o. moxifloxacin with ceftriaxone +/- azithromycin +/- metronidazole for the treatment of patients with community acquired pneumonia (CAP), a multi-centered, prospective, randomized, open label study was performed. CAP patients were randomized to moxifloxacin (400 mg/d-at least one i.v. dose) or ceftriaxone (at least one dose of 2 g i.v. q.d. followed by cefuroxime 500 mg p.o. b.i.d.) +/- azithromycin, +/- metronidazole (cephalosporin/macrolide control: CMC). The primary endpoint was clinical response at test-of-cure (TOC) visit. Bacteriological response at TOC was the secondary endpoint. Clinical cure was found in 83.3% (90/108) of moxifloxacin patients and 79.6% (90/113) of control patients. Microbiological responses were 81.8% (18/22) for moxifloxacin and 60.7% (17/28) for CMC patients. Drug-related adverse events occurred in 18.0% of moxifloxacin and 16% of CMC patients. It is concluded that i.v. to p.o. moxifloxacin is as effective as CMC for treatment of CAP and is a reliable alternative antimicrobial therapy.

Adult↗

PubMed2004

Discourse macrolevel processing after severe pediatric traumatic brain injury.

The purpose of this study was to determine if discourse macrolevel processing abilities differed between children with severe traumatic brain injury (TBI) at least 2 years postinjury and typically developing children. Twenty-three children had sustained a severe TBI either before the age of 8 (n = 10) or after the age of 8 (n = 13). The remaining 32 children composed a control group of typically developing peers. The groups' summaries and interpretive lesson statements were analyzed according to reduction and transformation of narrative text information. Compared to the control group, the TBI group condensed the original text information to a similar extent. However, the TBI group produced significantly less transformed information during their summaries, especially those children who sustained early injuries. The TBI and control groups did not significantly differ in their production of interpretive lesson statements. In terms of related skills, discourse macrolevel summarization ability was significantly related to problem solving but not to lexical or sentence level language skills or memory. Children who sustain a severe TBI early in childhood are at an increased risk for persisting deficits in higher level discourse abilities, results that have implications for academic success and therapeutic practices.

Adolescent↗

PubMed2004

Components of executive function in typically developing and head-injured children.

To identify the key components of executive functions (EFs) in children following traumatic brain injury (TBI), data from a series of EF tests administered to 286 pediatric TBI patients at least 3 years postinjury were subjected to an exploratory factor analysis. A 5-factor model included discourse, EFs (e.g., problem solving, planning), processing speed (e.g., coding), declarative memory, and motor speed. Confirmatory factor analysis based on data obtained from 265 pediatric TBI patients at 3 months postinjury disclosed that the 5-factor model provided a good fit to the data. A second exploratory analysis of the 3-month postinjury data disclosed a 4-factor model in which processing speed and motor speed measures loaded on a common factor. Severity of TBI and age at test had significant effects on all factors in both the 5- and 4-factor models. Adaptive functioning, as measured by the Vineland Adaptive Behavioral Scale-Revised, was moderately related to factor scores at 3 years or longer postinjury, but weakly related to factor scores obtained at 3 months postinjury. The factor scores could be used in clinical trials to facilitate data reduction and appear to have validity as indicators of TBI outcome.

Activities of Daily Living↗

PubMed2004

Childhood head injury and metacognitive processes in language and memory.

We studied the metacognitive functioning of children with severe and mild traumatic brain injury (TBI) and typically developing children. To test metacognition for memory, children were tested on a modified Judgment of Learning task. We found that children with severe TBI were impaired in their ability to predict recall of specific items prior to study-recall trials, but were unimpaired in predicting recall on a delayed test when the judgment was made after study-recall trials. Metacognitive knowledge impairment for memorial abilities was also demonstrated in children with severe TBI by poor estimation of memory span and exaggerated overconfidence in performance. To test metacognition within the language domain, we gave children a sentence anomaly detection and repair task in which spoken sentences were monitored for semantic anomalies. Children with severe TBI were impaired on the detection of semantic anomalies, especially under conditions of high memory load. However, metalinguistic knowledge in the form of adequate repairs of anomalous sentences, was preserved. Results are discussed in terms of effects of age at test and injury severity.

Adolescent↗

PubMed2004

Modeling of longitudinal academic achievement scores after pediatric traumatic brain injury.

In a prospective longitudinal study, academic achievement scores were obtained from youth 5 to 15 years of age who sustained mild-moderate (n = 34) or severe (n = 43) traumatic brain injuries (TBI). Achievement scores were collected from baseline to 5 years following TBI and were subjected to individual growth curve analysis. The models fitted age at injury, years since injury, duration of impaired consciousness, and interaction effects to Reading Decoding, Reading Comprehension, Spelling, and Arithmetic standard scores. Although scores improved significantly over the follow-up relative to normative data from the standardization sample of the tests, children with severe TBI showed persistent deficits on all achievement scores in comparison to children with mild-moderate TBI. Interactions of the slope and age parameters for the Arithmetic and Reading Decoding scores indicated greater increases over time in achievement scores of the children injured at an older age, but deceleration in growth curves for the younger children with both mild-moderate and severe TBI. These results are compatible with the hypothesis that early brain injuries disrupt the acquisition of some academic skills. Hierarchical regression models revealed that indexes of academic achievement obtained 2 years following TBI had weak relations with the duration of impaired consciousness and socioeconomic status. In contrast, concurrent cognitive variables such as phonological processing and verbal memory accounted for more variability in academic scores. Given the significant and persistent decrement in basic academic skills in youth with severe TBI, it is clear that head-injured youth require intensive, long-term remediation and intervention not only of the academic skills themselves, but also of those cognitive abilities that support the development and maintenance of reading and math.

Achievement↗

PubMed2004

Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis.

PURPOSE: We assessed the efficacy and safety of 1,000 mg extended release ciprofloxacin orally once daily vs conventional 500 mg ciprofloxacin orally twice daily, each for 7 to 14 days, in patients with a complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP). MATERIALS AND METHODS: In this prospective, randomized, double-blind, North American multicenter clinical trial adults were stratified based on clinical presentation of cUTI or AUP and randomized to extended release ciprofloxacin or ciprofloxacin twice daily. Efficacy valid patients had positive pretherapy urine cultures (105 or greater cFU/ml) and pyuria within 48 hours of study entry. Bacteriological and clinical outcomes were assessed at the test of cure visit (5 to 11 days after therapy) and the late followup visit (28 to 42 days after therapy). RESULTS: The intent to treat population comprised 1,035 patients (extended release ciprofloxacin in 517 and twice daily in 518), of whom 435 were efficacy valid (cUTI in 343 and AUP in 92). For efficacy valid patients (cUTI and AUP combined) bacteriological eradication rates at test of cure were 89% (183 of 206) vs 85% (195 of 229) (95% CI -2.4%, 10.3%) and clinical cure rates were 97% (198 of 205) vs 94% (211 of 225) (95% CI -1.2%, 6.9%) for extended release vs twice daily ciprofloxacin. Late followup outcomes were consistent with test of cure findings. Eradication rates for Escherichia coli, which accounted for 58% of pathogens, were 97% or greater per group. Drug related adverse event rates were similar for extended release and twice daily ciprofloxacin (13% and 14%, respectively). CONCLUSIONS: Extended release ciprofloxacin at a dose of 1,000 mg once daily was as safe and effective as conventional treatment with 500 mg ciprofloxacin twice daily, each given orally for 7 to 14 days in adults with cUTI or AUP. It provides a convenient, once daily, empirical treatment option.

Acute Disease↗

PubMed2002

Detection of herpes simplex virus type 2-specific immunoglobulin G antibodies in African sera by using recombinant gG2, Western blotting, and gG2 inhibition.

Sera (n = 781) from four African countries were used to determine the prevalence of herpes simplex virus type 2 (HSV-2) antibodies by using the HerpeSelect HSV-2 enzyme-linked immunosorbent assay (ELISA; Focus Technologies) and Western blotting (WB). Also, an HSV inhibition assay was developed to evaluate the discordant sample results between HerpesSelect and WB. The seroprevalence of HSV-2 ranged from 17% in the South African panel to nearly 70% in panels from Kenya, Uganda, and Zimbabwe. Overall, HerpeSelect was 100% sensitive and 88% specific compared to WB and 100% sensitive and 96% specific compared to the inhibition assay. There was 100% concordance among all three assays for samples from South Africa and Zimbabwe. The discordant results occurred in samples from Kenya and Uganda.

Africa↗

PubMed2002

The role of injury severity in neurobehavioral outcome 3 months after traumatic brain injury.

OBJECTIVE/BACKGROUND: To assess neurobehavioral outcome using the Neurobehavioral Rating Scale-Revised (NRS-R), an instrument with established specificity and validity in Traumatic Brain Injury (TBI) in a sample including the full spectrum of TBI severity 3 months after injury. METHOD: A cohort group of 102 subjects with mild TBI, 41 with moderate TBI, and 139 with severe TBI, from multiple academic trauma centers, were assessed using the NRS-R and the Glasgow Outcome Scale. RESULTS: Principal components analysis of the NRS-R resulted in a 3-factor model: (1) Cognitive, (2) Emotional, and (3) Hyperarousal. At 3 months, subjects with severe TBI show greater difficulties in cognitive and hyperarousal, but not emotional domains, than those with mild to moderate TBI. More than one third of subjects in all injury severity groups showed evidence of anxiety, depression, irritability, mental fatigability, and memory dysfunction. Scores on the NRS-R were related to outcome on the Glasgow Outcome Scale. CONCLUSIONS: Three months after injury, subjects with severe TBI have more dysfunction in cognitive and behavioral (but not emotional) domains than those with mild-to-moderate TBI. The NRS-R is a useful tool for assessing the full spectrum of neurobehavioral dysfunction at all ranges of TBI severity.

Adult↗