Acceptance and use of patient-carried health records.
The ultimate goals of providing health records to patients are to improve continuity of care, to improve patient understanding of instructions, and to encourage patients to take a more active role in maintaining their health. In the current study, four types of patient-carried health records were evaluated in a hospital-based outpatient service to determine whether records would be accepted and used, to estimate the cost of the process, and to obtain patient and provider reactions. Records were provided at moderate cost and the primary determinants in record acceptance and use were physicians' support of the process, the type of record, and the employment status of the patient. A small record which could be carried in a wallet seemed suited to most patients; other more elaborate participatory records appeared to have benefits for selected patients. More extensive use of participatory records appears to require changes in the way health care would be delivered.


Effects of oral alendronate on BMD in adult patients with osteogenesis imperfecta: a 3-year randomized placebo-controlled trial.
A 3-year, randomized, double-blind, placebo-controlled trial evaluated the effect of oral alendronate on the BMD of 64 adult patients with osteogenesis imperfecta. The mean increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Oral alendronate increases BMD in adult patients with osteogenesis imperfecta. This study evaluated the effect of oral alendronate on the BMD of adult patients with osteogenesis imperfecta. We carried out a 3-year, randomized, double-blind, placebo-controlled trial of oral alendronate in 64 adult patients with osteogenesis imperfecta. The primary endpoint was the difference between the groups in the mean percent change in lumbar spine BMD at 3 years. Secondary outcomes included changes in BMD of total hip, vertebral and peripheral fracture incidence, pain, hearing loss, and bone turnover biochemical markers. Patients were treated daily with either placebo or 10 mg alendronate. All received 1 g of calcium and 800 IU of vitamin D daily. The mean +/- SD increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Hip BMD increased in the alendronate group by 3.3 +/- 0.5% (p = 0.001) and decreased in the placebo group by 0.3 +/- 0.6%. The sample size was not sufficient to determine an effect of alendronate on fracture rate. A significant increase of the pain score was noted in the alendronate group (p = 0.04) in the intent-to-treat analysis but not in the per protocol analysis. There was no change in hearing in either group. Bone resorption and formation biochemical markers were significantly decreased in the alendronate group (p < 0.001). There were no differences in severe adverse effects between the groups, but there was an increase in nonsevere upper gastrointestinal effects in the alendronate group (p = 0.003). Oral alendronate increases BMD and increase nonsevere gastrointestinal adverse effects but does not modify the hearing loss in adult patients with osteogenesis imperfecta. More studies are needed to evaluate an effect on the fracture rate.


[Comparison of anti-influenza vaccines: whole adsorbed trivalent, trivalent subunit and tetravalent subunit].
Two different sub-unit polyvalent vaccines have been compared with the trivalent whole virus adsorbed vaccine, in two different groups of people, including both sexes, aging between 20 and 60 yrs. and between 65 and 85 yrs. respectively. Our findings show that all the three vaccines induced high seroconversion rates against the subtypes A/Mississippi/1/85 and A/Chile/1/83. As to the strain B/Ann Arbor/1/86 the sub-unit vaccine induced significantly higher seroconversion rates then the whole virus vaccine; the geometric mean titer has been higher in the groups given the vaccine than in the remaining group; in the latter group the GMTs of antibody against the A strains were consistently above the protective level, whereas the GMT of antibody against the B strain was fairly low. The authors consider useless including into the vaccine the strains A/Mississippi/1/85 and A/Chile/1/83, whereas it seems to be essential the incorporation of the strains A/Singapore/1/86 like and B/Ann Arbor/1/86. Moreover it turns out that the sub-unit vaccines, because of their better effectiveness, should substitute the whole virus adsorbed vaccine.


A T-DNA mutant screen that combines high-throughput phenotyping with the efficient identification of mutated genes by targeted genome sequencing.
Nitrogen dioxide (NO2) triggers hypersensitive response (HR)-like cell death in Arabidopsis thaliana. A high-throughput mutant screen was established to identify genes involved in this type of programmed cell death. Altogether 14,282 lines of SALK T-DNA insertion mutants were screened. Growing 1000 pooled mutant lines per tray and simultaneous NO2 fumigation of 4 trays in parallel facilitated high-throughput screening. Candidate mutants were selected based on visible symptoms. Sensitive mutants showed lesions already after fumigation for 1 h with 10 ppm (ppm) NO2 whereas tolerant mutants were hardly damaged even after treatment with 30 ppm NO2. Identification of T-DNA insertion sites by adapter ligation-mediated PCR turned out to be successful but rather time consuming. Therefore, next generation sequencing after T-DNA-specific target enrichment was tested as an alternative screening method. The targeted genome sequencing was highly efficient due to (1.) combination of the pooled DNA from 124 candidate mutants in only two libraries, (2.) successful target enrichment using T-DNA border-specific 70mer probes, and (3.) stringent filtering of the sequencing reads. Seventy mutated genes were identified by at least 3 sequencing reads. Ten corresponding mutants were re-screened of which 8 mutants exhibited NO2-sensitivity or -tolerance confirming that the screen yielded reliable results. Identified candidate genes had published functions in HR, pathogen resistance, and stomata regulation. The presented NO2 dead-or-alive screen combined with next-generation sequencing after T-DNA-specific target enrichment was highly efficient. Two researchers finished the screen within 3 months. Moreover, the target enrichment approach was cost-saving because of the limited number of DNA libraries and sequencing runs required. The experimental design can be easily adapted to other screening approaches e.g. involving high-throughput treatments with abiotic stressors or phytohormones.


Coupling Processes and Experiences of Never Married Heterosexual Black Men and Women: A Phenomenological Study.
Over the past decades, the decline in Black marriages and the upsurge of never-married Blacks have stimulated much theoretical focus, but researchers conducted few studies on never-married heterosexual Black adults' coupling unions. Guided by an integrated framework of Africana womanism and symbolic interactionism, this qualitative hermeneutic phenomenological study used comprehensive individual interviews to explore the experiences of 26 never-married heterosexual Black men and women between the ages 25 and 35 about their attempts to cultivate and maintain intimate romantic relationships as well as their desire for marriage. Findings revealed mixed emotions from participants' lived experiences in developing and sustaining romantic relationships. Clinical implications highlighted the need to effectively attend to Black romantic relationships and experiences in their sociohistorical and sociocultural contexts.


Personalized therapy of lung cancer.
The implementation of personalized approaches in the treatment of patients with non-small cell lung cancer (NSCLC) requires a precise understanding of tumor biology, a reorientation of clinical development with a strong focus on genetically stratified early phase 'proof of concept' trials, the availability of high-quality 'realtime' genetic diagnostics, and the establishment of networks for molecular screening of lung cancer patients. To achieve this goal, a close interaction between basic researchers, clinical scientists, molecular pathologists, and pharmaceutical companies is essential. We believe that this approach is worth the effort, since personalized therapy in lung cancer has the potential to substantially improve survival in an increasing number of patients. At the moment, established personalized treatment approaches include treatment of patients with NSCLC and activating epidermal growth factor receptor (EGFR) mutations with the EGFR-directed tyrosine kinase inhibitors gefitinib or erlotinib, and treatment of NSCLC patients with genetic aberrations in the anaplastic lymphoma kinase (ALK) oncogene with the mesenchymal-epithelial transition factor (MET)/ALK inhibitor crizotinib. A new approach, the treatment of fibroblast growth factor receptor 1 (FGFR1)-amplified squamous cell lung cancer patients with FGFR inhibitors, is currently being tested in phase I clinical trials.


Spectrum of renal failure in elderly patients.
This prospective study was undertaken to study the spectrum of renal failure and the outcome in elderly patients. Patients included in the study group were elderly (age>60 years) who either attended outpatient renal clinic and or were hospitalized. Renal failure was classified as acute renal failure (ARF), rapidly progressive renal failure (RPRF) and chronic renal failure (CRF). A total of 4255 elderly patients were seen, of these 236 (5.5%) had renal failure. Mean age was 65.1+/-4.2 years (60-86 years). CRF was the commonest, seen in 137 (58.1%) followed by ARF 69 (29.2%) and RPRF in 30 (12.7%) patients. Diabetic nephropathy was the commonest cause of CRF, seen in 58.4% followed by chronic interstitial nephritis in 9.5% and chronic glomerulonephritis in 8.7% of patients. Of 137 patients 53 (38.7%) presented in end stage renal disease (ESRD). Of these 41 (77.3%) were initiated on maintenance hemodialysis and 12 (22.6%) on continuous ambulatory peritoneal dialysis. Only 15 patients were on dialytic support at the end of 1 year. Sepsis contributed to ARF in 75.4% of cases. Forty of 69 patients (57.9%) needed dialytic support. Forty (57.9%) were critically ill, defined as presence of two or more organ system failures (excluding renal failure). Forty two patients (60.9%) died patients. Acute interstitial nephritis (AIN) was the commonest cause of RPRF seen in 10 (33.3%) patients followed by vasculitis in 7 (23.3%). Myeloma cast nephropathy contributed towards RPRF in 20% of patients. Of 30 patients, 10 (33.3%) reached ESRD at end of 3 months of follow up, 4 (13.3%) died due to sepsis. Only 2 showed complete recovery while 14 (46.6%) had partial improvement. AIN patients had a relatively better outcome.


Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes.
Ammonia is the principal neurotoxin implicated in the pathogenesis of hepatic encephalopathy, and astrocytes are the neural cells predominantly affected in this condition. Astrocyte swelling (cytotoxic edema) represents a critical component of the brain edema in acute form of hepatic encephalopathy (acute liver failure, ALF). Although mechanisms of astrocyte swelling by ammonia are not completely understood, cultured astrocytes exposed to pathophysiological levels of ammonia develop the mitochondrial permeability transition (mPT), a process that was shown to result in astrocyte swelling. Cyclosporin A (CsA), a traditional inhibitor of the mPT, was previously shown to completely block ammonia-induced astrocyte swelling in culture. However, the efficacy of CsA to protect cytotoxic brain edema in ALF is problematic because it poorly crosses the blood-brain barrier, which is relatively intact in ALF. We therefore examined the effect of agents that block the mPT but are also known to cross the blood-brain barrier, including pyruvate, magnesium, minocycline, and trifluoperazine on the ammonia-induced mPT, as well as cell swelling. Cultured astrocytes exposed to ammonia for 24 hr displayed the mPT as demonstrated by a CsA-sensitive dissipation of the mitochondrial inner membrane potential. Pyruvate, minocycline, magnesium, and trifluoperazine significantly blocked the ammonia-induced mPT. Ammonia resulted in a significant increase in cell volume, which was blocked by the above-mentioned agents to a variable degree. A regression analysis indicated a high correlation between the effectiveness of reducing the mPT and cell swelling. Our data suggest that all these agents have therapeutic potential in mitigating brain edema in ALF.


Increased iodine deficiency in Victoria, Australia: analysis of neonatal thyroid-stimulating hormone data, 2001 to 2006.
To use neonatal thyroid-stimulating hormone (TSH) concentration data to measure the iodine status of the population of the Australian state of Victoria. Retrospective analysis of the results of 368,552 neonatal heel-prick blood tests for TSH concentration in Victoria in the years 2001-2006. Iodine deficiency as indicated by a mean percentage of neonatal TSH concentrations > 5 mIU/L of over 3% in accordance with World Health Organization, United Nations Children's Fund and International Council for the Control of Iodine Deficiency Disorder criteria; comparison of findings for the nine Department of Human Services health regions in Victoria. The mean percentage of neonatal TSH concentrations > 5 mIU/L ranged from 4.07% in 2001 to 9.65% in 2006, and this increase was statistically significant (P < 0.001). The populations of all nine Victorian health regions showed increasing iodine deficiency over the study period. Metropolitan populations had higher iodine deficiency than non-metropolitan populations, and this difference was also statistically significant (P < 0.05). These results are consistent with urinary iodine excretion research in Victoria. The high percentage of elevated TSH concentrations among newborns is of concern and requires ongoing monitoring. Neonatal TSH assay is part of routine screening in Australia, and thus offers an effective and economical method of monitoring population iodine status.


Adrenal incidentaloma, clinical, metabolic, follow-up aspects: single centre experience.
To investigate clinical characteristics, metabolic parameters and follow-up findings of subjects with incidentally discovered adrenal tumors. 376 consecutive subjects who have been evaluated since 2002 were included. Initial radiological examination was CT. Hormonal evaluation included 8.00 a.m. cortisol, DHEA-S, ACTH and in hypertensive subjects, plasma renin activity, and serum aldosterone. Urinary free cortisol (UFC), urinary normetanephrine, and metanephrine were measured. Overnight 1 mg dexamethasone suppression test was performed. Radiological evaluation was performed at 6th and 12th months and annually in subsequent visits. Hormonal evaluation was performed 6 months after the initial visit and annually in subsequent visits. Additionally, patients were evaluated for the development of Type 2 diabetes mellitus, hypertension, hyperlipidemia, and metabolic syndrome in 6-month intervals. Mean age of the participants was 54.7 ± 13.1. Female subjects were more commonly affected (70%). CT was the most frequent radiological intervention that discovered adrenal masses (57%). The vast majority of the participants (85.6%) had benign adrenal adenomas. Primary adrenocortical malignancy was detected in 4 subjects (1.1%). Subjects with adrenal adenomas had significantly smaller tumor diameters (P ≤ 0.001 vs. other tumors). Sensitivity and specificity of 40 mm as a cut-off value in the differentiation of adrenal gland malignancies from benign tumors was 73.3 and 54.8%, respectively. Most of the adrenal adenomas were non-functioning (73.5%). Subclinical Cushing syndrome (sCS) was detected in 12.5%. The overall prevalence of Type 2 diabetes mellitus, hypertension, hyperlipidemia, and metabolic syndrome was 18.4, 54.9, 59.6, and 48.1%, respectively. They were significantly more common in middle-aged and elderly subjects. During 24 months follow-up 10.2% of adenomas featured increase in tumor diameter and 2.06% developed sCS. Young subjects featured more stable tumor diameter and hormonal status. Most of the incidentally discovered adrenal tumors were non-functioning adrenal adenomas. Clinically overt hormone hypersecretion syndromes were mainly shown in young subjects, while adrenal gland malignancies and sCS were more common in older ages. Mass enlargement and development of subclinical cortisol secretion were not rare and observed especially in middle-aged and elderly subjects. Metabolic derangements were common; however, a possible independent association between adrenal adenoma and metabolic problems need to be elucidated with prospective studies.


Gated listmode acquisition with the quadHIDAC animal PET to image mouse hearts.
The aim of this study was to develop ECG and respiratory gating in combination with listmode acquisition for the quadHIDAC small-animal PET scanner. ECG and respiratory gating was realized with the help of an external trigger device (BioVET) synchronized with the listmode acquisition. Listmode data of a mouse acquisition (injected with 6.5 MBq of 18F-FDG) were sorted according to three different gating definitions: 12 cardiac gates, 8 respiratory gates and a combination of 8 cardiac and 8 respiratory gates. Images were reconstructed with filtered back-projection (ramp filter), and parameters like left ventricular wall thickness (WT), wall-to-wall separation (WS) and blood to myocardium activity ratios (BMR) were calculated. Cardiac gated images show improvement of all parameters (WT 2.6 mm, WS 4.1 mm, BRM 2.3) in diastole compared to ungated images (WT 3.0 mm, WS 3.4 mm, BMR 1.3). Respiratory gating had little effect on calculated parameters. ECG gating with the quadHIDAC can improve myocardial image quality in mice. This could have a major impact on the calculation of an image-derived input function for kinetic modelling.


Fast real-time NMR methods for characterizing short-lived molecular states.
The characterization of both the structure and the conformational dynamics of biological macromolecules, namely proteins and nucleic acids, is required for understanding the molecular mechanisms underlying physiological function and disease. Molecular dynamics involves the transient departure from the ground-state structures to populate short-lived excited state conformations that can play important functional roles. Real-time multi-dimensional NMR spectroscopy represents a unique tool for investigating dynamic molecular processes occurring on time scales of seconds or longer, providing atomic-resolution information about short-lived states. In this minireview, we discuss recent progress made in the field of fast real-time multidimensional NMR. The potential of these new methods is illustrated for several biomolecular systems that have recently been studied by fast real-time multidimensional NMR.


Impact of aspirin resistance on outcomes among patients following coronary artery bypass grafting: exploratory analysis from randomized controlled trial (NCT01159639).
Individual variability in the response to aspirin, has been established by various platelet function assays, however, the clinical relevance of aspirin resistance (AR) in patients undergoing coronary artery bypass grafting (CABG) has to be evaluated. Our working group conducted a randomized controlled trial (NCT01159639) with the aim to assess impact of dual antiplatelet therapy (APT) on outcomes among patients with AR following CABG. Patients that were aspirin resistant on fourth postoperative day (POD 4) were randomly assigned to receive either dual APT with clopidogrel (75 mg) plus aspirin (300 mg)-intervention arm or monotherapy with aspirin (300 mg)-control arm. This exploratory analysis compares clinical outcomes between aspirin resistant patients allocated to control arm and patients that have had adequate platelet inhibitory response to aspirin at POD 4. Both groups were treated with 300 mg of aspirin per day following surgery. We sought to evaluate the impact of early postoperative AR on outcomes among patients following CABG. Exploratory analysis included a total number of 325 patients. Of those, 215 patients with adequate response to aspirin and 110 patients with AR allocated to aspirin monotherapy following randomization protocol. The primary efficacy end point (MACCEs-major adverse cardiac and cardiovascular events) occurred in 10 and 6 % of patients with AR and with adequate aspirin response, respectively (p = 0.27). Non-significant differences were observed in bleeding events occurrence. Subgroup analysis of the primary end point revealed that aspirin resistant patients with BMI > 30 kg/m(2) tend to have a higher occurrence of MACCEs 18 versus 5 % (relative risk 0.44 [95 % CI 0.16-1.16]; p = 0.05). This exploratory analysis did not reveal significant impact of aspirin resistance on outcomes among patients undergoing CABG. Further, sufficiently powered studies are needed in order to evaluate clinical relevance of AR in patients undergoing CABG.


Sequence analysis of the bovine herpesvirus type 1 genes homologous to the DNA polymerase (UL30), the major DNA-binding protein (UL29) and ICP18.5 assembly protein (UL28) genes of herpes simplex virus.
The nucleotide sequence of a 10.5 kb region (map position 0.332 to 0.410) of bovine herpesvirus type 1 (BHV-1) was determined. This region contained three open reading frames (ORFs) homologous to herpes simplex virus DNA polymerase catalytic subunit (DNApol, UL30), major DNA-binding protein (MDBP, UL29) and ICP18.5 assembly protein (ICP18.5, UL28). The BHV-1 DNApol. MDBP and ICP18.5 ORFs were 1246, 1203 and 826 amino acids long with a calculated molecular mass of 134.2 kDa, 124.4 kDa and 86.9 kDa, respectively. They showed a high homology with alphaherpesvirus homologs despite large differences in the G + C content of the UL30-UL28 segment ranging from 44.4% for varicella zoster virus to 71.5% for BHV-1. Particularly well conserved among Alphaherpesvirinae are the putative functional domains of the DNApol and MDBP proteins which are discussed. Phylogenetic analysis revealed that BHV-1 clustered in the Varicellovirus genus with the animal D-type viruses. In this group, the BHV-1 position was shown to vary according to the investigated genes. Indeed, pseudorabies virus clustered with BHV-1 in the DNApol tree but with equine herpesvirus 1 in the ICP18.5 tree.


Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy.
Activated protein C (APC) resistance phenotype/genotype discrepancy is a very rare event. The objective of this study was to characterize the molecular mechanisms in two cases of APC phenotype/genotype discrepancy. An approach using direct sequencing of each exon and splicing junctions of the factor V gene showed that two novel factor V null mutations combined with heterozygous factor V Leiden mutation were responsible for this discrepancy. Our results suggest the necessity to use both phenotypic and genotypic analyses in some cases to determine an accurate diagnosis.


Distribution of Ochlerotatus togoi along the Pacific coast of Washington.
Before this study, the mosquito Ochlerotatus (Finlaya) togoi (Theobald) had been reported from only 2 locations within the continental United States, both of which were documented in Washington State. This study used active and passive surveillance to determine the current distribution of Oc. togoi along the Pacific Coast of Washington. Results of the study show that small, but stable, populations of Oc. togoi exist in the northern San Juan Island region of Puget Sound. Geological formations in this region are conducive to rock holes and support populations of Oc. togoi. No members of Oc. togoi were found on the southwestern Washington coast, the coast of the Olympic Peninsula, or in the lower Puget Sound.


Pisrt1, a gene implicated in XX sex reversal, is expressed in gonads of both sexes during mouse development.
XX sex reversal syndromes not involving Sry provide an opportunity to identify and study genes important for sexual development. The polled intersex syndrome (PIS) in goats, which shares some features with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) in humans, exemplifies such syndromes. BPES is caused by defects in the forkhead transcription factor gene FOXL2, while PIS is caused by a large deletion of goat chromosome 1q43 that affects transcription of the genes Pisrt1 and Foxl2. Pisrt1 is a non-translated gene that has a sexually dimorphic expression pattern in goats. Here, we describe the structure and expression of the mouse Pisrt1 locus, to investigate its likely role in ovarian development more broadly in mammals. This gene showed some sequence similarity, and was found in a similar genomic context, to its goat and human orthologues. Expression analyses indicated that Pisrt1 is transcribed, and its mRNA polyadenylated and exported to the cytoplasm, but no significant open reading frames were found in a 1.5kb mouse genomic region corresponding to goat Pisrt1. Pisrt1 transcripts were expressed very broadly among tissues of the developing mouse embryo, and at similar levels in male and female gonads at each stage examined, as determined by in situ hybridisation and RT-PCR. This profile of expression suggests that Pisrt1 is unlikely to contribute to sex-specific events during gonadal development in mice and that divergent pathways of ovarian development operate among different mammalian species.


Is endoscopy necessary for the measurement of disease activity in ulcerative colitis?
Many disease activity indices are used to measure ulcerative colitis. Invasive indices incorporate an endoscopic score, while noninvasive indices do not require endoscopy. In clinical practice, many patients are treated based on their symptoms without endoscopic evaluation. However, invasive indices are commonly used in clinical research. Our objective was to determine whether endoscopy is necessary for the assessment of disease activity in patients with ulcerative colitis. Sixty-six consecutive ulcerative colitis patients were evaluated with invasive indices: the St. Mark's index and the Ulcerative Colitis Disease Activity Index (UCDAI); and noninvasive indices: the Simple Clinical Colitis Activity Index (SCCAI) and the Seo index. The correlations between the indices were measured. The contribution of the endoscopic items was measured with linear regression modeling. The overlap of endoscopy with other items in the standard indices was determined through factor analysis. The two noninvasive indices correlated well with the invasive St. Mark's Index (SCCAI 0.86, Seo 0.70). After adjusting for the three noninvasive UCDAI items, the UCDAI endoscopy item predicted only 0.04% of the variance in the St. Mark's index. Factor analysis demonstrated that this is because the endoscopy items in the invasive indices correlate with stool frequency and stool blood items. Endoscopy items contribute little additional information to indices of disease activity in ulcerative colitis. The clinical practice of treating patients based on reported symptoms is appropriate. The use of noninvasive indices in clinical trials could lower study costs and may increase subjects' willingness to participate.


Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women.
Cytokines, such as interleukin-1 (IL-1) and tumor necrosis factors (TNF), produced by cells of the monocyte-macrophage lineage in the local bone microenvironment, are potentially important local regulators of bone turnover. To investigate whether the protective effects of estrogen against postmenopausal bone loss may be mediated by inhibition of cytokine release, we studied the effects of 17 beta-estradiol, dihydrotestosterone, and hydrocortisone on TNF release from human peripheral blood mononuclear cells (PBMC) in vitro. In unstimulated cells derived from eight postmenopausal women, seven of whom had osteoporotic vertebral fractures, 17 beta-estradiol inhibited TNF release in a dose-dependent manner between 10(-6) and 10(-12) M but had no consistent effect on cells derived from men or premenopausal women. Dihydrotestosterone in concentrations of up to 10(-6) M had no effect on TNF release in any patient group, whereas hydrocortisone at 10(-6) M was a potent inhibitor of TNF release in all groups. Since TNF is a potent stimulator of bone resorption, the inhibitory effect of estrogen on TNF release may be part of the mechanism by which it exerts a protective effect on the skeleton in postmenopausal women. These observations may also be relevant in other inflammatory diseases of connective tissue, such as rheumatoid arthritis, in which disease activity may fluctuate as estrogen levels change--during the menstrual cycle, in pregnancy, and after the menopause.


Is There a Difference in the Outcome of Mid-Urethral Sling Operations Performed by Urogynecologists Compared with Supervised Residents?
To compare the operative results of midurethral sling (MUS) surgeries for stress urinary incontinence (SUI) performed by residents under the guidance of an attending specialist in urogynecology and those performed by attendings. Retrospective chart review (Canadian Task Force classification II-2). University hospital. A retrospective analysis of all MUS surgeries performed at a single public tertiary medical center between January 2009 and December 2013 was carried out. A total of 257 patients underwent transobturator tape (TOT) placement during the study period, including 136 (52.9%) placed by an attending specialist in urogynecology (group A) and 121 (47.1%) placed by a resident, under the guidance of an attending (group B). The efficacy of treatment was evaluated in terms of early postoperative course, reoperation, and symptom improvement, as based on the Pelvic Floor Distress Inventory short form (PFDI-20) questionnaire. The primary outcome was patient-reported symptoms of SUI, as assessed with the PFDI-20 questionnaire, as well as absence of surgical retreatment for SUI. Immediate postoperative complications were comparable in the 2 groups, as were subjective failure and self-reported SUI. The primary outcome-moderate and severe symptoms of SUI-were reported by 23.7% of the patients in group A and 23.6% of those in group B (p = .91). At a mean follow-up of 40 months in both groups, symptoms, as assessed using the urinary scale and prolapse scale of the PFDI-20, were also similar in the 2 groups. The rate of reoperation with repeated sling for SUI was 5% in both groups. The operative results of TOT surgery for SUI performed by residents under the guidance of an attending specialist in urogynecology did not differ significantly from those performed by the attendings themselves.


Copper(II)-catalyzed electrophilic amination of quinoline N-oxides with O-benzoyl hydroxylamines.
Copper acetate-catalyzed C-H bond functionalization amination of quinoline N-oxides was achieved using O-benzoyl hydroxylamine as an electrophilic amination reagent, thereby affording the desired products in moderate to excellent yields. Electrophilic amination can also be performed in good yield on a gram scale.


Multichannel intraluminal impedance in the evaluation of patients with persistent globus on proton pump inhibitor therapy.
Studies suggest an association between globus sensation ("globus") and gastroesophageal reflux. Although globus often persists despite proton pump inhibitor (PPI) therapy, the role of nonacid reflux has never been determined. Our goal was to use 24-hour multichannel intraluminal impedance (pH/MII) to determine 1) reflux characteristics in patients with globus despite PPI therapy; 2) whether there are differences in reflux patterns between patients with globus and patients with heartburn alone; and 3) whether there are differences in the number of positive symptom indices when standard pH testing is compared to pH/MII. Twenty-one adult patients with globus and 12 with heartburn symptoms alone underwent 24-hour pH/MII on PPI therapy. Reflux frequencies and characteristics were compared in both groups. For patients with globus, the symptom index and symptom sensitivity index were calculated. Logistic regression was performed to determine which reflux characteristics correlated with symptoms. With pH/MII, we detected 1,160 reflux episodes; 64.7% were nonacid, and 55% reached the proximal sensor. In identifying patients with positive symptom indices, pH/MII increased the yield of standard pH testing by 27.8%. Proximal reflux was a significant predictor of globus symptoms (p = .04). Nonacid reflux approached significance in predicting globus (p = .08). Compared to patients with heartburn alone, those with globus had a higher mean frequency of proximal reflux (27.76% versus 15.63%; p = .04). In adults on PPI therapy with refractory globus, acid reflux does not predict globus symptoms. Through detection of nonacid reflux, pH/MII increased the yield of standard pH testing in identifying positive symptom indices. Additionally, pH/MII provided important information regarding reflux-symptom correlation. Proximal reflux may be predictive of globus symptoms.


[Oligomerization triggered by foldon to enhance the catalytic efficiency of feruloyl esterase].
A new method to express oligomerized feruloyl esterase (FAE) in Pichia pastoris GS115 to improve the catalytic efficiency was developed. It was realized by fusing the foldon domain at the C-terminus of FAE, and the fusion protein was purified by histidine tag. Fusion of the feruloyl esterase with the foldon domain resulted spontaneously forming a trimer FAE to improve the catalytic performance. The oligomerized FAE and monomeric FAE were obtained by purification. The apparent molecular weight of the oligomerized FAE was about 110 kDa, while the monomeric FAE about 40 kDa, and the optimum temperature of the oligomerized FAE was 50 °C, which is the same as the monomeric one. The optimal pH of the oligomerized FAE is 5.0, while the optimal pH of the monomer FAE is 6.0. When compared with the monomeric ones, the catalytic efficiency (kcat/Km) of the oligomerized FAE increased 7.57-folds. The catalytic constant (kcat) of the oligomerized FAE increased 3.42-folds. The oligomerized FAE induced by foldon have advantages in the catalytic performances, which represents a simple and effective enzyme-engineering tool. The method proposed here for improving the catalytic efficiency of FAE would have great potentials for improving the catalytic efficiency of other enzymes.


12-core fiber with one ring structure for extremely large capacity transmission.
The feature of a multicore fiber with one-ring structure is theoretically analyzed and experimentally demonstrated. The one-ring structure overcomes the issues of the hexagonal close-pack structure. The possibility of 10-core fiber with Aeff of 110 μm(2) and 12-core fiber with Aeff of 80 μm(2) is theoretically presented. The fabricated 12-core fibers based on the simulation results realized Aeff of 80 μm(2) and crosstalk less than -40 dB at 1550 nm after 100-km propagation. The MCF with the number of core larger than seven and the small crosstalk was demonstrated for the first time.


Refining insulin concentrations in culture medium containing growth factors BMP15 and GDF9: An in vitro study of the effects on follicle development of goats.
The aim of the present study was to investigate the influence of two insulin concentrations (10ng/mL and 10μg/mL) combined or in the absence of BMP15 and/or GDF9, on the in vitro survival and development of preantral follicles of goat ovarian tissue. Ovarian slices from the same goat ovary pair were randomly assigned to a non-cultured control treatment or to be in vitro cultured for 1 or 7days in α-MEM containing 10ng/mL (Low) or 10μg/mL (High) of insulin in the absence or presence of BMP15 and/or GDF9. With the low insulin treatment, there was a greater percentage of normal follicles than with the high insulin treatment. The addition of BMP15 alone or in association with GDF9 to the medium containing low insulin resulted in a lesser percentage of normal follicles (P<0.05). The addition of BMP15 and GDF9 separately or in combination with the high insulin concentration enhanced the percentage of normal follicles. On day 7 of culture, the use of medium containing low insulin alone or high insulin supplemented with BMP15 and BMP15+GDF9 resulted in a greater percentage of secondary follicles than the non-cultured control, although follicles cultured with low insulin were smaller than those from the control group and had greater rates of oxidative stress. In conclusion, in the presence of physiological concentrations of insulin (10ng/mL), medium supplementation with GDF9 and BMP15 alone or in combination is unnecessary for normal follicle development in vitro.


High speed carrier-depletion modulators with 1.4V-cm V(pi)L integrated on 0.25microm silicon-on-insulator waveguides.
We demonstrate a very efficient high speed silicon modulator with an ultralow pi-phase-shift voltage-length product V(pi)L = 1.4V-cm. The device is based on a Mach-Zehnder interferometer (MZI) fabricated using 0.25microm thick silicon-on-insulator (SOI) waveguide with offset lateral PN junctions. Optimal carrier-depletion induced index change has been achieved through the optimization of the overlap region of carriers and photons. The 3dB bandwidth of a typical 1mm long device was measured to be more than 12GHz. An eye-diagram taken at a transmission rate of 12.5Gb/s confirms the high speed capability of the device.


Increase in capillary perfusion following low-intensity ultrasound and microbubbles during postischemic reperfusion.
We postulated that the increase in shear stress caused by microbubbles in the presence of low-intensity ultrasound increases vasodilation in ischemia/reperfusion. Prospective, randomized, and blinded experimental study. Research laboratory. Forty hamsters were subjected to ischemia/reperfusion and observed by intravital microscopy. Ultrasound (2.5 MHz, 1.3 mechanical index, 2.0 peak pressure) was applied to the hamster cheek pouch in ischemia/reperfusion with and without microbubbles (Levovist or Sono Vue) at baseline (15 mins) and at the beginning (15 mins) of reperfusion after ischemia (30 mins). Arterial diameter (A2-A3, 38.5 +/- 5.3 microm; A4,15.0 +/- 7.0 microm), red blood cell velocity, wall shear stress, permeability, perfused capillary length, and adherent leukocytes in venules were evaluated. Lipid peroxides were also determined in the systemic blood. Ultrasound and microbubbles in reperfusion significantly increased the diameter (A2-A3 Sono Vue, 33%; Levovist, 53% vs. ischemia/reperfusion, p < .05; A4, Sono Vue, 93%; Levovist, 104% vs. ischemia/reperfusion, p < .05), red blood cell velocity, flow, and shear stress in both A4 and A2-A3 arterioles. Shear stress was significantly higher with Levovist (A2-A3, 105%; A4, 185%) and Sono Vue (A2, 108%; A4, 140% vs. ischemia/reperfusion, p < .05) than ultrasound alone in arterioles. With ischemia/reperfusion, perfused capillary length was reduced significantly, whereas it increased with Levovist and Sono Vue (43%, 41% vs. ischemia/reperfusion p < .05). Lipid peroxides increased early during reperfusion and remained at increased levels throughout reperfusion. Lipid peroxides were unchanged after ultrasound alone or ultrasound with Sono Vue or Levovist during ischemia/reperfusion. With ultrasound there was a significant increase in vascular permeability vs. ischemia/reperfusion. Treatment with Sono Vue (-36%) and Levovist (-57%) decreased permeability vs. ischemia/reperfusion in reperfusion (p < .001). Ischemia/reperfusion had significantly increased leukocyte adhesion. Ultrasound alone (-39%) or with Sono Vue (-64%) and Levovist (-57%) caused smaller increases in leukocyte adhesion than ischemia/reperfusion (p < .05). Ultrasound and microbubbles equilibrate microvascular shear stress, thus avoiding the failure of capillary perfusion in postischemic reperfusion.


Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer.
Perineural invasion is associated with the high incidence of local recurrence and a dismal prognosis in pancreatic cancer. We previously reported a novel perineural invasion model and distinguished high- and low-perineural invasion groups in pancreatic cancer cell lines. This study aimed to elucidate the molecular mechanism of perineural invasion. To identify key biological markers involved in perineural invasion, differentially expressed molecules were investigated by proteomics and transcriptomics. Synuclein-gamma emerged as the only up-regulated molecule in high-perineural invasion group by both analyses. The clinical significance and the biological property of synuclein-gamma were examined in 62 resected cases of pancreatic cancer and mouse models. Synuclein-gamma overexpression was observed in 38 (61%) cases and correlated with major invasive parameters, including perineural invasion and lymph node metastasis (P < 0.05). Multivariate analyses revealed synuclein-gamma overexpression as the only independent predictor of diminished overall survival [hazard ratio, 3.4 (95% confidence interval, 1.51-7.51)] and the strongest negative indicator of disease-free survival [2.8 (1.26-6.02)]. In mouse perineural invasion and orthotopic transplantation models, stable synuclein-gamma suppression by short hairpin RNA significantly reduced the incidence of perineural invasion (P = 0.009) and liver/lymph node metastasis (P = 0.019 and P = 0.020, respectively) compared with the control. This is the first study to provide in vivo evidence that synuclein-gamma is closely involved in perineural invasion/distant metastasis and is a significant prognostic factor in pancreatic cancer. Synuclein-gamma may serve as a promising molecular target of early diagnosis and anticancer therapy.


Mechanism analysis of broad-spectrum disease resistance induced by expression of anti-apoptotic p35 gene in tobacco.
Studies have shown that transgenic plants expressing antiapoptotic genes from baculovirus and animals increase resistance to biotic and abiotic stress. However, the mechanism under these resistances is conjectural, or in some cases even controversy. In the present study, the p35 gene from baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) was expressed in tobacco, and for the first time P35 protein was detected in transgenic plants by Western blotting. Inoculation of T1 transgenic tobacco leaves with tobacco mosaic virus (TMV) showed enhanced resistance, and DNA laddering was observed after TMV infection in control but not in transgenic plants. DAB staining showed that TMV infection did not affect peroxide induction of transgenic plants, Western blotting analysis of PR1 protein also showed no difference of control and transgenic plants. Inoculation of fungus (Sclerotinia sclerotiorum) using a detached leaf assay showed enhanced resistance of transgenic leave tissue. RT-PCR analysis demonstrated that p35 gene expression induced earlier expression of PR1 gene after S. sclerotiorum infection. Taken together, our results suggest that the mechanism under enhanced disease resistance by P35 protein is possibly related to the activation of PR-related proteins in addition to the inhibition of programmed cell death, depending on the pathogens challenged.


Calculation and correction of piston phase aberration in synthesis imaging.
The principle of redundant spacings calibration has previously been described for the purpose of calibrating piston phase aberration affecting elements of a dilute aperture array using a system of linear equations in terms of the aperture phases as well as object phase information. Here we develop matrices for the correction of piston phase aberration by use of image sharpness and also by phase retrieval. These are both presented in wavefront sensor formulation in order to draw analogy between the approaches. We then discuss solution ambiguity affecting both methods and describe array design criteria to prevent such ambiguity. The problem of increased image aliasing under image sharpness correction is also highlighted.


Can long-term care insurance be fixed?
Long-term care insurance has not sold well in the United States. The issues are cost, complex financial problems, uncertainty about inflation, and concerns about the future of health care in general. The heart of the problem may well be that this insurance does not cover the relevant risk, and a solution is suggested in Section 6 of this article.


Competitive adsorption of water soluble plasma proteins from egg yolk at the oil/water interface.
Water soluble plasma proteins were fractionated from hen's egg yolk, and the molecular weight and pI of the most abundant protein species were characterized with gel electrophoresis. The proteins were identified by mass spectrometry. The protein fraction was used to produce oil-in-water emulsions, both at various protein concentrations and at various pH values, and the surface load was determined through serum depletion. The competitive adsorption was studied through the determination of nonadsorbing species with gel electrophoresis. The results show that it was possible to form an oil-in-water emulsion for which droplet size and maximum surface load depended on the protein concentration and pH. Serum albumin and YGP40 adsorbed selectively at the oil/water interface throughout the pH range investigated, and for albumin the selectivity increased close to its pI. It is suggested that this selective adsorption is due to long hydrophobic stretches in the polypeptide chain, which are present in the selectively adsorbing species but absent in less adsorbing species.


The gastric cytoprotective action of adenosine and prostaglandin E2 in rabbits.
The direct protective action of adenosine and prostaglandin E2 (PGE2) was examined in an isolated gastric gland preparation in rabbits. Ethanol (8%, v/v) incubation markedly increased the release of lactate dehydrogenase (LDH) and number of non-viable glands in the preparation. Both effects were prevented by PGE2 preincubation in a concentration (10(-6), 1.4 x 10(-5) or 2.8 x 10(-5) M)-dependent manner. The protective action was smaller in adenosine-treated groups, and yet the highest concentration (10(-4) M) of the compound also significantly inhibited the cytotoxic effects of ethanol. These findings indicate that both adenosine and PGE2 possess cytoprotective action on gastric glands in rabbits, but the former compound exerts its action beyond physiological concentrations. It is concluded that endogenous PGE2, but not adenosine may act as an ulcer modulator in the stomach.


The incretin system in healthy humans: The role of GIP and GLP-1.
The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohydrate/glucose ingestion. These include 1) amount and type of carbohydrates; 2) gastric emptying rate; 3) digestion and absorption of the carbohydrates; 4) secretion and effect of the incretin hormones; 5) disposition of absorbed nutrients/glucose. The incretin effect can also be viewed as the fraction of the ingested glucose load handled via gastrointestinal mechanisms (including the incretin effect); it is calculated by comparison of the amount of glucose required to copy, by intravenous infusion, the oral load. Typically, for 75 g of oral glucose, about 25 g are required. This means that the GastroIntestinal Glucose Disposal (GIGD) is 66%. Both the GIGD and the incretin effect depend on the amount of glucose ingested: for higher doses the GIGD may amount to 80%, which shows that this effect is a major contributor to glucose tolerance. The main mechanism behind it is stimulation of insulin secretion by a proportional secretion of the insulinotropic hormones GIP and GLP-1. Recently it has become possible to estimate their contributions in healthy humans using specific and potent receptor antagonists. Both hormones act to improve glucose tolerance (i.e. the antagonists impair tolerance) and their effects are additive. GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.


[Measuring body temperature in dairy cows--applications and influencing factors].
Measuring body temperature plays an integral role in early puerperal cow monitoring programs. Furthermore, body temperature is part of the definition of puerperal metritis. Antibiotic treatment decisions are based on body temperature in several international publications on intervention strategies widely adopted in the modern dairy industry. The objective of this article is to provide a brief overview of the most recent publications on this important criterion. Several factors can influence the measurement of the body temperature (type of thermometer, insertion depth, skills of the investigator) as well as the cow's body temperature (days in milk, parity, time of the day, climate at calving). Furthermore, the occurrence of increased body temperature in healthy cows was demonstrated independently by several investigations. In ambiguous cases (e.g. raised body temperature as the only symptom) results should be interpreted with caution.


Localization of the site for the nucleotide effectors of Escherichia coli carbamoyl phosphate synthetase using site-directed mutagenesis.
Replacement by alanine of Ser-948, Thr-974 and Lys-954 of Escherichia coli carbamoyl phosphate synthetase (CPS) shows that these residues are involved in binding the allosteric inhibitor UMP and the activator IMP. The mutant CPSs are active in vivo and in vitro and exhibit normal activation by ornithine, but the modulation by both UMP and IMP is either lost or diminished. The results demonstrate that the sites for UMP and IMP overlap and that the activator ornithine binds elsewhere. Since the mutated residues were found in the crystal structure of CPS near a bound phosphate, Ser-948, Thr-974 and Lys-954 bind the phosphate moiety of UMP and IMP.


PROFILE: Chemical Warfare Materiel: Unique Regulatory Issues.
/ The US Army manages an extensive program of environmental restoration that is carried out primarily under authority of the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), which establishes response authority for cleanup of inactive waste sites. The Resource Conservation and Recovery Act (RCRA) regulates the management and cleanup of hazardous materials at active hazardous waste facilities. Based on the definitions found in these acts, and corresponding promulgated regulations, environmental media contaminated with chemical warfare materiel (CWM) can be regulated as CERCLA "pollutants or contaminants" but do not appear to be regulated either as CERCLA hazardous substances or RCRA hazardous wastes.In those states that have not included CWM as hazardous materials in their RCRA programs, the RCRA requirements for management of hazardous waste would not strictly apply to any of the CWM. The Army has historically implemented procedures requiring that chemical warfare agents be managed as RCRA hazardous waste regardless of the concentration, physical form, or configuration of the agent. Such application of strict hazardous waste requirements to management of potentially nonhazardous CWM can result in remedial costs well out of proportion to potential human health and environmental benefits. Recent development of chronic toxicity values for the CWM has opened the door for development of cleanup and waste management standards for waste streams or media containing small residual amounts of CWM. Implementation of this health-based approach to management of CWM remediation wastes may, in part, help to reduce potentially unnecessary hazardous waste management costs for the nonhazardous CWM.


Acute lower extremity ischemia secondary to salivary gland tumor embolus.
Malignant arterial tumor emboli of sufficient size that is capable of causing organ infarction or ischemia are exceedingly rare. The majority of these emboli are associated with either primary or secondary pulmonary malignancies and commonly occur perioperatively or immediately postoperatively. This study describes an unusual case of acute lower extremity ischemia secondary to a malignant parotid tumor embolus with evidence of left ventricular involvement.


DNA methylation: a molecular lock.
In mammals, the promoters of expressed genes are generally unmethylated, whereas those of genes that are not expressed are methylated. Two recent papers help to explain the mechanism by which methylation modulates gene expression.


Immunohistochemical localization of endothelin-converting enzyme-1 in neuroendocrine tumors and normal human tissue.
Endothelin-converting enzyme-1 (ECE-1) is the key enzyme of endothelin biosynthesis, catalyzing the final step in the process. In this study, we investigated the cellular distribution of ECE-1 in 19 normal human tissues and 16 neuroendocrine tumors using immunohistochemical staining with antigen retrieval. ECE-1 was expressed in vessel endothelial cells as well as nearly all epithelial cells, glands and duct cells in normal human tissues including the esophagus, stomach, small intestine, appendix, colon, liver, gallbladder, pancreas, endometrium, cervix, breast, skin, prostate, urinary bladder, lung, kidney, sympathetic ganglion, thyroid gland, and adrenal gland. The most interesting finding was that ECE-1 was expressed in normal neuroendocrine cells. ECE-1 was also expressed in all 16 neuroendocrine tumors, including three paragangliomas, five pheochromocytomas, three carcinoid tumors, four medullary carcinomas of the thyroid, and one islet cell tumor of the pancreas. In conclusion, ECE-1 is enriched in neuroendocrine cells and neuroendocrine tumors, suggesting an important biologic role for the enzyme in the neuroendocrine system.


Quantitative correlations amongst alkaline DNA fragmentation, DNA covalent binding, mutagenicity in the Ames test and carcinogenicity, for 21 compounds.
21 compounds from different chemical classes were quantitatively compared for their carcinogenic potency according to 4 parameters: (1) potency in inducing covalent binding with DNA in vivo; (2) potency in inducing alkaline DNA fragmentation after treatment in vivo; (3) acute toxicity; (4) mutagenic potency in the Ames test. Establishing well-defined conditions for normalization of the different types of data and determination of the set that had to be submitted to statistical analysis appeared to be a difficult task, for which only compromise solutions were possible. A statistical analysis of the data suggested that all parameters considered were correlated with carcinogenic potency. However, we found that there are about 3 chances to 1 that carcinogenicity is better correlated with DNA covalent binding in vivo than it is to mutagenicity in the Ames test. With due precautions, even acute toxicity could be of predictive value. DNA adducts and DNA fragmentation, both in vivo, appeared to be 2 parameters strongly correlated between them. From a multivariate statistical analysis it appeared that: (1) a significant improvement of quantitative predictability is in principle obtainable with a battery of short-term test; and (2) the improvement is obtainable only if the short-term tests considered, while all correlated with carcinogenicity, are relatively independent amongst themselves.


Dichloroacetate reduces tissue necrosis in a rat transverse rectus abdominis musculocutaneous flap model.
Ischemia-related complications may occur during postmastectomy transverse rectus abdominis musculocutaneous (TRAM) flap reconstruction. The aim of our study was to investigate whether necrosis of susceptible flap regions could be reduced by dichloroacetate (DCA)-induced stimulation of oxidative metabolism in hypoxic tissue. The study was a randomized control trial using male Sprague-Dawley rats. A pedicled TRAM flap based upon the right inferior epigastric artery was elevated and reapproximated. Animals were randomly assigned to 1 of 5 treatment groups (n = 6). Group I received no DCA; groups II through V were administered 75 mg/kg DCA orally 24 hours preoperative; in addition, groups II through IV received 75 mg/kg/d DCA orally postoperative for 4 days; group III also received 75 mg/kg DCA (IP) intraoperatively; groups IV and V were given 15 mg/kg/d DCA orally for 6 days before the 24-hour preoperative treatment. Four days postsurgery, skin paddles were photographed and assessed for viability. Underlying TRAM muscle was biopsied for histologic analysis. Blood lactate levels were measured at pre- and postoperative time points. The mean percentages of viable skin paddle were as follows: 32.0%+/- 4.0% (group I), 68.1% +/- 6.2% (group II), 84.3% +/- 5.9% (group III), 92.8% +/- 2.0% (group IV), 82.6% +/- 5.8% (group V). Statistically significant differences were found in all experimental (DCA) groups relative to the controls (P < 0.01). Group IV (6-day DCA preconditioning, plus 24-hour preoperative and 4-day postoperative treatment) displayed the greatest improvement in flap viability, significantly better than other DCA groups (P < 0.01). Group IV also had significantly lower serum lactate levels than controls (P < 0.05). Histologic examination of muscle biopsies revealed reductions in inflammation and necrosis correlating with DCA treatment and skin paddle survival. This study indicates that DCA may provide a useful pharmacologic tool for reducing ischemia-related necrosis in TRAM flaps.


Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats.
Chronic, unhealed diabetic foot ulcer (DFU) is one of the most severe complications of diabetes mellitus (DM). Naringin, a flavanone glycoside antioxidant, was reported to have antidiabetic and anti-apoptotic properties. In the present study DM was induced experimentally by streptozotocin (STZ, 55 mg/kg, i.p.). In surgically introduced wounds on the dorsal surface of the hind paw of rats, the healing potential of naringin was investigated. Rats were treated with naringin (20, 40 and 80 mg/kg, p.o.), insulin (10 IU/kg, s.c.) and tetrachlorodecaoxide (TCDO) (1 drop, twice a day, topically) for 16 days. The wound area was measured every second day, and on day 17 various biochemical parameters were determined in serum, wound tissue, and histopathological examination of the wound was performed. Naringin (40 and 80 mg/kg) significantly (P<0.05) improved wound area, serum glucose level, glycated Hb and serum insulin. Naringin treatment at 40 and 80 mg/kg resulted in significant (P<0.05) up-regulation of mRNA expression of growth factor (IFG-1, TGF-β and VEGF-c), Ang-1 and collagen-1 whereas mRNA expression of inflammatory mediators (TNF-α, IL-1β and IL-6) was down-regulated. Furthermore, naringin significantly (P<0.05) attenuated STZ-induced apoptosis and stimulated angiogenesis in the wound tissue. Further results suggest that angiogenesis was improved via naringin-mediated inhibition of hyperglycemia, oxidative stress, down-regulation of inflammatory mediator expression and up-regulation of growth factor expression, leading to improved wound healing of DFU.


[Spinal cord stab injury by acupuncture needle: a case report].
It is very rare for neurosurgeons to encounter cases of spinal cord injury caused by a broken acupuncture needle. A 45-year-old man was referred to our clinic because of urinary retention about two weeks after acupuncture therapy (a needle was broken during treatment). The patient showed no motor weakness, or sensory disturbance. The needle was seen transversely stabbing the spinal cord at C1/2 on CT imaging and X-ray film. In all of the reported seven cases of longitudinal stab injuries (posterior puncture), sensorimotor disturbances were present. In transverse stab injuries (lateral puncture), however, two cases did not show motor weakness but sensory disturbance. The centrifugal pathway for micturition in the spinal cord lies in the middle one third of the lateral columns and in the width of the central canal. The patient complained of urinary retention because the bilateral descending fibers might have been stabbed by the needle. Surgical treatment relieved the patient from his complaint.


Measurement of intima-media thickness of common carotid arteries with high-resolution B-mode ultrasonography: inter- and intra-observer variability.
High-resolution B-mode ultrasonography enables quantitative measurement of the thickness of the intima-media layer of superficial large arteries noninvasively. We investigated the inter- and intra-observer variability of this measurement in the common carotid arteries in 10 randomly selected men. The maximal right and left carotid intima-media thickness (IMT) was measured with calipers during the scanning from frozen images by four observers in a blinded fashion. Three observers also repeated the scanning and the measurements twice with a week's intervals, with no knowledge of the previous readings. The inter-observer coefficient of variation (CV) was 10.5%. The intra-observer CV (mean of right and left CCA) was 5.4-5.8% for the three observers who carried out the measurements three times. The mean absolute difference between the first and third measurement was 0.087 mm. The intra-observer variation accounted for only 4% of the total measurement variability, 96% being attributable to inter-observer variation. These data show that most of the measurement variability in ultrasonographic B-mode IMT measurements is due to differences between observers, whereas the within-observer variability over time appears proportionately very small.


[Efficacy of protein-free calf blood extract ophthalmic gel for diffuse punctate corneal epithelial defects].
To evaluate the clinical efficacy of protein-free calf blood extract ophthalmic gel for diffuse punctate corneal epithelial defects. 36 patients (36 eyes) with diffuse punctate corneal epithelial defects were enrolled between Oct. 2008 and Apr. 2009 in outpatient clinic from Eye Ear Nose and Throat Hospital of Fudan University. Patients were randomized divided into protein-free calf blood extract ophthalmic gel group (the test group, 19 eyes) and recombinant bovine basic fibroblast growth factor ophthalmic gel group (the control group, 17 eyes). The drugs were delivered in both groups 4 times per day, one drop each time in the 14 days duration. Corneal staining, the tear break-up time, the Schirmer value and visual acuity were evaluated on the pre-delivery day and the post-delivery day 14. On day 14, both the test group and control group had a significant decrease from baseline in corneal staining (the test group t = 5.7083, P = 0.0000 and the control group t = 4.5019, P = 0.0004, respectively). And improvements of corneal staining in the test group was more significant than that in the control group (t = 2.2712, P = 0.0296). Improvements were seen in BUT values in both group on day 14, as compared to baseline (the test group Z = 2.226, P = 0.0260 and the control group Z = 2.527, P = 0.0115, respectively). However, there was no significant difference between groups (Z = 1.336, P = 0.1815). As to the Schirmer value, there were neither difference within groups from baseline (the test group t = 0.4207, P = 0.6790 and the control group t = 1.1255, P = 0.2770, respectively). Nor between groups (t = 0.9830, P = 0.3325). And no obvious changes from baseline in visual acuity were observed in both groups (the test group Z = 1.897, P = 0.0578 and the control group Z = 1.786, P = 0.0741, respectively). The efficacy of protein-free calf blood extract ophthalmic gel is prior to recombinant bovine basic fibroblast growth factor ophthalmic gel in patients with diffuse punctate corneal epithelial defects.


The association between specialty match and third-year clerkship performance.
The United States is experiencing an accelerating physician shortage, especially within primary care. Medical educators are actively seeking ways to predict student specialty match and workforce requirements. Previous studies investigating specialty match have focused on factors known at the time of matriculation. This study examined whether third-year clerkship performance could be used to predict specialty match later in medical school. The authors evaluated the clerkship performance of 802 students graduating from the Uniformed Services University between 2007 and 2011. They examined the relationship of students' clerkship grades and National Board of Medical Examiners' clinical subject examination scores to specialty match. In addition, the authors combined student performance in family medicine, internal medicine, and pediatrics to create composite variables and assessed their associations with the match. Among 802 students, 339 (42.4%) students matched to primary care specialties. There was a positive association between higher family medicine (Odds ratio [OR] 1.65, 95% confidence interval [CI] 1.05, 2.59), general surgery (OR 1.91, 95% CI 1.22, 2.99), internal medicine (OR 2.17, 95% CI 1.35, 3.49), and pediatrics (OR 2.59, 95% CI 1.52, 4.43) clerkship grades and students matching into family medicine, general surgery, internal medicine, and pediatrics, respectively. Only family medicine showed a weak correlation between higher National Board of Medical Examiners' scores and specialty match. Higher clerkship performance in four of six Uniformed Services University third-year clerkships is associated with matching into the corresponding specialty. Clerkship performance provides a potential tool for educators in counseling students and predicting future specialty match.


Subfornical organ: site of drinking elicitation by angiotensin II.
Angiotensin II applied directly to the subfornical organ in a dose as small as 0.1 nanogram elicited short-latency drinking behavior in water-sated rats. Lesions in the body of this structure blocked drinking induced by angiotensin II applied to the basal telencephalon (including preoptic area). These results call attention to the subfornical organ as an important central nervous structure involved in the conrol of drinking behavior.


Hunter-Gatherers Maintain Assortativity in Cooperation despite High Levels of Residential Change and Mixing.
Widespread cooperation is a defining feature of human societies from hunter-gatherer bands to nation states [1, 2], but explaining its evolution remains a challenge. Although positive assortment of cooperators is recognized as a basic requirement for the evolution of cooperation, the mechanisms governing assortment are debated. Moreover, the social structure of modern hunter-gatherers, characterized by high mobility, residential mixing, and low genetic relatedness [3], undermines assortment and adds to the puzzle of how cooperation evolved. Here, we analyze four years of data (2010, 2013, 2014, 2016) tracking residence and levels of cooperation elicited from a public goods game in Hadza hunter-gatherers of Tanzania. Data were collected from 56 camps, comprising 383 unique individuals, 137 of whom we have data for two or more years. Despite significant residential mixing, we observe a robust pattern of assortment that is necessary for cooperation to evolve; in every year, Hadza camps exhibit high between-camp and low within-camp variation in cooperation. We find little evidence that cooperative behavior within individuals is stable over time or that similarity in cooperation between dyads predicts their future cohabitation. Both sets of findings are inconsistent with models that assume stable cooperative and selfish types, including partner choice models. Consistent with social norms, culture, and reciprocity theories, the strongest predictor of an individual's level of cooperation is the mean cooperation of their current campmates. These findings underscore the adaptive nature of human cooperation-particularly its responsiveness to social contexts-as a feature that is important in generating the assortment necessary for cooperation to evolve.


Borna disease virus in human brains with a rare form of hippocampal degeneration but not in brains of patients with common neuropsychiatric disorders.
To estimate the frequency of persistent Borna disease virus (BDV) infections of the human central nervous system and to determine which neuropsychiatric disorders might be associated with this viral infection, reverse transcription-nested polymerase chain reaction was used to screen a large collection of autopsy brain samples for the presence of BDV-specific nucleic acids. The presence of BDV RNA was found in 3 brains of persons with psychiatric symptoms and prominent hippocampal degeneration previously reported to be positive by others. However, no BDV RNA was detected in 86 randomly collected brains from persons with various psychiatric disorders, including schizophrenia, affective disorders, and Alzheimer's disease, or from suicide victims or in 52 brains from healthy controls. Furthermore, no BDV-RNA was detected in 16 surgical brain samples from persons with epilepsy-associated hippocampal sclerosis. These results indicate that life-long persistent BDV infections are rare in humans and that such infections may be associated with certain forms of hippocampal degeneration.


The race to learn: spike timing and STDP can coordinate learning and recall in CA3.
The CA3 region of the hippocampus has long been proposed as an autoassociative network performing pattern completion on known inputs. The dentate gyrus (DG) region is often proposed as a network performing the complementary function of pattern separation. Neural models of pattern completion and separation generally designate explicit learning phases to encode new information and assume an ideal fixed threshold at which to stop learning new patterns and begin recalling known patterns. Memory systems are significantly more complex in practice, with the degree of memory recall depending on context-specific goals. Here, we present our spike-timing separation and completion (STSC) model of the entorhinal cortex (EC), DG, and CA3 network, ascribing to each region a role similar to that in existing models but adding a temporal dimension by using a spiking neural network. Simulation results demonstrate that (a) spike-timing dependent plasticity in the EC-CA3 synapses provides a pattern completion ability without recurrent CA3 connections, (b) the race between activation of CA3 cells via EC-CA3 synapses and activation of the same cells via DG-CA3 synapses distinguishes novel from known inputs, and (c) modulation of the EC-CA3 synapses adjusts the learned versus test input similarity required to evoke a direct CA3 response prior to any DG activity, thereby adjusting the pattern completion threshold. These mechanisms suggest that spike timing can arbitrate between learning and recall based on the novelty of each individual input, ensuring control of the learn-recall decision resides in the same subsystem as the learned memories themselves. The proposed modulatory signal does not override this decision but biases the system toward either learning or recall. The model provides an explanation for empirical observations that a reduction in novelty produces a corresponding reduction in the latency of responses in CA3 and CA1.


Androgen deprivation therapy, insulin resistance, and cardiovascular mortality: an inconvenient truth.
Prostate cancer (PCa) is the most common cancer in men. Androgen deprivation therapy (ADT) is used in the treatment of locally advanced and metastatic PCa. Although its use as an adjuvant therapy has resulted in improved survival in some patients, ADT has negative consequences. Complications like osteoporosis, sexual dysfunction, gynecomastia, and adverse body composition are well known. Recent studies have also found metabolic complications in these men. Studies show that short-term ADT (3-6 months) results in development of hyperinsulinemia without causing hyperglycemia. Studies of men undergoing long-term (>or=12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. In addition, men undergoing ADT also experience higher cardiovascular mortality. Long-term prospective studies of ADT are needed to determine the timing of onset of these complications and to employ strategies to prevent them. In the meantime, baseline and serial screening for fasting glucose and other cardiac risk factors in men receiving ADT is prudent. In selected cases, glucose tolerance testing and cardiac evaluation may be required.


Rescattering Effects in the Hadronic-Light-by-Light Contribution to the Anomalous Magnetic Moment of the Muon.
We present a first model-independent calculation of ππ intermediate states in the hadronic-light-by-light (HLBL) contribution to the anomalous magnetic moment of the muon (g-2)_{μ} that goes beyond the scalar QED pion loop. To this end, we combine a recently developed dispersive description of the HLBL tensor with a partial-wave expansion and demonstrate that the known scalar-QED result is recovered after partial-wave resummation. Using dispersive fits to high-statistics data for the pion vector form factor, we provide an evaluation of the full pion box a_{μ}^{π box}=-15.9(2)×10^{-11}. We then construct a suitable input for the γ^{*}γ^{*}→ππ helicity partial waves, based on a pion-pole left-hand cut and show that for the dominant charged-pion contribution, this representation is consistent with the two-loop chiral prediction and the COMPASS measurement for the pion polarizability. This allows us to reliably estimate S-wave rescattering effects to the full pion box and leads to our final estimate for the sum of these two contributions a_{μ}^{π box}+a_{μ,J=0}^{ππ,π-pole LHC}=-24(1)×10^{-11}.


Nitric oxide suppresses the secretion of vascular endothelial growth factor and hepatocyte growth factor from human mesenchymal stem cells.
The production of growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) by human bone marrow mesenchymal stem cells (MSCs) may play an important role in their paracrine effects on proliferation, differentiation, and protection. NO is produced during ischemia and may affect MSC function. However, it is unknown whether NO alters the production of VEGF and HGF from MSCs. To study this, human MSCs were stimulated to produce growth factors with TNF or LPS with and without various doses of NO donors or NOS inhibitors. We found that FK409, an NO donor, significantly suppressed the production of VEGF and HGF from human MSCs. Vascular endothelial growth factor in the supernatants of cells treated by 20 nM FK409 (497 +/- 19 pg/mL) was significantly lower compared with controls (625 +/- 34 pg/mL). Similarly, NO donor significantly suppressed the amount of HGF from controls (118 +/- 3 to 40 +/- 2 pg/mL) after treatment with 20 nM FK409. NO donor also abolished the augmentation of VEGF production induced by LPS. The amount of VEGF in the supernatant was 571 +/- 11 pg/mL when cells were treated with 20 nM FK409 and LPS (200 ng/mL), which was significantly lower than groups treated with LPS alone (941 +/- 30 pg/mL). This study constitutes an initial report regarding the effect of NO on human MSC growth factor production.


[Measurement of changes in parietal tonus of the abomasum in sheep].
An inflatable bag of 250 ml at the pressure of 2 mm Hg inside the abomasal lumen was used to identify the abomasal smooth muscle tone. Reduced tone of the ovine abomasum was assessed, like for the fundic part of the canine stomach, in relation with the cyclic motor activity of the proximal duodenum. Opposite effects were obtained following parasympathomimetic drug injection versus peptides of the gastrin group, suggesting a high responsiveness of the abomasal smooth muscle tone to both neural and hormonal influences.


[Demonstration of Clostridium difficile and toxin B in patients at a university clinic].
107 stool specimens from not hospitalized individuals and 69 stool specimens from 61 hospitalized patients (Internal Medicine) were examined for C. difficile and toxin B. Included were 42 specimens of 33 female patients of the department of maxillo-facial surgery, receiving prophylactic clindamycin and 7 samples from the ward staff. From the samples of the first group, C. difficile was isolated in one case (0.93%), whereas 8 out of 61 internal patients (13%) were positive for C. difficile by culture and/or toxin test. In 12 out of 33 surgical patients (36%), C. difficile and/or toxin could be detected in the stool. Examination of the ward staff was negative. Environmental samplings on the ward, comprehending 246 contact cultures, resulted in the isolation of C. difficile from 25 plates (10.1%). The majority of the patients showed no symptoms or slight diarrhea. Only 5 patients required vancomycin therapy. Frequency and clinical significance of C. difficile isolation is discussed under these aspects.


[Femoral neck fracture in osteopoikilosis].
Osteopoikilosis was discovered in a 53-year-old patient who suffered a fracture of the right femoral neck. Plain X-rays demonstrated symmetrical bilateral stippling of variable size. No images were seen in the skull and spine. The fracture of the femoral neck was treated by total hip replacement. At surgery, the joint cartilage of the femoral head and the acetabulum had a normal aspect. Pathology examination of the femoral head demonstrated regular thick dense lamellae. Functional outcome at ten months was good (Postel-Merle-d'Aubigné score). Osteopoikilosis is an uncommon clinically latent condensing bone disease which can be revealed by bone fracture.


1997 Peritoneal Dialysis-Core Indicators Study: Dialysis Adequacy and Nutritional Indicators Report.
The 1997 Peritoneal Dialysis-Core Indicators Study: Dialysis Adequacy and Nutritional Indicators Report documents the current status of peritoneal dialysis within the United States. A national random sample of adult peritoneal dialysis (PD) patients participating in the United States End Stage Renal Disease (ESRD) program was surveyed. PD subjects were large, with a mean body weight of 76 +/- 18.9 kg (mean +/- 1 SD) and a body mass index (BMI) of 27 +/- 6.4. The dialysis prescriptions documented achieved a mean weekly Kt/Vurea (wKt/V) and weekly creatinine clearance (wCrCl) of 2. 45 +/- 2.29 and 65.5 +/- 35.2 L/wk/1.73m2, respectively. The serum albumin of these patients was 3.5 +/- 0.48 g/dL, their normalized protein equivalent of nitrogen appearance (nPNA) 1.0 +/- 0.63 g/kg/d, and their normalized creatinine appearance rate (nCAR) 14 +/- 6.0 mg/kg/d. Serum albumin correlated meagerly but in a positive fashion with BMI, nPNA, and nCAR, and negatively with wCrCl. Among adult US PD patients, serum albumin values appear to correlate poorly with alternative measures of nutritional status and are inversely related to the intensity of renal replacement therapy. The presumptive dietary protein intake (nPNA) and creatinine appearance rate (nCAR) derived for PD patients do correlate in a positive fashion with dialysis delivery, at least up to a wCrCl of 60 to 80 L/wk/1.73 m2 and wKt/V = 2.1, but their values suggest that 30% to 50% of PD patients have marginal nutritional status.


Total body water reduction in subjects with chronic kidney disease on peritoneal dialysis is associated with a better hypertension control.
Hypertension is highly prevalent in patients with chronic kidney disease and hypervolemia is one of the principal causes. To evaluate the influence of the reduction of volemia on blood pressure as well as on echocardiographic parameters in patients on continuous ambulatory peritoneal dialysis. Twelve patients with no clinical evidence of hypervolemia were submitted to an increase in the rate of the dialysis with the purpose of reducing body weight by 5%. The volemia was evaluated by electrical bioimpedance and by ultrasound of the inferior cava vena (ICV). Blood pressure was measured by ambulatory blood pressure monitoring and cardiac function was evaluated by echocardiography both at baseline and 5 weeks after the intervention period. After the increase in the ultrafiltration, body weight, extracellular water and the inspiratory diameter of the ICV decreased significantly in parallel with a non-significant increase in the collapsing ICV index. Despite the reduction of anti-hypertensive drugs, systolic blood pressure during the sleep period decreased from 138.4 ± 18.6 to 126.7 ± 18.0 mmHg, the nocturnal blood pressure drop increased and the final systolic left ventricular diameter decreased significantly. Reduction of the volemia of patients on peritoneal dialysis, with no signs of hypervolemia, was associated with a better blood pressure control and with a decrease of the final systolic left ventricular diameter.


Seat belt fractures of the cervical spine.
Three unusual injuries of the cervical spine in wearers of safety belts are reported. In each case, the presence of diagonal bruising and abrasions in the line of the sash strap indicated its involvement in the mechanism of the injury.


Applications of fluorescence for detecting rare sequence rearrangements in vivo.
Homologous recombination (HR) is an important pathway for the accurate repair of potentially cytotoxic or mutagenic double strand breaks (DSBs), as well as double strand ends that arise due to replication fork breakdown. Thus, measuring HR events can provide information on conditions that induce DSB formation and replicative stress. To study HR events in vivo, we previously developed Fluorescent Yellow Direct Repeat (FYDR) mice in which a recombination event at an integrated transgene yields a fluorescent signal. Recently, we published an application of these mice demonstrating that fluorescent recombinant cells can be directly detected within intact pancreatic tissue. Here, we show that in situ imaging is a more sensitive method for detecting exposure-induced recombinant cells, yielding statistical significance with smaller cohorts. In addition, we show inter-mouse and gender-dependent variation in transgene expression, examine its impact on data interpretation, and discuss solutions to overcoming the effects of such variation. Finally, we also present data on enhanced yellow fluorescent protein (EYFP) expression, showing that several tissues, in addition to the pancreas, may be amenable for in situ detection of recombinant cells in the FYDR mice. The FYDR mice provide a unique tool for identifying genetic conditions and environmental exposures that induce genotoxic stress in a variety of tissues.


Intronic and promoter polymorphisms of hMLH1/hMSH2 and colorectal cancer risk in Heilongjiang Province of China.
Given that mismatch repair (MMR) system plays an important role in recognizing and removing insertion/deletion mutations which occur during DNA replication, common variants associated with impaired MMR system may thus increase risk of colorectal cancer (CRC). Therefore, we aimed to demonstrate the associations between common variants in two MMR genes (hMLH1 and hMSH2) and CRC risk. We genotyped 10 intronic/promoter single-nucleotide polymorphisms (SNPs) of hMLH1 and hMSH2 in 451 CRC patients and 630 controls. Associations between genotypes and CRC risk were estimated using odds ratios and 95 % confidence intervals. Gene-gene interactions, as well as gene-environment interactions on CRC risk were also investigated. We found that IVS15-214T>C and IVS11 + 107A>G of hMSH2 were significantly associated with CRC risk. In dominant model, variant carriers of the two SNPs could decrease risk of CRC by 31 % (ORadj = 0.69, 95 % CI 0.53-0.91, p < 0.01) and 33 % (ORadj = 0.67, 95 % CI 0.47-0.95, p = 0.02), respectively. In addition, IVS7-212T>A, IVS11+183A>G and IVS8+719T>C of hMSH2 were associated with the susceptibility to colon cancer rather than rectal cancer. ATTTGGGT and TCTTAGAC haplotypes were associated with 44 and 45 % decreased risk of CRC, respectively, while ATTTGAGT and TTTCAGAC haplotypes were associated with 1.37-fold and 2.49-fold increased risk of CRC, respectively. There was a significant three-way gene-gene interaction among hMSH2 IVS11+107A>G, IVS11+183A>G and IVS8+719T>C (p < 0.01). Significant gene-environment interactions were observed between hMSH2 IVS15-214T>C and IVS11+107A>G and cereals consumption (both with p < 0.01). Our findings suggested that intronic SNPs, gene-gene and gene-environment interactions in hMSH2 might be associated with susceptibility to CRC.


Subsequent Malignant Neoplasms in a Population-Based Cohort of Pediatric Cancer Patients: A Focus on the First 5 Years.
The purpose was to describe the development of subsequent malignant neoplasms (SMN) among a population-based cohort of pediatric cancer patients, with a focus on SMNs that occurred within the first 5 years from diagnosis. The cohort was identified from POGONIS, an active provincial registry. Cohort members were Ontario residents ages 0 to 14.9 years at primary diagnosis between January 1985 and December 2008. SMNs that developed <18 years were captured by POGONIS, whereas SMNs diagnosed later were identified through linkage. Cumulative incidence and standardized incidence ratios (SIR) were calculated, and proportional hazards models were estimated to examine factors associated with SMN development. A total of 7,920 patients were eligible. 2.4% (188/7,920) developed 197 SMNs. Mean follow-up time was 10.7 years (SD = 7.6 years; range, 0.0-26.4 years) with mean time to SMN of 8.5 years (SD = 6.3 years; range, 0.0-24.9 years). The SIR for the development of a SMN was 9.9 [95% confidence interval (CI), 8.6-11.4]. 40.6% of SMNs (80/197) developed within 5 years. Early SMNs were more likely to be leukemia and lymphoma. Factors associated with early SMN were primary diagnosis of a bone tumor (OR, 4.88; 95% CI, 1.52-15.60), exposure to radiotherapy (OR, 1.82; 95% CI, 1.02-3.22), and the highest dose of epipodophyllotoxin (OR, 3.74; 95% CI, 1.88-7.42). Over 40% of SMNs diagnosed in childhood cancer patients occurred in the first 5 years after diagnosis, suggesting a need for early and ongoing surveillance. The early development of certain SMNs reinforces the need for early and continued surveillance at all stages for pediatric cancer patients.


The oxidation of the calcium probe quin2 and its analogs by prostaglandin H synthase.
Quin2 and its analogs BAPTA, 5,5'-dimethyl BAPTA, 5,5'-difluoro BAPTA, fura-2, and indo-1 were developed to measure intracellular calcium concentrations. In this study we investigated whether quin2 and its analogs are susceptible to peroxidase-catalyzed oxidation. The hydroperoxidase activity of prostaglandin H synthase, like other peroxidases, is capable of oxidizing a wide variety of substrates. It was found that quin2 and its analogs served as reducing cofactors for the hydroperoxidase activity of prostaglandin H synthase, undergoing oxidation in the process. Furthermore, arachidonic acid metabolism was stimulated. Oxidation of quin2 and its analogs resulted in the formation of a carbon-centered radical, as could be detected by ESR, and in the formation of formaldehyde. Quin2 fluorescence decreased upon addition of arachidonic acid and prostaglandin H synthase. Furthermore, addition of calcium no longer resulted in an increase in quin2 fluorescence, as was observed prior to the addition of arachidonic acid and the enzyme. This indicates that one or more of the -N-CH2-COOH groups, which are responsible for the binding of calcium, were oxidized by the hydroperoxidase. Since prostaglandin H synthase is present in many cellular systems in which calcium concentrations are modulated, oxidation of the calcium probe might not only affect the measurement of intracellular calcium but could activate arachidonic acid metabolism as well.


Evaluation of the specificity and sensitivity of indirect immunofluorescence tests for IgG to human herpesviruses-6 and -7.
Sera from 118 children aged up to 4 years were tested by indirect immunofluorescence for human herpesvirus-6 and -7 (HHV-6 and HHV-7) antibodies. Antibody results were confirmed as true positives if the relevant viral DNA was detected in saliva or, in some cases of primary infection, by the finding of the relevant DNA in cerebrospinal fluid or serum. Results from samples taken from the 15 children less than 6 months old showed that HHV-6 and/or HHV-7 antibody was either absent or present at low titre suggesting persistent maternal antibody rather than true infection. The sensitivity, specificity, positive and negative predictive values of the HHV-6 IgG test were therefore based on the data from the 103 children older than 6 months and the results were 95, 84, 91 and 90%, respectively. Likewise, the sensitivity, specificity, positive and negative predictive values of the HHV-7 IgG test were 95, 76, 84 and 93%, respectively. There was limited cross-reactivity between HHV-6 and HHV-7 antibodies; where both HHV-6 and HHV-7 antibodies are detected, titres above 32 may be accepted as true positives but lower titres require confirmation by detection of the relevant viral DNA or, in the case of primary infection, by a rising antibody titre.


Syringomycin action gene SYR2 is essential for sphingolipid 4-hydroxylation in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae gene SYR2, necessary for growth inhibition by the cyclic lipodepsipeptide syringomycin E, is shown to be required for 4-hydroxylation of long chain bases in sphingolipid biosynthesis. Four lines of support for this conclusion are presented: (a) the predicted Syr2p shows sequence similarity to diiron-binding membrane enzymes involved in oxygen-dependent modifications of hydrocarbon substrates, (b) yeast strains carrying a disrupted SYR2 allele produced sphingoid long chain bases lacking the 4-hydroxyl group present in wild type strains, (c) 4-hydroxylase activity was increased in microsomes prepared from a SYR2 overexpression strain, and (d) the syringomycin E resistance phenotype of a syr2 mutant strain was suppressed when grown under conditions in which exogenous 4-hydroxysphingoid long chain bases were incorporated into sphingolipids. The syr2 strain produced wild type levels of sphingolipids, substantial levels of hydroxylated very long chain fatty acids, and the full complement of normal yeast sphingolipid head groups. These results show that the SYR2 gene is required for the 4-hydroxylation reaction of sphingolipid long chain bases, that this hydroxylation is not essential for growth, and that the 4-hydroxyl group of sphingolipids is necessary for syringomycin E action on yeast.


The estrogen receptor pathway in rhabdomyosarcoma: a role for estrogen receptor-beta in proliferation and response to the antiestrogen 4'OH-tamoxifen.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Highly malignant, RMS frequently fails to respond to conventional aggressive multimodal radiation, surgery, and chemotherapy treatment protocols that also cause significant sequelae in the growing child. Other tumors of mesenchymal origin, such as locally aggressive fibromatoses and desmoid tumors, have been successfully treated with a selective estrogen receptor (ER) modulator, tamoxifen. In an effort to identify new targets for RMS therapy, our group investigated the previously uncharacterized ER pathway in RMS cell culture and primary tumors. We detected ER isoform beta (ER beta), but not isoform alpha, RNA, and protein in five RMS cell lines. Immunohistochemical staining of primary RMS tumor sections confirmed high levels of ER beta but not ER alpha protein. RMS cell growth was dramatically inhibited in steroid-free conditions, and this growth inhibition was rescued with 17-beta-estradiol (E2) supplementation. Exposure of RMS cells to 4'OH-tamoxifen (4OHT) decreased cell viability and inhibited colony formation as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony-forming assays. 4OHT also induced apoptotic signaling in RMS cells as detected by cleavage of caspase-3 and poly(ADP)ribose polymerase. This effect increased 3- to 8-fold in steroid-deprived conditions but was rescued by supplementation with E2. Immunofluorescence studies detected a change in the subcellular localization of ER beta in response to 4OHT. Together, these data suggest an active ER beta-mediated signal transduction pathway in RMS. The ability of 4OHT to induce apoptotic signaling and disrupt estradiol-mediated proliferation provides a rationale to explore a role for selective ER modulators in the treatment of RMS.


Limb salvage in severe diabetic foot infection.
The purpose of our study was to determine the efficacy of a management algorithm that includes negative pressure wound therapy (NPWT) in diabetic feet with limb-threatening infection. Forty-five septic diabetic feet were treated with NPWT between 2006 and 2008. After emergent abscess evacuation, early vascular intervention was performed if necessary. Debridement, with or without partial foot amputation, was followed by NPWT. Wound progress was measured using a digital scanner. A limb was considered salvaged if complete healing was achieved without any or with minor amputation through or below the ankle. The mean followup after complete wound healing was 17 (range, 6 to 35) months. Thirty-two cases (71%) were infected with two or more organisms. Negative pressure wound therapy was applied for 26.2±14.3 days. The median time to achieve more than 75% wound area granulation was 23 (range, 4 to 55) days and 104 (range, 38 to 255) days to complete wound healing. Successful limb salvage was achieved in 44 cases (98%); 14 (31%) without any amputation and 30 (67%) with partial foot amputations. Total number of operations per limb was 2.4±1.3. One case of repeated infection and necrosis was managed with a transtibial amputation. There were no complications associated with NPWT. This study provides the outcome of a management algorithm which includes NPWT in salvaging severely infected diabetic feet. With emergent evacuation of abscess, early vascular intervention and appropriate debridement, NPWT can be a useful adjunct to the management of limb-threatening diabetic foot infections.


[A case of polymyositis with repeated dysphagia and muscle weakness associated with peculiar findings of skin].
A case of polymyositis with repeated dysphagia and muscle weakness associated with peculiar findings of skin was reported. The patient was a 67-year-old man. His birth and development was normal. There was no family history of neuromuscular disease. On 26th March 1987 he was admitted to a hospital because of dysarthria and dysphagia after fever and diagnosed as having viral myositis. His conditions improved spontaneously with bed rest and he left hospital on 14th April. On 23rd April he had chill and sore throat with fever. On 27th he was admitted to the same hospital because of dysarthria and muscle weakness of the proximal portion of the upper limbs. These symptoms also improved with bed rest. He had repeated these symptoms several times and then he was admitted to our hospital on 12th June. On examination he showed the skin pigmentation under the right eye and the eruption in the back of hands and the buttocks. Muscle weakness was observed in the proximal portion of the upper limbs and the neck flexor. Laboratory tests in admission were as follows: sGOT 49 mU/ml, sGPT 104 mU/ml, LDH 1064 mU/ml, CPK 565 mM/ml, aldolase 25.2 IU/1/37 degrees C. Electromyography showed the typical myogenic changes and biopsy of left biceps brachii revealed inflammatory cells in the muscle fiber which are specific to polymyositis. Immuno-histochemical study is performed to analyse the subpopulation of mononuclear cells in biopsied muscle and skin. Mononuclear cells infiltrated into perimysium, endomysium and epidermis were positive for T11 and T8, but less positive for T4, B1 and Leu11. On the basis of these findings he was diagnosed as having "polymyositis syndrome".


Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1.
Activation of the anaphase-promoting complex (APC) is required for anaphase initiation and for exit from mitosis. We show that APC is activated during mitosis and G1 by two regulatory factors, hCDC20 and hCDH1. These proteins directly bind to APC and activate its cyclin ubiquitination activity. hCDC20 confers a strict destruction-box (D-box) dependence on APC, while hCDH1 shows a much more relaxed specificity for the D-box. In HeLa cells, the protein levels of hCDC20 as well as its binding to APC peak in mitosis and decrease drastically at early G1. Thus, hCDC20 is the mitotic activator of APC and directs the degradation of substrates containing the D-box. The hCDH1 protein level remains constant during the cell cycle and may target specific substrates lacking the D-box in G1, such as polo-like kinase, for ubiquitination.


Polyamines, androgens, and skeletal muscle hypertrophy.
The naturally occurring polyamines, spermidine, spermine, and their precursor putrescine, play indispensible roles in both prokaryotic and eukaryotic cells, from basic DNA synthesis to regulation of cell proliferation and differentiation. The rate-limiting polyamine biosynthetic enzymes, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase, are essential for mammalian development, with knockout of the genes encoding these enzymes, Odc1 and Amd1, causing early embryonic lethality in mice. In muscle, the involvement of polyamines in muscle hypertrophy is suggested by the concomitant increase in cardiac and skeletal muscle mass and polyamine levels in response to anabolic agents including β-agonists. In addition to β-agonists, androgens, which increase skeletal mass and strength, have also been shown to stimulate polyamine accumulation in a number of tissues. In muscle, androgens act via the androgen receptor to regulate expression of polyamine biosynthetic enzyme genes, including Odc1 and Amd1, which may be one mechanism via which androgens promote muscle growth. This review outlines the role of polyamines in proliferation and hypertrophy, and explores their possible actions in mediating the anabolic actions of androgens in muscle.