Time-series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis.
Chronological age is a powerful epidemiologic risk factor for osteoarthritis (OA), a multifactorial disease that is characterized by articular cartilage (AC) degradation. It is unclear from a molecular perspective how aging interacts with OA to produce this risk to AC integrity. To address this key question, we used in vivo time-course analysis of OA development and murine interstrain variability in natural susceptibility to OA to examine changes in non-OA-prone CBA mice versus OA-prone STR/Ort mice, which develop disease that bears significant histologic resemblance to human OA. Through global transcriptome profiling, we attempted to discover the molecular signature linked with both OA vulnerability and progression. Affymetrix Mouse Gene 1.0 ST Array profiles were generated from AC samples derived from CBA and STR/Ort mice at 3 different ages, corresponding to the stages prior to, at, and late after the natural onset of OA in the STR/Ort mice. We found that the OA in STR/Ort mice exhibited a molecular phenotype resembling human OA, and we pinpointed a central role of NF-κB signaling and the emergence of an immune-related signature in OA cartilage over time. We discovered that, strikingly, young healthy AC has a highly expressed skeletal muscle gene expression program, which is switched off during maturation, but is intriguingly retained in AC during OA development in STR/Ort mice. This study is the first to show that AC chondrocytes share a high-abundance gene-expression program with skeletal muscle. We show that failure to switch this program off, as well as the restoration of this program, is associated with inappropriate expression of NF-κB signaling pathways, skeletal muscle-related genes, and induction and/or progression of OA.


Lake Nutrient Responses to Integrated Conservation Practices in an Agricultural Watershed.
Watershed-scale management efforts to reduce nutrient loads and improve the conservation of lakes in agricultural watersheds require effective integration of a variety of agricultural conservation best management practices (BMPs). This paper documents watershed-scale assessments of the influence of multiple integrated BMPs on oxbow lake nutrient concentrations in a 625-ha watershed of intensive row-crop agricultural activity during a 14-yr monitoring period (1996-2009). A suite of BMPs within fields and at field edges throughout the watershed and enrollment of 87 ha into the Conservation Reserve Program (CRP) were implemented from 1995 to 2006. Total phosphorus (TP), soluble reactive phosphorus (SRP), ammonium, and nitrate were measured approximately biweekly from 1996 to 2009, and total nitrogen (TN) was measured from 2001 to 2009. Decreases in several lake nutrient concentrations occurred after BMP implementation. Reductions in TP lake concentrations were associated with vegetative buffers and rainfall. No consistent patterns of changes in TN or SRP lake concentrations were observed. Reductions in ammonium lake concentrations were associated with conservation tillage and CRP. Reductions in nitrate lake concentrations were associated with vegetative buffers. Watershed simulations conducted with the AnnAGNPS (Annualized Agricultural Non-Point Source) model with and without BMPs also show a clear reduction in TN and TP loads to the lake after the implementation of BMPs. These results provide direct evidence of how watershed-wide BMPs assist in reducing nutrient loading in aquatic ecosystems and promote a more viable and sustainable lake ecosystem.


Electrophysiological properties of dopamine neurons in the ventral tegmental area of Sardinian alcohol-preferring rats.
Sardinian alcohol-preferring (sP) or -nonpreferring (sNP) rats are one of the few pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, respectively. Ventral tegmental area (VTA) dopamine (DA) neurons have long been implicated in many drug-related behaviors, including alcohol self-administration. However, the electrophysiological properties of these cells in sP and sNP rats remain unknown. This study was designed to examine the properties of posterior VTA DA neurons and to unveil functional differences between sP and sNP rats. The electrophysiological properties of DA cells were examined performing either single-cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. Extracellular single-unit recordings revealed an increased spontaneous activity in sP rats. However, a corresponding difference was not found in vitro. Moreover, DA cells of sP and sNP rats showed similar intrinsic properties, suggesting changes at synaptic level. Therefore, inhibitory- and excitatory-mediated currents were studied. A decreased probability of GABA release was found in sP rats. Additionally, sP rats showed a reduced depolarization-induced suppression of inhibition, which is an endocannabinoid-mediated form of short-term plasticity. Additionally, the effect of cannabinoid-type 1 (CB1) receptor agonist WIN55,212-2 on GABAA IPSCs was smaller in sP rats, suggesting either a reduced number or functionality of CB1 receptors in the VTA. Our findings suggest that both decreased GABA release and endocannabinoid transmission in the VTA play a role in the increased impulse activity of DA cells and, ultimately, in alcohol preference displayed by sP rats.


The impact of healthcare reform proposals on radiology practice.
Current healthcare reform proposals (especially the Clinton administration's Health Security Act) are daunting in their detail, scope and possible effect on radiology--daunting, but crucial for understanding the immediate future of the profession. Ms. Cahill reveals some of the most important proposed changes, the context within which they are framed and their implications.


[Male circumcision and HIV heterosexual transmission].
Since the early years of the AIDS epidemic significant geographic differences in HIV prevalence were reported within neighboring countries and neighboring regions within the same country in sub-Saharan Africa. These differences could not be fully explained by factors such as sexual behavior and condom use. Mounting epidemiological data have demonstrated that male circumcision is a major protective factor against male heterosexual HIV infection in sub-Saharan Africa and probably contributes to these significant differences in HIV prevalence. This is a review of African studies on the association between male circumcision and HIV infection, the origin of circumcision practices in human societies, potential prepuce mechanisms for increasing male vulnerability to heterosexual HIV infection, its association with other infectious and neoplastic diseases, controversies on the convenience of male circumcision as an HIV control strategy in Africa, the scarce Brazilian literature on male circumcision and perspectives of future research.


Chemical drying agents for alfalfa hay: effect on nutrient digestibility and lactational performance.
Effects of chemical drying agents for hay on plasma profile, lactational performance, and nutrient digestibility by cows were studied. First-cutting alfalfa (late bud) was harvested as hay and treated when cut by applying untreated control, a commercial drying agent (7.64 kg/ha), or a mixture of active ingredients, potassium carbonate and sodium carbonate (7.47 kg/ha). Six multiparous Holstein cows (120 to 150 d postpartum) were fed diets (two cows per treatment) containing 55% hay and 45% concentrate (DM basis) in a balanced two period changeover design. Plasma profiles were similar for all cows, regardless of hay treatment. There were no differences in milk yield, milk fat, or milk protein percentages for control, drying agent, or mixture. Intake of DM was not different among treatments. Apparent digestibilities of DM, OM, CP, NDF, and ADF were not different among treatments. Treatment of alfalfa hay with chemical drying agents did not alter plasma profile, milk production, or nutrient digestibility in midlactation cows.


Mutational Analysis of the Rhodopsin Gene in Sector Retinitis Pigmentosa.
To determine the role of rhodopsin (RHO) gene mutations in patients with sector retinitis pigmentosa (RP) from Northern Ireland. A case series of sector RP in a tertiary ocular genetics clinic. Four patients with sector RP were recruited from the Royal Victoria Hospital (Belfast, Northern Ireland) and Altnagelvin Hospital (Londonderry, Northern Ireland) following informed consent. The diagnosis of sector RP was based on clinical examination, International Society for Clinical Electrophysiology of Vision (ISCEV) standard electrophysiology, and visual field analysis. DNA was extracted from peripheral blood leucocytes and the coding regions and adjacent flanking intronic sequences of the RHO gene were polymerase chain reaction (PCR) amplified and cycle sequenced. Rhodopsin mutational status. A heterozygous missense mutation in RHO (c.173C > T) resulting in a non-conservative substitution of threonine to methionine (p. Thr58Met) was identified in one patient and was absent from 360 control individuals. This non-conservative substitution (p.Thr58Met) replaces a highly evolutionary conserved polar hydrophilic threonine residue with a non-polar hydrophobic methionine residue at position 58 near the cytoplasmic border of helix A of RHO. The study identified a RHO gene mutation (p.Thr58Met) not previously reported in RP in a patient with sector RP. These findings outline the phenotypic variability associated with RHO mutations. It has been proposed that the regional effects of RHO mutations are likely to result from interplay between mutant alleles and other genetic, epigenetic and environmental factors.


The spontaneous development of biology from chemistry.
Biology arose as a spontaneous development from the chemistry of the early Earth by Free Energy-driven processes that occurred in common environments involving significant populations of systems. Molecular imprinting to matrices is capable of catalysis of polymer formation and reproduction that, in association with self-assembled membranes, could lead to proto-enzymes, proto-ribosomes, and proto-cells. Proto-cells would evolve via processes analogous to Darwinian natural selection. These hypotheses are testable by controlled laboratory experiments. What we call "life" is the sum of properties of such highly evolved systems.


Lattice Strain and Charge Redistribution of Pt Cluster/Ir Metallene Heterostructure for Ethylene Glycol to Glycolic Acid Conversion Coupled with Hydrogen Production.
Upgrading overall water splitting (OWS) system and developing high-performance electrocatalysts is an attractive way to the improve efficiency and reduce the consumption of hydrogen (H2 ) production from electrolyzed water. Here, a Pt cluster/Ir metallene heterojunction structure (Pt/Ir hetero-metallene) with a unique Pt/Ir interface is reported for the conversion of ethylene glycol (EG) to glycolic acid (GA) coupled with H2 production. With the assistance of ethylene glycol oxidation (EGOR), the Pt/Ir||Pt/Ir hetero-metallene two-electrode water electrolysis system exhibits a lower cell voltage of 0.36 V at 10 mA cm-2 . Furthermore, the Faradaic efficiency of EG to GA is as high as 87%. The excellent performance of this new heterostructure arise from the charge redistribution and strain effects induced by Pt-Ir interactions between the heterogeneous interfaces, as well as the larger specific surface area and more active sites due to the metallene structure.


Experimental modeling of spinal cord injury: characterization of a force-defined injury device.
We examined the ability of a novel spinal cord injury (SCI) device to produce graded morphological and behavioral changes in the adult rat following an injury at thoracic level 10 (T10). The injury device uses force applied to the tissue as the control variable rather than tissue displacement. This has the advantage of eliminating errors that may arise from tissue movement prior to injury. Three different injury severities, defined by the amount of force applied to the exposed spinal cord at T10 (100, 150, and 200 kdyn), were evaluated at two different survival times (7 and 42 d). Unbiased stereology was employed to evaluate morphological differences following the injury. Quantitative behavioral assessment employed the Basso, Beattie, and Bresnahan locomotive rating scale. There was a significant force-related decline in locomotive ability following the injury. Animals subjected to a 200-kdyn injury performed significantly worse than animals subjected to a 100- and 150-kdyn injury. The locomotor ability at different days post injury significantly correlated with the amount of force applied to the spinal cord. Statistical analysis revealed several significant force-related morphological differences following the injury. The greatest loss of white and gray matter occurred at the site of injury impact and extended in both a rostral and caudal direction. Animals subjected to the greatest force (200 kdyn) displayed the least amount of spared tissue at both survival times indicative of the most severe injury. The amount of spared tissue significantly correlated with the locomotor ability. This novel rodent model of SCI provides a significant improvement over existing devices for SCI by reducing variability with a constant preset force to define the injury.


Role of duration of catheterization and length of hospital stay on the rate of catheter-related hospital-acquired urinary tract infections.
Our aim is to prove that duration of catheterization and length of hospital stay (LOS) are associated with the rate of hospital-acquired urinary tract infections (UTI), while taking into account type of urinary catheter used, the most common organisms found, patient diagnosis on admission, associated comorbidities, age, sex, precautions that should be taken to avoid UTI, and comparison with other studies. The study was done in a university teaching hospital with a 920-bed capacity; this hospital is a tertiary care center in Riyadh, Saudi Arabia. The study was done on 250 selected patients during the year 2010 as a retrospective descriptive study. Patients were selected as purposive sample, all of them having been exposed to urinary catheterization; hospital-acquired UTI were found in 100 patients. Data were abstracted from the archived patients' files in the medical record department using the annual infection control logbook prepared by the infection control department. The data collected were demographic information about the patients, clinical condition (diagnosis and the LOS), and possible risk factors for infection such as duration of catheterization, exposure to invasive devices or surgical procedures, and medical condition. There was a statistically significant association between the rate of UTI and duration of catheterization: seven patients had UTI out of 46 catheterized patients (15%) at 3 days of catheterization, while 30 patients had UTI out of 44 catheterized patients (68%) at 8 days of catheterization (median 8 days in infected patients versus 3 days in noninfected patients; P-value <0.05), which means that the longer the duration of catheterization, the higher the UTI rate. There was a statistically significant association between the rate of UTI and LOS: three patients had UTI out of 37 catheterized patients (8%) at 10 days LOS, while 42 patients had UTI out of 49 catheterized patients (85.7%) at 18 days LOS. The longer the LOS, the higher the UTI rate: LOS for each patient (median 18 days for infected patients versus 10 days for noninfected patients; P-value <0.05), and number of hospital-acquired catheter-related UTI (100 patients had UTI out of 250 catheterized patients, P=0.04). Reduction of the duration of catheterization and LOS of the patient have a positive impact in reduction of catheter-related UTI.


Microbial and Metabolite Signatures of Stress Reactivity in Ulcerative Colitis Patients in Clinical Remission Predict Clinical Flare Risk.
Stress reactivity (SR) is associated with increased risk of flares in ulcerative colitis (UC) patients. Because both preclinical and clinical data support that stress can influence gut microbiome composition and function, we investigated whether microbiome profiles of SR exist in UC. Ninety-one UC subjects in clinical and biochemical remission were classified into high and low SR groups by questionnaires. Baseline and longitudinal characterization of the intestinal microbiome was performed by 16S rRNA gene sequencing and fecal and plasma global untargeted metabolomics. Microbe, fecal metabolite, and plasma metabolite abundances were analyzed separately to create random forest classifiers for high SR and biomarker-derived SR scores. High SR reactivity was characterized by altered abundance of fecal microbes, primarily in the Ruminococcaceae and Lachnospiraceae families; fecal metabolites including reduced levels of monoacylglycerols (endocannabinoid-related) and bile acids; and plasma metabolites including increased 4-ethyl phenyl sulfate, 1-arachidonoylglycerol (endocannabinoid), and sphingomyelin. Classifiers generated from baseline microbe, fecal metabolite, and plasma metabolite abundance distinguished high vs low SR with area under the receiver operating characteristic curve of 0.81, 0.83, and 0.91, respectively. Stress reactivity scores derived from these classifiers were significantly associated with flare risk during 6 to 24 months of follow-up, with odds ratios of 3.8, 4.1, and 4.9. Clinical flare and intestinal inflammation did not alter fecal microbial abundances but attenuated fecal and plasma metabolite differences between high and low SR. High SR in UC is characterized by microbial signatures that predict clinical flare risk, suggesting that the microbiome may contribute to stress-induced UC flares.


Quality of oral and parenteral chloroquine in Kampala.
Malaria remains an important public health problem in Uganda. The mainstay of treatment is still chloroquine. However, recently there have been several reports of poor response to chloroquine treatment. We do not know whether the reported poor response is due to true resistance or poor quality of the drug in the market. This study was done to assess the quality of chloroquine dosage forms in Kampala. The study was cross-sectional; end-point designed to assess the amount of the active ingredient in the tablet and injection dosage forms of the drug. The quality assay was based on the BP, 1988 standard, using both visual and potentiometric analysis technique. The study demonstrated that there is a problem with the quality of chloroquine in the market. Upto 30% of the tablet samples and 33% of injection samples contained less than the stated amount of the active ingredient. This may be one of the reasons for the reported poor response of malaria to chloroquine treatment in Uganda. Given that routine laboratory testing of active ingredients in pharmaceuticals is not practised in Uganda, this study has demonstrated the necessity for establishment of a drug quality control laboratory in the country.


Multicentric survey on dose reduction/interruption of cancer drug therapy in 12.472 patients: indicators of suspected adverse reactions.
Antiblastic drugs have a high number of potential side-effects. Paradoxically, according to the National Network of Pharmacovigilance, the number of reported adverse reactions to these agents is proportionally lower than that registered for non antiblastic drugs. Critical phenomena such as treatment interruptions and significant dose reductions within the first two months of use may be indicators of adverse drug reactions. The aim of the present study was to increase our knowledge of pharmacovigilance to facilitate the actions taken to improve the risk-benefit profile of cancer drugs and, consequently, their safety. This retrospective observational survey was carried out on prescriptions from 1st January 2012 to 31st December 2012.Dose reductions of more than 10% during the first 90 days of therapy were considered as a surrogate indicator of an adverse reaction. Dose interruptions during the first 60 days of therapy were taken into consideration. Of the12,472 patients 1,248 underwent a dose reduction. The drugs that most often required a dose reduction were paclitaxel and oxaliplatin (17.4% and 17.3%, respectively), docetaxel (14.8%), carboplatin (15%), fluorouracil (10.7%) and, among oral medications, capecitabine (6.9%). Of the 1896 patients treated with the same drugs, 9.7% interrupted treatment. Patients required a lower dose reduction than that reported by other authors. Around 15% of cases underwent a 30% dose reduction within three months of starting therapy, indicating a possible adverse reaction. Constant monitoring of dose prescription and continuous training of medical and nursing staff are clearly needed to increase awareness of the importance of reporting adverse events.


Incidence of unintended durotomy in spine surgery based on 108,478 cases.
Unintended durotomy is a common complication of spinal surgery. However, the incidences reported in the literature vary widely and are based primarily on relatively small case numbers from a single surgeon or institution. To provide spine surgeons with a reliable incidence of unintended durotomy in spinal surgery and to assess various factors that may influence the risk of durotomy. We assessed 108,478 surgical cases prospectively submitted by members of the Scoliosis Research Society to a deidentified database from 2004 to 2007. Unintended durotomy occurred in 1.6% (1745 of 108 478) of all cases. The incidence of unintended durotomy ranged from 1.1% to 1.9% on the basis of preoperative diagnosis, with the highest incidence among patients treated for kyphosis (1.9%) or spondylolisthesis (1.9%) and the lowest incidence among patients treated for scoliosis (1.1%). The most common indication for spine surgery was degenerative spinal disorder, and among these patients, there was a lower incidence of durotomy for cervical (1.0%) vs thoracic (2.2%; P = .01) or lumbar (2.1%, P < .001) cases. Scoliosis procedures were further characterized by etiology, with the highest incidence of durotomy in the degenerative subgroup (2.2% vs 1.1%; P < .001). Durotomy was more common in revision compared with primary surgery (2.2% vs 1.5%; P < .001) and was significantly more common among elderly (> 80 years of age) patients (2.2% vs 1.6%; P = .006). There was a significant association between unintended durotomy and development of a new neurological deficit (P < .001). Unintended durotomy occurred in at least 1.6% of spinal surgeries, even among experienced surgeons. Our data provide general benchmarks of durotomy rates and serve as a basis for ongoing efforts to improve safety of care.


Mammary tumor virus DNA as a marker for genotypic variance within hormone-responsive GR mouse mammary tumors.
Mammary tumors of GR mice acquire extra mammary tumor virus (MMTV) DNA information within their DNA during tumor growth and development. These extra MMTV genes have been used by us as genotypic markers to investigate the heterogeneity of GR mammary tumors and their loss of hormone dependence during serial transplantation. Our studies reveal that the various subpopulations of cells within individual GR mammary tumors are characterized by differences in number and location of acquired extra MMTV DNA fragments. Losses of certain of these extra MMTV DNA fragments occur when mammary tumors become hormone independent, indicating a loss of hormone-dependent cells. The study of MMTV DNA markers also reveals that low levels of autonomous cells are already present in some hormone-dependent mammary tumors at an early stage of their development. The genotypic analysis strongly indicates that mammary tumor progression is not due to phenotypic adaptation but to clonal selection of the more aggressive sublines.


Interactive informed consent: randomized comparison with paper consents.
Informed consent is the cornerstone of human research subject protection. Many subjects sign consent documents without understanding the study purpose, procedures, risks, benefits, and their rights. Proof of comprehension is not required and rarely obtained. Understanding might improve by using an interactive system with multiple options for hearing, viewing and reading about the study and the consent form at the subject's own pace with testing and immediate feedback. This prospective randomized study compared the IRB-approved paper ICF for an actual clinical research study with an interactive presentation of the same study and its associated consent form using an iPad device in two populations: clinical research professionals, and patients drawn from a variety of outpatient practice settings. Of the 90 participants, 69 completed the online test and survey questions the day after the session (maximum 36 hours post-session). Among research professionals (n = 14), there was a trend (p = .07) in the direction of iPad subjects testing better on the online test (mean correct = 77%) compared with paper subjects (mean correct = 57%). Among patients (n = 55), iPad subjects had significantly higher test scores than standard paper consent subjects (mean correct = 75% vs 58%, p < .001). For all subjects, the total time spent reviewing the paper consent was 13.2 minutes, significantly less than the average of 22.7 minutes total on the three components to be reviewed using the iPad (introductory video, consent form, interactive quiz). Overall satisfaction and overall enjoyment slightly favored the interactive iPad presentation. This study demonstrates that combining an introductory video, standard consent language, and an interactive quiz on a tablet-based system improves comprehension of research study procedures and risks.


Responses to welding fumes: lung injury, inflammation, and the release of tumor necrosis factor-alpha and interleukin-1 beta.
Possible mechanisms were examined whereby welding fumes may elicit injury and inflammation in the lungs. The effects of different welding fumes on lung macrophages and on the in vivo production of two inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta), were assessed. Fume was collected during flux-covered manual metal are welding using a stainless steel consumable electrode (MMA-SS) and gas metal are welding using a mild steel electrode (GMA-MS). For the in vitro study, bronchoalveolar lavage was performed on untreated rats to recover lung macrophages, and the effects of the welding fumes on macrophage viability and respiratory burst were examined. In vivo, additional rats were intratracheally instilled with the welding fumes at a dose of 1 mg/100 g body weight. These rats were lavaged 1, 14, and 35 days postinstillation, and indicators of lung damage (cellular differential, albumin. TNF-alpha and IL-1 beta release, and lactate dehydrogenase and beta-n-acetyl glucosaminidase activities) were measured. In vitro, the MMA-SS fume was more cytotoxic to the macrophages and induced a greater release of reactive oxygen species as measured by the respiratory burst compared to the GMA-MS fume. In vivo, evidence of lung damage was observed for both fumes 1 day postinstillation. By 14 days, lung responses to the GMA-MS fume had subsided and were not different from the saline vehicle control group. Significant lung damage was still observed for the MMA-SS group at 14 days, but by 35 days, the responses had returned to control values. One day after the instillations, both welding fumes had detectable levels of TNF-alpha and IL 1 beta within the lavage fluid. However, the MMA-SS particles caused a significantly greater release of both cytokines in the lavage fluid than did the GMA-MS group. The results demonstrate that MMA-SS fume caused more pneumoloxicity than GMA-MS. This increased response may reflect enhanced macrophage activation, the increased production of reactive oxygen species, as well as secretion of TNF-alpha and IL-1 beta.


Accuracy of image-guided pedicle screw placement using intraoperative computed tomography-based navigation with automated referencing, part I: cervicothoracic spine.
Image-guided spinal instrumentation reduces the incidence of implant misplacement. To assess the accuracy of intraoperative computed tomography (iCT)-based neuronavigation (iCT-N). In 35 patients (age range, 18-87 years), a total of 248 pedicle screws were placed in the cervical (C1-C7) and upper and midthoracic (T1-T8) spine. An automated iCT registration sequence was used for multisegmental instrumentation, with the reference frame fixed to either a Mayfield head clamp and/or the most distal spinous process within the instrumentation. Pediculation was performed with navigated drill guides or Jamshidi cannulas. The angular deviation between navigated tool trajectory and final implant positions (evaluated on postinstrumentation iCT or postoperative CT scans) was calculated to assess the accuracy of iCT-N. Final screw positions were also graded according to established classification systems. Mean follow-up was 16.7 months. Clinically significant screw misplacement or iCT-N failure mandating conversion to conventional technique did not occur. A total of 71.4% of patients self-rated their outcome as excellent or good at 12 months; 99.3% of cervical screws were compliant with Neo classification grades 0 and 1 (grade 2, 0.7%), and neurovascular injury did not occur. In addition, 97.8% of thoracic pedicle screws were assigned grades I to III of the Heary classification, with 2.2% grade IV placement. Accuracy of iCT-N progressively deteriorated with increasing distance from the spinal reference clamp but allowed safe instrumentation of up to 10 segments. Image-guided spinal instrumentation using iCT-N with automated referencing allows safe, highly accurate multilevel instrumentation of the cervical and upper and midthoracic spine. In addition, iCT-N significantly reduces the need for reregistration in multilevel surgery.


Vascular tracheobronchial compression syndromes-- experience in surgical treatment and literature review.
Between January 1988 and December 1997 a total of 22 patients (age: 8 days-46 years) were operated for vascular airway compression syndromes with respiratory insufficiency. Vascular anomalies in tracheal compression were double aortic arch in 7 patients, (2 previously operated elsewhere), right aortic arch + left ligamentum arteriosum in 1, and pulmonary artery sling in 3. Three of these patients had secondary long-segment tracheomalacia. Compression of trachea and a main bronchus existed in 2 patients with right aortic arch + left ligamentum. Isolated main bronchus obstruction was present in 9 patients (abnormal insertion of ligamentum arteriosum in 1, status post (s.p.) previous operation for PDA in 4, s. p. surgery for coarctation in 1, right aortic arch + left ligamentum arteriosum in 2, and right lung aplasia + left ligamentum in 1). 3 of these cases had secondary long-segment bronchomalacia. All patients had a complex respiratory anamnesis [long-term intubation in 7, s.p. tracheostomy in 2 (over 3 months - 3 years), and progressive respiratory insufficiency in 13). In tracheal compression, surgical correction included transsection of the underlying ring or sling components (with additional anterior aortic arch translocation in 5 patients resection-reimplantation of left pulmonary artery in 3, segmental tracheal resection in 1, and external tracheal suspension in 2). In the 2 cases with compression of the trachea and a main bronchus, aortic "extension" by a prosthetic tube was necessary. In isolated main bronchus obstruction, surgical decompression basically consisted of transsection of the ligamentum arteriosum or resection of its scarry remnant forming the "corner point" of a compression between aorta and pulmonary artery. In 3 patients with secondary long-segment malacia, additional external bronchus suspension was performed. Effective decompression and re-expansion of the airway segment concerned was achieved, and was demonstrated by intraoperative endoscopy in all patients. There were 3 postoperative deaths (sepsis 2; massive, irreversible edema of the tracheal mucosa 1). Of the 19 surviving patients 16 could be extubated between the 1st and 17th (mean = 7.5) postoperative day. In 1 case the preoperative long-term tracheostomy had to be left in place for inoperable additional laryngeal stricture. 2 patients had to be reoperated (segmental cervical tracheal resection after 5 months for primary long-term intubation-related subglottic stenosis in 1, esophageal decompression for residual dysphagia after 57 months related to a traction phenomenon at the right descending aorta in the other), both with gratifying results. In all other patients clinical, endoscopic, and radiographic examinations (follow-up = 2 months - 6 years) demonstrate good results.


Improved functional recovery of denervated skeletal muscle after temporary sensory nerve innervation.
Prolonged muscle denervation results in poor functional recovery after nerve repair. The possible protective effect of temporary sensory innervation of denervated muscle, prior to motor nerve repair, has been examined in the rat. Soleus and gastrocnemius muscles were denervated by cutting the tibial nerve, and the peroneal nerve was then sutured to the transected distal tibial nerve stump either immediately or after two, four or six months. In half of the animals with delayed repair, the saphenous (sensory) nerve was temporarily attached to the distal nerve stump. Muscles were evaluated three months after the peroneal-to-tibial union, and were compared with each other, with unoperated control muscles and with untreated denervated muscles. After four to six months of sensory "protection", gastrocnemius muscles weighed significantly more than unprotected muscles, and both gastrocnemius and soleus muscles exhibited better preservation of their structure, with less fiber atrophy and connective tissue hyperplasia. The maximum compound action potentials were significantly larger in gastrocnemius and soleus muscles following sensory protection, irrespective of the delay in motor nerve union. Isometric force, although less than in control animals and in those with immediate nerve repair, remained reasonably constant after sensory protection, while in unprotected muscles there was a progressive and significant decline as the period of denervation lengthened. We interpret these results as showing that, although incapable of forming excitable neuromuscular junctions, sensory nerves can nevertheless exert powerful trophic effects on denervated muscle fibers. We propose that these findings indicate a useful strategy for improving the outcome of peripheral nerve surgery.


Reorganization of brain function after a short-term behavioral intervention for stuttering.
This study investigated changes in brain function that occurred over a 7-day behavioral intervention for adults who stutter (AWS). Thirteen AWS received the intervention (AWS+), and 13 AWS did not receive the intervention (AWS-). There were 13 fluent controls (FC-). All participants were scanned before and after the intervention. Whole-brain analysis pre-intervention showed significant differences in task-related brain activation between AWS and FC- in the right inferior frontal cortex (IFC) and left middle temporal cortex, but there were no differences between the two AWS groups. Across the 7-day period of the intervention, AWS+ alone showed a significant increase of brain activation in the left ventral IFC/insula. There were no changes in brain function for the other two groups. Further analysis revealed that the change did not correlate with resting-state functional connectivity (RSFC) that AWS showed in the cerebellum (Lu et al., 2012). However, both changes in task-related brain function and RSFC correlated with changes in speech fluency level. Together, these findings suggest that functional reorganization in a brain region close to the left IFC that shows anomalous function in AWS, occurs after a short-term behavioral intervention for stuttering.


Expression of heat shock protein 90 alpha (Hsp90α) in primary neonatal rat myocardial cells exposed to various periods of heat stress in vitro.
The objective of this study was to investigate the mechanism of heat shock protein 90 alpha (Hsp90α) protection against heart damage resulting from heat stress by detecting Hsp90α mRNA, Hsp90α protein, protein localization, and cell damage in primary myocardial cells of neonatal rats in response to heat stress in vitro. The cells were heat-stressed at 42°C in an incubator with 95% air and 5% CO2 for different periods. Levels of Hsp90α, protein localization, enzymes, and cytopathological lesions were detected using Western blot, immunocytochemistry enzymatic assays, and cytopathological techniques. Aspartate aminotransferase, lactate dehydrogenase, and creatine kinase enzyme levels were elevated during heat stress, and acute cellular lesions that were characterized by vacuolar degeneration and necrosis were observed. Hsp90α levels decreased between 10 and 60 min of heat stress and increased after 360 and 480 min, while Hsp90α mRNA decreased after 360 min. These results indicate that heat stress might induce irreversible damage in certain myocardial cells. The elevated Hsp90α level at the end of heat stress and its positive signal in the cytoplasm of myocardial cells after heat stress could be associated with its protective role. Additionally, the consumption of Hsp90α exceeded its production in the first period of treatment.


Pancreatic calcification: formation constants of CaHCO3+ and CaC03(0) complexes determined with Ca2+ electrode.
Pancreatic calcification is a frequent complication of chronic pancreatitis, and pancreatic stones (95% CaCO3 as calcite) are observed in both humans and cattle, but little is known about the complex equilibriums governing calcium solubility. Using the Ca2+ electrode and equilibrium dialysis of NaHCO3-CaCl2-NaCl solutions (24 +/- 2 degrees C; total ionic strength = 0.153-0.161), studies were made at variable pH and total calcium and carbonate concentrations to determine the formation constants of the three possible calcium complexes: CaHCO3+, CaC03(0), and Ca(HCO3)20. If the first two complexes were present, a plot of ([Ca]/[Ca2+]-1)/[HCO3-] against the ionic ratio [C03(2)-]/[HCO3-] should be linear with intercept of the CaHCO3+ formation constant (K'aB) and slope of the CaC03(0) formation constant (K'aC). This was found to be the case in both dialysands and dialysates, using two different methods ("pH" and "K'sp") for estimation of [CO32-] values. Two other methods of data analysis were also used: simultaneous equations and multiple linear regression by matrix analysis. For all three methods, mean K'aB = 12.48 and mean K'aC = 1,870. There was no evidence for a Ca(HCO3)2(0) complex. We conclude that CaHCO3+ and CaC03(0) complexes may account for a substantial fraction of total soluble calcium is pancreatic juice. These studies provide a necessary step toward the construction of a quantitative physicochemical model of pancreatic calcium solubility.


Phase-transition thresholds and vaporization phenomena for ultrasound phase-change nanoemulsions assessed via high-speed optical microscopy.
Ultrasonically activated phase-change contrast agents (PCCAs) based on perfluorocarbon droplets have been proposed for a variety of therapeutic and diagnostic clinical applications. When generated at the nanoscale, droplets may be small enough to exit the vascular space and then be induced to vaporize with high spatial and temporal specificity by externally-applied ultrasound. The use of acoustical techniques for optimizing ultrasound parameters for given applications can be a significant challenge for nanoscale PCCAs due to the contributions of larger outlier droplets. Similarly, optical techniques can be a challenge due to the sub-micron size of nanodroplet agents and resolution limits of optical microscopy. In this study, an optical method for determining activation thresholds of nanoscale emulsions based on the in vitro distribution of bubbles resulting from vaporization of PCCAs after single, short (<10 cycles) ultrasound pulses is evaluated. Through ultra-high-speed microscopy it is shown that the bubbles produced early in the pulse from vaporized droplets are strongly affected by subsequent cycles of the vaporization pulse, and these effects increase with pulse length. Results show that decafluorobutane nanoemulsions with peak diameters on the order of 200 nm can be optimally vaporized with short pulses using pressures amenable to clinical diagnostic ultrasound machines.


Outcomes in children with Clostridium difficile infection: results from a nationwide survey.
Hospital- and population-based studies demonstrate an increasing incidence of Clostridium difficile infection (CDI) in adults and children; although pediatric CDI outcomes are incompletely understood. We analysed United States National Hospital Discharge Survey (NHDS) data to study CDI in hospitalized children. NHDS data for 2005-2009 (demographics, diagnoses and discharge status) were obtained; cases and comorbidities were identified using ICD-9 codes. Weighted univariate and multivariate analyses were performed to ascertain incidence of CDI; associations between CDI and outcomes [length of stay (LOS), colectomy, all-cause in-hospital mortality and discharge to a care facility (DTCF)]. Of an estimated 13.8 million pediatric inpatients; 46 176 had CDI; median age was 3 years; overall incidence was 33.5/10 000 hospitalizations. The annual frequency of CDI did not vary from 2005 to 2009 (0.24-0.43%; P = 0.64). On univariate analyses, children with CDI had a longer median LOS (6 vs 2 days), higher rates of colectomy [odds ratio (OR) 2.0; 95% confidence interval (CI) 1.7-2.4], mortality (OR 2.5; 95% CI 2.3-2.7), and DTCF (OR 1.6; 95% CI 1.6-1.7) (all P < 0.0001). After adjusting for age, sex and comorbidities, CDI was an independent and the strongest predictor of increased LOS (adjusted mean difference, 6.4 days; 95% CI 5.4-7.4), higher rates of colectomy (OR 2.1; 95% CI 1.8-2.5), mortality (OR 2.3; 95% CI 2.2-2.5), and DTCF (OR 1.7; 95% CI 1.6-1.8) (all P < 0.0001). On excluding infants from the analysis, children with CDI had higher rates of mortality, DTCF and longer LOS than children without CDI. Despite increased awareness and advancements in management, CDI remains a significant problem and is associated with increased LOS, colectomy, in-hospital mortality and DTCF in hospitalized children.


IL-17A inhibits autophagic activity of HCC cells by inhibiting the degradation of Bcl2.
Hepatocellular carcinoma (HCC) is associated with poor prognosis due to many unknowns about its inflammatory microenvironment. As a pivotal proinflammatory cytokine, IL-17A exerts a protective effect on the survival and function of HCC cells. It is widely accepted that IL-17A plays an important role in regulating autophagy. Bcl2, a key molecule promoting the survival of HCC cells, also plays an indispensable role as an autophagy regulator. The aim of this study was to investigate the role of Bcl2 in IL-17A-regulated autophagy of HCC cells. The results showed that IL-17A not only inhibited autophagic activity, but also increased Bcl2 levels in HCC cells under starvation. Besides, IL-17A could prevent the dissociation of autophagy protein Beclin1 from Bcl2-Beclin1 complex upon starvation. Overexpression of Beclin1 rescued the autophagy deficiency of HCC cells in presence of IL-17A. Moreover, RNAi-induced Bcl2 silencing impaired the function of IL-17A in inhibiting the activation of autophagy, subsequently reducing the viability and migration of HCC cells, while the inhibition of Beclin1 by spautin-1 could reduce autophagic activity to a certain degree, thus restoring the viability and migration of HCC cells. In summary, it was suggested that the inhibition of Bcl2 degradation may be an important mechanism by which IL-17A inhibits autophagy response, subsequently maintaining the survival in HCC cells.


Responses of aortic baroreceptors to changes of aortic blood flow and pressure in rat.
To test the hypothesis that aortic baroreceptors may respond not only to changes of aortic pressure but also to changes of aortic flow, sinusoidal flow waves were applied at 1 Hz to the aorta of urethan-anesthetized rats by infusion and withdrawal of 90 microliters blood with a pump while aortic blood pressure and single baroreceptor fiber activity were monitored. Averages from 20 to 30 pressure wave forms and nerve impulse histograms were established by computer for each single fiber during control (no pump), pump instroke (I), and outstroke (O). Fiber activity increased 20 +/- 3% (mean +/- SEM, n = 28 fibers) and decreased 23 +/- 4% with respect to control during I and O, respectively, whereas estimated changes of aortic flow were +/- 21%. The number of nerve impulses increased (I) and decreased (O) mainly during late systolic pressure rise did not change significantly, but the rate of late systolic pressure fall decreased 42 +/- 7 mmHg/s (I) and increased 39 +/- 11 mmHg/s (O). These results suggest that, because of the rate sensitivity of aortic baroreceptors, changes in aortic flow are reflected in changes of nerve impulse firing patterns during the blood pressure decrease in late systole, even in the absence of significant changes in systolic, diastolic, and pulse pressure.


Penetrating eye injuries in children in Ibadan.
A retrospective study was carried out on 60 children under 12 years of age with penetrating eye injuries. This formed 28.7% of all penetrating eye injuries seen in the University College Hospital, Ibadan. Corneal lacerations extending to the limbus was the main type of injury occurring in 65% of the patients. In all, 63% of the patient were males. Visual outcomes was poor in this age group with only 19.3% (11 patients) retaining good vision of 6/12 or better.


Treatment of thrombotic thrombocytopenic purpura. Plasmapheresis, plasma transfusion, and vincristine.
In four patients with thrombotic thrombocytopenic purpura (TTP), the administration of plasma exchange and vincristine sulfate was associated with reversal of clinical and hematologic evidence of disease. Plasmapheresis with fresh frozen plasma replacement appears effective in acutely improving neurologic and hematologic abnormalities of patients with TTP and provides time for vincristine to become effective and induce lasting remissions. One patient with early relapse responded to a second short course of vincristine without other therapy. These data suggest that these treatment modalities should be considered as the initial treatment of TTP.


Chemical characterization of new antibiotics, cerexins A and B. (Studies on antibiotics from the genus Bacillus. II)
Acid hydrolysis revealed that the antibiotic cerexin A is constructed with aspartic acid (3), threonine (1), serine (1), valine (2), allo-isoleucine (1), gamma-hydroxylysine (1), tryptophan (1), and a variety of fatty acid residues. The essential difference between cerexins A and B is concluded to be replacement of serine and one valine residue in cerexin A by glycine and phenylalanine in cerexin B. Isolation of a new amino acid L-threo-gamma-hydroxylysine is also described.


Determination of parabens in human urine by optimal ultrasound-assisted emulsification microextraction and on-line acetylation gas chromatography-mass spectrometry.
An effective and solvent-less method for the rapid determination of four commonly detected parabens (methyl-, ethyl-, propyl- and butyl-) in human urine samples is described. This method employed ultrasound-assisted emulsification microextraction (USAEME) before identification and quantitation of the parabens via on-line acetylation gas chromatography-mass spectrometry (GC-MS). Urine samples were enzymatically de-conjugated with β-glucuronidase and then extracted by an optimal USAEME procedure for the measurement of total concentrations of target analytes. The optimal USAEME parameters for one mL of urine sample (containing 0.1-g of sodium chloride), according to the Box-Behnken design method, are thus described: extractant of 200-μL of ethyl acetate, and ultrasonication for 1.0min and centrifugation at 7000rpm (3min). The supernatant was collected and evaporated until dry. Then the residue was re-dissolved in methanol (100-μL), and the extract was subjected to on-line acetylation GC-MS analysis. The limits of quantitation (LOQs) were less than 0.06ng/mL. Precisions for both intra- and inter-day analysis were calculated, and were less than 8%. Mean extraction recovery (known as trueness) was between 83 and 101% on three concentration levels. In human urine, the total concentrations of the four selected parabens, according to preliminary results, range from 0.3 to 124.5ng/mL for male, and from 27.2 to 246.3ng/mL for female. Female urine samples showed higher concentrations for the target parabens, which may indicate higher exposure due to lifestyle. This method permits accurate and high-throughput analysis of parabens for epidemiological studies.


Multiple, consecutive, fully-extended 2.0₅-helix peptide conformation.
The peptide 2.0(5)-helix does exist. It has been experimentally authenticated both in the crystalline state (by X-ray diffraction) and in solution (by several spectroscopic techniques). It is the most common conformation for C(α)-tetrasubstituted α-amino acids with at least two atoms in each side chain, provided that cyclization on the C(α)-atom is absent. X-Ray diffraction has allowed a detailed description of its geometrical and three-dimensional (3D)-structural features. The infrared absorption and the nuclear magnetic resonance parameters characteristics of this multiple, consecutive, fully-extended structure have been described. Conformational energy calculations are in agreement with the experimental findings. As the contribution per amino acid residue to the length of this helix is the longest possible, its exploitation as a molecular spacer is quite promising. However, it is a rather fragile 3D-structure and particularly sensitive to solvent polarity. Interestingly, in such a case, it may reversibly convert to the much shorter 3(10)-helix, thus generating an attractive molecular spring.


An Exploration Into Short-Interval Maintenance of Adult Hemispheric Cortical Thickness at an Individual Brain Level.
Adult cerebral cortical structure is thought to be statically maintained over short intervals. This view is based on group average findings but has never been studied at the individual level. This issue was examined with an unconventional longitudinal magnetic resonance imaging design which measured hemispheric mean cortical thickness of an adult man repeatedly at week intervals over 6 months. These measures were compared with measurement error estimates to test the current prediction that thickness measures would be statically maintained within measurement error variation. The results did not support this prediction. Thickness underwent incremental and decremental fluctuations which ranged up to 0.12 mm and 5.83% over week and multiweek intervals and which differed from measurement error variation. These exploratory analyses suggest a working hypothesis that short-interval cortical structural maintenance in an individual can involve fluctuations in thickness. If confirmed, this hypothesis has potential implications for cortical maintenance mechanisms and precision medicine approaches.


Disseminated primary cutaneous histoplasmosis successfully treated with itraconazole.
A 60-year-old immunocompetent lady with disseminated primary cutaneous histoplasmosis is reported. Histology showed a granulomatous skin infiltrate with numerous intracellular PAS positive rounded yeast cells within macrophages. Culture on Sabouraud's dextrose agar yielded a typical cottony white colony characteristic of Histoplasma capsulatum. Treatment with itraconazole showed an excellent response.


Diagnosis of genital herpes simplex virus infection in the clinical laboratory.
Since the type of herpes simplex virus (HSV) infection affects prognosis and subsequent counseling, type-specific testing to distinguish HSV-1 from HSV-2 is always recommended. Although PCR has been the diagnostic standard method for HSV infections of the central nervous system, until now viral culture has been the test of choice for HSV genital infection. However, HSV PCR, with its consistently and substantially higher rate of HSV detection, could replace viral culture as the gold standard for the diagnosis of genital herpes in people with active mucocutaneous lesions, regardless of anatomic location or viral type. Alternatively, antigen detection-an immunofluorescence test or enzyme immunoassay from samples from symptomatic patients--could be employed, but HSV type determination is of importance. Type-specific serology based on glycoprotein G should be used for detecting asymptomatic individuals but widespread screening for HSV antibodies is not recommended. In conclusion, rapid and accurate laboratory diagnosis of HSV is now become a necessity, given the difficulty in making the clinical diagnosis of HSV, the growing worldwide prevalence of genital herpes and the availability of effective antiviral therapy.


How to Determine the Role of the Microbiome in Drug Disposition.
With a paradigm shift occurring in health care toward personalized and precision medicine, understanding the numerous environmental factors that impact drug disposition is of paramount importance. The highly diverse and variant nature of the human microbiome is now recognized as a factor driving interindividual variation in therapeutic outcomes. The purpose of this review is to provide a practical guide on methodology that can be applied to study the effects of microbes on the absorption, distribution, metabolism, and excretion of drugs. We also highlight recent examples of how these methods have been successfully applied to help build the basis for researching the intersection of the microbiome and pharmacology. Although in vitro and in vivo preclinical models are highlighted, these methods are also relevant in late-phase drug development or even as a part of routine after-market surveillance. These approaches will aid in filling major knowledge gaps for both current and upcoming therapeutics with the long-term goal of achieving a new type of knowledge-based medicine that integrates data on the host and the microbiome.


Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates.
Human and chimpanzee genomes are almost identical, yet humans express higher brain capabilities. Deciphering the basis for this superiority is a long sought-after challenge. Adenosine-to-inosine (A-to-I) RNA editing is a widespread modification of the transcriptome. The editing level in humans is significantly higher compared with nonprimates, due to exceptional editing within the primate-specific Alu sequences, but the global editing level of nonhuman primates has not been studied so far. Here we report the sequencing of transcribed Alu sequences in humans, chimpanzees, and rhesus monkeys. We found that, on average, the editing level in the transcripts analyzed is higher in human brain compared with nonhuman primates, even where the genomic Alu structure is unmodified. Correlated editing is observed for pairs and triplets of specific adenosines along the Alu sequences. Moreover, new editable species-specific Alu insertions, subsequent to the human-chimpanzee split, are significantly enriched in genes related to neuronal functions and neurological diseases. The enhanced editing level in the human brain and the association with neuronal functions both hint at the possible contribution of A-to-I editing to the development of higher brain function. We show here that combinatorial editing is the most significant contributor to the transcriptome repertoire and suggest that Alu editing adapted by natural selection may therefore serve as an alternate information mechanism based on the binary A/I code.


Hormone receptors of the baboon cardiovascular system. Biochemical characterization of myocardial cytoplasmic androgen receptors.
Using the synthetic androgen R1881 (17 beta-hydroxy-17alpha-methyl-estra-4, 9, 11-trien-3-one) as probe, we identified cytoplasmic androgen receptors in baboon myocardium. The relative binding affinity of selected steroids for the androgen receptor was R1881, 100%; 5alpha-dihydrotestosterone, 32.6%; testosterone, 29.6%, progesterone, 7.2%; R5020, 1.0%; and estradiol-17beta, 5.8%. The androgen receptor migrated on low ionic strength linear sucrose density gradients as a macromolecule with a sedimentation coefficient of 8.5S. Saturation analysis performed at 2 degrees C (available sites) showed that the androgen receptor content of baboon myocardial cytoplasmic extracts was 5.9 +/- 1.4 fmol/mg protein and that the dissociation constant for R1881 was 1.16 +/- 0.30 nM. These cytoplasmic androgen receptors are indicated to be physiologically functional by previous autoradiographic studies (McGill et al., 1980; McGill and Sheridan, 1981) that showed localization of radioisotope in nuclei of myocardial fibers following injection of baboons with 5 alpha-dihydrotestosterone.


Statin-inhibited endothelial permeability could be associated with its effect on PECAM-1 in endothelial cells.
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to inhibit leukocyte recruitment to endothelium but the mechanism is less understood. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an endothelial junction protein involved in leukocyte diapedesis. We hypothesize that in endothelial cells, statins may well recruit PECAM-1 to exert their inhibitory effect on leukocyte trans-endothelial migration (TEM). In lovastatin-treated resting human umbilical vein endothelial cells (HUVECs), increased levels of mRNA and protein of PECAM-1 as well as its bio-synthesis (all approximately 2-fold) were observed by real-time PCR, Western blotting and 35S-labeled methionine incorporation assay, respectively. Moreover, in lovastatin treated resting cells as well as TNF-alpha activated endothelial cells, unanimously decreased Triton X-100 insoluble and soluble PECAM-1 ratio was observed. Such changes were accompanied by decreased TEM of U-937 cells (a promonocyte cell line). All lovastatin's effects were abrogated by mevalonic acid. In resting HUVECs, geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP) (both are isoprenoid intermediates in the cholesterol biosynthesis pathway) compromised the effect of lovastatin on PECAM-1 expression, whereas C3 toxin, an inhibitor of small G proteins, exerted statin-like effect. Statin-reduced endothelial permeability could be attributed to altered intracellular distribution of PECAM-1 in endothelial cells. We speculate that lovastatin regulates PECAM-1 expression in HUVECs through the mevalonate-GGPP pathway by inhibiting of Rho small GTPase.


Evolving Treatment Paradigms for Low-Risk Ductal Carcinoma In Situ: Imaging Needs.
Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive cancer that classically presents as asymptomatic calcifications on screening mammography. The increase in DCIS diagnoses with organized screening programs has raised concerns about overdiagnosis, while a patient-centric push for more personalized care has increased awareness about DCIS overtreatment. The standard of care for most new DCIS diagnoses is surgical excision, but non-surgical management via active monitoring is gaining attention, and multiple ongoing clinical trials are ongoing. Imaging, along with demographic and pathologic information, is a critical component of active monitoring efforts. Commonly used imaging modalities including mammography, ultrasound, and MRI, as well as newer modalities such as contrast-enhanced mammography and dedicated breast PET, can provide prognostic information to risk stratify patients for DCIS active monitoring eligibility. Furthermore, radiologists will be responsible for closely surveilling patients on active monitoring and identifying if invasive progression occurs. Active monitoring is a paradigm shift for DCIS care, but the success or failure will rely heavily on the interpretations and guidance of radiologists.


Rapid susceptibility testing of fungi by flow cytometry using vital staining.
A 1-h assay for antifungal susceptibility testing measuring the impairment of fungal metabolic activity was developed. Yeast viability was analyzed by flow cytometry with a novel fluorescent probe, FUN-1, which emits a red fluorescence when the yeast is metabolically active. For nine Candida albicans strains tested, this method yielded results comparable to those obtained by the standard M27 procedure for amphotericin B, flucytosine, fluconazole, and ketoconazole. Whether the flow cytometry antifungal susceptibility test results correlate with the in vivo activities of the drugs remains to determined.


Human Error in Autonomous Underwater Vehicle Deployment: A System Dynamics Approach.
The use of autonomous underwater vehicles (AUVs) for various applications have grown with maturing technology and improved accessibility. The deployment of AUVs for under-ice marine science research in the Antarctic is one such example. However, a higher risk of AUV loss is present during such endeavors due to the extremities in the Antarctic. A thorough analysis of risks is therefore crucial for formulating effective risk control policies and achieving a lower risk of loss. Existing risk analysis approaches focused predominantly on the technical aspects, as well as identifying static cause and effect relationships in the chain of events leading to AUV loss. Comparatively, the complex interrelationships between risk variables and other aspects of risk such as human errors have received much lesser attention. In this article, a systems-based risk analysis framework facilitated by system dynamics methodology is proposed to overcome existing shortfalls. To demonstrate usefulness of the framework, it is applied on an actual AUV program to examine the occurrence of human error during Antarctic deployment. Simulation of the resultant risk model showed an overall decline in human error incident rate with the increase in experience of the AUV team. Scenario analysis based on the example provided policy recommendations in areas of training, practice runs, recruitment policy, and setting of risk tolerance level. The proposed risk analysis framework is pragmatically useful for risk analysis of future AUV programs to ensure the sustainability of operations, facilitating both better control and monitoring of risk.


Rat liver microsomal induction of the oxidation of drugs and alcohols, and sodium dodecyl sulfate-gel profiles after in vivo treatment with pyrazole or 4-methylpyrazole.
Studies were carried out to characterize and compare the effects of pyrazole and 4-methylpyrazole, potent inhibitors of alcohol dehydrogenase, on microsomal oxidation of a variety of drugs and alcohols. Whereas pyrazole treatment of rats (200 mg/kg b.wt./day for 2 days) resulted in an enrichment of a cytochrome P-450 isozyme with a molecular weight of about 52,000 on sodium dodecyl sulfate gels, 4-methylpyrazole treatment resulted in increased amounts of two or three P-450 isozymes, one of which appeared to be similar to the isozyme increased by pyrazole. The qualitative induction of two or three isozymes of P-450 as shown by sodium dodecyl sulfate-gel electrophoresis correlates with a 2-fold increase in total content of P-450 by 4-methylpyrazole. Microsomes from the pyrazole-treated rats displayed increased activity (expressed per milligram of protein or per nanomole of P-450) with aniline, p-nitroanisole, dimethylnitrosamine (low-Km enzyme) and ethanol as substrates, but not with aminopyrine, ethoxycoumarin or dimethylnitrosamine (high-Km enzyme). A stereochemical preference for the (+)-2-butanol isomer over the (-)-isomer was also observed. Kinetic experiments indicated that the pyrazole treatment increased the Vmax for ethanol, aniline and (+)-2-butanol oxidation. These properties are similar to those found with microsomes from chronic ethanol-fed rats and suggest that, in rats, pyrazole and ethanol may induce similar isozymes of P-450, and that the former may serve as a convenient model for the latter. This comparable induction between ethanol and pyrazole is in contrast to results using imidazole, which has been reported by others not to induce an alcohol-preferring P-450 in rats.(ABSTRACT TRUNCATED AT 250 WORDS)


An Examination of Changes in Emotion Co-Regulation Among Mother and Child Dyads During the Strange Situation.
The present study applied State Space Grid analysis to describe how preschooler-mother dyads co-regulate emotion in the Strange Situation. Second-to-second mother and child affect during pre-separation play (baseline) and the final reunion (post perturbation) episodes of the Strange Situation were coded for 80 dyads. Change in emotion co-regulation across the two Strange Situation episodes was examined with linear mixed models for groups with secure and insecure classifications. The groups did not differ at baseline. Change in content-specific emotion co-regulation but not content-free emotion co-regulation was found to be significantly different within and between groups. Both secure and insecure dyads reduced the time spent in positive interaction but increased the time in negative interaction across two episodes; the change in secure dyads was less pronounced than in the insecure dyads. After the separation, secure dyads had more positive interactions and fewer negative interactions compared to insecure dyads. Results highlight how secure dyads adapted to the stressful change, whereas insecure dyads were more reactive and less resilient to the stress of the study's brief imposed separation.


Cu(II)-Catalyzed [3 + 1 + 1 + 1] Cyclization of 1,3-Diketones and 2-Naphthols Using N,N-Dimethylethanolamine as a Dual Carbon Synthon for the Synthesis of 2H-Chromenes.
Reactions with diverse C1 synthons to realize homologation were well explored. However, homologations occurring twice with one C1 synthon in a reaction were less reported. We disclose herein a Cu(II)-catalyzed novel and efficient synthesis of 2H-chromenes from 2-naphthols, 1,3-diketones, and N,N-dimethylethanolamine (DMEA) as a dual carbon synthon. Various 2H-chromenes with different functional groups are constructed in moderate to good yields. This is the first report that DMEA acts as a dual C1 synthon.


The Ross operation in adolescents.
The pulmonary autograft aortic valve replacement (Ross AVR) is the AVR of choice for children below the teenage years. Recent literature has questioned the durability of the Ross AVR in older children and young adults that present predominantly with aortic regurgitation and a dilated aortic root. At our center, the Ross AVR has been an excellent choice for most children and young and middle-aged adults. The Ross AVR is an especially good choice in young females who plan on becoming pregnant. We reviewed our experience with the Ross AVR in older children and young adults (10-20 years old) and analyzed mortality, early and late complications, and the need for reoperation and compared it to non-Ross AVR patients of the same age group during the same time period. Between 1993 and 2013, 79 children and young adults, of which 19 were female, between the age of 10 and 20, mean of 16.0 ± 2.7 years, underwent the Ross AVR. Follow-up ranged from 1 month to 20 years with a mean of 6.9 ± 5.8 years. Patients with primary and/or predominant aortic regurgitation and a dilated aortic root and/or ascending aorta at any level were called the "primarily aortic insufficiency (AI) group" (PAIG); 38 (48%) met this criteria. Because we saw some pathologic root enlargement and/or progressive aortic regurgitation in our early Ross experience (1993-2000), we modified our technique and postoperative management in 2000; 51 (65%) of 79 patients underwent the modified technique while 28 underwent our original Ross root replacement technique. The modified technique included reinforcing the aortic valve annulus and sinotubular junction and resecting or replacing the ascending aorta if it was dilated (>30 mm). Twenty-six patients during this same time period and in the same age group underwent the non-Ross AVR with a mean age of 16.5 ± 2 years. Seven of these 26 non-Ross patients were female, and 16 (62%) presented with aortic regurgitation as their primary lesion. The early mortality for the Ross group and the non-Ross group was 0% and 4%, respectively. Late mortality for the Ross group was 2.5% and 0% for the non-Ross group. Of the 28 patients, 14 (50%) receiving the early Ross operation prior to 2000 have required reoperations. Only three (5.9%) of the 51 patients done after 2000 have required surgical reintervention (P <.01). In all, 11 (34%) of our Ross patients operated prior to 2000 and three (6%) after 2000 have required reintervention on their autografts. Patients in the PAIG had zero early and late deaths and a 16% rate of reoperation on the autograft compared to zero early and two late deaths and 20% rate of reoperation in patients not in the PAIG group (P = .266 and .467 respectively). The actuarial survival for the Ross group at 5 (N = 42), 10 (N = 24), and 20 (N = 1) years was 100%, 97%, and 73% respectively. Survival for the non-Ross group at 5 (N = 18), 10 (N = 8), and 20 (N = 1) years was 96%, 96%, and 96%, respectively; this difference in survival was not statistically significant (P =.90). Differences in survival without reoperation for both the groups were not statistically significant (P =.55). When comparing patients who had the newer Ross AVR technique and the non-Ross AVR patients, there was a significantly lower incidence of late aortic stenosis (AS) with a resting gradient greater than 20 mm Hg, 0% versus 53% (P <.001). The Ross AVR is the procedure of choice for adolescents requiring AVR who have a normal pulmonary valve. There was no difference between the outcomes in patients who were in the PAIG group compared to non-PAIG patients. There was no difference in survival without reoperation between the Ross AVR and the non-Ross AVR within the 10- to 20-year age group. The Ross AVR patients had lower incidences of nonoperative complications. The Ross AVR patients had excellent hemodynamic outcomes with a significantly lower incidence of late AS when compared to the non-Ross AVR group. Reports of 15- to 20-year survival for the Ross AVR are encouraging. Long-term follow-up is necessary in all patients with aortic valve disease regardless of the treatment modality.


Outpatient parenteral antibiotic therapy for the treatment of prosthetic knee and hip infections in Belgium, a cost minimization analysis.
Prosthetic joint infections (PJI) are treated with prolonged periods of intravenous (IV) antibiotics combined with one or more appropriate surgical procedures. In Belgium, patients receive their IV treatments as inpatients, whereas in other parts of the world similar IV antibiotics can be given as outpatient parenteral antibiotic therapy (OPAT), without jeopardising patient outcomes. The purpose of this paper was to analyse the financial feasibility of OPAT for PJI in Belgium. Patients with PJI treated with a two-stage revision between January 2013 and June 2016 were selected for analysis of in-hospital costs. An OPAT cost simulation was made for comparable lengths of stay, for the different antimicrobial regimens used. A cost minimization analysis comparing the non-OPAT costs and the OPAT cost simulation was performed, with a sensitivity analysis accounting for cost uncertainties. Based on the financial data of 12 two-stage revisions and 4 different antibiotic regimens, the average simulated cost difference for OPAT was €2.402 surplus for the patient, €-25.950 for health care and €-23.548 in total. Projected cost savings for OPAT-treatment of PJI are substantial. However, OPAT within the current Belgian system was significantly more expensive for the patients. This can be attributed to the Belgian health insurance system; its current reimbursement regulations prevent OPAT from truly making a breakthrough in Belgium.


Critical care of military burn casualties at Role 3 facilities.
Burn casualties will inevitably occur in the military environment during both conflict and peacetime. The number and type of casualties will vary on the nature of warfare and the type of troops deployed. New preventative measures have decreased the number and severity of burns found on the battlefield however with new weapon systems casualties suffering from thermal injuries are still to be expected in modern warfare. Over the last 4 decades great advances have been made in the treatment of thermal injuries. These advances are reviewed here with emphasis on those that can be accomplished in the Role 3 facility by non-specialist clinicians. It is beyond the scope of this review to produce didactic treatment protocols but it is hoped that in the near future Clinical Guidelines for Operations will soon reflect these. Where advances have occurred that can not be mirrored in the field hospital early evacuation to specialist facilities back at Role 4 facilities should be a priority.


Objectively-measured sleep and its association with adiposity and physical activity in a sample of Canadian children.
Cross-sectional associations between objectively-measured sleep duration, sleep efficiency and sleep timing with adiposity and physical activity were examined in a cohort of 567 children from Ottawa, Canada. Five-hundred and fifteen children (58.8% female; age: 10.0 ± 0.4 years) had valid sleep measurements and were included in the present analyses. Physical activity, sedentary time and sleep parameters were assessed over 7 days (actigraphy). Height, weight and waist circumference were measured according to standardized procedures. Percentage body fat was assessed using bioelectric impedance analysis. Light physical activity and sedentary time were greater in children with the shortest sleep durations (P < 0.0001), whereas children with the highest sleep efficiencies had lower light physical activity and more sedentary time across tertiles (P < 0.0001). In multivariable linear regression analyses, and after adjusting for a number of covariates, sleep efficiency was inversely related to all adiposity indices (P < 0.05). However, sleep duration and sleep timing were not associated with adiposity indices after controlling for covariates. Inverse associations were noted between sleep duration and light physical activity and sedentary time (P < 0.0001). Sleep efficiency (P < 0.0001), wake time and sleep timing midpoint (P < 0.05) were negatively associated with light physical activity, but positively associated with sedentary time. In conclusion, only sleep efficiency was independently correlated with adiposity in this sample of children. Participants with the shortest sleep durations or highest sleep efficiencies had greater sedentary time. More research is needed to develop better sleep recommendations in children that are based on objective measures of sleep duration, sleep efficiency and sleep timing alike.


Clinical and Onychoscopic Features of Benign and Malignant Conditions in Longitudinal Melanonychia in the Thai Population: A Comparative Analysis.
Longitudinal melanonychia can arise from many underlying conditions, both benign and malignant. Practitioners tend to be reluctant to perform a biopsy of this condition due to procedure-related pain and the possibility of permanent nail dystrophy. Onychoscopy has become a useful tool to provide a provisional diagnosis and assist in deciding on a nail biopsy. To investigate and differentiate the clinical and onychoscopic features of subungual melanoma (SUM)/subungual melanoma in situ (SMIS) and other benign melanocytic conditions (BM). In this cross-sectional study, a total of 32 cases of longitudinal melanonychia were examined, and baseline characteristics were recorded. Onychoscopic pictures were taken by handheld dermoscopy with 10x and 50x magnification. A biopsy was then performed in each case, and a pathological diagnosis was obtained. Of the 32 cases, 6 were diagnosed with SMIS and 26 with BM (21 simple lentigines, 5 junctional nevi). The median age was significantly higher among the SMIS group (56 vs 31 years) (p = 0.034). Regarding onychoscopic findings, cases with SMIS were significantly associated with a greater band width percentage (p = 0.014), multicolor presentation (p = 0.005), the presence of granular pigmentation (p = 0.034), and micro-Hutchinson's sign (p = 0.015). In addition, subungual hyperkeratosis, a newly recognized onychoscopic feature, was more significantly associated with SMIS in comparison to BM (p = 0.002). Onychoscopy provides useful information to aid in the differential diagnosis of longitudinal melanonychia. From our study, onychoscopy can be utilized to assist in making a decision whether to perform a biopsy in patients with longitudinal melanonychia suspicious of malignant melanocytic conditions.


17beta-hydroxysteroid dehydrogenase type 11 is a major peroxisome proliferator-activated receptor alpha-regulated gene in mouse intestine.
In order to study the role of peroxisome proliferator-activated receptor alpha in mouse intestine, its agonist-induced proteins were identified by peptide mass fingerprinting followed by Northern blot analysis using their cDNAs. One of the most remarkably induced proteins was identified as 17beta-hydroxysterol dehydrogenase type 11. Its very rapid induction by various agonists was most efficient in intestine and then in liver. These findings together with recently reported results showing the enzyme family's wide substrate spectrum, including not only glucocorticoids and sex steroids but also bile acids, fatty acids and branched chain amino acids, suggest new roles for both peroxisome proliferator-activated receptor alpha and 17beta-hydroxysterol dehydrogenase type 11 in lipid metabolism and/or detoxification in the intestine.


Orientational instability and spontaneous rotation of active nematic droplets.
In experiments, an individual chemically-active liquid crystal (LC) droplet submerged in the bulk of a surfactant solution may self-propel along a straight, helical, or random trajectory. In this paper, we develop a minimal model capturing all three types of self-propulsion trajectories of a drop in the case of a nematic LC with homeotropic anchoring at the LC-fluid interface. We emulate the director field within the drop by a single preferred polarization vector that is subject of two reorientation mechanisms, namely, the internal flow-induced displacement of the hedgehog defect and the droplet's rotation. Within this reduced-order model, the coupling between the nematic ordering of the drop and the surfactant transport is represented by variations of the droplet's interfacial properties with nematic polarization. Our analysis reveals that a novel mode of orientational instability emerges from the competition of the two reorientation mechanisms and is characterized by a spontaneous rotation of the self-propelling drop responsible for helical self-propulsion trajectories. In turn, we also show that random trajectories in isotropic and nematic drops alike stem from the advection-driven transition to chaos. The succession of the different propulsion modes is consistent with experimentally-reported transitions in the shape of droplet trajectories as the drop size is varied.


CO2 Transoral Microsurgery for Supraglottic Squamous Cell Carcinoma.
The present study analyzed the results of the endoscopic approach to T1, T2 and selected T3 supraglottic carcinoma with the aim of reviewing functional and oncologic outcomes after different types of endoscopic supraglottic laryngectomies. This is a retrospective clinical study of 42 consecutive patients (mean age of 61.8 years, 33 males, 9 females) treated by the senior author for supraglottic squamous cell carcinoma with a transoral CO2 laser approach and reviewed from November 2010 to September 2017. Surgical procedures were classified according to the European Laryngological Society. In addition to the standardized transoral supraglottic laryngectomies, we introduced a modified type IVb by sparing the inferior third of the arytenoid if not directly involved in the tumor. Swallowing was evaluated with the Swallowing Performance Status Scale reported by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. Survival probabilities were estimated using Kaplan-Meier curves. Two type I, 2 type IIa, 2 type IIb, 3 type IIIa, 12 type IIIb, 13 type IVa, 3 type modified IVb, and 5 type IVb supraglottic laryngectomies were performed. Twenty-one patients (50%) underwent primary neck dissection. The pathologic TNM classification according to the 8th edition of the American Joint Committee on Cancer system was as follows: 9 pT1cN0, 2 pT1N0, 1 pT1N1, 7 pT2cN0, 1 rypT2cN0, 9 pT2N0, 4 pT2N1, 2 ypT2N1, 2 pT3cN0, 2 rypT3cN0, 1 pT3N1, and 2 pT3N2b. Mean follow-up was 3.4 years (range of 9 months to 6 years). According to the Kaplan-Meier analysis, 5-year disease-specific survival, local-relapse-free survival, nodal-relapse-free survival, overall laryngeal preservation and overall survival of patients without previous head and neck radiotherapy/open surgery were 100%, 95.2%, 87.8%, 100%, and 64.6%, respectively. Patients who underwent type I, IIa, and IIb resections (n = 6) started oral feeding the day after surgery, patients who underwent type III-IVb modified resections (n = 31) started oral feeding 3-4 days after surgery, and patients who underwent standard type 4b resections (n = 5) started oral feeding 7 days after surgery. Three months after surgery, patients without a clinical history of previous head and neck radiotherapy/open surgery who underwent type III, IVa, and modified IVb resections showed significantly better swallowing compared to patients who underwent standard type IVb resection: grade 4-6 impairment of swallowing in 8 and 66.7% of cases, respectively (p = 0.006072); patients with a clinical history of previous head and neck radiotherapy/open surgery who underwent type III, IVa, and modified IVb resections showed not statistically significant better swallowing compared to patients who underwent standard type IVb resection: grade 4-6 impairment of swallowing at 3 months in 16.7% and 50% of cases, respectively (p = 0.23568). Transoral CO2 laser supraglottic laryngectomy is an oncologic sound alternative to traditional open neck surgery and chemo-radiotherapy. Recovery of swallowing is significantly worsened after total resection of the arytenoid. Modified type IVb procedure leaving intact, when possible, the inferior third of the arytenoid and consequently the glottic competence, improves functional outcome.


Chinese health care system and clinical epidemiology.
China has gone through a comprehensive health care insurance reform since 2003 and achieved universal health insurance coverage in 2011. The new health care insurance system provides China with a huge opportunity for the development of health care and medical research when its rich medical resources are fully unfolded. In this study, we review the Chinese health care system and its implication for medical research, especially within clinical epidemiology. First, we briefly review the population register system, the distribution of the urban and rural population in China, and the development of the Chinese health care system after 1949. In the following sections, we describe the current Chinese health care delivery system and the current health insurance system. We then focus on the construction of the Chinese health information system as well as several existing registers and research projects on health data. Finally, we discuss the opportunities and challenges of the health care system in regard to clinical epidemiology research. China now has three main insurance schemes. The Urban Employee Basic Medical Insurance (UEBMI) covers urban employees and retired employees. The Urban Residence Basic Medical Insurance (URBMI) covers urban residents, including children, students, elderly people without previous employment, and unemployed people. The New Rural Cooperative Medical Scheme (NRCMS) covers rural residents. The Chinese Government has made efforts to build up health information data, including electronic medical records. The establishment of universal health care insurance with linkage to medical records will provide potentially huge research opportunities in the future. However, constructing a complete register system at a nationwide level is challenging. In the future, China will demand increased capacity of researchers and data managers, in particular within clinical epidemiology, to explore the rich resources.


Therapeutic effects of the euglenoid ichthyotoxin, euglenophycin, in colon cancer.
Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and the 3rd leading cause of cancer-related mortality. The emergence of drug resistance poses a major challenge in CRC care or treatment. This can be addressed by determining cancer mechanisms, discovery of druggable targets, and development of new drugs. In search for novel agents, aquatic microorganisms offer a vastly untapped pharmacological source that can be developed for cancer therapeutics. In this study, we characterized the anti-colorectal cancer potential of euglenophycin, a microalgal toxin from Euglena sanguinea. The toxin (49.1-114.6 μM) demonstrated cytotoxic, anti-proliferative, anti-clonogenic, and anti-migration effects against HCT116, HT29, and SW620 CRC cells. We identified G1 cell cycle arrest and cell type - dependent modulation of autophagy as mechanisms of growth inhibition. We validated euglenophycin's anti-tumorigenic activity in vivo using CRL:Nu(NCr)Foxn1nu athymic nude mouse CRC xenograft models. Intraperitoneal toxin administration (100 mg/kg; 5 days) decreased HCT116 and HT29 xenograft tumor volumes (n=10 each). Tumor inhibition was associated with reduced expression of autophagy negative regulator mechanistic target of rapamycin (mTOR) and decreased trend of serum pro-inflammatory cytokines. Together, these results provide compelling evidence that euglenophycin can be a promising anti-colorectal cancer agent targeting multiple cancer-promoting processes. Furthermore, this study supports expanding natural products drug discovery to freshwater niches as prospective sources of anti-cancer compounds.


Nuclear magnetic resonance studies of carbohydrate metabolism and substrate cycling in Fasciola hepatica.
We have been interested in clarifying unique features of glycolytic metabolism in parasitic trematodes and in developing improved methods for monitoring the effects of pharmacologic agents that may alter functions of the pathway. In the present study metabolism of [1-13C]glucose by the common liver fluke, Fasciola hepatica, was studied both directly with 13C NMR and indirectly by observation of 13C-induced multiplet splitting of the 1H NMR resonances from the glycolytic end-products propionate and acetate. The extent of 13C enrichment of the end-products demonstrated that exogenous glucose was the predominant source of glycolytic substrate under the incubation conditions used. Specific enrichments of propionate and acetate in 13C were similar and enrichments at the acetate C-1 carboxyl and C-2 methyl were identical, demonstrating that acetate is generated preferentially from pyruvate formed by the malic enzyme reaction. End-product synthesized in substrate-free medium following incorporation of a small fraction of [1-13C]glucose into endogenous glycogen demonstrates that glucose equivalents from the most recently synthesized polymeric chains, which have a specific activity in 13C equal to that of the exogenous glucose, are preferentially used for glycogenolysis. Stimulation of flukes with 0.1 mM serotonin results in a reduction of the propionate/acetate 13C enrichment ratio consistent with functional "compartmentation" of glycogen pools having different structures and/or specific enrichment in 13C. Glucose equivalents were incorporated into glycogen in intact flukes with label at both the C-1 and C-6 positions during perfusion with [1-13C]glucose as a consequence of "substrate cycling" at the phosphofructokinase/fructosebisphosphatase enzyme couple. The observed glycogen C-6/C-1 labeling ratio of 0.42 and the net glycolytic flux of 11 mumol/g wet weight/hr imply a total forward flux of about 29 mumol/g wet weight/hr through phosphofructokinase with a reverse flux of about 17 mumol/g wet weight/hr through fructosebisphosphatase. Net glycolytic flux is therefore a poor estimate of the true flux through phosphofructokinase in this preparation.


Coaxial oblique interface shearing: tunable generation and sorting of double emulsions for spatial gradient drug release.
We propose a coaxial oblique interface shearing (COIS) process for one-step generation of double emulsions which are synchronously sorted with spatial gradient distributions. As a coaxial needle supplying the inner and outer liquids obliquely vibrates across an air-liquid interface, the pinch-off of the compound liquid neck arises and the resultant double emulsions moves with tunable lateral displacements in the receiving phase. In the COIS process, the morphology and size of the double emulsions are heavily dependent on the vibration frequency and the inner and outer liquid flow rates. The lateral droplet displacements changing with process parameters can be precisely controlled in experiments and predicted theoretically by the Stokes drift model. Furthermore, the feasibility of the COIS process in spatial gradient drug release is verified. The double emulsions sorted along a specific direction are available for spatial gradient release under thermal and chemical environments, respectively. The COIS technique has great potential in fields of sensors, spatial gradient materials, advanced drug delivery and biomedical applications.


Upper body 3-dimensional kinematics during gait in psychotic patients: a pilot-study.
Gait is recognized as a key item related to mental function. Anomalous gait in psychotic individuals has been described for the lower extremities, whereas irregularities for upper body dynamics are not described, explained or verified with unbiased methods. Reduced walking velocity and increased somatic tension defined in this patient category may influence upper body dynamics during gait. The aim of this pilot-study was to describe upper body kinematics and investigate the biomechanical association with walking velocity and muscle tension. Twelve inpatients in a psychiatric ward with first-episode psychosis and 18 healthy control subjects walked at different self-chosen velocities. Movement and walking velocity were registered, and 3D kinematics was analysed for thorax and shoulder joint. Time-synchronized EMG from the trapezius muscle, chosen as indicator for general somatic tension, was analysed for maximal amplitude and variability. Results showed that patients walked with reduced arm swing at the shoulder joint and increased lateral thorax movements. Thorax rotations about the vertical axis, walking velocity and EMG measures were similar in patients and healthy subjects. The present study could not provide a biomechanical explanation for kinematic findings based on walking velocity or somatic tension.


Long-term outcomes of major upper extremity replantations.
Long-term outcomes of major upper extremity replantations are infrequently reported. It is believed that replantation is indicated for amputations at all levels in children and for all distal amputations in adults. Replantations of arm or proximal forearm amputations in adults are controversial. To evaluate the results of major upper extremity replantations, defined as those that are transmetacarpal, through the wrist, forearm, elbow or arm. A review of these types of replantations performed at the authors' institution from 2002 to 2012 was conducted. Patients' strength, range of motion and two-point discrimination were assessed. Patients completed the Disabilities of the Arm, Shoulder and Hand (DASH), the Michigan Hand Questionnaire (MHQ), and the Hospital Anxiety and Depression scale (HADS). Seventeen patients underwent major upper extremity replantation surgery. The majority (16 of 17 [94%]) of the included patients were male. Of 17 patients, 13 (76.5%) required reoperations. The mean (± SD) DASH score of seven patients who consented to completing all questionnaires was 75.4±14.2 of 100 (range 59.2 to 91.1). On the MHQ, the mean score for affected hand function was 16% compared with 84% in the unaffected hand. Patients generally demonstrated at least mild levels of anxiety and depression on the HADS. The results suggest that major upper extremity injuries and replantations have a significant impact on patients' long-term hand function, and produce long-term anxiety and depressive symptoms.


GTPase Era at the heart of ribosome assembly.
Ribosome biogenesis is a key process in all organisms. It relies on coordinated work of multiple proteins and RNAs, including an array of assembly factors. Among them, the GTPase Era stands out as an especially deeply conserved protein, critically required for the assembly of bacterial-type ribosomes from Escherichia coli to humans. In this review, we bring together and critically analyze a wealth of phylogenetic, biochemical, structural, genetic and physiological data about this extensively studied but still insufficiently understood factor. We do so using a comparative and, wherever possible, synthetic approach, by confronting observations from diverse groups of bacteria and eukaryotic organelles (mitochondria and chloroplasts). The emerging consensus posits that Era intervenes relatively early in the small subunit biogenesis and is essential for the proper shaping of the platform which, in its turn, is a prerequisite for efficient translation. The timing of Era action on the ribosome is defined by its interactions with guanosine nucleotides [GTP, GDP, (p)ppGpp], ribosomal RNA, and likely other factors that trigger or delay its GTPase activity. As a critical nexus of the small subunit biogenesis, Era is subject to sophisticated regulatory mechanisms at the transcriptional, post-transcriptional, and post-translational levels. Failure of these mechanisms or a deficiency in Era function entail dramatic generalized consequences for the protein synthesis and far-reaching, pleiotropic effects on the organism physiology, such as the Perrault syndrome in humans.


[Effect of weight gain on the development of gestational diabetes].
Gestational diabetes mellitus (GDM) refers to diabetes diagnosed in the second or third trimester of pregnancy. Assessing the weight gain in each pregnant women's appointment is a common task of primary care during their visit. However, the implications of this increase in weight for the development of GDM are unknown. Evaluate if the greater than expected weight gain (HEWG) in pregnancy is a risk factor for the development of GDM. Analytical, observational, longitudinal, retrolective study, which included pregnant women between 15 and 40 years of age with complete follow-up of the preg-nancy with > 2 prenatal check-ups, somatometry and complete medical history was made. During follow-up, the GPME was determined. Odds ratio (OR) and 95% confi-dence intervals (95% CI) were calculated. Variables with significance were entered into a multiple logistic regression model (MLR), where the dependent variable was DMG. The sample size calculation was for convenience. 1000 pregnant women with a median age of 28 years were included. In the MLR The pre-gestational body mass index (BMI) with overweight had an RM of 1.3 (95% CI 0.86-1.98), BMI with obesity an OR of 2.57 (95% CI 1.6-4.14), the HEWG during pregnancy had an OR 1.14 95% CI (0.71-1.81), Age> 30 years shows an RM of 2.24 (95% CI 1.55-3.25). HEWG during pregnancy is not an independent risk factor for the devel-opment of GDM. The main ones are age> 30 years and pre-gestational obesity.


Emergency cardiac CT for suspected acute coronary syndrome: qualitative and quantitative assessment of coronary, pulmonary, and aortic image quality.
The purpose of this study was to determine whether a dedicated coronary CT protocol provides adequate contrast enhancement and artifact-free depiction of coronary, pulmonary, and aortic circulation. Dedicated coronary 64-MDCT data sets of 50 patients (27 men; mean age, 54 +/- 12.4 years) consecutively admitted from the emergency department with suspected acute coronary syndrome were analyzed. Two independent observers graded overall coronary arterial image quality and qualitative and quantitative contrast opacification, motion, and streak artifacts within the pulmonary arteries and aorta. Coronary image quality was excellent in 48 patients (96%) and moderate in two patients (4%). Eleven left main and 22 left upper lobar pulmonary arteries were not visualized. Qualitative evaluation showed pulmonary arterial tree opacification to be excellent except for the right and left lower lateral and posterior segmental branches (52-54% rate of poor opacification). Quantitative evaluation showed four central (8%), six lobar (8%), and 206 segmental (29%) branches had poor contrast opacification (< 200 HU). Nineteen right upper lobar arteries (38%) were slightly and one was severely affected by streak artifact. At the segmental pulmonary artery level, marked differences in contrast enhancement were detected between the upper (292 +/- 72 HU) and both the middle (249 +/- 85 HU) and the lower lobes (248 +/- 76 HU) (p < 0.01). Mean aortic opacification was 300 +/- 34 HU with excellent contrast homogeneity without severe motion or streak artifacts. In the evaluation of patients presenting to the emergency department with suspected acute coronary syndrome, a dedicated coronary CT protocol enables excellent assessment of the coronary arteries and proximal ascending aorta but does not depict the pulmonary vasculature well enough for exclusion of pulmonary embolism.