Implementation of three innovative interventions in a psychiatric emergency department aimed at improving service use: a mixed-method study.
Emergency department (ED) use is often viewed as an indicator of health system quality. ED use for mental health (MH) reasons is increasing and costly for health systems, patients, and their families. Patients with mental disorders (MD) including substance use disorders (SUD) and suicidal behaviors are high ED users. Improving ED services for these patients and their families, and developing alternatives to ED use are thus key issues. This study aimed to: (1) describe the implementation of three innovative interventions provided by a brief intervention team, crisis center team, and family-peer support team in a Quebec psychiatric ED, including the identification of implementation barriers, and (2) evaluate the impacts of these ED innovations on MH service use and response to needs. Using mixed methods with data triangulation, the implementation and impact of the three above-named ED interventions were studied. Quantitative data were collected from 101 participants (81 patients, 20 family members) using a user questionnaire and patient medical records. Qualitative data were gathered from focus groups (n = 3) with key intervention staff members (n = 14). The user questionnaire also included open-ended questions. Descriptive, comparative and content analyses were produced. Key implementation issues were identified in relation to system, organizational and patient profiles, similar to results identified in most studies in the ED implementation literature aimed at improving responsiveness to patients with MD. Results were encouraging, as the innovations had a significant impact for improved patient MH service use and adequacy of care. Services also seemed adapted to patient profiles. Family members were grateful for the help received in the ED. Before implementing innovations, managers need to recognize the basic issues common to all new healthcare interventions: the need for staff training and strong involvement, particularly among physicians, development of collaborative tools especially in cases of potential cultural clash between staff and organizations, and continuous quality assessment. Future research needs to confirm the pertinence of these interventions, especially use of family-peer support teams in ED, as a highly innovative intervention. Broader ED strategies could also be deployed to improve MH services and decrease ED use for MH reasons.


Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: A review.
Cervical cancer (CC) is the fourth most common cause of cancer death in women. The most important risk factor for the development of CC is cervical infection with human papilloma virus (HPV). Inflammation is a protective strategy that is triggered by the host against pathogens such as viral infections that acts rapidly to activate the innate immune response. Inflammation is beneficial if it is brief and well controlled; however, if the inflammation is excessive or it becomes of chronic duration, it can produce detrimental effects. HPV proteins are involved, both directly and indirectly, in the development of chronic inflammation, which is a causal factor in the development of CC. However, other factors may also have a potential role in stimulating chronic inflammation. MicroRNAs (miRNAs) (a class of noncoding RNAs) are strong regulators of gene expression. They have emerged as key players in several biological processes, including inflammatory pathways. Abnormal expression of miRNAs may be linked to the induction of inflammation that occurs in CC. Exosomes are a subset of extracellular vesicles shed by almost all types of cells, which can function as cargo transfer vehicles. Exosomes contain proteins and genetic material (including miRNAs) derived from their parent cells and can potentially affect recipient cells. Exosomes have recently been recognized to be involved in inflammatory processes and can also affect the immune response. In this review, we discuss the role of HPV proteins, miRNAs and exosomes in the inflammation associated with CC.


Intestinal transplant: the long and short of it.
Intestinal failure (IF), typically due to short bowel syndrome in adults and congenital disorders in pediatric patients, is universally managed with parenteral nutrition (PN). When patients fail PN due to recurrent infection, loss of central venous access or PN-induced liver disease, intestinal transplant (ITx) is indicated. ITx consists of transplant of the small bowel, small bowel plus liver, or intestine plus multiple abdominal viscera. ITx allows for freedom from PN but is complicated by rejection and infection. Early referral of patients with IF to centers with experience in intestinal rehabilitation and transplantation is essential to improve patient outcome.


Efficacy of electrical stimulation and exercise for dysphagia in patients with head and neck cancer: A randomized clinical trial.
Neuromuscular electrical stimulation (NMES) is a highly sought after but poorly studied treatment for dysphagia among patients with head and neck cancer with dysphagia. This study investigated the efficacy of NMES in this patient population. In this double-blinded, randomized controlled trial, 170 patients with head and neck cancer experiencing posttreatment dysphagia were randomized into active NMES + swallow exercise versus sham NMES + swallow exercise groups. Outcomes after a 12-week program included changes in fluoroscopy measures, diet, and quality of life. After the 12-week program, the active NMES group had significantly worse Penetration Aspiration Scale scores than the sham group. Both groups reported significantly better diet and quality of life. No other measures were significant. NMES did not add benefit to traditional swallow exercises. Unfortunately, swallow exercises were not effective by themselves either. For patients with head and neck cancer with moderate to severe dysphagia caused by radiation therapy, current behavioral therapies are of limited help in reversing long-term dysphagia. © 2015 Wiley Periodicals, Head Neck 38: E1221-E1231, 2016.


[Molecular bases of virulence in Neisseria gonorrhoeae].
Gonorrhea remains of clinical concern, due to its frequency, complications, sequelae, increasing prevalence of antibiotic-resistant strains and absence of vaccine. A better understanding of the first stages of infection as well as of mechanisms of escape to immune response appears important. Many pathogenic bacteria express pili on their all surfaces. These structures mediate binding of bacteria to host tissues. Furthermore, gonococcal pili are submitted to a high rate antigenic variation, allowing the escape to host immune response. Pilin antigenic variation occurs by DNA recombination between one of the silent partial variant gene segments and an expressed pilin genes. We have shown that transformation of living bacteria by DNA liberated from lysed cells is a critical strep for antigenic variation. This constitutes the first specific function for a DNA transformation system. Piliation and virulence can change with culture conditions. This observation suggests that pilin expression would be subjected to an adaptative response. We have identified and characterized two genes which act in trans to regulate pilus expression. They determine synthesis of a response regulator and a membrane located sensor. They appear to regulate expression of other genes, possibly also involved in virulence. We present evidence for several environmental factors which may control the degree of piliation.


The Influence of X-Ray Computed Tomography Acquisition Parameters on Image Quality and Probability of Detection of Additive Manufacturing Defects.
X-ray computed tomography (XCT) is a promising nondestructive evaluation technique for additive manufacturing (AM) parts with complex shapes. Industrial XCT scanning is a relatively new development, and XCT has several acquisition parameters that a user can change for a scan whose effects are not fully understood. An artifact incorporating simulated defects of different sizes was produced using laser powder bed fusion (LPBF) AM. The influence of six XCT acquisition parameters was investigated experimentally based on a fractional factorial designed experiment. Twenty experimental runs were performed. The noise level of the XCT images was affected by the acquisition parameters, and the importance of the acquisition parameters was ranked. The measurement results were further analyzed to understand the probability of detection (POD) of the simulated defects. The POD determination process is detailed, including estimation of the POD confidence limit curve using a bootstrap method. The results are interpreted in the context of the AM process and XCT acquisition parameters.


Behavioral and neurochemical effects of chronic administration of reserpine and SKF-38393 in rats.
Alterations in the density of dopamine receptor subtypes and behaviors mediated by the D1-selective agonist SKF-38393 were examined in rats treated chronically with reserpine, SKF-38393 or the combination of these drugs. Animals received either vehicle or reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with [3H]SCH-23390 and D2 receptors labeled with [3H]spiroperidol revealed that chronic administration of reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic drug treatments also altered behavioral responses. Chronic administration of SKF-38393 alone produced sensitization of the oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of SKF-38393 in rats treated with reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of reserpine alone produced a spontaneous oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist spiroperidol. These findings are discussed in terms of their relevance to Parkinson's disease and tardive dyskinesia.


Impact of polymeric membrane filtration of oil sands process water on organic compounds quantification.
The interaction between organic fractions in oil sands process-affected water (OSPW) and three polymeric membranes with varying hydrophilicity (nylon, polyvinylidene fluoride and polytetrafluoroethylene) at different pHs was studied to evaluate the impact of filtration on the quantification of acid-extractable fraction (AEF) and naphthenic acids (NAs). Four functional groups predominated in OSPW (amine, phosphoryl, carboxyl and hydroxyl) as indicated by the linear programming method. The nylon membranes were the most hydrophilic and exhibited the lowest AEF removal at pH of 8.7. However, the adsorption of AEF on the membranes increased as the pH of OSPW decreased due to hydrophobic interactions between the membrane surfaces and the protonated molecules. The use of ultra pressure liquid chromatography-high resolution mass spectrometry (UPLC/HRMS) showed insignificant adsorption of NAs on the tested membranes at pH 8.7. However, 26±2.4% adsorption of NAs was observed at pH 5.3 following the protonation of NAs species. For the nylon membrane, excessive carboxylic acids in the commercial NAs caused the formation of negatively charged assisted hydrogen bonds, resulting in increased adsorption at pH 8.2 (25%) as compared to OSPW (0%). The use of membranes for filtration of soluble compounds from complex oily wastewaters before quantification analysis of AEF and NAs should be examined prior to application.


Adolescent primary care visit patterns.
Many clinical preventive care services are recommended for adolescents. Little is known about whether most adolescents have a sufficient number of preventive care services visits over time to receive those services. We wanted to measure how frequently adolescents who are insured either through private insurance or government programs have preventive vs nonpreventive care visits. We conducted a retrospective descriptive analysis based on claims data from a large health plan in Minnesota with about 700,000 members. All study patients were aged 11 to 18 years between January 1, 1998, and December 31, 2007. Our outcome measure was rates of preventive and nonpreventive care visits. One-third of adolescents with 4 or more years of continuous enrollment had no preventive care visits from age 13 through 17 years, and another 40% had only a single such visit. Nonpreventive care visits were more frequent in all age-groups, averaging about 1 per year at age 11 years, climbing to about 1.5 per year at age 17 years. Differences in rates between government insurance and commercial insurance were small. In older adolescence, girls had more preventive care visits and more nonpreventive care visits than did boys. Most adolescents come in infrequently for preventive care visits but more often for nonpreventive care visits. We recommend using the same approach in adolescence for preventive care that is being used in adults: the no-missed-opportunities paradigm. All visits by adolescents should be viewed as an opportunity to provide preventive care services, and systems should be set up to make that possible, even in busy practices with short encounters with a clinician.


MISTIC: Mutual information server to infer coevolution.
MISTIC (mutual information server to infer coevolution) is a web server for graphical representation of the information contained within a MSA (multiple sequence alignment) and a complete analysis tool for Mutual Information networks in protein families. The server outputs a graphical visualization of several information-related quantities using a circos representation. This provides an integrated view of the MSA in terms of (i) the mutual information (MI) between residue pairs, (ii) sequence conservation and (iii) the residue cumulative and proximity MI scores. Further, an interactive interface to explore and characterize the MI network is provided. Several tools are offered for selecting subsets of nodes from the network for visualization. Node coloring can be set to match different attributes, such as conservation, cumulative MI, proximity MI and secondary structure. Finally, a zip file containing all results can be downloaded. The server is available at http://mistic.leloir.org.ar. In summary, MISTIC allows for a comprehensive, compact, visually rich view of the information contained within an MSA in a manner unique to any other publicly available web server. In particular, the use of circos representation of MI networks and the visualization of the cumulative MI and proximity MI concepts is novel.


Characterization of CpG sites that escape methylation on the inactive human X-chromosome.
In many whole genome studies of gene expression or modified cytosines, data from probes localized to the X-chromosome are removed from analyses due to gender bias. Previously, we observed population differences in cytosine modifications between Caucasian and African lymphoblastoid cell lines (LCLs) on the autosomes using whole genome arrays to measure modified cytosines. DNA methylation plays a critical role in establishment and maintenance of X-chromosome inactivation in females. Therefore, we reasoned that by investigating cytosine modification patterns specifically on the X-chromosome, we could obtain valuable information about a chromosome that is often disregarded in genome-wide analyses. We investigated population differences in cytosine modification patterns along the X-chromosome between Caucasian and African LCLs and identified novel sites that escape methylation on the inactive X-chromosome (Xi) in females. We characterized the chromatin state of these loci by incorporating the extensive histone modification ChIP-seq data generated by ENCODE. To explore the relationship between DNA and histone modifications further, we hypothesized that BRD4, a protein that binds acetylated histones, could be preventing some sites from becoming de novo methylated. To test this, we treated 4 female LCLs with JQ1, a small molecule inhibitor of BRD4, but found that JQ1 treatment induced minor changes in cytosine modification levels, and the majority of sites escaping methylation on the Xi remained unmethylated. This suggests that other epigenetic mechanisms or transcription factors are likely playing a larger role in protecting these sites from de novo methylation on the Xi.


The interplay between movement, morphology and dispersal in Tetrahymena ciliates.
Understanding how and why individual movement translates into dispersal between populations is a long-term goal in ecology. Movement is broadly defined as 'any change in the spatial location of an individual', whereas dispersal is more narrowly defined as a movement that may lead to gene flow. Because the former may create the condition for the latter, behavioural decisions that lead to dispersal may be detectable in underlying movement behaviour. In addition, dispersing individuals also have specific sets of morphological and behavioural traits that help them coping with the costs of movement and dispersal, and traits that mitigate costs should be under selection and evolve if they have a genetic basis. Here, we experimentally study the relationships between movement behaviour, morphology and dispersal across 44 genotypes of the actively dispersing unicellular, aquatic model organism Tetrahymena thermophila. We used two-patch populations to quantify individual movement trajectories, as well as activity, morphology and dispersal rate. First, we studied variation in movement behaviour among and within genotypes (i.e. between dispersers and residents) and tested whether this variation can be explained by morphology. Then, we addressed how much the dispersal rate is driven by differences in the underlying movement behaviour. Genotypes revealed clear differences in terms of movement speed and linearity. We also detected marked movement differences between resident and dispersing individuals, mediated by the genotype. Movement variation was partly explained by morphological properties such as cell size and shape, with larger cells consistently showing higher movement speed and higher linearity. Genetic differences in activity and movement were positively related to the observed dispersal and jointly explained 47% of the variation in dispersal rate. Our study shows that a detailed understanding of the interplay between morphology, movement and dispersal may have potential to improve dispersal predictions over broader spatio-temporal scales.


Grading of Gliomas by Using Monoexponential, Biexponential, and Stretched Exponential Diffusion-weighted MR Imaging and Diffusion Kurtosis MR Imaging.
To quantitatively compare the potential of various diffusion parameters obtained from monoexponential, biexponential, and stretched exponential diffusion-weighted imaging models and diffusion kurtosis imaging in the grading of gliomas. This study was approved by the local ethics committee, and written informed consent was obtained from all subjects. Both diffusion-weighted imaging and diffusion kurtosis imaging were performed in 69 patients with pathologically proven gliomas by using a 3-T magnetic resonance (MR) imaging unit. An isotropic apparent diffusion coefficient (ADC), true ADC, pseudo-ADC, and perfusion fraction were calculated from diffusion-weighted images by using a biexponential model. A water molecular diffusion heterogeneity index and distributed diffusion coefficient were calculated from diffusion-weighted images by using a stretched exponential model. Mean diffusivity, fractional anisotropy, and mean kurtosis were calculated from diffusion kurtosis images. All values were compared between high-grade and low-grade gliomas by using a Mann-Whitney U test. Receiver operating characteristic and Spearman rank correlation analysis were used for statistical evaluations. ADC, true ADC, perfusion fraction, water molecular diffusion heterogeneity index, distributed diffusion coefficient, and mean diffusivity values were significantly lower in high-grade gliomas than in low-grade gliomas (U = 109, 56, 129, 6, 206, and 229, respectively; P < .05). Pseudo-ADC and mean kurtosis values were significantly higher in high-grade gliomas than in low-grade gliomas (U = 98 and 8, respectively; P < .05). Both water molecular diffusion heterogeneity index (area under the receiver operating characteristic curve [AUC] = 0.993) and mean kurtosis (AUC = 0.991) had significantly greater AUC values than ADC (AUC = 0.866), mean diffusivity (AUC = 0.722), and fractional anisotropy (AUC = 0.500) in the differentiation of low-grade and high-grade gliomas (P < .05). Water molecular diffusion heterogeneity index and mean kurtosis values may provide additional information and improve the grading of gliomas compared with conventional diffusion parameters.


Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem.
Individuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem - two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades. A total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants' performance. Saccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups. Deficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD.


Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial.
Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Pleurodesis with tetracycline or other sclerosing agents is the usual treatment for malignant pleural effusions. In contrast to this approach, intrapleural chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the effusion. Intracavitary cisplatin-based chemotherapy, which is cytotoxic rather than sclerosing, has proven safe and effective via the intraperitoneal route in ovarian cancer and malignant mesothelioma. There has been little previous experience, however, with intrapleural cisplatin-based chemotherapy. As part of a planned series of trials in malignant mesothelioma, the Lung Cancer Study Group first evaluated intrapleural cisplatin and cytarabine in patients with malignant pleural effusions from a variety of solid tumors. From April 1986 to November 1987, 46 patients with cytologically proven, symptomatic, and previously untreated malignant pleural effusions were entered on study. A single dose of cisplatin 100 mg/m2 plus cytarabine 1,200 mg was instilled into the pleural space via a chest tube, which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1, 2, and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity, four patients had grade 3 hematologic toxicity, and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma.


Diminished HIV-1 sensitivity to stavudine in patients on prolonged therapy occurs only at low levels and cannot be attributed to any single amino acid substitution in reverse transcriptase.
To study the extent to which phenotypic resistance to stavudine occurs under therapy, we studied 18 pairs of human immunodeficiency virus type 1 (HIV-1) isolates from patients both prior to and following 24-48 weeks of treatment with stavudine monotherapy or stavudine in combination with either didanosine or lamivudine. We also used a nested polymerase chain reaction (PCR) assay to probe for the presence of specific mutations associated in culture with stavudine resistance. The results showed that resistance to stavudine (approximately 3-10 fold) was observed in nine of ten cases of monotherapy, in three of four cases of therapy involving both stavudine and didanosine, and in two of four cases involving stavudine and lamivudine. Viruses from the four patients receiving stavudine plus didanosine became resistant to didanosine in only one instance while the use of lamivudine plus stavudine yielded resistance to lamivudine each time. Whereas changes in the reverse transcriptase (RT) genes of resistant isolates were frequently observed, two mutations, previously identified with stavudine resistance in tissue culture (i.e., V75T and I50T), could not be identified in the clinical samples by either direct sequencing of the RT gene or by PCR amplification. Thus, resistance to stavudine can occur, albeit at low levels, in the context of prolonged therapy with this drug but is not associated with specific mutations in HIV RT at either codons 75 or 50 in clinical samples.


Theoretical considerations of tissue electroporation with high-frequency bipolar pulses.
This study introduces the use of high-frequency pulsed electric fields for tissue electroporation. Through the development of finite element models and the use of analytical techniques, electroporation with rectangular, bipolar pulses is investigated. The electric field and temperature distribution along with the associated transmembrane potential development are considered in a heterogeneous skin fold geometry. Results indicate that switching polarity on the nanosecond scale near the charging time of plasma membranes can greatly improve treatment outcomes in heterogeneous tissues. Specifically, high-frequency fields ranging from 500 kHz to 1 MHz are best suited to penetrate epithelial layers without inducing significant Joule heating, and cause electroporation in underlying cells.


Prospective study of intravitreal triamcinolone acetonide versus bevacizumab for macular edema secondary to central retinal vein occlusion.
To compare the efficacy and safety of intravitreal triamcinolone acetonide (IVT) versus intravitreal bevacizumab (IVB) for the treatment of macular edema (ME) secondary to central retinal vein occlusion. Prospective, consecutive, clinical interventional study. A total of 31 consecutive patients (32 eyes) with ME associated with central retinal vein occlusion were randomized to 2 groups. Sixteen eyes were treated with intravitreal injection of 4 mg/0.1 mL preservative-free triamcinolone acetonide; 16 eyes received IVB 1.25 mg/0.05 mL. Patients were given additional injections if they had ME as determined by optical coherence tomography 3 months after the first treatment or visual acuity loss of at least 2 lines in a Snellen chart. Best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure, fundus fluorescein angiography, optical coherence tomography, the number of required injections, and adverse events were recorded during the 9-month follow-up period. Best-corrected visual acuity was significantly improved at 2 weeks and 1, 3, 6, and 9 months after injection in both the IVT and IVB groups, but no statistical difference was found between the 2 treatment groups during the 9-month follow-up period. The mean central macular thickness decreased at 1, 3, 6, and 9 months after injection within each treatment group, and no statistical difference was found between the 2 treatment groups at any time during the follow-up period (P > 0.05). Patients who received IVT treatment appeared to have quicker visual recovery and improved central macular thickness at Week 2 compared with those who received IVB treatment. Five of 16 eyes in the IVT group and 12 of 16 eyes in the IVB group required a repeated injection because of recurrent ME or unresolved intraretinal or subretinal fluid. The mean number of treatment was 1.31 ± 0.48 in the IVT group, as compared with 2.38 ± 1.04 in the IVB group. Significant intraocular pressure increase was found only in the IVT group, and six patients received topical intraocular pressure lowering medication, and one patient required trabeculectomy. Premacular membranes were developed in 2 patients in the IVT group. This is a prospective interventional study evaluating the efficacy and safety outcomes of IVT and IVB treatment for ME secondary to central retinal vein occlusion. Both IVT and IVB treatments can effectively improve best-corrected visual acuity and reduce central macular thickness in patients with ME secondary to central retinal vein occlusion without systemic side effects; no statistical differences were found in either best-corrected visual acuity or mean central macular thickness measurement between the two treatment groups. Both the effect of triamcinolone acetonide and that of bevacizumab were not permanent, and less injections were performed in the IVT group. However, triamcinolone acetonide causes more adverse events than bevacizumab.


Incremental cost-effectiveness of dobutamine stress cardiac magnetic resonance imaging in patients at intermediate risk for coronary artery disease.
The effectiveness of stress cardiac magnetic resonance (CMR) as a gatekeeper for coronary angiography (CA) has been established. Level five HTA studies according to the hierarchical model of diagnostic test evaluation are not available. This cohort study included 1,158 consecutive patients (mean age 63 ± 11 years, 42 % women) presenting at our institution between January 1, 2003 and December 31, 2004 with suspected coronary artery disease (CAD) for an elective CA. The patients were assessed for eligibility and propensity score matching was applied to address selection bias regarding the patients' allocation to CMR or direct CA. Median patient follow-up was 7.9 years (95 % CI 7.8-8.0 years). The primary effect was calculated as relative survival difference. The cost unit calculation (per patient) at our institute was the source of costs. Survival was similar in CMR and CA (p = 0.139). Catheterizations ruling out CAD were significantly reduced by the CMR gate-keeper strategy. Patients with prior CMR had significantly lower costs at the initial hospital stay and at follow-up (CMR vs. CA, initial: 2,904<euro> vs. 3,421<euro>, p = 0.018; follow-up: 2,045<euro> vs. 3,318<euro>, p = 0.037). CMR was cost-effective in terms of a contribution of 12,466<euro> per life year to cover a part of the CMR costs. Stress CMR prior to CA was saving 12,466<euro> of hospital costs per life year. Lower costs at follow-up suggest sustained cost-effectiveness of the CMR-guided strategy.


Shedding light on the use of Cu(ii)-salen complexes in the A3 coupling reaction.
One Cu(ii) complex, {Cu(ii)L} (1S), has been synthesised, in two high yielding steps under ambient conditions, and characterised by single-crystal X-Ray diffraction (SXRD), IR, UV-Vis, circular dichroism (CD), elemental analysis, thermogravimetric analysis (TGA) and electron spray ionization mass spectroscopy (ESI-MS). This air-stable compound enables the generation, at room temperature and in open-air, of twenty propargylamines, nine new, from secondary amines, aliphatic aldehydes and alkynes with a broad scope with yields up to 99%. Catalyst loadings can be as low as 1 mol%, while the recovered material retains its structural integrity and can be used up to 5 times without loss of its activity. Control experiments, SXRD, cyclic voltammetry and theoretical studies shed light on the mechanism revealing that the key to success is the use of phenoxido salen based ligands. These ligands orchestrate topological control permitting alkyne binding with concomitant activation of the C-H bond and simultaneously acting as a template temporarily accommodating the abstracted acetylenic proton, and continuously generating, via in situ formed radicals and a Single Electron Transfer (SET) mechanism, a transient Cu(i) active site to facilitate this transformation. The scope and limitations of this protocol are discussed and presented.


Psychophysics of reading. XI. Comparing color contrast and luminance contrast.
Text can be depicted by luminance contrast (i.e., differences in luminance between characters and background) or by color contrast (i.e., differences in chromaticity). We used a psychophysical method to measure the reading speeds of eight normal and ten low-vision subjects for text displayed on a color monitor. Reading speed was measured as a function of luminance contrast, color contrast (derived from mixtures of red and green), and combinations of the two. When color contrast is high, normal subjects can read as rapidly as with high luminance contrast (greater than 300 words/min). Curves of reading speed versus contrast have the same shape for the two forms of contrast and are superimposed when contrast is measured in multiples of a threshold value. When both color and luminance contrast are present, there is no sign of additive interaction, and performance is determined by the form of contrast yielding the highest reading rate. Our findings suggest that color contrast and luminance contrast are coded in similar ways in the visual system but that the neural signals used in letter recognition are carried by different pathways for color and luminance. We found no advantages of color contrast for low-vision reading. For text composed of 6 degrees characters, all low-vision subjects read better with luminance contrast than with color contrast.


A genome-wide search for local adaptation in a terrestrial-breeding frog reveals vulnerability to climate change.
Terrestrial-breeding amphibians are likely to be vulnerable to warming and drying climates, as their embryos require consistent moisture for successful development. Adaptation to environmental change will depend on sufficient genetic variation existing within or between connected populations. Here, we use Single Nucleotide Polymorphism (SNP) data to investigate genome-wide patterns in genetic diversity, gene flow and local adaptation in a terrestrial-breeding frog (Pseudophryne guentheri) subject to a rapidly drying climate and recent habitat fragmentation. The species was sampled across 12 central and range-edge populations (192 samples), and strong genetic structure was apparent, as were high inbreeding coefficients. Populations showed differences in genetic diversity, and one population lost significant genetic diversity in a decade. More than 500 SNP loci were putatively under directional selection, and 413 of these loci were correlated with environmental variables such as temperature, rainfall, evaporation and soil moisture. One locus showed homology to a gene involved in the activation of maturation in Xenopus oocytes, which may facilitate rapid development of embryos in drier climates. The low genetic diversity, strong population structuring and presence of local adaptation revealed in this study shows why management strategies such as targeted gene flow may be necessary to assist isolated populations to adapt to future climates.


Minimally Invasive vs. Open Hepatectomy: a Comparative Analysis of the National Surgical Quality Improvement Program Database.
While minimally invasive surgery (MIS) to treat liver tumors has increased, data on perioperative outcomes of MIS relative to open liver resection (O-LR) are lacking. We sought to compare short-term outcomes among patients undergoing MIS vs. O-LR in a nationally representative database. The National Surgical Quality Improvement Program database was used to identify patients undergoing hepatectomy between January 1 and December 31, 2014. Propensity score matching algorithm was used to balance differences in baseline characteristics among MIS and O-LR groups. A total of 3064 patients were included in the study. After propensity matching, the baseline characteristics for O-LR and MIS groups were comparable (minimum p value = 0.12). Incidence of superficial surgical site infections, intraoperative or postoperative blood transfusions, and pulmonary embolism was lower among patients in MIS group compared to O-LR (p < 0.02). Liver failure and biliary leakage were also less frequent among patients undergoing MIS (p < 0.01). Similarly, MIS was associated with a shorter length of hospital stay (LOS) compared to O-LR (p < 0.001). Of note, 30-day postoperative mortality and readmission were comparable between the two groups. Patients undergoing MIS had a lower postoperative morbidity and shorter LOS compared with patients undergoing O-LR. MIS is safe and may be associated with improved short-term outcomes following hepatic surgery.


Maintenance of basal levels of autophagy in Huntington's disease mouse models displaying metabolic dysfunction.
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein. Neuropathology in the basal ganglia and in the cerebral cortex has been linked to the motor and cognitive symptoms whereas recent work has suggested that the hypothalamus might be involved in the metabolic dysfunction. Several mouse models of HD that display metabolic dysfunction have hypothalamic pathology, and expression of mutant huntingtin in the hypothalamus has been causally linked to the development of metabolic dysfunction in mice. Although the pathogenic mechanisms by which mutant huntingtin exerts its toxic functions in the HD brain are not fully known, several studies have implicated a role for the lysososomal degradation pathway of autophagy. Interestingly, changes in autophagy in the hypothalamus have been associated with the development of metabolic dysfunction in wild-type mice. We hypothesized that expression of mutant huntingtin might lead to changes in the autophagy pathway in the hypothalamus in mice with metabolic dysfunction. We therefore investigated whether there were changes in basal levels of autophagy in a mouse model expressing a fragment of 853 amino acids of mutant huntingtin selectively in the hypothalamus using a recombinant adeno-associate viral vector approach as well as in the transgenic BACHD mice. We performed qRT-PCR and Western blot to investigate the mRNA and protein expression levels of selected autophagy markers. Our results show that basal levels of autophagy are maintained in the hypothalamus despite the presence of metabolic dysfunction in both mouse models. Furthermore, although there were no major changes in autophagy in the striatum and cortex of BACHD mice, we detected modest, but significant differences in levels of some markers in mice at 12 months of age. Taken together, our results indicate that overexpression of mutant huntingtin in mice do not significantly perturb basal levels of autophagy.


Mapping the role of structural and interpersonal violence in the lives of women: implications for public health interventions and policy.
Research on interpersonal violence towards women has commonly focused on individual or proximate-level determinants associated with violent acts ignores the roles of larger structural systems that shape interpersonal violence. Though this research has contributed to an understanding of the prevalence and consequences of violence towards women, it ignores how patterns of violence are connected to social systems and social institutions. In this paper, we discuss the findings from a scoping review that examined: 1) how structural and symbolic violence contributes to interpersonal violence against women; and 2) the relationships between the social determinants of health and interpersonal violence against women. We used concept mapping to identify what was reported on the relationships among individual-level characteristics and population-level influence on gender-based violence against women and the consequences for women's health. Institutional ethics review was not required for this scoping review since there was no involvement or contact with human subjects. The different forms of violence-symbolic, structural and interpersonal-are not mutually exclusive, rather they relate to one another as they manifest in the lives of women. Structural violence is marked by deeply unequal access to the determinants of health (e.g., housing, good quality health care, and unemployment), which then create conditions where interpersonal violence can happen and which shape gendered forms of violence for women in vulnerable social positions. Our web of causation illustrates how structural factors can have negative impacts on the social determinants of health and increases the risk for interpersonal violence among women. Public health policy responses to violence against women should move beyond individual-level approaches to violence, to consider how structural and interpersonal level violence and power relations shape the 'lived experiences' of violence for women.


[Risk factors associated to mortality by upper GI bleeding in patients from a public hospital. A case control study].
Identify and establish risk factors associated with mortality secondary to upper gastrointestinal bleeding up to 30 days after the episode, at the Hospital Nacional Cayetano Heredia. A retrospective analytic observational case-control study was made with a case: control proportion of 1:3, analyzing 180 patient from which 135 were the controls and 45 the cases. It was determined by biological plausibility as potential risk factors to 14 variables, with which were performed bivariate and multivariate logistic analyses. It was found in the bivariate logistic analysis as variables statistically related to mortality: age (OR=1.02), hematemesis (OR=2.57), in-hospital upper gastrointestinal bleeding (OR=4), cirrhosis (OR=2.67), malignancy (OR=5,37), admittance to intensive care unit/Shock-Trauma (OR=9.29), Rockall score greater than 4 (OR=19.75), rebleeding (OR=5.65), and number of packed red blood cell transfusions(OR=1.22). While in the multivariate logistic analysis, the only variables statistically related to mortality were: malignancy (OR=5.35), admittance to intensive care unit/Shock-Trauma (OR=8.29), and Rockall score greater than 4 (OR=8.43). The factors that increase the risk of mortality in patient with upper gastrointestinal bleeding are: Rockall score greater than 4, admittance to intensive care unit/Shock-Trauma, rebleeding, in-hospital upper gastrointestinal bleeding, cirrhosis, hematemesis, malignancy, the number of red blood cell transfusion, and age.


Jail recidivism in a forensic case management program.
This article explores the factors related to jail recidivism among clients receiving case management services who were seriously mentally ill, homeless, and former inmates in a large urban jail. The authors interviewed six case managers about 51 clients and examined the use of treatment stipulations as a condition of probation, clients' major diagnostic and behavioral problems, and case management strategies. Clients whose case managers actively sought legal stipulations to case management as a condition of probation and parole were more likely to return to jail. Implications for service planning and future research are discussed.


Dendrites of the dorsal and ventral hippocampal CA1 pyramidal neurons of singly housed female rats exhibit lamina-specific growths and retractions during adolescence that are responsive to pair housing.
Adolescence is accompanied by increased vulnerability to psychiatric illnesses, including anxiety, depression, schizophrenia, and eating disorders. The hippocampus is important for regulating emotional state through its ventral compartment and spatial cognition through its dorsal compartment. Previous animal studies have examined hippocampal development at stages before, after or at single time points during adolescence. However, only one study has investigated morphological changes at multiple time points during adolescence, and no study has yet compared developmental changes of dorsal versus ventral hippocampi. We analyzed the dorsal and ventral hippocampi of rats to determine the developmental trajectory of Golgi-stained hippocampal CA1 neurons by sampling at five time points, ranging from postnatal day (P) 35 (puberty) to 55 (end of adolescence). We show that the dorsal hippocampus undergoes transient dendritic retractions in stratum radiatum (SR), while the ventral hippocampus undergoes transient dendritic growths in SR. During adulthood, stress and hormonal fluctuations have been shown to alter the physiology and morphology of hippocampal neurons, but studies of the impact of these factors upon adolescent hippocampi are scarce. In addition, we show that female-female pair housing from P 36-44 significantly increases branching in the dorsal SR and reduces branching in the ventral SR. Taken together with data on spine density, these results indicate that pyramidal cells in the dorsal and ventral CA1 of female adolescents are remodeled differently following single housing. Social housing during adolescence elicits pathway-specific changes in the hippocampus that may underlie behavioral benefits, including stability of emotion regulation and superior cognition.


A single mutation in cytochrome P450 BM3 induces the conformational rearrangement seen upon substrate binding in the wild-type enzyme.
The multidomain fatty-acid hydroxylase flavocytochrome P450 BM3 has been studied as a paradigm model for eukaryotic microsomal P450 enzymes because of its homology to eukaryotic family 4 P450 enzymes and its use of a eukaryotic-like diflavin reductase redox partner. High-resolution crystal structures have led to the proposal that substrate-induced conformational changes lead to removal of water as the sixth ligand to the heme iron. Concomitant changes in the heme iron spin state and heme iron reduction potential help to trigger electron transfer from the reductase and to initiate catalysis. Surprisingly, the crystal structure of the substrate-free A264E heme domain mutant reveals the enzyme to be in the conformation observed for substrate-bound wild-type P450, but with the iron in the low-spin state. This provides strong evidence that the spin-state shift observed upon substrate binding in wild-type P450 BM3 not only is caused indirectly by structural changes in the protein, but is a direct consequence of the presence of the substrate itself, similar to what has been observed for P450cam. The crystal structure of the palmitoleate-bound A264E mutant reveals that substrate binding promotes heme ligation by Glu(264), with little other difference from the palmitoleate-bound wild-type structure observable. Despite having a protein-derived sixth heme ligand in the substrate-bound form, the A264E mutant is catalytically active, providing further indication for structural rearrangement of the active site upon reduction of the heme iron, including displacement of the glutamate ligand to allow binding of dioxygen.


Plasma and urinary levels of dermatan sulfate and heparan sulfate derived disaccharides after long-term enzyme replacement therapy (ERT) in MPS I: correlation with the timing of ERT and with total urinary excretion of glycosaminoglycans.
Mucopolysaccharidosis type I (MPS I) results in a defective breakdown of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, which leads to a progressive disease. Enzyme replacement therapy (ERT) results in clearance of these GAGs from a range of tissues and can significantly ameliorate several symptoms. The biochemical efficacy of ERT is generally assessed by the determination of the total urinary excretion of GAGs. However, this has limitations. We studied the concentrations of heparan sulfate and dermatan sulfate derived disaccharides (HS and DS, respectively) in the plasma and urine of seven patients and compared these levels with total urinary GAGs (uGAGs) levels. Plasma and urine samples were collected at different time points relative to the weekly ERT for three non-consecutive weeks in seven MPS I patients who had been treated with ERT for at least 2.5 years. Heparan and dermatan sulfate in plasma and urine were enzymatically digested into disaccharides, and HS and DS levels were determined by HPLC-MS/MS analysis. uGAGs were measured by the DMB test. The levels of HS and DS were markedly decreased compared with the levels before the initiation of ERT. However, the concentrations of DS in plasma and of both HS and DS in urine remained significantly elevated in all studied patients, while in six patients the level of total uGAGs had normalized. The concentrations of plasma and urinary HS during the weekly ERT followed a U-shaped curve. However, the effect size is small. The concentrations of plasma and urinary DS and uGAGs appeared to be in a steady state. HS and DS are sensitive biomarkers for monitoring the biochemical treatment efficacy of ERT and remain elevated despite long-term treatment. This finding may be related to the labeled dose or antibody status of the patient. The timing of the sample collection is not relevant, at least at the current dose of 100 IU/kg/weekly.


When what you have is who you are: self-uncertainty leads individualists to see themselves in their possessions.
Four studies tested whether uncertainty about the self-concept can motivate people, particularly individualists who define themselves in terms of their personal traits and characteristics, to perceive their material possessions as extensions of themselves (i.e., as self-expressive). In Study 1, European American participants rated their favorite pair of blue jeans as more self-expressive after being induced to feel self-uncertain, whereas Asian American participants did not. In Study 2, participants who scored high on a measure of individualism rated their cars as more self-expressive following a self-uncertainty manipulation. In Study 3, individualists (but not collectivists) rated their favorite possessions as more self-expressive after being subject to self-uncertainty; a manipulation of self-irrelevant uncertainty did not produce these results. In Study 4, thinking about a self-expressive (relative to utilitarian) possession bolstered self-certainty among individualists, but not collectivists. Implications for research on culture, the self-concept, and possessions are discussed.


Food reward in active compared to inactive men: Roles for gastric emptying and body fat.
Habitual exercise could contribute to weight management by altering processes of food reward via the gut-brain axis. We investigated hedonic processes of food reward in active and inactive men and characterised relationships with gastric emptying and body fat. Forty-four men (active: n=22; inactive: n=22, BMI range 21-36kg/m(2); percent fat mass range 9-42%) were studied. Participants were provided with a standardised fixed breakfast and an ad libitum lunch meal 5h later. Explicit liking, implicit wanting and preference among high-fat, low-fat, sweet and savoury food items were assessed immediately post-breakfast (fed state) and again pre-lunch (hungry state) using the Leeds Food Preference Questionnaire. Gastric emptying was assessed by (13)C-octanoic acid breath test. Active individuals exhibited a lower liking for foods overall and a greater implicit wanting for low-fat savoury foods in the fed state, compared to inactive men. Differences in the fed state remained significant after adjusting for percent fat mass. Active men also had a greater increase in liking for savoury foods in the interval between breakfast and lunch. Faster gastric emptying was associated with liking for savoury foods and with an increase in liking for savoury foods in the postprandial interval. In contrast, greater implicit wanting for high-fat foods was associated with slower gastric emptying. These associations were independent of each other, activity status and body fat. In conclusion, active and inactive men differ in processes of food reward. The rate of gastric emptying may play a role in the association between physical activity status and food reward, via the gut-brain axis.


Cortico-striatal connections predict control over speed and accuracy in perceptual decision making.
When people make decisions they often face opposing demands for response speed and response accuracy, a process likely mediated by response thresholds. According to the striatal hypothesis, people decrease response thresholds by increasing activation from cortex to striatum, releasing the brain from inhibition. According to the STN hypothesis, people decrease response thresholds by decreasing activation from cortex to subthalamic nucleus (STN); a decrease in STN activity is likewise thought to release the brain from inhibition and result in responses that are fast but error-prone. To test these hypotheses-both of which may be true-we conducted two experiments on perceptual decision making in which we used cues to vary the demands for speed vs. accuracy. In both experiments, behavioral data and mathematical model analyses confirmed that instruction from the cue selectively affected the setting of response thresholds. In the first experiment we used ultra-high-resolution 7T structural MRI to locate the STN precisely. We then used 3T structural MRI and probabilistic tractography to quantify the connectivity between the relevant brain areas. The results showed that participants who flexibly change response thresholds (as quantified by the mathematical model) have strong structural connections between presupplementary motor area and striatum. This result was confirmed in an independent second experiment. In general, these findings show that individual differences in elementary cognitive tasks are partly driven by structural differences in brain connectivity. Specifically, these findings support a cortico-striatal control account of how the brain implements adaptive switches between cautious and risky behavior.


Material-specific properties applied to an environmental risk assessment of engineered nanomaterials - implications on grouping and read-across concepts.
Engineered nanomaterials (ENMs) are intentionally designed in different nano-forms of the same parent material in order to meet application requirements. Different grouping and read-across concepts are proposed to streamline risk assessments by pooling nano-forms in one category. Environmental grouping concepts still are in their infancy and mainly focus on grouping by hazard categories. Complete risk assessments require data on environmental release and exposure not only for ENMs but also for their nano-forms. The key requirement is to identify and to distinguish the production volumes of the ENMs regarding nano-form-specific applications. The aim of our work was to evaluate whether such a grouping is possible with the available data and which influence it has on the environmental risk assessment of ENMs. A functionality-driven approach was applied to match the material-specific property (i.e. crystal form/morphology) with the functions employed in the applications. We demonstrate that for nano-TiO2, carbon nanotubes (CNTs), and nano-Al2O3 the total production volume can be allocated to specific nano-forms based on their functionalities. The differentiated assessments result in a variation of the predicted environmental concentrations for anatase vs. rutile nano-TiO2, single-wall vs. multi-wall CNTs and α- vs. γ-nano-Al2O3 by a factor of 2 to 13. Additionally, the nano-form-specific predicted no-effect concentrations for these ENMs were derived. The risk quotients for all nano-forms indicated no immediate risk in freshwaters. Our results suggest that grouping and read-across concepts should include both a nano-form release potential for estimating the environmental exposure and separately consider the nano-forms in environmental risk assessments.


Interface chemistry and molecular bonding of functional ethoxysilane-based self-assembled monolayers on magnesium surfaces.
The modification of magnesium implants with functional organic molecules is important for increasing the biological acceptance and for reducing the corrosion rate of the implant. In this work, we evaluated by a combined experimental and theoretical approach the adsorption strength and geometry of a functional self-assembled monolayer (SAM) of hydrolyzed (3-aminopropyl)triethoxysilane (APTES) molecules on a model magnesium implant surface. In time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS), only a minor amount of reverse attachment was observed. Substrate-O-Si signals could be detected, as well as other characteristic APTES fragments. The stability of the SAM upon heating in UHV was investigated additionally. Density-functional theory (DFT) calculations were used to explore the preferred binding mode and the most favorable binding configuration of the hydrolyzed APTES molecules on the hydroxylated magnesium substrate. Attachment of the molecules via hydrogen bonding or covalent bond formation via single or multiple condensation reactions were considered. The impact of the experimental conditions and the water concentration in the solvent on the thermodynamic stability of possible APTES binding modes is analyzed as a function of the water chemical potential of the environment. Finally, the influence of van der Waals contributions to the adsorption energy will be discussed.


Is it necessary to administer anti-D to prevent RhD immunization after the transfusion of RhD-positive platelet concentrates?
Serology for the presence of anti-D after RhD-incompatible platelet transfusions was performed in 24 RhD-negative patients with haematological disease and 59 RhD-negative patients with non-haematological disease. None of the patients were given prophylaxis with anti-D to prevent RhD immunization. Eight out of 59 (13.5%) non-haematology patients developed detectable anti-D, whereas 0 out of 24 (0%) of the haematology patients formed anti-D (P = 0.06). The risk of alloimmunization after RhD-incompatible platelet transfusions using platelet concentrates prepared by modern technical methods appears to be small in patients with haematological disease, but is significant in non-immunocompromised patients.


Effects of benzoic Acid and dietary calcium:phosphorus ratio on performance and mineral metabolism of weanling pigs.
In a 2×2 factorial experiment the hypotheses tested were that the metabolic acid load caused by benzoic acid (BA) added to the feed affects bone mineralization of weanling pigs, and that a wide dietary calcium (Ca) to phosphorus (P) ratio in phytase-supplemented feeds with a marginal P concentration has a positive effect on bone mineralization. The four experimental diets, which contained 0.4% P and were supplemented with 1,000 FTU phytase/kg, contained either 5 g BA/kg or no BA and either 0.77% Ca or 0.57% Ca. The 68 four-week-old Large White pigs were fed the experimental diets ad libitum for six weeks and were then slaughtered. Benzoic acid increased feed intake (p = 0.009) and growth rate (p = 0.051), but did not influence the feed conversion ratio (p>0.10). Benzoic acid decreased the pH of the urine (p = 0.031), but did not affect breaking strength and mineralization of the tibia (p>0.10). The wide Ca:P ratio decreased feed intake (p = 0.034) and growth rate (p = 0.007) and impaired feed the conversion ratio (p = 0.027), but increased the mineral concentration in the fat-free DM of the tibia (p = 0.013) without influencing its breaking strength (p>0.10). The observed positive effect of the wide Ca:P ratio on bone mineralization may be attributed, at least in part, to the impaired feed conversion ratio, i.e. to the higher feed intake and consequently to the higher mineral intake per kg BW gain. The negative impact on animal performance of the wide dietary Ca:P ratio outweighs its potentially positive effect on bone mineralization, precluding its implementation under practical feeding conditions.


[An increase in serum phenytoin concentration by changes of dosage form: case reports and its mechanism].
Phenytoin (PHT) exhibits nonlinear pharmacokinetics in the therapeutic range. Therefore a slight increase in dose may lead to considerable elevation of the serum PHT level. Although its bioavailability is dependent on the formulation, bioequivalence is considered to be preserved between the three major formulations, of tablet, 97% fine granules, and 10% powder. However, we experienced many cases of increases serum PHT concentration after changes in formulation from 97% fine granules to 97/4% hospital-made fine granules, and from the latter to 10% powder. Retrospective analysis revealed that these alterations were accompanied by 55% and 16% increases in the serum concentration-to-dose ratio of PHT, respectively. We investigated the factors of this increase by analyzing the weight of remaining powder in a package and the PHT content of each formulation. Each package of PHT formulation prepared with 97% fine granules and 10% powder was unsealed, and the contents were weighed to calculate the rate of recovery. The rate of ingestion was estimated by correcting the rate of recovery by PHT strength (i.e., 1.0 for 10% powder and 0.97 for fine granules). The rates of recovery and ingestion for 10% powder were 13% and 16% higher than those for 97% fine granules, respectively (p < 0.01). In conclusion, Changing the PHT formulation from 97% fine granules to 10% powder may lead to a considerable increase in the serum PHT concentration and possibly induce PHT toxicity.


Volumetric analysis of subarachnoid hemorrhage: assessment of the reliability of two computerized methods and their comparison with other radiographic scales.
There were two main purposes to this study: first, to assess the feasibility and reliability of 2 quantitative methods to assess bleeding volume in patients who suffered spontaneous subarachnoid hemorrhage (SAH), and second, to compare these methods to other qualitative and semiquantitative scales in terms of reliability and accuracy in predicting delayed cerebral ischemia (DCI) and outcome. A prospective series of 150 patients consecutively admitted to the Hospital 12 de Octubre over a 4-year period were included in the study. All of these patients had a diagnosis of SAH, and diagnostic CT was able to be performed in the first 24 hours after the onset of the symptoms. All CT scans were evaluated by 2 independent observers in a blinded fashion, using 2 different quantitative methods to estimate the aneurysmal bleeding volume: region of interest (ROI) volume and the Cavalieri method. The images were also graded using the Fisher scale, modified Fisher scale, Claasen scale, and the semiquantitative Hijdra scale. Weighted κ coefficients were calculated for assessing the interobserver reliability of qualitative scales and the Hijdra scores. For assessing the intermethod and interrater reliability of volumetric measurements, intraclass correlation coefficients (ICCs) were used as well as the methodology proposed by Bland and Altman. Finally, weighted κ coefficients were calculated for the different quartiles of the volumetric measurements to make comparison with qualitative scales easier. Patients surviving more than 48 hours were included in the analysis of DCI predisposing factors and analyzed using the chi-square or the Mann-Whitney U-tests. Logistic regression analysis was used for predicting DCI and outcome in the different quartiles of bleeding volume to obtain adjusted ORs. The diagnostic accuracy of each scale was obtained by calculating the area under the receiver operating characteristic curve (AUC). Qualitative scores showed a moderate interobserver reproducibility (weighted κ indexes were always < 0.65), whereas the semiquantitative and quantitative scores had a very strong interobserver reproducibility. Reliability was very high for all quantitative measures as expressed by the ICCs for intermethod and interobserver agreement. Poor outcome and DCI occurred in 49% and 31% of patients, respectively. Larger bleeding volumes were related to a poorer outcome and a higher risk of developing DCI, and the proportion of patients suffering DCI or a poor outcome increased with each quartile, maintaining this relationship after adjusting for the main clinical factors related to outcome. Quantitative analysis of total bleeding volume achieved the highest AUC, and had a greater discriminative ability than the qualitative scales for predicting the development of DCI and outcome. The use of quantitative measures may reduce interobserver variability in comparison with categorical scales. These measures are feasible using dedicated software and show a better prognostic capability in relation to outcome and DCI than conventional categorical scales.


Mapping Human Fetal Brain Maturation In Vivo Using Quantitative MRI.
On the basis of a single multidynamic multiecho sequence acquisition, SyMRI generates a variety of quantitative image data that can characterize tissue-specific properties. The aim of this retrospective study was to evaluate the feasibility of SyMRI for the qualitative and quantitative assessment of fetal brain maturation. In 52 fetuses, multidynamic multiecho sequence acquisitions were available. SyMRI was used to perform multidynamic multiecho-based postprocessing. Fetal brain maturity was scored qualitatively on the basis of SyMRI-generated MR imaging data. The results were compared with conventionally acquired T1-weighted/T2-weighted contrasts as a standard of reference. Myelin-related changes in T1-/T2-relaxation time/relaxation rate, proton density, and MR imaging signal intensity of the developing fetal brain stem were measured. A Pearson correlation analysis was used to detect correlations between the following: 1) the gestational age at MR imaging and the fetal brain maturity score, and 2) the gestational age at MR imaging and the quantitative measurements. SyMRI provided images of sufficient quality in 12/52 (23.08%) (range, 23 + 6-34 + 0) fetal multidynamic multiecho sequence acquisitions. The fetal brain maturity score positively correlated with gestational age at MR imaging (SyMRI: r = 0.915, P < .001/standard of reference: r = 0.966, P < .001). Myelination-related changes in the T2 relaxation time/T2 relaxation rate of the medulla oblongata significantly correlated with gestational age at MR imaging (T2-relaxation time: r = -0.739, P = .006/T2-relaxation rate: r = 0.790, P = .002). Fetal motion limits the applicability of multidynamic multiecho-based postprocessing. However, SyMRI-generated image data of sufficient quality enable the qualitative assessment of maturity-related changes of the fetal brain. In addition, quantitative T2 relaxation time/T2 relaxation rate mapping characterizes myelin-related changes of the brain stem prenatally. This approach, if successful, opens novel possibilities for the evaluation of structural and biochemical aspects of fetal brain maturation.


[Template-primer-dependent inactivation of DNA polymerase alpha from human placenta by 2',3'-epoxyadenosine-5'-triphosphate].
Modification of the human placenta DNA polymerase alpha by 2',3'-epoxyadenosine 5'-triphosphate (eATP) was investigated. The latter binds to the protein both in absence and in presence of template-primer complex. However for inactivation of the enzyme, reagent-complementary template, primer and Me2(+)-ions are required. The inactivation is apparently due to the affinity modification of dNTP-binding site by eATP; covalent binding of the reagent off the enzyme's active site without affecting the DNA polymerase activity is also suggested. The enzyme inactivation by eATP and its protection from inactivation in the presence of dATP were used to determine Kd values of complexes of the enzyme with eATP (90 microM) and dATP (1 microM), the latter value being 13-times lower than Km for dATP (13 microM) in the polymerisation reaction. Using the dependence of the DNA polymerase inactivation by eATP on the primer concentration, Kd for enzyme-primer complexes were estimated. The Kd value for d(pA)10 (0.33 microM) was close to Km value (0.43 microM) for this primer. eATP was concluded to be a useful reagent for estimating the efficiency of the complex formation of different ligands with dNTP- and primer-binding sites of DNA polymerase.


Measuring self-rated productivity: factor structure and variance component analysis of the Health and Work Questionnaire.
To test the factor structure and variance components of the productivity subscales of the Health and Work Questionnaire (HWQ). A total of 272 individuals from one company answered the HWQ scale, including three dimensions (efficiency, quality, and quantity) that the respondent rated from three perspectives: their own, their supervisor's, and their coworkers'. A confirmatory factor analysis was performed, and common and unique variance components evaluated. A common factor explained 81% of the variance (reliability 0.95). All dimensions and rater perspectives contributed with unique variance. The final model provided a perfect fit to the data. Efficiency, quality, and quantity and three rater perspectives are valid parts of the self-rated productivity measurement model, but with a large common factor. Thus, the HWQ can be analyzed either as one factor or by extracting the unique variance for each subdimension.


Accuracy of measurements of small changes in soft tissue mass by use of dual-photon absorptiometry.
Dual-photon absorptiometry (DPA) has recently been applied to the assessment of body composition. To evaluate the accuracy of DPA in detecting small changes in the lean soft tissue mass, we performed DPA with the use of the Norland 2600 Dichromatic densitometer on six healthy adult males before and after a 30-ml/kg transfusion of saline and before and after exercise in a warm environment, resulting in a greater than or equal to 1-kg weight loss. Absolute weight [baseline pretransfusion r2 = 0.999, standard error of estimate (SEE) = 590 g; posttransfusion r2 = 0.999, SEE = 300 g; baseline pretranspiration r2 = 0.999, SEE = 230 g; posttranspiration r2 = 0.999, SEE = 240 g] was accurately reflected in DPA total mass. Weight changes due to transfusion were poorly reflected by changes in DPA total mass (r2 = 0.417, SEE = 404 g). However, changes posttranspiration were accurately reflected in the DPA total mass (r2 = 0.886, SEE = 106 g posttranspiration). Similarly, weight changes due to transfusion were poorly measured by changes in DPA soft mass (r2 = 0.478, SEE = 365 g), but changes posttranspiration were highly correlated with DPA soft mass changes (r2 = 0.909, SEE = 92 g). Weight changes were not reflected by changes in the DPA lean soft tissue mass (r2 = 0.006, SEE = 1,737 posttransfusion, r2 = 0.094, SEE = 1,038 g posttranspiration). DPA-derived nonfat mass was highly correlated with skinfold-derived nonfat mass (r2 = 0.96, SEE = 2,400 g). Accuracy of total and soft tissue measurements implied correct mineral mass assessment.(ABSTRACT TRUNCATED AT 250 WORDS)


Alteration autonomic control of cardiac function during hemodialysis predict cardiovascular outcomes in end stage renal disease patients.
Dialysis-induced hemodynamic instability has been associated with increased risk of cardiovascular (CV) mortality. However, the control mechanisms beneath the dynamic BP changes and cardiac function during hemodialysis and subsequent CV events are not known. We hypothesize that the impaired hemodynamic control can be prognostic indicators for subsequent CV events in end stage renal diseaes (ESRD) patients. To explore the association of hemodynamic parameters and CV events in hemodialysis patients, we enrolled ESRD patients who received chronic hemodialysis without documented atherosclerotic cardiovascular disease and hemodynamic parameters were continuously obtained from the impedance cardiography during hemodialysis. A total of 35 patients were enrolled. 16 patients developed hospitalized CV events. The statistical properties [coefficient of variance (standard deviation / mean value; CoV)] of hourly beat-to-beat dynamics of hemodynamic parameters were calculated. The CoV of stroke volume (SV) and cardiac index (CI) between the 1st and 2nd hour of dialysis were significantly increased in patients without CV events compared to those with CV events. Higher CoV of SVdiff and CIdiff were significantly correlated with longer CV event-free survival, and the area under the receiver operating characteristic (ROC) curve showed fair overall discriminative power (0.783 and 0.796, respectively). The responses of hemodynamic control mechanisms can be independent predictive indexes for lower hospitalized CV events, which implies that these patients who have better autonomic control systems may have better CV outcomes.


Spectrum of disease and outcome of primary amputation for diabetic foot sepsis in rural KwaZulu-Natal.
Primary amputation (stump closure) for diabetic foot sepsis is perceived to have a higher re-amputation rate due to stump sepsis. A guillotine amputation with elective stump closure is widely practised due to the lower risk of stump sepsis and re-amputation. To provide an epidemiological analysis of the spectrum of disease and outcomes of primary amputation for diabetic foot sepsis in a regional rural hospital. A prospective cohort study of 100 patients who underwent surgery for diabetic foot sepsis over a 5-year period was undertaken at Madadeni Provincial Hospital, in northern KwaZulu-Natal. Demographic data, co-morbid profile, radiographic features, anatomical level of vascular occlusion and type of surgery performed were recorded. The Wagner classification (Wag) was used to classify disease severity. Outcome measures included length of hospital stay, in-hospital mortality and re-amputation rates. Of the 100 patients, females (n = 50) accounted for 50% of admissions. The median age was 61 years (range: 29 to 80 years). Most patients presented with advanced disease: Wag 5, n = 71 (71%); Wag 4, n = 20 (20%); Wag 3, n = 7 (7%); Wag 2, n = 2 (2%). The anatomic levels of vascular occlusion comprised: aortoiliac disease n = 2 (2%), femoropopliteal n=21(21%) and tibioperoneal disease n = 77 (77%). The following surgical procedures were undertaken: above knee amputation (AKA), n = 35 (35%); below knee amputation (BKA), n = 46 (46%); transmetatarsal amputation (TMA), n = 8 (8%); toe ectomy, n = 8 (8%) and debridement, n = 3 (3%). The re-amputation rate to above knee amputation was n = 2/46 (4.3%). All AKA stumps healed completely. The overall in-hospital mortality was n = 7 (7%) and median length of hospital stay was 7.8 ± 3.83 days. Most patients present with advanced disease requiring a major amputation. A definitive one stage primary amputation is a safe and effective procedure for diabetic foot sepsis with distinct advantages of a short hospital stay, low reamputation rates and mortality. A guillotine amputation should be reserved for physiologically unstable patients.


Genotypic diagnosis of familial Mediterranean fever (FMF) using new microsatellite markers: example of two extensive non-Ashkenazi Jewish pedigrees.
Familial Mediterranean fever is an autosomal recessive disease characterised by multiple attacks of serosal inflammation in the absence of treatment. In the absence of timely diagnosis, renal amyloidosis is a life threatening complication. The diagnosis is often missed because no specific test is available. Early colchicine treatment prevents attacks and renal complications. The FMF gene (MEF) has been mapped to chromosome 16p 13.3 but has not yet been identified. We compared the suitability of a series of microsatellite markers (four of them were new) and propose the routine use of seven of these markers, exhibiting alleles in strong linkage disequilibrium with the disease and informative in 100% of diagnosed patients. Moreover, the discovery of a homozygous status for the 3-3-9 (or 3-3-18) haplotype at the core loci (D16S3070, D16S3082, and D16S3275), which was found in 73% non-Ashkenazi Jewish patients, points to a diagnosis of FMF, even in sporadic cases, with a risk of error of only 2.10(-5). Two extensive pedigrees covering most indications for genetic counselling are presented, showing that it is now possible both prospectively and retrospectively to identify members likely to have MEF mutations. With the help of this accurate test, colchicine treatment can be better targeted, especially where the symptomatology is mild or atypical.


Phylogenetic analysis as a forensic tool in HIV transmission investigations.
: Because HIV is a fast-evolving virus, HIV genomic sequences of several individuals can be used to investigate whether they belong to a transmission network. Since the infamous 'Florida dentist case' in the beginning of the 1990s, phylogenetic analyses has been recurrently used in court settings as a forensic tool in HIV transmission investigations, for example cases where one or more complainants allege that a defendant has unlawfully infected them with HIV. Such cases can arise both in the context of HIV-specific criminal laws - in countries where transmission of HIV infection is specifically criminalized - or in the context of general laws, for example, by applying physical or sexual assault laws to HIV-related cases. Although phylogenetic analysis as a forensic technique for HIV transmission investigations has become common in several countries, the methodologies have not yet been standardized, sometimes giving rise to unwarranted conclusions. In this literature review, we revisit HIV court case investigations published in the scientific literature, as well as the methodological aspects important for the application and standardization of phylogenetic analyses methods as a forensic tool. Phylogenetic methodologies are improving quickly, such that more recently, phylogenetic relatedness, directionality of transmission and timing of nodes in the tree are used to assess whether the phylogenetic transmission analysis is consistent with or contradicting the charges. We find that there has been a lack of consistency between methods used in court case investigations and that it is essential to define guidelines to be used by phylogenetic forensic experts in HIV transmission cases in court.


Impact of human-associated Escherichia coli clonal groups in Antarctic pinnipeds: presence of ST73, ST95, ST141 and ST131.
There is growing concern about the spreading of human microorganisms in relatively untouched ecosystems such as the Antarctic region. For this reason, three pinniped species (Leptonychotes weddellii, Mirounga leonina and Arctocephalus gazella) from the west coast of the Antartic Peninsula were analysed for the presence of Escherichia spp. with the recovery of 158 E. coli and three E. albertii isolates. From those, 23 harboured different eae variants (α1, β1, β2, ε1, θ1, κ, ο), including a bfpA-positive isolate (O49:H10-A-ST206, eae-k) classified as typical enteropathogenic E. coli. Noteworthy, 62 of the 158 E. coli isolates (39.2%) exhibited the ExPEC status and 27 (17.1%) belonged to sequence types (ST) frequently occurring among urinary/bacteremia ExPEC clones: ST12, ST73, ST95, ST131 and ST141. We found similarities >85% within the PFGE-macrorrestriction profiles of pinniped and human clinic O2:H6-B2-ST141 and O16:H5/O25b:H4-B2-ST131 isolates. The in silico analysis of ST131 Cplx genomes from the three pinnipeds (five O25:H4-ST131/PST43-fimH22-virotype D; one O16:H5-ST131/PST506-fimH41; one O25:H4-ST6252/PST9-fimH22-virotype D1) identified IncF and IncI1 plasmids and revealed high core-genome similarities between pinniped and human isolates (H22 and H41 subclones). This is the first study to demonstrate the worrisome presence of human-associated E. coli clonal groups, including ST131, in Antarctic pinnipeds.


Plasma concentration of Gc-globulin is associated with organ dysfunction and sepsis after injury.
Clinical and experimental studies suggest that the proteins of the extracellular actin scavenger system have a role in the pathophysiological processes taking place in critically ill and injured patients. Circulating levels of Gc-globulin and gelsolin are reduced shortly after severe trauma, and admission levels of Gc-globulin are associated with survival. Herein, we sought to measure the association between admission levels of Gc-globulin and postinjury organ dysfunction and infection. We also wanted to describe the serial changes in Gc-globulin in these severely injured patients. Prospective cohort. Intensive care unit at a county hospital that serves as a level one trauma center. Ninety-eight consecutive trauma victims admitted to the intensive care unit for >24 hrs during a 4-month period. Circulating levels of Gc-globulin were measured by using immunonephelometry. All patients were evaluated daily to obtain the necessary data for assessment of organ dysfunction and sepsis. The median Gc-globulin concentration at admission was 127 mg/L in patients who developed severe multiple organ dysfunction compared with 184 mg/L in patients who did not (p =.001). The admission level of Gc-globulin was comparable to known risk factors such as age and injury severity score, regarding development of organ dysfunction. Plasma concentrations of Gc-globulin remained significantly lower in patients who developed respiratory failure and sepsis, compared with patients who did not develop these complications (p =.02 and p=.015, respectively). Admission plasma concentration of Gc-globulin is lower in patients who develop organ dysfunction and sepsis after traumatic injury. These data, combined with the work of others, support the hypothesis that actin release and depletion of the extracellular actin scavenger system proteins are associated with, and may contribute in part to, the complications of sepsis and organ dysfunction, particularly respiratory failure and thrombocytopenia.


Pseudomonas syringae HrpJ is a type III secreted protein that is required for plant pathogenesis, injection of effectors, and secretion of the HrpZ1 Harpin.
The bacterial plant pathogen Pseudomonas syringae requires a type III protein secretion system (TTSS) to cause disease. The P. syringae TTSS is encoded by the hrp-hrc gene cluster. One of the genes within this cluster, hrpJ, encodes a protein with weak similarity to YopN, a type III secreted protein from the animal pathogenic Yersinia species. Here, we show that HrpJ is secreted in culture and translocated into plant cells by the P. syringae pv. tomato DC3000 TTSS. A DC3000 hrpJ mutant, UNL140, was greatly reduced in its ability to cause disease symptoms and multiply in Arabidopsis thaliana. UNL140 exhibited a reduced ability to elicit a hypersensitive response (HR) in nonhost tobacco plants. UNL140 was unable to elicit an AvrRpt2- or AvrB1-dependent HR in A. thaliana but maintained its ability to secrete AvrB1 in culture via the TTSS. Additionally, UNL140 was defective in its ability to translocate the effectors AvrPto1, HopB1, and AvrPtoB. Type III secretion assays showed that UNL140 secreted HrpA1 and AvrPto1 but was unable to secrete HrpZ1, a protein that is normally secreted in culture in relatively large amounts, into culture supernatants. Taken together, our data indicate that HrpJ is a type III secreted protein that is important for pathogenicity and the translocation of effectors into plant cells. Based on the failure of UNL140 to secrete HrpZ1, HrpJ may play a role in controlling type III secretion, and in its absence, specific accessory proteins, like HrpZ1, may not be extracellularly localized, resulting in disabled translocation of effectors into plant cells.


The avian influenza virus nucleoprotein gene and a specific constellation of avian and human virus polymerase genes each specify attenuation of avian-human influenza A/Pintail/79 reassortant viruses for monkeys.
Reassortant viruses which possessed the hemagglutinin and neuraminidase genes of wild-type human influenza A viruses and the remaining six RNA segments (internal genes) of the avian A/Pintail/Alberta/119/79 (H4N6) virus were previously found to be attenuated in humans. To study the genetic basis of this attenuation, we isolated influenza A/Pintail/79 X A/Washington/897/80 reassortant viruses which contained human influenza virus H3N2 surface glycoprotein genes and various combinations of avian or human influenza virus internal genes. Twenty-four reassortant viruses were isolated and first evaluated for infectivity in avian (primary chick kidney [PCK]) and mammalian (Madin-Darby canine kidney [MDCK]) tissue culture lines. Reassortant viruses with two specific constellations of viral polymerase genes exhibited a significant host range restriction of replication in mammalian (MDCK) tissue culture compared with that in avian (PCK) tissue culture. The viral polymerase genotype PB2-avian (A) virus, PB1-A virus, and PA-human (H) virus was associated with a 900-fold restriction, while the viral polymerase genotype PB2-H, PB1-A, and PA-H was associated with an 80,000-fold restriction of replication in MDCK compared with that in PCK. Fifteen reassortant viruses were subsequently evaluated for their level of replication in the respiratory tract of squirrel monkeys, and two genetic determinants of attenuation were identified. First, reassortant viruses which possessed the avian influenza virus nucleoprotein gene were as restricted in replication as a virus which possessed all six internal genes of the avian influenza A virus parent, indicating that the nucleoprotein gene is the major determinant of attenuation of avian-human A/Pintail/79 reassortant viruses for monkeys. Second, reassortant viruses which possessed the viral polymerase gene constellation of PB2-H, PB1-A, and PA-H, which was associated with the greater degree of host range restriction in vitro, were highly restricted in replication in monkeys. Since the avian-human influenza reassortant viruses which expressed either mode of attenuation in monkeys replicated to high titer in eggs and in PCK tissue culture, their failure to replicate efficiently in the respiratory epithelium of primates must be due to the failure of viral factors to interact with primate host cell factors. The implications of these findings for the development of live-virus vaccines and for the evolution of influenza A viruses in nature are discussed.


Research review: the neurobiology and genetics of maltreatment and adversity.
The neurobiological mechanisms by which childhood maltreatment heightens vulnerability to psychopathology remain poorly understood. It is likely that a complex interaction between environmental experiences (including poor caregiving) and an individual's genetic make-up influence neurobiological development across infancy and childhood, which in turn sets the stage for a child's psychological and emotional development. This review provides a concise synopsis of those studies investigating the neurobiological and genetic factors associated with childhood maltreatment and adversity. We first provide an overview of the neuroendocrine findings, drawing from animal and human studies. These studies indicate an association between early adversity and atypical development of the hypothalamic-pituitary-adrenal (HPA) axis stress response, which can predispose to psychiatric vulnerability in adulthood. We then review the neuroimaging findings of structural and functional brain differences in children and adults who have experienced childhood maltreatment. These studies offer evidence of several structural differences associated with early stress, most notably in the corpus callosum in children and the hippocampus in adults; functional studies have reported atypical activation of several brain regions, including decreased activity of the prefrontal cortex. Next we consider studies that suggest that the effect of environmental adversity may be conditional on an individual's genotype. We also briefly consider the possible role that epigenetic mechanisms might play in mediating the impact of early adversity. Finally we consider several ways in which the neurobiological and genetic research may be relevant to clinical practice and intervention.


ATR and ATRIP are recruited to herpes simplex virus type 1 replication compartments even though ATR signaling is disabled.
Although the herpes simplex virus type 1 (HSV-1) genome might be expected to induce a DNA damage response, the ATR kinase is not activated in infected cells. We previously proposed that spatial uncoupling of ATR from its interaction partner, ATRIP, could be the basis for inactivation of the ATR kinase in infected cells; however, we now show that ATR and ATRIP are in fact both recruited to HSV-1 replication compartments and can be coimmunoprecipitated from infected-cell lysates. ATRIP and replication protein A (RPA) are recruited to the earliest detectable prereplicative sites, stage II microfoci. In a normal cellular DNA damage response, ATR/ATRIP are recruited to stretches of RPA-coated single-stranded DNA in an RPA- and kinase-dependent manner, resulting in the phosphorylation of RPA by ATR in damage foci. In contrast, in HSV-1-infected cells, RPA is not phosphorylated, and endogenous phosphorylated RPA is excluded from stage II microfoci; in addition, the recruitment of ATR/ATRIP is independent of RPA and the kinase activity of ATR. Furthermore, we show that ATR/ATRIP play a beneficial role in viral gene expression and virus production. Although ICP0 has been shown to be important for partial inactivation of other cellular DNA repair pathways, we show that ICP0 is not responsible for the inactivation of ATR signaling and, furthermore, that neither ATR nor ATRIP is a target of ICP0 degradation. Thus, ATR and ATRIP may function outside the context of the canonical ATR damage signaling pathway during HSV-1 infection to participate in the viral life cycle.


Modular Fluted Tapered Stems in Aseptic Revision Total Hip Arthroplasty.
Modular fluted tapered stems have become the most commonly employed category of femoral component in revision hip arthroplasty in North America as a result of favorable early results and simplicity of use. Despite wide adoption, the majority of published data are limited to relatively small series with modest follow-up. The goal of the current study was to determine the success rate and factors associated with success, failure, and complications of the use of modular fluted tapered stems in aseptic revision total hip arthroplasties (THAs) in a large patient cohort. We identified 519 aseptic femoral revisions during which a modular fluted tapered stem was utilized. Clinical outcomes, Kaplan-Meier survivorship, radiographic outcomes, and complications were assessed. The mean age at revision arthroplasty was 70 years, the mean body mass index (BMI) was 29 kg/m, and the mean duration of follow-up was 4.5 years (range, 2 to 14 years). The mean Harris hip score (HHS) improved significantly from 51 points preoperatively to 76 points at 2 years (p < 0.001). This improvement was maintained at the last follow-up evaluation (mean HHS = 75 points). At the time of the most recent follow-up, 16 femoral revisions had been performed: 6 because of aseptic loosening, 4 because of infection, 3 because of instability, 2 because of periprosthetic fracture, and 1 because of stem fracture. The 10-year survivorship was 96% with revision for any reason as the end point and 90% with any reoperation as the end point. Of the patients who were alive and had not undergone revision at the time of final follow-up, 12 had stem subsidence but all but 1 of these stems had stabilized after subsiding. Postoperative complications were noted in 12% of the cases. Repeat revision due to femoral component loosening was not correlated with the preoperative bone-loss category or patient demographic factors. In this large series, femoral revision with a modular fluted tapered stem provided a high rate of osseointegration and sustained improvement in clinical scores at the time of the last follow-up. There was also a high rate of successful implant fixation across all categories of preoperative bone loss and an acceptable rate of complications. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Abdominal wall reconstruction following severe loss of domain: the R Adams Cowley Shock Trauma Center algorithm.
Large, complex, posttraumatic and recurrent abdominal hernias present a reconstructive challenge. Multiple techniques have been described to restore the integrity of the abdominal wall, although the indications and applications can be difficult to navigate. The authors propose an algorithm that facilitates the assessment and treatment of secondary large ventral defects. The algorithm described involves a systematic approach to abdominal wall reconstruction and was applied to 23 consecutive patients at the R Adams Cowley Shock Trauma Center. Data collected from the chart review included age, body mass index, mechanism of injury, placement of skin graft and use of resorbable mesh before definitive reconstruction, size of defect, number of tissue expanders placed, length of follow-up, and complications. There were six female patients and 17 male patients, with an average age of 36 years. The average follow-up was 7 months. Seventeen patients had posttraumatic laparotomies, five patients had aggressive abdominal wall debridement following necrotizing fasciitis, and one patient developed a large abdominal wall hernia following complications from gastric bypass surgery. All patients underwent delayed abdominal wall reconstruction, with an average time to initial reconstruction of 19.5 months. Sixteen patients had no postoperative complications. Seven patients had complications, including one with an enterocutaneous fistula, one with a partial small bowel obstruction, two with seromas, one with a superficial wound infection, and two with recurrent abdominal wall laxity. The reconstructive ladder for large, complex abdominal hernias is poorly defined. The proposed algorithm provides a systematic staged approach that incorporates available techniques used for delayed reconstruction of the abdominal wall.


Comparison of perceptions and treatment practices between neurosurgeons and plastic surgeons for infants with deformational plagiocephaly.
Deformational plagiocephaly (DP) is the leading cause of head shape abnormalities in infants. Treatment options include conservative measures and cranial molding. Pediatric neurosurgeons and craniofacial plastic surgeons have yet to agree on an ideal therapy, and no definable standards exist for initiating treatment with helmets. Furthermore, there may be differences between specialties in their perceptions of DP severity and need for helmet therapy. Requests to participate in a web-based questionnaire were sent to diplomates of the American Board of Pediatric Neurological Surgery and US and Canadian members of the Pediatric Joint Section of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons and the American Cleft Palate-Craniofacial Association. Questions focused on educational background; practice setting; volume of DP patients; preferences for evaluation, treatment, follow-up; and incentives or deterrents to treat with helmet therapy. Six examples of varying degrees of DP were presented to delineate treatment preferences. Requests were sent to 302 neurosurgeons and 470 plastic surgeons, and responses were received from 71 neurosurgeons (24%) and 64 plastic surgeons (14%). The following responses represented the greatest variations between specialties: 1) 8% of neurosurgeons and 26% of plastic surgeons strongly agreed with the statement that helmet therapy is more beneficial than conservative therapy (p < 0.01); and 2) 25% of neurosurgeons and 58% of plastic surgeons would treat moderate to severe DP with helmets (p < 0.01). Survey responses suggest that neurosurgeons are less likely to prescribe helmet therapy for DP than plastic surgeons. Parents of children with DP are faced with a costly treatment decision that may be influenced more strongly by referral and physician bias than medical evidence.