Once-daily single-tablet regimens: a long and winding road to excellence in antiretroviral treatment.
Once-daily single-tablet regimens represent the paramount simplification of antiretroviral treatment achieved so far. They include drugs with favorable pharmacokinetics that allow once-daily administration, that do not need dose adjustments, have no additional toxicities, and do not require dissimilar intake conditions. Co-formulated efavirenz/tenofovir disoproxil fumarate/emtricitabine has been a gold standard of initial therapy since its approval in 2006. Galenic research and industry patent agreements may allow availability of single-tablet regimens with HIV-1 nonnucleoside reverse transcriptase inhibitors (efavirenz or rilpivirine), integrase inhibitors (cobicistat-boosted elvitegravir or dolutegravir), and protease inhibitors (cobicistat-boosted darunavir), combined with either tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. The introduction of the new phamacoenhancer cobicistat as a potential substitution for ritonavir and the investigational agent GS-7340, with one-tenth the tenofovir mass, is a breakthrough in antiretroviral drug development. Many HIV-1-infected patients who are treatment-naive or treatment-experienced with susceptible virus will potentially have more options to reduce pill burden and optimize dosage schedules with one pill once-daily regimens.


Hyperlactataemia and metabolic acidosis during haemofiltration using lactate-buffered fluids.
We have investigated the effect of an exogenous lactate load given during machine haemofiltration treatment in 22 patients with acute renal failure and 12 patients with chronic renal failure, without any overt evidence of liver disease. Hyperlactataemia occurred in all patients, but the expected changes in acid base status, an increase in bicarbonate and a reduction in arterial hydrogen ions were observed in less than 40% of the treatments in the acute renal failure group. Ultrafiltrate losses of lactate and bicarbonate could not alone explain the changes in acid-base status. There was a positive correlation between the increase in arterial lactate and hydrogen ion concentrations, r = 0.52, p less than 0.01. Lactate accumulation in patients at, or close to, their threshold for lactate utilisation may result in further depression of cardiac function and peripheral lactate utilisation. Hyperlactataemia due to use of lactate-based dialysis/haemofiltration solutions in critically ill patients may result in a worsening of the acid-base status, and arterial pH should be monitored so that bicarbonate solutions can be substituted if the changes are progressive.


Characterization of HSP90 isoforms in transformed bovine leukocytes infected with Theileria annulata.
HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterization was undertaken for three and localization confirmed for cytoplasmic (TA12105), endoplasmic reticulum (TA06470), and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin were demonstrated for recombinant TA12105, and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing, and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata-infected counterpart was utilized to test the effects of geldanamycin and the derivative 17-AAG. T. annulata-infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17-AAG. These findings suggest that parasite HSP90 isoform(s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation.


Negative and Positive Factors Associated With the Well-Being of Lesbian, Gay, Bisexual, Transgender, Queer, and Questioning (LGBTQ) Youth.
Factors associated with the well-being of lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth were qualitatively examined to better understand how these factors are experienced from the youths' perspectives. Largely recruited from LGBTQ youth groups, 68 youth participated in focus groups (n = 63) or individual interviews (n = 5). The sample included 50% male, 47% female, and 3% transgender participants. Researchers used a consensual methods approach to identify negative and positive factors across 8 domains. Negative factors were associated with families, schools, religious institutions, and community or neighborhood; positive factors were associated with the youth's own identity development, peer networks, and involvement in the LGBTQ community. These findings suggest a pervasiveness of negative experiences in multiple contexts, and the importance of fostering a positive LGBTQ identity and supportive peer/community networks. Efforts should work towards reducing and eliminating the prejudicial sentiments often present in the institutions and situations that LGBTQ youth encounter.


Warts Signaling Controls Organ and Body Growth through Regulation of Ecdysone.
Coordination of growth between individual organs and the whole body is essential during development to produce adults with appropriate size and proportions [1, 2]. How local organ-intrinsic signals and nutrient-dependent systemic factors are integrated to generate correctly proportioned organisms under different environmental conditions is poorly understood. In Drosophila, Hippo/Warts signaling functions intrinsically to regulate tissue growth and organ size [3, 4], whereas systemic growth is controlled via antagonistic interactions of the steroid hormone ecdysone and nutrient-dependent insulin/insulin-like growth factor (IGF) (insulin) signaling [2, 5]. The interplay between insulin and ecdysone signaling regulates systemic growth and controls organismal size. Here, we show that Warts (Wts; LATS1/2) signaling regulates systemic growth in Drosophila by activating basal ecdysone production, which negatively regulates body growth. Further, we provide evidence that Wts mediates effects of insulin and the neuropeptide prothoracicotropic hormone (PTTH) on regulation of ecdysone production through Yorkie (Yki; YAP/TAZ) and the microRNA bantam (ban). Thus, Wts couples insulin signaling with ecdysone production to adjust systemic growth in response to nutritional conditions during development. Inhibition of Wts activity in the ecdysone-producing cells non-autonomously slows the growth of the developing imaginal-disc tissues while simultaneously leading to overgrowth of the animal. This indicates that ecdysone, while restricting overall body growth, is limiting for growth of certain organs. Our data show that, in addition to its well-known intrinsic role in restricting organ growth, Wts/Yki/ban signaling also controls growth systemically by regulating ecdysone production, a mechanism that we propose controls growth between tissues and organismal size in response to nutrient availability.


The E-cadherin gene polymorphism 160C->A and cancer risk: A HuGE review and meta-analysis of 26 case-control studies.
A single nucleotide polymorphism, - 160C-->A, has been identified in the promoter region of the E-cadherin gene and has been shown to alter its transcriptional activity. To assess susceptibility of -160A allele carriers to seven types of cancers, the authors conducted a comprehensive meta-analysis, up to November 2006, of 26 case-control studies comprising 7,042 cases and 7,011 controls. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analyses were also performed, which showed that -160A allele carriers, compared with noncarriers, had about a 17-19% increased risk of several invasive/metastatic tumors. Analyses of various types of cancers revealed that, in Europeans, the -160AA homozygote was associated with an increased risk of urothelial cancer, carriers of -160A were at increased risk of lung and prostate cancers, and carriers of -160A with gastric cancer were found to suffer a significantly increased risk, whereas their Asian counterparts seemed to be tolerant. No evidence was found that the -160A allele predisposed its carriers to breast, colorectal, or esophageal cancers. These findings indicate that -160A of the E-cadherin gene is emerging as a low-penetrance tumor susceptibility allele for the development of gastric, lung, prostate, and urothelial cancers.


An analysis of canal centering using mechanical instrumentation techniques.
The purpose of this study was to compare canal transportation in moderately curved canals using mechanical instrumentation systems. Mesial roots of mandibular first or second molars were mounted in resin using a modified Bramante muffle system and divided into four groups. The roots were cross-sectioned 2 mm from the working length and at the height of root curvature. Tracings of the canal were made from preinstrumentation slides of the cross-sections. The canals were prepared using ProFile Series 29 rotary instruments, Quantec 2000 rotary instruments, Flex-R files in the Endo Gripper contra-angle handpiece, and Shaping Hedstrom files in the M4 contra-angle handpiece. Tracings of the prepared canals were made onto the originals from postinstrumentation slides. A canal centering ratio was calculated along the line of maximum transportation. Quantec 2000 rotary instruments yielded significantly greater transportation at the apical level when compared with the Profile Series 29 system. There were no other significant differences in transportation at either level. There were no differences in the direction of canal transportation between instrument systems, and the direction of canal transportation was not related to the direction of canal curvature. Canal preparation time was shortest with Profile Series 29 system followed by Flex-R files in the Endo Gripper, Quantec 2000, and Shaping Hedstrom files in the M4.


The effect of pay-for-performance in hospitals: lessons for quality improvement.
The payment approach known as "pay-for-performance" has been widely adopted with the aim of improving the quality of health care. Nonetheless, little is known about how to use the approach most effectively to improve care. We examined the effects in 260 hospitals of a pay-for-performance demonstration project carried out by the Centers for Medicare and Medicaid Services in partnership with Premier Inc., a nationwide hospital system. We compared these results to those of a control group of 780 hospitals not in the demonstration project. The performance of the hospitals in the project initially improved more than the performance of the control group: More than half of the pay-for-performance hospitals achieved high performance scores, compared to fewer than a third of the control hospitals. However, after five years, the two groups' scores were virtually identical. Improvements were largest among hospitals that were eligible for larger bonuses, were well financed, or operated in less competitive markets. These findings suggest that tailoring pay-for-performance programs to hospitals' specific situations could have the greatest effect on health care quality.


p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma.
The survival rate for head and neck squamous cell carcinoma remains poor despite therapeutic advances over the last two decades. For patients with disease confined to the head and neck, there are two major and biologically distinct patterns of treatment failures after definitive therapy: recurrence of primary disease and development of second primary tumors. Understanding the biological basis of patterns of treatment failure after definitive therapy is needed to guide the development of adjuvant treatment and strategies to prevent second primary tumors. To determine whether expression of the p53 protein has prognostic significance and/or is associated with patterns of treatment failure, we examined protein expression in primary tumor specimens of patients with head and neck squamous cell carcinoma. Immunohistochemical analysis with a monoclonal antibody (DO7) specific for p53 protein was used to detect expression of the protein in formalin-fixed, paraffin-embedded tumor samples from 69 head and neck cancer patients treated with definitive local therapy (surgery and/or radiotherapy) between January 1980 and October 1983 at The University of Texas M. D. Anderson Cancer Center. We quantitated p53 protein expression and assessed its association with duration of patient survival, patterns of treatment failure (recurrence of primary tumor and development of second primary tumor), and other clinical parameters. All reported P values resulted from two-sided statistical tests. We found detectable levels of p53 protein expression in the tumor cell nuclei of 41 of 69 patients. Thirty-six (52%) of 69 patients whose tumors exhibited p53 protein expression in greater than or equal to 10% of the cell nuclei were grouped as p53 positive, and 33 (48%) of 69 patients whose tumors exhibited less than 10% nuclear expression were groups as p53 negative. The clinical characteristics of the patients in the p53-positive, and p53-negative groups were well balanced. Overall survival was significantly lower, and the times to tumor recurrence, to second primary tumors, and to any treatment failure were significantly shorter in the p53-positive group that in the p53-negative group (P=.0002, P=.047, P=.003, and P=.0009, respectively), mainly because the p53 positivity was associated with earlier development of tumor recurrence and second primary tumors. The rate of second primary tumor development per person per year was also significantly higher in the p53-positive group that in the p53-negative group. By use of multivariate analysis according to the Cox regression model, p53 expression status was identified as the most significant predictor of overall survival duration (P=.007), time to tumor recurrence (P=.053), time to second primary tumors (P=.035), and time to any treatment failure (P=.004). The expression of p53 protein in primary head and neck squamous cell carcinoma was significantly predictive of shorter survival because of its association with earlier development of both tumor recurrence and second primary tumors. Thus, p53 expression may be a valuable marker for identifying individuals at high risk of developing a recurrence of primary disease and second primary tumors who may benefit from adjuvant therapy and chemoprevention after definitive local therapy.


Determinants of bicycle crashes at urban signalized intersections.
Bicycle volumes are increasing in many regions worldwide leading to higher relevance of an in-depth understanding of bicyclist safety mechanisms. Detailed studies on bicyclist safety that consider exposure and distinguish by intersection category and crash types are missing for urban signalized intersections, which are of particular relevance for bicyclist safety. Based on a comprehensive dataset of motorist and bicyclist volumes and infrastructure characteristics for a sample of 269 signalized intersections in two German cities, we utilize a top-down approach to analyze firstly, bicycle crashes of all types and secondly, bicycle crashes by type including turning, right-of-way and loss-of-control. A combination of descriptive statistics and Accident Prediction Models (APM) are applied as analysis methods. Bicycle volumes are relevant for all types of intersections and crashes, whereas the effect of motor vehicle volumes differ between these different applications. The separation of bicyclists from motor vehicles in time and space increases their safety but also leads to behavioral adaption and risk compensation. The likelihood of right-of-way crashes even increases with more separation in the signaling scheme. The main predictor for loss-of-control crashes in terms of infrastructure are tram tracks. This study provides insights on relevant determinants of bicycle crashes at urban signalized intersections at several levels of detail. Exposure variables as well as the physical separation of bicyclists from motor vehicles show consistent effects on bicycle crash numbers whereas the effects of signaling differ between crash types. The different types of intersections and crashes follow each specific mechanism of bicyclist safety. The separation of bicyclists and motorists in time and space are paramount at intersections with high bicycle volumes. Risk compensation such as red light running becomes more important as intersections get smaller and motor vehicle volumes decrease.


Meta-Analysis of the Association Between Autobiographical Memory Specificity and Exposure to Trauma.
Cognitive models of emotional disorders suggest that reduced autobiographical memory specificity that results from exposure to traumatic events may play an important role in the aetiology and maintenance of these disorders. However, there has yet to be a comprehensive meta-analysis of the association between trauma exposure and memory specificity, and the role of posttraumatic stress symptoms on this association. We searched PsycINFO and MEDLINE databases and extracted data from studies regarding the mean number or proportion of specific memories that participants with and without trauma exposure recalled on the Autobiographical Memory Test. We also extracted data on differences between groups in terms of posttraumatic stress and depressive symptoms, along with data on trauma timing and participants' ages at the time of assessment. The effect size of memory specificity between participants with and without exposure to trauma was large, d = 0.77, and differed significantly from zero, p < .001. In metaregression, trauma timing was a significant predictor of the heterogeneity in trauma-exposure specificity effect sizes, but posttraumatic stress and depressive symptoms were not. Compromised memory specificity represents an important cognitive consequence of trauma exposure that might have an important influence on risk for, and maintenance of, subsequent emotional pathologies.


Norm-referenced scoring system for the Brief Infant Sleep Questionnaire - Revised (BISQ-R).
To develop an age-based norm-referenced scoring system for the Brief Infant Sleep Questionnaire - Revised (BISQ-R). In sum, 33,835 submissions (data sample 1) of the expanded and revised BISQ-R by caregivers of infants and toddlers (1-36 months) were analyzed in the US via a publicly-available smartphone application, Johnson's® Bedtime®. Three subscales were created: Infant Sleep (IS; 5 items), Parent Perception (PP; 3 items), and Parent Behavior (PB; 11 items). The scoring algorithm was based on an age-based normative system, and each subscale was scored using a weighted average of items. Primary application of the scoring model was performed on a follow up set of 16,531 submissions (data sample 2). Secondary application was tested on an original web-based ecology study (data sample 3). Tertiary application was tested using previously published datasets consisting of a longitudinal study (data sample 4) and randomized control trial behavioral intervention study (data sample 5). Overall application of the scoring algorithm was confirmed across multiple samples. Each subscale (IS, PP, PB) and total score (T) is age referenced (scores range from 0 to 100). Cross-comparison between subscales across studies reveal consistent and convergent relationships. The BISQ-R provides a comprehensive assessment of infant and toddler sleep patterns, as well as parent perception and parent behaviors that may contribute to sleep outcomes. The age-based norm-referenced scoring system is publicly available to be used by researchers and clinicians.


Signaling pathway and pepsinogen secretion in Helicobacter pylori-infected human gastric adenocarcinoma.
Although in vitro studies have suggested that Helicobacter pylori not only attaches to cultured cells but also induces signal transduction events in host cells, the underlying mechanism of H. pylori action has yet to be fully investigated. In the present study, a cytotoxin-positive H. pylori was used to infect and examined for its effect on the stimulation of second messengers in human gastric adenocarcinoma (AGS). Results showed that H. pylori increased cytosolic free calcium concentration [Ca2+]i in host cells in a dose-dependent manner. The increase of [Ca2+]i was due to release from the intracellular Ca2+ store as well as entry to the extracellular Ca2+. H. pylori infection on host cells was also found to induce the generations of inositol phosphates, adenosine 3', 5'-cyclic monophosphate, and guanosine 3',5'-cyclic monophosphate, and to stimulate the secretion of pepsinogen.


Evolution of brain region volumes during artificial selection for relative brain size.
The vertebrate brain shows an extremely conserved layout across taxa. Still, the relative sizes of separate brain regions vary markedly between species. One interesting pattern is that larger brains seem associated with increased relative sizes only of certain brain regions, for instance telencephalon and cerebellum. Till now, the evolutionary association between separate brain regions and overall brain size is based on comparative evidence and remains experimentally untested. Here, we test the evolutionary response of brain regions to directional selection on brain size in guppies (Poecilia reticulata) selected for large and small relative brain size. In these animals, artificial selection led to a fast response in relative brain size, while body size remained unchanged. We use microcomputer tomography to investigate how the volumes of 11 main brain regions respond to selection for larger versus smaller brains. We found no differences in relative brain region volumes between large- and small-brained animals and only minor sex-specific variation. Also, selection did not change allometric scaling between brain and brain region sizes. Our results suggest that brain regions respond similarly to strong directional selection on relative brain size, which indicates that brain anatomy variation in contemporary species most likely stem from direct selection on key regions.


Population estimation of the effects of cytochrome P450 2C9 and 2C19 polymorphisms on phenobarbital clearance in Japanese.
A nonlinear mixed-effect modeling (NONMEM) program was used to evaluate the effects of cytochrome P450 (CYP) 2C9 and CYP2C19 polymorphisms on the phenobarbital (PB) population clearance for Japanese epileptics. The pharmacokinetics of the 260 PB concentrations at a steady-state obtained from 79 patients was described with a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight (BW), age, gender, PB daily dose, CYP2C9 and CYP2C19 genotypes, the coadministered antiepileptic drugs (AEDs), and complications. The final model of PB apparent clearance was as follows: CL = 0.23 x (BW/40)0.21 x 0.52CYP2C9*1/*3 x 0.68VPA x 0.85PHT x 0.85SMID x (1 + etaCL) where CL = the clearance of PB; CYP2C9*1/*3 = 1, otherwise 0; VPA = 1 if valproic acid is coadministered, otherwise 0; PHT = 1 if phenytoin is coadministered, otherwise 0; SMID = 1 if complications of severe or profound mental retardation with a significant behavior impairment are presented, otherwise 0; and etaCL = the independent random error distributed normally with the mean zero and variance equal to omegaP2. The total clearance of PB decreased by 48% in patients with CYP2C9*1/*3 genotype in comparison with those with CYP2C9*1/*1 genotype (P < 0.001). An effect of CYP2C19 polymorphisms was not detected. To our knowledge, this is the first report to demonstrate that the CYP2C9 genotype affects the PB metabolism in routine care, but the results should be further verified in other ethnic populations.


[Biosynthesis of cholesterol and formation of cholesta-4-dien-3-one in stomach and intestine of rats with experimental D-hypovitaminosis].
Inhibition of cholesterol biosynthesis with D-hypovitaminosis is shown to occur in the secretary and esophageal regions of the stomach, mucose and serous membranes of small intestine at the stages of methylsterol demelthylation and transformation of lathosterol into 7-dehydrocholesterol. With this pathology under study there occurs considerable increase in the content of the 7-dehydrocholesterol oxidation product--cholesta-4,7-dien-3-one in the above-mentioned tissues. A problem on possible inhibition of cholesterol biosynthesis with D-hypovitaminosis by this oxycompound is under discussion.


Inhibition of osteogenic differentiation of human adipose-derived stromal cells by retinoblastoma binding protein 2 repression of RUNX2-activated transcription.
Histone methylation is regarded as an important type of histone modification defining the epigenetic program during the lineage differentiation of stem cells. A better understanding of this epigenetic mechanism that governs osteogenic differentiation of human adipose-derived stromal cells (hASCs) can improve bone tissue engineering and provide new insights into the modulation of hASC-based cell therapy. Retinoblastoma binding protein 2 (RBP2) is a histone demethylase that specifically catalyzes demethylation of dimethyl or trimethyl histone H3 lysine 4 (H3K4me2 or H3K4me3), which is normally associated with transcriptionally active genes. In this study, the roles of RBP2 in osteogenic differentiation of hASCs were investigated. We found that RBP2 knockdown by lentiviruses expressing small interfering RNA promoted osteogenic differentiation of hASCs in vitro and in vivo. In addition, we demonstrated that knockdown of RBP2 resulted in marked increases of mRNA expression of osteogenesis-associated genes such as alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX). RBP2 was shown to occupy the promoters of OSX and OC to maintain the level of the H3K4me3 mark by chromatin immunoprecipitation assays. Furthermore, coimmunoprecipitation and luciferase reporter experiments suggested that RBP2 was physically and functionally associated with RUNX2, an essential transcription factor that governed osteoblastic differentiation. Significantly, RUNX2 knockdown impaired the repressive activity of RBP2 in osteogenic differentiation of hASCs. Altogether, our study is the first to demonstrate the functional and biological roles of H3K4 demethylase RBP2 in osteogenic differentiation of hASCs and to link RBP2 to the transcriptional regulation of RUNX2.


Intrahost evolution of envelope glycoprotein and OrfA sequences after experimental infection of cats with a molecular clone and a biological isolate of feline immunodeficiency virus.
Feline immunodeficiency virus (FIV) is a member of the genus Lentivirus and causes AIDS-like disease in its natural host, the cat. Like other lentiviruses, FIV displays a high degree of nucleotide sequence variability that is reflected in both the geographic distribution of the viruses and the different cat species that are infected. Although a lot of data on sequence variation at the population level is available, relatively little is known about the intrahost variation of FIV sequences. In the present study, cats were infected with either a biological isolate of FIV or a molecular clone that was derived from the same isolate, AM19. After infection, the cats were monitored for up to 3 years and at various time points sequences were obtained of virus circulating in the plasma. Regions of the env gene and the orfA gene were amplified, cloned and their nucleotide sequence analyzed. Furthermore, the extent of sequence variation in the original inocula was also determined. It was found that FIV is displaying relative little sequence variation during infection of its host, both in the env and the orfA gene, especially after infection with molecular clone 19k1. Although the extent of variation was higher after infection with biological isolate AM19, a large portion of these variant sequences was already present in the inoculum.


Identifying, reporting and preventing elder abuse in the practice setting.
The purpose of this article is to raise awareness of elder abuse as an issue and its changing policy and legislative context. It highlights nurses' roles and responsibilities, enabling the reader to explore the complexities that surround elder abuse as a phenomenon and recognise effective strategies for identifying, reporting and preventing elder abuse in the practice setting.


An experimental investigation into the surface and hydrodynamic characteristics of marine coatings with mimicked hull roughness ranges.
There are limited scientific data on contributors to the added drag of in-service ships, represented by modern-day coating roughness and biofouling, either separately or combined. This study aimed to gain an insight into roughness and hydrodynamic performance of typical coatings under in-service conditions of roughened ships' hull surfaces. Comprehensive and systematic experimental data on the boundary layer and drag characteristics of antifouling coating systems with different finishes are presented. The coating types investigated were linear-polishing polymers, foul-release and controlled-depletion polymers. The data were collected through state-of-the-art equipment, including a 2-D laser Doppler velocimetry (LDV) system for hydrodynamic data in a large circulating water tunnel. Three coating systems were first applied on flat test panels with 'normal' finishes in the first test campaign to represent coating applications under idealised laboratory conditions. In order to address more realistic roughness conditions, as typically observed on ships' hulls, 'low' and 'high' roughness densities were introduced into the same types of coating, in the second test campaign. The data collected from the first test campaign served as the baseline to demonstrate the effect on the surface roughness and hydrodynamic drag characteristics of these coating types as a result of 'in-service' or 'severely flawed' coating application scenarios. Data collected on coatings with a range of in-service surface conditions provided a basis to establish correlation between the surface roughness characteristics and hydrodynamic performance (roughness function). The findings of the study indicate that the estimations of drag penalties based on well-applied, relatively smooth coating conditions underestimate the importance of hull roughness, which although undesirable, is commonplace in the world's commercial fleet.


Dose intensified hypofractionated intensity-modulated radiotherapy with synchronous cetuximab for intermediate stage head and neck squamous cell carcinoma.
For stage II and III head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy alone, loco-regional recurrence is the main cause of treatment failure. Strategies to improve loco-regional control should not be at the expense of increased late normal tissue toxicity. We investigated dose-intensified hypofractionated intensity-modulated radiotherapy (IMRT) with synchronous cetuximab. In a phase I/II trial, 27 patients with stage III or high risk stage II HNSCC were recruited. They received three dose level simultaneous integrated boost IMRT, 62.5 Gy in 25 daily fractions to planning target volume one over five weeks with synchronous cetuximab. The primary endpoint was acute toxicity. Secondary endpoints included: late toxicity and quality of life; loco-regional control, cause-specific and overall survival. Radiotherapy was completed by 26/27 patients; for one (4%) the final fraction was omitted due to skin toxicity. All cycles of cetuximab were received by 23/27 patients. Grade 3 acute toxicities included: pain (81%), oral mucositis (78%) and dysphagia (41%). There were few grade 3 physician-recorded late toxicities, including: pain (11%), problems with teeth (8%) and weight loss (4%). At 12 months, only one (4%) patient required a feeding tube, inserted prior to treatment due to dysphagia. The maximal/peak rates of patient-reported late toxicities included: severe pain (11%), any dry mouth (89%) and swallowing dysfunction that required a soft/liquid diet (23%). At 12 months, all quality of life and most symptoms mean scores had resolved to baseline or were only a little worse; dry mouth, sticky saliva and dentition scores remained very much worse. At a median follow-up of 47 months, there were five (18.5%) loco-regional recurrences and the overall cause-specific survival was 79% (95% CI 53-92). This regimen is safe with acceptable acute toxicity, low rates of late toxicity and impact on quality of life at 12 months following treatment. Further evaluation is recommended.


16S rDNA-based analysis reveals cosmopolitan occurrence but limited diversity of two cyanobacterial lineages with contrasted patterns of intracellular carbonate mineralization.
Cyanobacteria are mainly thought to induce carbonate precipitation extracellularly via their photosynthetic activity combined with the nucleation potential of exopolymeric substances. The discovery in microbialites of the alkaline lake Alchichica (Mexico) of Candidatus Gloeomargarita lithophora, a cyanobacterium forming large amounts of intracellular Mg-Ca-Sr-Ba carbonate spherules, showed that intracellular biomineralization in cyanobacteria is also possible. A second cyanobacterium isolated from the same environment, Candidatus Synechococcus calcipolaris G9, has been recently shown to also form intracellular calcium carbonates at the cell poles, a capability shared by all cultured species of the Thermosynechococcus clade, to which it belongs. To explore the diversity of these two distant cyanobacterial lineages representing two different patterns of intracellular calcification, we designed specific primers against their 16S rRNA genes and looked for their occurrence in a wide variety of samples. We identified the presence of members of the Gloeomargarita and Thermosynechococcus/S. calcipolaris lineages in microbialites collected from Lake Alchichica and three other neighboring Mexican lakes. The two clades also occurred in karstic areas and in some thermophilic or hypersaline microbial mats collected in South America and/or Southern Europe. Surprisingly, the within-group diversity in the two clades was low, especially within the S. calcipolaris clade, with all 16S rRNA gene sequences retrieved sharing more than 97% identity. This suggests that these clades are composed of a limited number of operational taxonomic units (OTUs) with cosmopolitan distribution. Moreover, scanning electron microscopy coupled with energy dispersive x-ray spectrometry showed the presence of intracellularly calcifying Gloeomargarita-like cyanobacteria in fresh samples where this clade was relatively abundant, suggesting that these cyanobacteria do precipitate carbonates intracellularly under natural conditions.


Age at natural menopause and its associated factors in Canada: cross-sectional analyses from the Canadian Longitudinal Study on Aging.
Early onset of menopause is associated with long-term disease and higher mortality risks. Research suggests that age at natural menopause (ANM) varies across populations. Little is known about factors that affect ANM in Canadian women. This study aims to estimate the median ANM and examine factors associated with earlier ANM among Canadian women. Baseline data from the Tracking cohort of the Canadian Longitudinal Study on Aging was used for this analysis. The relation of sociodemographic, lifestyle, and health-related factors with ANM was examined among 7,719 women aged 40 and above. Nonparametric Kaplan-Meier cumulative survivorship estimates were used to assess the timing of natural menopause. Univariate and multivariate Cox proportional hazard regression models were used to characterize ANM and its association with relevant covariates. Overall, median ANM was 51 years. Having no partner, low household income and education levels, current and former smoking, and cardiovascular disease were all associated with an earlier ANM, whereas current employment, alcohol consumption, and obesity were associated with later ANM. These findings provide a national estimate of ANM in Canada and show the importance of lifestyle factors and health conditions in determining menopausal age. These factors might help in risk assessment, prevention and early management of chronic disease risk during the menopausal transition.


Perceiving expatriate coworkers as foreigners encourages aid: social categorization and procedural justice together improve intergroup cooperation and dual identity.
We propose that social categorization can encourage particular forms of intergroup cooperation because it differentiates a group in need from a group that can give aid. Moreover, social categorization is most likely to occur when individuals perceive procedural justice (i.e., fair treatment) from authorities in a superordinate group that includes the individuals' subgroup. Two field studies investigating relations between local and foreign coworkers tested not only this prediction, but also whether high social categorization and procedural justice would yield a dual identity, in which group members identify simultaneously with their social category and the superordinate group. Both studies supported our predictions: Local employees engaged a dual identity and offered knowledge to aid a foreign coworker's adjustment more often when local-foreign categorization and procedural justice from organizational authorities were high than when these variables were low. These discoveries point to controllable mechanisms that enable intergroup cooperation, and our findings have important implications for intergroup aid, expatriate adjustment, immigration, and multiculturalism.


Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals.
Family studies of individual tissues have shown that gene expression traits are genetically heritable. Here, we investigate cis and trans components of heritability both within and across tissues by applying variance-components methods to 722 Icelanders from family cohorts, using identity-by-descent (IBD) estimates from long-range phased genome-wide SNP data and gene expression measurements for approximately 19,000 genes in blood and adipose tissue. We estimate the proportion of gene expression heritability attributable to cis regulation as 37% in blood and 24% in adipose tissue. Our results indicate that the correlation in gene expression measurements across these tissues is primarily due to heritability at cis loci, whereas there is little sharing of trans regulation across tissues. One implication of this finding is that heritability in tissues composed of heterogeneous cell types is expected to be more dominated by cis regulation than in tissues composed of more homogeneous cell types, consistent with our blood versus adipose results as well as results of previous studies in lymphoblastoid cell lines. Finally, we obtained similar estimates of the cis components of heritability using IBD between unrelated individuals, indicating that transgenerational epigenetic inheritance does not contribute substantially to the "missing heritability" of gene expression in these tissue types.


Quality control of laboratory tests run in a neonatal intensive care unit.
We examined the accuracy of laboratory screening tests in eight neonatal intensive care units. Analytes were provided by the EXCEL proficiency testing program of the College of American Pathologists (CAP), Skokie, III, samples were analyzed for hematocrit values and urine specific gravity. "Dipstick" tests were also performed for urinary protein, bilirubin, blood, glucose, pH, and ketones. The one intensive care unit that adhered to a formal quality control program for all these tests uniformly reported results well within statistically acceptable limits as defined by CAP. The seven other centers reported 14 instances of results that were either greater than 1 SD of the mean or considered by the consensus method to be outside acceptable CAP limits. Three of these results may have led to inappropriate clinical action in neonates. We conclude that there is a real potential for errors to be made in screening tests run by nurses in a neonatal intensive care unit when a formalized quality control program is not in effect.


Mycobacterial research at the N.H. Swellengrebel Laboratory of Tropical Hygiene.
The N.H. Swellengrebel Laboratory of Tropical Hygiene has as its central research theme the analysis of genes and antigens of agents of tropical diseases. This is in practice the development of simple and reliable methods for the early detection of tropical diseases ultimately in the interest of the control of these diseases. In the fields of leprosy and tuberculosis, monoclonal antibodies against specific epitopes were prepared allowing a quick and reliable identification, specific antibodies were detected in patients' sera, and with methods from the molecular genetics very small amounts of mycobacterial DNA could be detected in clinical specimens. The achievements of modern biotechnology offer novel approaches to the study of old and hard to solve clinical and epidemiological problems.


Colour processing in complex environments: insights from the visual system of bees.
Colour vision enables animals to detect and discriminate differences in chromatic cues independent of brightness. How the bee visual system manages this task is of interest for understanding information processing in miniaturized systems, as well as the relationship between bee pollinators and flowering plants. Bees can quickly discriminate dissimilar colours, but can also slowly learn to discriminate very similar colours, raising the question as to how the visual system can support this, or whether it is simply a learning and memory operation. We discuss the detailed neuroanatomical layout of the brain, identify probable brain areas for colour processing, and suggest that there may be multiple systems in the bee brain that mediate either coarse or fine colour discrimination ability in a manner dependent upon individual experience. These multiple colour pathways have been identified along both functional and anatomical lines in the bee brain, providing us with some insights into how the brain may operate to support complex colour discrimination behaviours.


Monitoring the severe acute respiratory syndrome epidemic and assessing effectiveness of interventions in Hong Kong Special Administrative Region.
To estimate the infection curve of severe acute respiratory syndrome (SARS) using the back projection method and to assess the effectiveness of interventions. Statistical method. The daily reported number of SARS and interventions taken by Hong Kong Special Administrative Region (HKSAR) up to 24 June 2003 are used. To use a back projection technique to construct the infection curve of SARS in Hong Kong. The estimated epidemic curve is studied to identify the major events and to assess the effectiveness of interventions over the course of the epidemic. The SARS infection curve in Hong Kong is constructed for the period 1 March 2003 to 24 June 2003. Some interventions seem to be effective while others apparently have little or no effect. The infections among the medical and health workers are high. Quarantine of the close contacts of confirmed and suspected SARS cases seems to be the most effective intervention against spread of SARS in the community. Thorough disinfection of the infected area against environmental hazards is helpful. Infections within hospitals can be reduced by better isolation measures and protective equipments.


Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma.
STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5. An in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization. LY5 was evaluated in vitro demonstrating good biologic activity against rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma cell lines at high nanomolar/low micromolar concentrations, as well as specific inhibition of STAT3 phosphorylation without effects on other STAT3 family members. LY5 exhibited excellent oral bioavailability in both mice and healthy dogs, and drug absorption was enhanced in the fasted state with tolerable dosing in mice at 40 mg/kg BID. However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines. Moreover, concentrations needed to inhibit ex vivo metastasis growth using the PuMA assay were significantly higher than those needed to inhibit STAT3 phosphorylation in vitro. Lastly, LY5 treatment did not inhibit the growth of sarcoma xenografts or prevent pulmonary metastasis in mice. LY5 is a novel small molecule inhibitor that effectively inhibits STAT3 phosphorylation and cell proliferation at nanomolar concentrations. LY5 demonstrates good oral bioavailability in mice and dogs. However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects. These data suggest that the anti-cancer effects of LY5 identified in vitro were not mediated through STAT3 inhibition.


Thin ferrihydrite sediment capping sequestrates phosphorus experiencing redox conditions in a shallow temperate lacustrine wetland.
Synthesized ferrihydrite (Fh) with the dosages of 0.3, 0.6 and 0.9 cm thickness (labeled as Fh, 2Fh and 3Fh respectively, equivalent to 248-774 g/m2) were deployed to serve as the reactive capping layer covering the Ornamental Lake sediments, the Royal Botanic Garden of Melbourne. The sediments were exposed to an alternating regime of oxic/anoxic conditions using laboratory reactors for 45 days. Dynamics of dissolved oxygen (DO), pH, filterable reactive phosphorus (FRP), filterable ammonium (NH4+), nitrate and nitrite (NOx), total dissolved nitrogen (TDN) and dissolved iron (Fe) of overlying water were examined. After incubation, O2 and H2S profiles across the water-sediment interface were observed with microelectrodes. The element distributions in the upper sediments were tested as well. Results showed that DO and pH kept relatively stable during oxic period, while decreased significantly during anoxic period. Fh cappings decreased both DO and pH, and inhibited the release of FRP. No significant increments of FRP in overlying waters were observedduring anoxic period. Fh cappings prompted the releases of NH4+ and TDN, while inhibited that of NOx.NH4+increased while NOx decreased during anoxic period. Fe(II) and TFe increased only in 3Fh, especially during anoxic conditions. Fh cappings increased O2 and H2S concentrations across the water-sediment interfaces. TP and TN in the sediments decreased after capping, while TFe increased significantly. We concluded that 0.6 cm thickness of (496 g/m2) Fh capping could sequestrate P, even experiencing redox conditions.


Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex.
Both presynaptic and postsynaptic alterations are associated with plastic changes of brain circuits, such as learning and memory, drug addiction and chronic pain. However, the dissection of the relative contributions of pre- and postsynaptic components to brain functions is difficult. We have previously shown peripheral inflammation caused both presynaptic and postsynaptic changes and calcium-stimulated cyclic AMP (cAMP) pathway in the anterior cingulate cortex (ACC) is critical in the synaptic plasticity and behavioral sensitization to pain. It remains to be elucidated whether presynaptic or postsynaptic modulation by cAMP in the ACC could be sufficient for enhancing inflammatory pain. In order to address this question, we took advantage of a novel transgenic mouse model, heterologously expressing an Aplysia octopamine receptor (Ap oa1). This receptor is G protein-coupled and selectively activates the cAMP pathway. We found that activation of Ap oa1 by octopamine enhanced glutamatergic synaptic transmission in the ACC by increasing presynaptic glutamate release in vitro. Bilateral microinjection of octopamine into the ACC significantly facilitated behavioral responses to inflammatory pain but not acute pain. The present study provides the first evidence linking enhanced presynaptic glutamate release in the ACC to behavioral sensitization caused by peripheral inflammation.


Characterization of Matrigel interfaces during defined human embryonic stem cell culture.
Differences in attachment, proliferation, and differentiation were measured for human embryonic stem (hES) cells cultured on various substrata coated with Matrigel, a blend of extracellular matrix proteins derived from murine tumor cells. The authors observed that hES cells attach and grow poorly on Matrigel adsorbed onto polystyrene, while they proliferate when exposed to Matrigel adsorbed onto glass or oxygen plasma treated polystyrene (e.g., "tissue culture" treated polystyrene). Furthermore, hES cells grown on the Matrigel-coated tissue culture polystyrene are less likely to differentiate than those grown on the Matrigel-coated glass. To assess the mechanism for these observations, they replicated the cell culture interface in a quartz crystal microbalance with dissipation monitoring. In addition, they used ellipsometry and scanning electron microscopy to determine the thickness and topography of Matrigel on the varying surfaces. Matrigel formed a viscoelastic multilayer with similar thickness on all three surfaces; however, the network structure was different, where the adsorbed proteins formed a globular network on polystyrene, and fibrillar networks on the hydrophilic substrates. Matrigel networks on glass were denser than on oxygen plasma treated polystyrene, suggesting that the density and structure of the Matrigel network affects stem cell differentiation, where a denser network promoted uncontrolled hES cell differentiation and did not maintain the self-renewal phenotype.


Computer-aided speckle interferometry using spectral amplitude fringes.
A fully automatic speckle metrology technique is developed. Two speckle patterns of a specimen, one before and one after the specimen deformation, are captured by a video camera. An equivalent double-exposure speckle pattern is obtained by superimposing the two digital images. The superimposed speckle pattern is then segmented into a series of small subimages. For each subimage a fast-Fourier transform is applied and a computer-generated Young's fringe pattern is obtained. The fringe pattern, which characterizes the local displacement vector, is analyzed by a second fast-Fourier transform. The local displacement vector is determined by a cardinal interpolation and a crest searching around a signal peak in the second spectral domain. An artificial rigid shift between the two images is introduced in the cases of extremely large or small displacements. From analysis of all subimage pairs of the whole superimposed speckle pattern a complete two-dimensional displacement field is deduced. Experimental results using laser as well as white-light speckle patterns are demonstrated.


Ginkgo Biloba Extract in Ophthalmic and Systemic Disease, With a Focus on Normal-Tension Glaucoma.
Glaucoma is a neurodegenerative eye disease that results in retinal ganglion cell loss and ultimately loss of vision. Elevated intraocular pressure (IOP) is the most common known risk factor for retinal ganglion cell damage and visual field loss, and the only modifiable risk factor proven to reduce the development and progression of glaucoma. This has greatly influenced our approach and assessment in terms of diagnosis and treatment. However, as many as ≥50% of patients with progressive vision loss from primary open angle glaucoma without IOP elevation (≤22 mm Hg) have been reported in the United States and Canada; 90% in Japan and 80% in Korea. Extensive research is currently underway to identify the etiology of risk factors for glaucoma other than or in addition to elevated IOP (so-called "normal-tension" glaucoma; NTG) and use this knowledge to expand available treatment options. Currently, Food and Drug Administration-approved medications for glaucoma exclusively target elevated IOP, suggesting the need for additional approaches to treatment options beyond the current scope as the definition of glaucoma changes to encompass cellular and molecular mechanisms. This review focuses on alternative medical approaches, specifically Ginkgo Biloba extract, as a potential treatment option for normal-tension glaucoma.


Effects of homologous pituitary hormone treatment on serum insulin-like growth-factor-binding proteins (IGFBPs) in hypophysectomized tilapia, Oreochromis mossambicus, with special reference to a novel 20-kDa IGFBP.
In the circulation, insulin-like growth factors (IGFs) bind to high-affinity-binding proteins. Insulin-like growth-factor-binding proteins (IGFBPs) appear to be present in all vertebrates. To examine the hormonal regulation of serum IGFBPs in a fish, tilapia (Oreochromis mossambicus) were hypophysectomized (Hx) and then treated with homologous tilapia growth hormone (tGH) or either form of tilapia prolactin (tPRL177, tPRL188). Hormones were administered at three doses: 15, 150, and 500 ng/g of body weight. Serum IGFBP profiles were analyzed by SDS-PAGE and Western ligand blotting using 125I-rhIGF-I as a probe. A prominent IGFBP (ca 20 kDa), termed IGFBP-20K, appeared after hypophysectomy. Administration of tGH at all dose levels suppressed this BP and restored levels back to those seen in sham-operated control fish. tPRL177 and tPRL188 were also effective in lowering IGFBP-20K levels. Levels of the 29-kDa IGFBP (termed IGFBP-29K) increased after hypophysectomy; tGH at all doses and tPRL177 at the two lower doses further increased these levels. All doses of tGH, tPRL177, and tPRL188 significantly increased levels of the 32-kDa IGFBP (termed IGFBP-32K). Hypophysectomy significantly lowered levels of the 40-kDa IGFBP (termed IGFBP-40K) below levels seen in the sham-operated controls. tGH treatment significantly raised IGFBP-40K levels at all doses examined, but not to the levels seen in intact tilapia. The 42-kDa IGFBP (termed IGFBP-42K) was not affected by hypophysectomy or hormone replacement. Our data suggest that the novel 20-kDa IGFBP and the 40-kDa IGFBP species may be similar in function to mammalian IGFBP-1 and IGFBP-3, respectively.


Approach to the patient with drug allergy.
Clinicians commonly encounter patients who report to have drug allergy. In a large part, such allergy corresponds to adverse drug reactions, which are not immune mediated. The incriminated drug need not always be avoided for further therapy. On the other hand, drug allergy may manifest in many unexpected clinical pictures and thus not be recognized. There is no single standardized diagnostic test to confirm the immune-mediated mechanism and to identify the causative drug. Therefore, immune-mediated drug hypersensitivity reactions and their causative drugs have to be considered by the constellation of exposure, timing, and clinical features, including the pattern of organ manifestation. Prior experience with the drug is also an important feature. An allergologic workup with additional investigation may provide some help. Patients should be informed carefully about their drug allergy, whereby symptoms, drug that elicits reaction, modes of diagnosis of drug allergy, and possibly alternatives should be indicated in their allergy passport.


Spray-Dried Influenza Antigen with Trehalose and Leucine Produces an Aerosolizable Powder Vaccine Formulation that Induces Strong Systemic and Mucosal Immunity after Pulmonary Administration.
Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules. Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes. The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (Tg) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma. The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored.


Assessment of Emergency Medicine Resident Performance in an Adult Simulation Using a Multisource Feedback Approach.
The Accreditation Council for Graduate Medical Education (ACGME) specifically notes multisource feedback (MSF) as a recommended means of resident assessment in the emergency medicine (EM) Milestones. High-fidelity simulation is an environment wherein residents can receive MSF from various types of healthcare professionals. Previously, the Queen's Simulation Assessment Tool (QSAT) has been validated for faculty to assess residents in five categories: assessment; diagnostic actions; therapeutic actions; interpersonal communication, and overall assessment. We sought to determine whether the QSAT could be used to provide MSF using a standardized simulation case. Prospectively after institutional review board approval, residents from a dual ACGME/osteopathic-approved postgraduate years (PGY) 1-4 EM residency were consented for participation. We developed a standardized resuscitation after overdose case with specific 1-5 Likert anchors used by the QSAT. A PGY 2-4 resident participated in the role of team leader, who completed a QSAT as self-assessment. The team consisted of a PGY-1 peer, an emergency medical services (EMS) provider, and a nurse. Two core faculty were present to administer the simulation case and assess. Demographics were gathered from all participants completing QSATs. We analyzed QSATs by each category and on cumulative score. Hypothesis testing was performed using intraclass correlation coefficients (ICC), with 95% confidence intervals. Interpretation of ICC results was based on previously published definitions. We enrolled 34 team leader residents along with 34 nurses. A single PGY-1, a single EMS provider and two faculty were also enrolled. Faculty provided higher cumulative QSAT scores than the other sources of MSF. QSAT scores did not increase with team leader PGY level. ICC for inter-rater reliability for all sources of MSF was 0.754 (0.572-0.867). Removing the self-evaluation scores increased inter-rater reliability to 0.838 (0.733-0.910). There was lesser agreement between faculty and nurse evaluations than from the EMS or peer evaluation. In this single-site cohort using an internally developed simulation case, the QSAT provided MSF with excellent reliability. Self-assessment decreases the reliability of the MSF, and our data suggest self-assessment should not be a component of MSF. Use of the QSAT for MSF may be considered as a source of data for clinical competency committees.


The Effect of Vitamin D Supplementation on Skeletal Muscle in the mdx Mouse Model of Duchenne Muscular Dystrophy.
Vitamin D (VitD) has shown to be beneficial in reversing muscle weakness and atrophy associated with VitD deficiency. Duchenne muscular dystrophy is characterized by worsening muscle weakness and muscle atrophy, with VitD deficiency commonly observed. This study aimed to investigate the effect of VitD supplementation on dystrophic skeletal muscle. Eight-week old female control (C57BL/10; n = 29) and dystrophic (C57BL/mdx; n = 23) mice were randomly supplemented with one of three VitD enriched diets (1000, 8000 & 20,000 IU/kg chow). Following a four-week feeding period, the extensor digitorum longus (EDL) and soleus muscles contractile and fatigue properties were tested ex vivo, followed by histological analysis. As expected, mdx muscles displayed higher mass yet lower specific forces and a rightward shift in their force frequency relationship consistent with dystrophic pathology. There was a trend for mdx muscle mass to be larger following the 20,000 IU/kg diet, but this did not result in improved force production. Fiber area in the EDL was larger in mdx compared to controls, and there were higher amounts of damage in both muscles, with VitD supplementation having no effect. Four weeks of VitD supplementation did not appear to have any impact upon dystrophic skeletal muscle pathology at this age.


The successful use of pronuclear embryo transfers the day following oocyte retrieval.
A retrospective analysis of results from 114 initiated in-vitro fertilization cycles utilizing pronuclear embryo transfer is presented. Patients were unselected for age or infertility criteria, constituted a continuous series and were grouped according to response to stimulation (Group 1, ideal; Group 2, suboptimal) or ovarian reserve (Group 3, poor). At 16-18 h post-insemination, embryos were scored for alignment of pronuclei and nucleoli and the appearance of the cytoplasm, generating an embryo score (ES). Transfers were performed 24-26 h post-insemination using two to six embryos with the highest ES. A corrected score was calculated (total score/number of embryos; CS). A total of 114 initiated cycles resulted in 97 oocyte retrievals with 38 clinical pregnancies (39%; 15% implantation). Pregnancy rates were significantly different between the three groups; 37 pregnancies in Group 1 (55% clinical pregnancy; 20% implantation), none in Group 2 and one in Group 3 (6%; 2% implantation: P < 0.001). The ES of transferred embryos correlated with groups. There was a strong correlation between CS and implantation and delivery rates. CS >15 resulted in a 28% implantation; 65% delivery rate. CS <14 resulted in four pregnancies, one delivered. The data show that oocyte quality and pronuclear embryo morphology are related to implantation and that pronuclear embryos can be successfully selected for embryo transfer.


Simultaneous pitches are encoded separately in auditory cortex: an MMNm study.
This study examined whether two simultaneous pitches have separate memory representations or an integrated representation in preattentive auditory memory. Mismatch negativity fields were examined when a pitch change occurred in either the higher-pitched or the lower-pitched tone at 25% probability each, thus making the total deviation rate of the two-tone dyad 50%. Clear MMNm was obtained for deviants in both tones confirming separate memory traces for concurrent tones. At the same time, deviants to the lower-pitched, but not higher-pitched, tone within the two-tone dyad elicited a reduced MMNm compared to when each tone was presented alone, indicating that the representations of two pitches are not completely independent.


Life on the rocks: Multilocus phylogeography of rock hyrax (Procavia capensis) from southern Africa.
Understanding the role of geography and climatic cycles in determining patterns of biodiversity is important in comparative and evolutionary biology and conservation. We studied the phylogeographic pattern and historical demography of a rock-dwelling small mammal species from southern Africa, the rock hyrax Procavia capensis capensis. Using a multilocus coalescent approach, we assessed the influence of strong habitat dependence and fluctuating regional climates on genetic diversity. We sequenced a mitochondrial gene (cytochrome b) and two nuclear introns (AP5, PRKC1) supplemented with microsatellite genotyping, in order to assess evolutionary processes over multiple temporal scales. In addition, distribution modelling was used to investigate the current and predicted distribution of the species under different climatic scenarios. Collectively, the data reveal a complex history of isolation followed by secondary contact shaping the current intraspecific diversity. The cyt b sequences confirmed the presence of two previously proposed geographically and genetically distinct lineages distributed across the southern African Great Escarpment and north-western mountain ranges. Molecular dating suggests Miocene divergence of the lineages, yet there are no discernible extrinsic barriers to gene flow. The nuclear markers reveal incomplete lineage sorting or ongoing mixing of the two lineages. Although the microsatellite data lend some support to the presence of two subpopulations, there is weak structuring within and between lineages. These data indicate the presence of gene flow from the northern into the southern parts of the southern African sub-region likely following the secondary contact. The distribution modelling predictably reveal the species' preference for rocky areas, with stable refugia through time in the northern mountain ranges, the Great Escarpment, as well as restricted areas of the Northern Cape Province and the Cape Fold Mountains of South Africa. Different microclimatic variables appear to determine the distributional range of the species. Despite strong habitat preference, the micro-habitat offered by rocky crevices and unique life history traits likely promoted the adaptability of P. capensis, resulting in the widespread distribution and persistence of the species over a long evolutionary period. Spatio-temporal comparison of the evolutionary histories of other co-distributed species across the rocky landscapes of southern Africa will improve our understanding of the regional patterns of biodiversity and local endemism.


Human retroviruses and herpes viruses: their role in immune dysfunctions and neoplasia.
Human retroviruses (HTLV-I, HTLV-II, HIV-1, and HIV-2) and some human herpes viruses (notably EBV and HHV-6 or HBLV) infect chiefly target cells of the immune system. They can alter function of these cells, leading to many side effects, including mild (HTLVs), transient (EBV, HHV-6), or profound (HIVs) immune impairment with the associated clinical consequences. The retroviruses can also cause injury to the central nervous system but the mechanisms are poorly understood. An almost opposite effect of all of these immunocytotropic viruses is their capacity to directly induce abnormal cell growth of their target cells or indirectly of other cells. In addition to their importance in human disease, studies of these viruses are helping to provide new insights into the molecular mechanisms of gene regulation, fundamental aspects of the immune system, and of the origin, cellular and molecular pathogenesis of human tumors.


CD61 and fibrinogen immunohistochemical study to improve the post-mortem diagnosis in a fat embolism syndrome clinically demonstrated by transesophageal echocardiography.
Fat embolization following major trauma is reported to be a quite common event, while the clinical fat embolism syndrome (FES) seems to be a much rarer event. Fat embolism occurs in 2 up to 23% of patients with isolated femoral shaft fractures. This complication appears to be related not only to the fracture, but also to the timing of stabilization. Sometimes it may be impossible to perform histochemical reactions on frozen sections to detect fat emboli thus confirming diagnosis or suspicion of FES. The finding of fibrinogen and platelets around the apparently empty spaces in the blood vessels has been proposed as an evidence for vital reaction due to either a vital cellular reaction or a flotation mechanism, thus supporting an intravital fat embolism. We report a fatal case due to fat embolism syndrome in a young man hospitalized for a right femoral neck fracture, treated with orthopaedic surgery and subjected to an intra-surgery transesophageal echocardiography that revealed embolization of numerous highly echogenic bodies. Four hours after the onset of clinical symptoms the man died from respiratory failure. The autopsy confirmed the clinical diagnosis of fat embolism syndrome. The histological examination revealed a large amount of fat globules in cerebral and pulmonary arteries and in glomerular capillaries, as well as fibrin and platelet deposition confirmed by the positive results by Sudan III staining for lipids and immunohistochemistry with anti-CD61 and anti-fibrinogen antibodies. The quantitative classification of fat embolism was grade 3 of Sevitt's classification or grade 4 of Fineschi's quantification, according to the current quantitative microscopic methods used for grading fat embolism in pulmonary tissue.


A comparison between wellness awareness among medical students.
To assess and compare the dimensions of spiritual wellness as elements of quality care in medical students of private and public medical universities. The cross-sectional study was carried out at private and public medical universities in Karachi from November 2013 to January 2015.Students from both genders and all ethnic groups19-23 years of age were included. The responses of spiritual wellness were obtained and evaluated on a four-point Likert's scale; score ranging from 0-3. Data was analysed using Predictive Analysis Software version 18. Out of 736 students, 286 (38.9%) were from public medical universities and 450 (61.1%) were from private-sector institutions. Students of both types of universities were aware of the concept of spiritual wellness but the level of awareness needed scaling up. Public-sector students had a stronger will, were more physically and mentally alert, more compassionate, empathetic and enthusiastic about their relationship with patients than their private-sector counterparts (p<0.05). They used spiritual wellness as a coping strategy to deal with difficult situations through religious activities. Though attentive listening was a predominant feature in both groups, the use of communication skills required particular attention to improve the element of compassionate care. Empowerment of spiritual wellness is more likely to enable medical students to be more compassionate towards their patients and strengthen doctor-patient relationship.


Does the amount of tagged stool and fluid significantly affect the radiation exposure in low-dose CT colonography performed with an automatic exposure control?
To determine whether the amount of tagged stool and fluid significantly affects the radiation exposure in low-dose screening CT colonography performed with an automatic tube-current modulation technique. The study included 311 patients. The tagging agent was barium (n = 271) or iodine (n = 40). Correlation was measured between mean volume CT dose index (CTDI (vol)) and the estimated x-ray attenuation of the tagged stool and fluid (ATT). Multiple linear regression analyses were performed to determine the effect of ATT on CTDI (vol ) and the effect of ATT on image noise while adjusting for other variables including abdominal circumference. CTDI (vol) varied from 0.88 to 2.54 mGy. There was no significant correlation between CTDI (vol) and ATT (p = 0.61). ATT did not significantly affect CTDI (vol) (p = 0.93), while abdominal circumference was the only factor significantly affecting CTDI (vol) (p < 0.001). Image noise ranged from 59.5 to 64.1 HU. The p value for the regression model explaining the noise was 0.38. The amount of stool and fluid tagging does not significantly affect radiation exposure.


Effects of ocean acidification on population dynamics and community structure of crustose coralline algae.
Calcification and growth of crustose coralline algae (CCA) are affected by elevated seawater pCO2 and associated changes in carbonate chemistry. However, the effects of ocean acidification (OA) on population and community-level responses of CCA have barely been investigated. We explored changes in community structure and population dynamics (size structure and reproduction) of CCA in response to OA. Recruited from an experimental flow-through system, CCA settled onto the walls of plastic aquaria and developed under exposure to one of three pCO2 treatments (control [present day, 389±6 ppm CO2], medium [753±11 ppm], and high [1267±19 ppm]). Elevated pCO2 reduced total CCA abundance and affected community structure, in particular the density of the dominant species Pneophyllum sp. and Porolithon onkodes. Meanwhile, the relative abundance of P. onkodes declined from 24% under control CO2 to 8.3% in high CO2 (65% change), while the relative abundance of Pneophyllum sp. remained constant. Population size structure of P. onkodes differed significantly across treatments, with fewer larger individuals under high CO2. In contrast, the population size structure and number of reproductive structures (conceptacles) per crust of Pneophyllum sp. was similar across treatments. The difference in the magnitude of the response of species abundance and population size structure between species may have the potential to induce species composition changes in the future. These results demonstrate that the impacts of OA on key coral reef builders go beyond declines in calcification and growth, and suggest important changes to aspects of population dynamics and community ecology.


MRI-based high-dimensional hippocampal mapping in mesial temporal lobe epilepsy.
MRI-based evaluation of the hippocampus is important in the assessment and treatment of patients with mesial temporal lobe epilepsy (MTLE). Using MRI-based large-deformation high-dimensional mapping (HDM-LD), which allows structural evaluation of regions of the hippocampus, we document the HDM-LD-defined pattern of hippocampal deformation in MTLE patients compared with matched controls. In 30 subjects with MTLE and confirmed medial temporal lobe sclerosis (MTS), we performed measurements of intracranial area, brain parenchymal volume and deformation-based hippocampal segmentations, and then grouped patients into right and left MTS groups (resulting in 15 subjects in each group). Using HDM-LD techniques, we compared the right and left MTS groups with a group of 15 matched controls. Analysis included both the MTS and contralateral hippocampi, and covariance for changes in brain parenchymal volume. Final results were interpreted using a segmentation showing normal hippocampal surface subfield anatomy. Comparing the MTS groups with controls, after covarying with brain parenchymal volume, the MTS hippocampi showed significant volume loss (P < 0.0001), contralateral hippocampi showed no significant volume loss. HDM-LD techniques showed significant shape changes, with marked inward deviation in the Sommer sector of the MTS hippocampi. In the contralateral hippocampi, the inferior surface of the hippocampal body showed inward deformation in the medial aspect of the subiculum, with minimal involvement of the Sommer sector. HDM-LD shows involvement of subregions of the hippocampus which are consistent with MTS histopathology. Contralateral hippocampi show different HDM-LD changes, suggesting that the underlying disease process in the contralateral hippocampi is different from MTS.


[The work in oral health of the Community Health Agent in Family Health Units].
The present study aimed at understanding the work of the Community Health Agent (CHA) in the field of Oral Health in Brazilian Family Health Units (FHU) in 2005. This study represents a qualitative approach to the meanings and feelings that underlie the know-how in Oral Health of the CHA, showing his experience in this process. The sample consisted of nine CHAs from two Family Health Units. Data were collected in interviews with four guiding questions. The statements were analyzed using discourse analysis. It was observed that the CHAs recognize the importance and demand for more qualification and re-qualification opportunities enabling them to overcome the feeling of limitation expressed in their discourse.


Structural mechanisms of DREAM complex assembly and regulation.
The DREAM complex represses cell cycle genes during quiescence through scaffolding MuvB proteins with E2F4/5 and the Rb tumor suppressor paralog p107 or p130. Upon cell cycle entry, MuvB dissociates from p107/p130 and recruits B-Myb and FoxM1 for up-regulating mitotic gene expression. To understand the biochemical mechanisms underpinning DREAM function and regulation, we investigated the structural basis for DREAM assembly. We identified a sequence in the MuvB component LIN52 that binds directly to the pocket domains of p107 and p130 when phosphorylated on the DYRK1A kinase site S28. A crystal structure of the LIN52-p107 complex reveals that LIN52 uses a suboptimal LxSxExL sequence together with the phosphate at nearby S28 to bind the LxCxE cleft of the pocket domain with high affinity. The structure explains the specificity for p107/p130 over Rb in the DREAM complex and how the complex is disrupted by viral oncoproteins. Based on insights from the structure, we addressed how DREAM is disassembled upon cell cycle entry. We found that p130 and B-Myb can both bind the core MuvB complex simultaneously but that cyclin-dependent kinase phosphorylation of p130 weakens its association. Together, our data inform a novel target interface for studying MuvB and p130 function and the design of inhibitors that prevent tumor escape in quiescence.


Vector radiative transfer model for coupled atmosphere and ocean systems including inelastic sources in ocean waters.
Inelastic scattering plays an important role in ocean optics. The main inelastic scattering mechanisms include Raman scattering, fluorescence by colored dissolved organic matter (FDOM), and fluorescence by chlorophyll. This paper reports an implementation of all three inelastic scattering mechanisms in the exact vector radiative transfer model for coupled atmosphere and ocean Systems (CAOS). Simulation shows that FDOM contributes to the water radiation field in the broad visible spectral region, while chlorophyll fluorescence is limited in a narrow band centered at 685 nm. This is consistent with previous findings in the literature. The fluorescence distribution as a function of depth and viewing angle is presented. The impacts of fluorescence to the degree of linear polarization (DoLP) and orientation of the polarization ellipse (OPE) are studied. The DoLP is strongly influenced by inelastic scattering at wavelengths with strong inelastic scattering contribution. The OPE is less affected by inelastic scattering but it has a noticeable impact, in terms of the angular region of positive polarization, in the backward direction. This effect is more apparent for deeper water depth.


Using genomic sequencing for classical genetics in E. coli K12.
We here develop computational methods to facilitate use of 454 whole genome shotgun sequencing to identify mutations in Escherichia coli K12. We had Roche sequence eight related strains derived as spontaneous mutants in a background without a whole genome sequence. They provided difference tables based on assembling each genome to reference strain E. coli MG1655 (NC_000913). Due to the evolutionary distance to MG1655, these contained a large number of both false negatives and positives. By manual analysis of the dataset, we detected all the known mutations (24 at nine locations) and identified and genetically confirmed new mutations necessary and sufficient for the phenotypes we had selected in four strains. We then had Roche assemble contigs de novo, which we further assembled to full-length pseudomolecules based on synteny with MG1655. This hybrid method facilitated detection of insertion mutations and allowed annotation from MG1655. After removing one genome with less than the optimal 20- to 30-fold sequence coverage, we identified 544 putative polymorphisms that included all of the known and selected mutations apart from insertions. Finally, we detected seven new mutations in a total of only 41 candidates by comparing single genomes to composite data for the remaining six and using a ranking system to penalize homopolymer sequencing and misassembly errors. An additional benefit of the analysis is a table of differences between MG1655 and a physiologically robust E. coli wild-type strain NCM3722. Both projects were greatly facilitated by use of comparative genomics tools in the CoGe software package (http://genomevolution.org/).


Transmission of COVID-19 to Health Care Personnel During Exposures to a Hospitalized Patient - Solano County, California, February 2020.
On February 26, 2020, the first U.S. case of community-acquired coronavirus disease 2019 (COVID-19) was confirmed in a patient hospitalized in Solano County, California (1). The patient was initially evaluated at hospital A on February 15; at that time, COVID-19 was not suspected, as the patient denied travel or contact with symptomatic persons. During a 4-day hospitalization, the patient was managed with standard precautions and underwent multiple aerosol-generating procedures (AGPs), including nebulizer treatments, bilevel positive airway pressure (BiPAP) ventilation, endotracheal intubation, and bronchoscopy. Several days after the patient's transfer to hospital B, a real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) test for SARS-CoV-2 returned positive. Among 121 hospital A health care personnel (HCP) who were exposed to the patient, 43 (35.5%) developed symptoms during the 14 days after exposure and were tested for SARS-CoV-2; three had positive test results and were among the first known cases of probable occupational transmission of SARS-CoV-2 to HCP in the United States. Little is known about specific risk factors for SARS-CoV-2 transmission in health care settings. To better characterize and compare exposures among HCP who did and did not develop COVID-19, standardized interviews were conducted with 37 hospital A HCP who were tested for SARS-CoV-2, including the three who had positive test results. Performing physical examinations and exposure to the patient during nebulizer treatments were more common among HCP with laboratory-confirmed COVID-19 than among those without COVID-19; HCP with COVID-19 also had exposures of longer duration to the patient. Because transmission-based precautions were not in use, no HCP wore personal protective equipment (PPE) recommended for COVID-19 patient care during contact with the index patient. Health care facilities should emphasize early recognition and isolation of patients with possible COVID-19 and use of recommended PPE to minimize unprotected, high-risk HCP exposures and protect the health care workforce.


Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.
Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.


Characteristics of an adult photosensitive cohort.
Intermittent Photic Stimulation (IPS) is a well recognized provocation maneuver during EEG recording which helps in identifying underlying photosensitivity. The frequency and characteristics of various responses to photosensitivity among our adult patients was determine. EEGs of subjects > or =15 years from 2003-2006, were reviewed. Two main photosensitive responses were observed: Photoparoxysmal (PPR) and Photic-driving response (PDR). Demographic and clinical data was also collected. Out of 5950 EEG's performed, response to IPS were detected in 1.2% (n=73) of EEGs. Out of which 49 (67%) had PDR and 24 (33%) had PPR. Mean age of PPR group was 25.7 +/- 12 years with equal gender distribution. In PPR subjects, epilepsy was the final EEG conclusion in majority of patients 96% (n=23) p-value < 0.001. Primary Generalized Epilepsy being the most common 52% (n=12). In contrast, PDR observed in normal EEG's was 45% (n=22). This study revealed low frequency 1.2% of photosensitive responses. PPR is seen frequently in patients with epilepsy (96%, p-value < 0.001), and highest rate (52%) of photosensitivity was observed in patients with primary generalized epilepsy.


Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier.
Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.


Mpox (Monkeypox) in Pregnancy: Viral Clade Differences and Their Associations with Varying Obstetrical and Fetal Outcomes.
In African countries where mpox (monkeypox) is endemic, infection is caused by two genetically related clades-Clade I (formerly Congo Basin), and Clade IIa (formerly West Africa), both of which are potentially life-threatening infections. Prior to the 2022-2023 global outbreak, mpox infections among pregnant women caused by Clade I were reported to have a 75% perinatal case fatality rate in the Democratic Republic of Congo, including the only documented case of placental infection and stillbirth from the Congenital Mpox Syndrome, and the Clade IIa mpox infection was associated with stillbirths in Nigeria. The 2022-2023 global mpox outbreak, caused by a genetically distinct strain, Clade IIb, has focused attention on the effects of mpox on pregnant women and fetal outcomes. There have been at least 58 cases of mpox infection occurring in pregnant women during the 2022-2023 outbreak. No confirmed cases of adverse perinatal outcome, including stillbirth, have been reported. The absence of perinatal morbidity and mortality from Clade IIb corresponds to the overall case fatality rate among non-pregnant women of <0.1%, as this clade has been demonstrated to produce a less-severe disease than the mpox Clade I or IIa variants. Thus, there are apparently important differences between mpox clades affecting pregnant women and perinatal outcomes.


Distinct developmental requirements for isolated lymphoid follicle formation in the small and large intestine: RANKL is essential only in the small intestine.
Cryptopatches (CPs) and isolated lymphoid follicles (ILFs) are organized intestinal lymphoid tissues that develop postnatally in mice and include stromal cells expressing the receptor activator of nuclear factor kappa-B ligand (RANKL). We investigated how stromal RANKL influences the development and differentiation of CPs and ILFs by analyzing the development of these lymphoid structures in knockout mice lacking RANKL. We found that RANKL(-/-) mice had a fourfold reduction in the overall density of CPs in the small intestine compared to control mice, with the largest decrease in the proximal small intestine. No B cells were present in CPs from the small intestine of RANKL(-/-) mice and ILF formation was completely blocked. In sharp contrast, colonic ILFs containing B cells were present in RANKL(-/-) mice. Stromal cells within CPs in the small intestine of RANKL(-/-) mice did not express CXCL13 (originally called B lymphocyte chemoattractant) and often lacked other normally expressed stromal cell antigens, whereas colonic lymphoid aggregates in RANKL(-/-) mice retained stromal CXCL13 expression. The CXCL13-dependent maturation of precursor CPs into ILFs is differentially regulated in the small intestine and colon, with an absolute requirement for RANKL only in the small intestine.


Long-range temporal correlations in the spontaneous spiking of neurons in the hippocampal-amygdala complex of humans.
The spontaneous or background discharge patterns of in vivo single neuron is mostly considered as neuronal noise, which is assumed to be devoid of any correlation between successive inter-spike-intervals (ISI). Such random fluctuations are modeled only statistically by stochastic point process, lacking any temporal correlation. In this study, we have investigated the nature of spontaneous irregular fluctuations of single neurons from human hippocampus-amygdala complex by three different methods: (i) detrended fluctuation analysis (DFA), (ii) multiscale entropy (MSE), (iii) rate estimate convergence. Both the DFA and MSE analysis showed the presence of long-range power-law correlation over time in the ISI sequences. Moreover, we observed that the individual spike trains presented non-random structure on longer time-scales and showed slow convergence of rate estimates with increasing counting time. This power-law correlation and the slow convergence of statistical moments were eliminated by randomly shuffling the ISIs even though the distributions of ISIs were preserved. Thus the power-law relationship arose from long-term correlations among ISIs that were destroyed by shuffling the data. Further, we found that neurons which showed long-range correlations also showed statistically significant correlated firing as measured by correlation coefficient or mutual information function. The presence of long-range correlations indicates the history-effect or memory in the firing pattern by the associative formation of a neuronal assembly.


A preliminary histopathological study of the effect of agmatine on diffuse brain injury in rats.
The present study evaluates the effects of agmatine on histopathological damage following traumatic injury using a clinically relevant model of diffuse brain injury. A total of 27 male Sprague-Dawley rats weighing 200-225 g were anaesthetised and subjected to head trauma using Marmarou's impact-acceleration model. The rats were then separated into two main groups: one was treated with agmatine and the other with saline for up to 4 days immediately after head trauma. Rats from both groups were killed 1, 3 or 8 days post-injury. The brains were examined histopathologically and scored according to the axonal, neuronal and vascular changes associated with diffuse brain injury. There were no significant differences between the groups at 1 day or 3 days after trauma, but evaluation after 8 days revealed a significant improvement in the group treated with agmatine. Our data indicate that agmatine has a beneficial effect in diffuse brain injury and should be trialled for therapeutic use in the management of this condition.


Wegener's granulomatosis: patient-reported effects of disease on health, function, and income.
To evaluate the patient-perceived effects of Wegener's granulomatosis (WG) on health, function, income, and interpersonal relationships. A self-administered questionnaire, originally designed by the authors and subsequently revised with the aid of a patient focus group, was completed by 60 patients with well-defined features of WG. Patients had WG for a median period of 5 years. Patients with chronic WG experienced substantial medical and functional morbidity and incurred significant socioeconomic losses. A prolonged delay in diagnosis (mean 16.8 months) and the need for multiple consultations prior to initiation of therapy may have contributed to medical morbidity. Although 73% of patients perceived their disease to be in remission following therapy, 78% of these patients required continuing immunosuppressive treatment many years after diagnosis. Eighty percent of patients reported that their normal activities of daily living were compromised. Half of those who were employed prior to diagnosis were required to modify their job or accept total disability (31%). A 26% (median) reduction in income within 1 year after diagnosis was reported. The effects of the disease on interpersonal relationships with a patient's spouse, family, and friends varied considerably. Advances in medical care have, for most patients, transformed WG from being a disease with a high potential for short-term mortality to being a chronic illness. This is the first study that has evaluated patients' assessments of the medical, socioeconomic, and quality of life effects of WG and its treatment. The effects of mortality, disability, and outpatient medical expenses indicate that the financial impact alone substantially exceeds prior estimates of $30 million per year in charges for hospitalizations in the US.


Periampullary cysts: endoscopic management.
Periampullary cysts are a rare but remediable cause of recurrent pancreatitis. Hitherto, the management of such cysts was mainly surgical. We report on two cases of periampullary cysts. The first patient, who had a cyst of the minor papilla (Santorini cyst), presented with upper gastrointestinal hemorrhage and a history of recurrent pancreatitis. The second patient presented with cholangitis. Both were successfully and safely treated by endoscopic methods alone. Details of the cases and the endoscopic techniques used are fully described.


c-MYC deregulation is involved in melphalan resistance of multiple myeloma: role of PDGF-BB.
Oncogenes are important regulators of cancer growth and progression and their action may be modulated by proteins of the growth factor family, such as angiogenic cytokines, known to be strongly involved in neoplastic evolution. Reciprocal interactions between oncogenes and angiogenic modulators may represent, in haematological neoplasms, including multiple myeloma (MM), a possible mechanism of drug resistance. The aim of this work is to investigate in vitro and in vivo whether or not c-myc deregulation is involved in the melphalan resistance elicited by myeloma patients and consequently to clarify the role of the angiogenic factor PDGF-BB in modulating c-myc protein expression. Fifty-one MM patients on chemotherapy with melphalan were analyzed for structural alterations of the c-myc gene, c-Myc protein expression, as well as for serum PDGF-BB release. For the in vitro study, two M14-derived established cell clones, differing for the c-Myc protein expression (c-Myc low -expressing or constitutively expressing clones) were used. Our results show that PDGF-BB is able to up-regulate Myc expression and reduce melphalan sensitivity of tumor cell clones, constitutively expressing c-myc gene product. In addition, down-regulation of c-Myc protein induces the expression of PDGF-beta receptor molecules and reduces PDGF-BB release. In agreement with these results, in vivo data show that melphalan-resistant MM patients present overexpressed c-Myc protein and higher serum PDGF-BB receptor levels compared to minor responding patients.