β-Lactam monotherapy vs β-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial.
The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. clinicaltrials.gov Identifier: NCT00818610.


Dementia-friendly communities: The involvement of people living with dementia.
Dementia Friendly Communities (DFCs) offer an approach to community engagement to improve the lives of people living with dementia and their family supporters. The involvement of those living with dementia is key to creating successful DFCs. This paper examines how people affected by dementia were involved in developing and designing DFCs in England, and the impact of their involvement. This study used a mixed method case study design in six DFCs in England. Data collection involved documentary analysis, a survey, and interviews and focus groups with service providers and people living with dementia and their supporters. All six DFCs aspired to involve people living with dementia and their family supporters, but often relied on a small number of people living with dementia. The range of involvement activities in DFCs included Steering Group meetings, wider public consultations, and enabling feedback through data collection methods such as surveys and 'ad hoc' conversations. Organisations within the DFCs with experience of public consultation offered structured opportunities for involvement. There was no evidence of people living with dementia initiating or co-leading the organisation, its direction and/or the activities of the DFCs. The involvement of people living with dementia in DFCs went beyond rhetoric, with some evidence of context sensitive and meaningful participation. Approaches towards involvement should focus on involvement in strategic planning, and on harnessing expertise in delivering different involvement activities to optimise participation of a greater breadth of people living with dementia. Engagement with local organisations who work with, and for, people living with dementia, and dedicating the resources needed for involvement work, are crucial for creating DFCs. The success of DFCs are determined by how the needs of people living with dementia are identified, discussed and reviewed by those within the community who are most affected.


Alternative live-attenuated influenza vaccines based on modifications in the polymerase genes protect against epidemic and pandemic flu.
Human influenza is a seasonal disease associated with significant morbidity and mortality. Influenza vaccination is the most effective means for disease prevention. We have previously shown that mutations in the PB1 and PB2 genes of the live-attenuated influenza vaccine (LAIV) from the cold-adapted (ca) influenza virus A/Ann Arbor/6/60 (H2N2) could be transferred to avian influenza viruses and produce partially attenuated viruses. We also demonstrated that avian influenza viruses carrying the PB1 and PB2 mutations could be further attenuated by stably introducing a hemagglutinin (HA) epitope tag in the PB1 gene. In this work, we wanted to determine whether these modifications would also result in attenuation of a so-called triple reassortant (TR) swine influenza virus (SIV). Thus, the TR influenza A/swine/Wisconsin/14094/99 (H3N2) virus was generated by reverse genetics and subsequently mutated in the PB1 and PB2 genes. Here we show that a combination of mutations in this TR backbone results in an attenuated virus in vitro and in vivo. Furthermore, we show the potential of our TR backbone as a vaccine that provides protection against the 2009 swine-origin pandemic influenza H1N1 virus (S-OIV) when carrying the surface of a classical swine strain. We propose that the availability of alternative backbones to the conventional ca A/Ann Arbor/6/60 LAIV strain could also be useful in epidemic and pandemic influenza and should be considered for influenza vaccine development. In addition, our data provide evidence that the use of these alternative backbones could potentially circumvent the effects of original antigenic sin (OAS) in certain circumstances.


Perceptual learning of spectrally degraded speech and environmental sounds.
Adaptation to the acoustic world following cochlear implantation does not typically include formal training or extensive audiological rehabilitation. Can cochlear implant (CI) users benefit from formal training, and if so, what type of training is best? This study used a pre-/posttest design to evaluate the efficacy of training and generalization of perceptual learning in normal hearing subjects listening to CI simulations (eight-channel sinewave vocoder). Five groups of subjects were trained on words (simple/complex), sentences (meaningful/anomalous), or environmental sounds, and then were tested using an open-set identification task. Subjects were trained on only one set of materials but were tested on all stimuli. All groups showed significant improvement due to training, which successfully generalized to some, but not all stimulus materials. For easier tasks, all types of training generalized equally well. For more difficult tasks, training specificity was observed. Training on speech did not generalize to the recognition of environmental sounds; however, explicit training on environmental sounds successfully generalized to speech. These data demonstrate that the perceptual learning of degraded speech is highly context dependent and the type of training and the specific stimulus materials that a subject experiences during perceptual learning has a substantial impact on generalization to new materials.


Contamination of public transports by Staphylococcus aureus and its carriage by biomedical students: point-prevalence, related risk factors and molecular characterization of methicillin-resistant strains.
To analyse the contamination of public transports by Staphylococcus aureus and assess its carriage by biomedical students, focussing on the point-prevalence, related risk factors and molecular characterization of methicillin-resistant strains. Cross-sectional survey. Methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) isolated from handrails of buses (n = 112) and trains (n = 79) circulating in Porto and from nasal swabs of local university students (n = 475) were quantified, characterized by molecular typing methods and related to possible risk factors. The MRSA prevalence in buses (16.1%) was not significantly different from trains (8.9%). There was also no identifiable association between the counts of MSSA and MRSA in buses and trains and the number of travellers in each sampling day, specific routes (including those passing by main hospitals) or other risk factors. Of the students, 37.1% carried S. aureus, and having a part-time job or smoking were found to be risk factors for carriage. EMRSA-15 (ST22-SCCmecIVh) was the prevalent MRSA clonal lineage, found not only in the buses (n = 14) and trains (n = 2) but also in the single MRSA-carrier among the students. The characteristics of the community-associated Southwest Pacific MRSA clone were found in a single ST30-IVa isolate, which may suggest a recent SCCmec acquisition by an MSSA background in the community. The spread of EMRSA-15, a common hospital-associated lineage, among different public transports and as a nasal coloniser is of concern and warrants adequate public health control measures.


The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors.
We have investigated the mechanism of inhibition and site of action of the novel human metabotropic glutamate receptor 5 (hmGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), which is structurally unrelated to classical metabotropic glutamate receptor (mGluR) ligands. Schild analysis indicated that MPEP acts in a non-competitive manner. MPEP also inhibited to a large extent constitutive receptor activity in cells transiently overexpressing rat mGluR5, suggesting that MPEP acts as an inverse agonist. To investigate the molecular determinants that govern selective ligand binding, a mutagenesis study was performed using chimeras and single amino acid substitutions of hmGluR1 and hmGluR5. The mutants were tested for binding of the novel mGluR5 radioligand [(3)H]2-methyl-6-(3-methoxyphenyl)ethynyl pyridine (M-MPEP), a close analog of MPEP. Replacement of Ala-810 in transmembrane (TM) VII or Pro-655 and Ser-658 in TMIII with the homologous residues of hmGluR1 abolished radioligand binding. In contrast, the reciprocal hmGluR1 mutant bearing these three residues of hmGluR5 showed high affinity for [(3)H]M-MPEP. Radioligand binding to these mutants was also inhibited by 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt), a structurally unrelated non-competitive mGluR1 antagonist previously shown to interact with residues Thr-815 and Ala-818 in TMVII of hmGluR1. These results indicate that MPEP and CPCCOEt bind to overlapping binding pockets in the TM region of group I mGluRs but interact with different non-conserved residues.


Profiles in Leadership: Donald E. Francke, MSc, DSc (Hon).
The Director's Forum series is designed to guide pharmacy leaders in establishing patient-centered services in hospitals and health systems. August 2013 marked the 50th anniversary of the publication of the Mirror to Hospital Pharmacy, the results of a federally funded comprehensive study of pharmacy services in the United States. The late Don E. Francke, MS, DSc, was the lead author of the Mirror and the principal investigator for the US Public Health Service grant W-45. To celebrate the anniversary of the Mirror, the Director's Forum is profiling the leadership styles of Drs. Latiolais and Francke. September's article highlighted Dr. Clifton J. Latiolais; this month's Director's Forum reviews Dr. Francke's biography and key career accomplishments, describes his leadership philosophy, and translates that philosophy to today's health care challenges. Don's influence on health system pharmacy serves as an example of effective leadership. This historical perspective provides directors of pharmacy a valuable leadership view as they develop strategies to enhance patient-centered pharmacy services.


Recursive partitioning for risk stratification in men undergoing repeat prostate biopsies.
The current study was performed to identify risk factors and risk groups for carcinoma detection in men undergoing repeat prostate biopsies. The medical records of all men who had a negative initial prostate biopsy and underwent at least one repeat biopsy between 1992 and 2003 were reviewed to extract age, race, family history of prostate carcinoma, body mass index, referral indication, all prostate-specific antigen (PSA) values, digital rectal examination, PSA density (PSAD), the presence of a hypoechoic lesion, and the presence of high-grade prostatic intraepithelial neoplasia (HGPIN) on initial biopsy. Risk factors for a subsequent diagnosis of prostate carcinoma were identified using the log-rank test and a stepwise, stratified Cox regression model. Based on the risk factors identified by Cox regression analysis, recursive partitioning was further used for risk stratification. A total of 373 patients underwent 975 biopsy procedures. During a median follow-up of 37.0 months, prostate carcinoma was detected in 107 of 373 patients (28.9%). Independent predictors of a positive biopsy (P < 0.05) were PSA doubling time (PSADT), PSAD, referral indication, the presence of HGPIN, patient age, and family history of prostate carcinoma. Recursive partitioning identified 4 distinct risk groups that were characterized by their PSADT and PSAD and the presence of HGPIN and had estimated 2-year and 5-year carcinoma detection rates of 3 +/- 1% and 21 +/- 4%, 28 +/- 5% and 40 +/- 7%, 22 +/- 6% and 58 +/- 8%, and 66 +/- 9% and 100%, respectively. The authors identified a series of independent risk factors for prostate carcinoma detection after an initial negative prostate biopsy and characterized clinically meaningful and distinct patient risk groups. Despite a negative initial biopsy, patients with high-risk features remain at risk for the detection of prostate carcinoma.


Observations on tissue grafts established in rabbit ear chambers. A combined light and electron microscopic study.
An in vivo microscopic and ultrastructural study of tissues transferred to the transparent rabbit ear chamber is presented. Fragments of liver, kidney, thyroid, and myometrium were successfully auto- or allografted into the chamber from donors of all ages and allowed continuous in vivo observation of parenchymal structure and function, as well as of the graft vasculature which plays such an active role during rejection. Circulation was quickly reestablished by anastomosis of graft vessels to those of the ear chamber membrane and only minor reversible parenchymal changes occurred. Both vessels and parenchyma retained the characteristics of the organs of origin on both light and electron microscopy and were observed functioning in vivo for periods up to 1 yr in the case of autografts, and until rejection occurred in allografts. In the latter case, rejection did not occur in tissues obtained from adult and neonatal donors for nearly 3 months, while tissues of fetal origin were generally rejected much earlier. The kidney grafts provide a unique opportunity for a close comparative study of mammalian fetal and adult glomerular blood flow under varying rates of perfusion, and the tubular epithelium could be observed regenerating after initial acute tubular necrosis. Renal tubules from fetal, neonatal, and adult donors were all capable of metaplastic change to form a highly ciliated epithelium. Grafts of these tissues will allow the fine detail of the processes of rejection to be studied continuously in vivo.


Preliminary clinical results of proton (1H) imaging of cranial neoplasms: in vivo measurements of T1 and mobile proton density.
Proton nuclear magnetic resonance (NMR) images reflecting T1 relaxation time and approximating proton density were acquired and used to generate T1 rate (1/T1) maps. By region-of-interest selection, measurements of T1 relaxation time were made from discrete volumes of the imaging plane. Such techniques were applied to the study of human cranial neoplasia and associated conditions of differential diagnostic importance (e.g., postoperative changes, radiation necrosis). Inversion-recovery NMR images exhibit a high lesion-detection sensitivity. In all patients, the specificity of NMR imaging is low since all abnormal areas appear as lesions darker than surrounding normal brain, reflecting a decreased proton density, prolonged T1 values, or both. T1 relaxation times are prolonged within neoplastic foci; however, absolute T1 values overlap with those found in other lesions.


Single-bone forearm reconstruction for malignant and aggressive tumors.
Limb-salvage surgery for malignant and aggressive forearm tumors presents a unique surgical challenge. We performed single-bone forearm reconstructions after extensive resections of the radius and ulna in four patients for such tumors. Radiocarpal arthrodesis was performed in three patients. We recorded the presence of metastases or local recurrences, Musculoskeletal Tumor Society upper extremity scores, and complications. One patient had local recurrence and one died of metastases. The average Musculoskeletal Tumor Society score at the last followup was 26 of 30 (88%; range, 24-28). Complications included wound infection/necrosis, delayed union, nonunion, and acute carpal tunnel syndrome. Single-bone forearm reconstructive surgery provided satisfactory functional outcomes in these four patients, and we believe it is a reasonable treatment option for individuals with malignant or aggressive tumors of the forearm requiring massive bone resection. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.


Surgical reconstruction of the iliac arteries prior to endovascular aortic aneurysm repair.
To explore a method of combined endovascular/conventional treatment of abdominal aortic aneurysm (AAA), in which the iliac arteries are reconstructed by conventional surgical techniques to provide the anatomic substrate for subsequent endovascular repair of the aortic aneurysm. A 77-year-old patient with severe cardiac disease was found to have a 6.5-cm AAA, bilateral common iliac artery (CIA) aneurysms, and diffusely narrowed, tortuous external iliac arteries. The left internal iliac artery was occluded. At operation, the right CIA was exposed through a transverse retroperitoneal incision under epidural anesthesia. An iliobifemoral bypass was constructed using a preformed bifurcated graft. A stent-graft was delivered through the right limb of the bifurcated iliobifemoral graft. The proximal end of the stent-graft was implanted in the neck of the aneurysm, and the distal end was deployed in the common trunk of the iliobifemoral graft, thereby excluding the AAA and both native iliac arteries from prograde arterial flow. Completion angiography and follow-up contrast computed tomography showed the aneurysm to be excluded from the circulation. The patient was not intubated, was never hemodynamically unstable, and had aortic blood flow interrupted for no more than 20 seconds. In addition, he was able to resume his usual diet on the first postoperative day. He continues to be well and without evidence of endoleak at 6-month follow-up. This case demonstrates that iliac artery stenosis, tortuosity, and aneurysmal dilatation are not impediments to endovascular AAA exclusion. Any necessary surgical modifications of pelvic arterial anatomy can be performed before stent-graft insertion to minimize aortic occlusion time.


The value of ultrasonography in the diagnosis of varicocele.
A varicocele is described as pathologically enlarged, tortuous veins of the pampiniform plexus, leading to an increased testicular temperature and adrenal metabolite reflux into the testes. Varicocele can impair spermatogenesis and is considered to be the most common cause of male infertility. Patients may palpate a thickening in the scrotum or complain of dull scrotal or inguinal pain, which increases when standing or during erection. In the case of a sudden onset of varicocele in elderly men, it is necessary to exclude renal tumor and extend diagnostic ultrasound with the assessment of the abdominal cavity. The diagnosis of varicocele is based on medical history and physical examination, which involves palpation and observation of the scrotum at rest and during the Valsalva maneuver. Ultrasound is the imaging method of choice. The width and the number of vessels in the pampiniform plexus as well as the evaluation and measurement of regurgitation during the Valsalva maneuver are typical parameters analyzed during ultrasound assessment. However, diagnostic ultrasound is still a controversial method due to numerous and often divergent classification systems for varicocele assessment as well as its poor correlation with clinical manifestations. As a result of introduction of clear ultrasound criteria as well as the development of elastography and nuclear magnetic resonance, diagnostic imaging can play an important role in assessing the risk of damage to the testicular parenchyma, qualifying patients for surgical treatment and predicting the effects of therapy.


Excess risk thresholds in ultrasound safety studies: statistical methods for data on occurrence and size of lesions.
Concerns about the safe use of clinical ultrasound (US) at diagnostic pressure levels (below a mechanical index, or MI, = 1.9) have stimulated considerable research in US risk assessment. The objective of the present study was to develop probability-based risk thresholds for US safety studies, to present statistical methods for estimating the thresholds and their standard errors and to compare these methods with the analysis based on a piecewise linear ("hockey stick") model. The excess risk at exposure level x > 0 was defined as the relative increase in the probability of a lesion at that level compared with the background probability of a lesion at exposure x = 0. The risk threshold was then defined as the exposure level at which the excess risk exceeded a specified level (e.g. 5% or 50%). Thus, given pressure-dependent estimates of the excess risk, the thresholds were estimated by solving the risk equation to obtain the pressure at which the target level of excess risk occurs. Threshold estimates of this type have been developed extensively in the literature for incidence (presence or absence) data. Only recently, however, have excess risk threshold estimates been derived for data in which lesion size (depth, surface area) is measured if present and a zero is recorded if the lesion is absent. Tobit regression was used to estimate pressure-dependent percentiles of the size distribution, and the excess risks were estimated from the tobit probability of a positive-valued response. The tobit model provides a well-established approach to modeling data constrained to be nonnegative. Solving the risk equation for the tobit model leads to risk threshold estimates that incorporate the information on size of observed lesions. Results using these probability-based risk estimates were compared with results for a piecewise linear ("hockey stick") model, which has also been used in the US safety literature, although it does not explicitly address the nonnegativity constraint in the sampling model. The comparisons were carried out for data from two previously published studies, from different laboratories, on US-induced lung hemorrhage. The thresholds derived from logistic regression of lesion occurrence and tobit regression of lesion size were quite consistent with each other and within sampling error. The hockey stick thresholds, defined as the exposure level at which the piecewise linear model for the probability of the expected size of a lesion bends upward, corresponded to quite different excess risk values for incidence (lesion occurrence) compared with size (lesion surface area or depth), although these methods have been developed previously for both types of data. The use of probability-based excess risk thresholds is recommended to obtain consistent incidence vs. size thresholds and to ensure that the thresholds are well-defined and interpretable independent of the details of the statistical model.


Quorum sensing modulates bacterial virulence and colonization dynamics of the gastrointestinal pathogen Citrobacter rodentium.
Quorum Sensing (QS) is a form of cell-to-cell communication that enables bacteria to modify behavior according to their population density. While QS has been proposed as a potential intervention against pathogen infection, QS-mediated communication within the mammalian digestive tract remains understudied. Using an LC-MS/MS approach, we discovered that Citrobacter rodentium, a natural murine pathogen used to model human infection by pathogenic Escherichia coli, utilizes the CroIR system to produce three QS-molecules. We then profiled their accumulation both in vitro and across different gastrointestinal sites over the course of infection. Importantly, we found that in the absence of QS capabilities the virulence of C. rodentium is enhanced. This highlights the role of QS as an effective mechanism to regulate virulence according to the pathogen's spatio-temporal context to optimize colonization and transmission success. These results also demonstrate that inhibiting QS may not always be an effective strategy for the control of virulence.


Impact of the cardiac troponin testing algorithm on excessive and inappropriate troponin test requests.
Cardiac troponin (cTn) is a key biomarker for the assessment of myocardial injury, but overutilization of this test has increased workload and costs. We developed and implemented an algorithm to eliminate excessive utilization. Significant reduction was observed after the implementation of the algorithm in total cTnI requests (29.9%; P = .007), requests from outpatient clinics (70.7%; P = .003), and other wards (42.8%; P = .003). Stat requests, the number of third requests, and more than 3 requests per patient were reduced significantly by 42.8% (P = .004), 35.8% (P = .003), and 49.4% (P = .008), respectively. The test and labor costs each were reduced by 29.9% (P = .007 for each). There was no significant change in cTnI orders from emergency and critical care departments. The cTnI testing algorithm reduced unnecessary orders for cTnI tests with no reduction in meeting patients'critical needs. Reduction in unnecessary and inappropriate requests reduces labor and test costs.


Phylogeny of Porphyromonas gingivalis by ribosomal intergenic spacer region analysis.
Periodontitis has been associated with the presence of Porphyromonas gingivalis, and previous studies have shown phenotypic differences in the pathogenicities of strains of P. gingivalis. An accurate and comprehensive phylogeny of strains of P. gingivalis would be useful in determining if there is an evolutionary basis to pathogenicity in this species. Previous phylogenies of P. gingivalis strains based on random amplified polymorphic DNA (RAPD) analysis and multilocus enzyme electrophoresis (MLEE) show little agreement. While the 16S ribosomal gene is the standard for phylogenetic reconstruction among bacterial species, it is insufficiently variable for this purpose. In the present study, the phylogeny of P. gingivalis was constructed on the basis of the sequence of the most variable region of the ribosomal operon, the intergenic spacer region (ISR). Heteroduplex analysis of the ISR has been used to study the variability of P. gingivalis strains in periodontitis. In the present study, typing by heteroduplex analysis was compared to ISR sequence-based phylogeny and close agreement was observed. The two strains of P. gingivalis whose heteroduplex types are strongly associated with periodontitis were found to be closely related and were well separated from strains whose heteroduplex types are less strongly associated with disease, suggesting a relationship between pathogenicity and phylogeny.


Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome.
Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZDs) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZDs in PCOS is, in part, mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy women. Treatment with pioglitazone improved insulin-stimulated glucose metabolism and plasma adiponectin, and reduced fasting serum insulin (all P<0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes representing mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome degradation in PCOS after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1alpha expression (P<0.05). Pretreatment expression of genes representing OXPHOS and ribosomal proteins was down-regulated in PCOS patients compared to healthy women. These data indicate that pioglitazone therapy restores insulin sensitivity, in part, by a coordinated upregulation of genes involved in mitochondrial OXPHOS and ribosomal protein biosynthesis in muscle in PCOS. These transcriptional effects of pioglitazone may contribute to prevent the onset of type 2 diabetes in these women.


Independent evaluation of the California Tobacco Education Program.
To monitor the implementation of tobacco control programs and research in accordance with California's Proposition 99, approved by the voters in 1988, which increased the state's cigarette tax by 25 cents and designated one quarter of the increased revenue-approximately $100 million per year-to develop statewide media campaigns and to fund local health departments, community-based organizations, schools, and agencies working with high risk populations. The authors evaluated the extent and the effectiveness of the implementation independently with standardized forms developed to track any tobacco-related information and activities, local media campaigns, changes in local policies and ordinances, training sessions, and prevention and cessation programs. Activities were reported on the forms to the authors monthly or quarterly. The evaluation indicated that local health departments, community-based organizations, and other group produced an exceedingly high volume of diverse tobacco control activities throughout the state. They reached a variety of ethnic groups and high risk populations with their programs. The data also show that local health departments and competitive grantees responded with an overall shift in their approach to tobacco control and moved from interventions focused primarily on individual people to broader, more community- and environment-oriented interventions. Additionally, analysis of the wholesale tobacco tax revenues revealed that per capita purchasing continued to decline in California at a rate greater than in the rest of the United States. The evaluation demonstrated that Proposition 99 accomplished much of what it set out to do-reducing tobacco prevalence, reaching out to underserved populations, and heightening the awareness of the dangers of environmental tobacco smoke.


Survey of discomfort glare from the headlamps of cars widely used in Iran.
On 2-lane roads, discomfort glare can cause annoyance, discomfort, inconvenience, stress, and fatigue to drivers, posing a risk of accidents. The aim of this study is to evaluate discomfort glare from the headlamps of cars widely used in Iran. The discomfort glare of new vehicles including Pride Saba model GTX, Pride Model 131SL, Samand Soren, Peugeot 405, Megane, and Peugeot Pars was examined at distances of 5 to 100 m at a background luminance of 50 cd/m2 (late twilight/early dawn lighting) and 1 cd/m2 (nighttime) using Schmidt-Clausen and Bindels model and de Boer's subjective scale. According to the de Boer scale, at a background luminance of 50 cd/m2, the discomfort glare for all studied vehicles was between 1.98 and 4.05 in high-beam mode and between 3.5 and 5.4 in low-beam mode. At a background luminance of 1 cd/m2, discomfort glare was between 0.41 and 2.48 in high-beam mode and between 1.93 and 3.84 in low-beam mode. In high-beam mode, the average levels of discomfort glare of these vehicles gradually increased when the distance between cars was reduced by up to about 20 m. In low-beam mode, there was no discomfort glare up to a vehicle distance of 40 m. In addition, at an angle of 1.15°-5.73° between the line of sight and light of vehicles in high-beam mode, the level of discomfort glare was increased, but at an angle of 5.73°-22.9° the level of discomfort glare was reduced. In low-beam mode at an angle of 2.86°-22.9°, the level of discomfort glare was almost identical. The results show that in high-beam mode and with a 100-m distance between vehicles as well as in low-beam mode at intervals of less than 40 m between cars, discomfort glare is created. It can be concluded that by providing solutions such as installing road lighting system, an increase in luminance of roads, separating or widening road lanes, increasing the lateral distance between vehicles, and increasing the angle between lighted vehicles and drivers can noticeably reduce discomfort glare.


Latent profile analysis of depression among empty nesters in China.
The study aimed to explore the depression profile of empty nesters and to identify heterogeneous subgroups in the elderly population. It explored the influencing factors of depression in elderly people with different depression profiles, with a view to provide a reference basis for improving the depression situation of empty-nesting elderly people. This study used the Chinese Longitudinal Healthy Lifespan Survey (CLHLS) survey data, with empty nesters over 60 as the research subjects. Latent profile analysis (LPA) was used to fit potential classes of depression in empty nesters; chi-square tests, Kruskal-Wallis, and multinomial logistic regression were used to explore the factors influencing different depression profiles in older adults. A total of 4481 subjects were included in this study and were classified as low-level (11.6 %), moderate-level (51.6 %), and high-level (36.8 %). Compared to the low-level, the influencing factors for the high-level were IADL, anxiety, self-rated health, exercise, and education; and the influencing factors for the medium level group were anxiety, self-rated health, drink, and education. Factors influencing high-level relative to the mid-level group were IADL, anxiety, residence, self-rated health, exercise, and limited in activities. The CESD-10, as a screening tool, could not completely determine the presence of depression in high levels of empty nesters. Psychological problems arising from depression among empty nesters seriously affected their overall health, and targeted intervention strategies should be developed for different categories of older adults to improve depression and enhance health-related quality of life.


A conserved plan for wiring up the fan-shaped body in the grasshopper and Drosophila.
The central complex comprises an elaborate system of modular neuropils which mediate spatial orientation and sensory-motor integration in insects such as the grasshopper and Drosophila. The neuroarchitecture of the largest of these modules, the fan-shaped body, is characterized by its stereotypic set of decussating fiber bundles. These are generated during development by axons from four homologous protocerebral lineages which enter the commissural system and subsequently decussate at stereotypic locations across the brain midline. Since the commissural organization prior to fan-shaped body formation has not been previously analyzed in either species, it was not clear how the decussating bundles relate to individual lineages, or if the projection pattern is conserved across species. In this study, we trace the axonal projections from the homologous central complex lineages into the commissural system of the embryonic and larval brains of both the grasshopper and Drosophila. Projections into the primordial commissures of both species are found to be lineage-specific and allow putatively equivalent fascicles to be identified. Comparison of the projection pattern before and after the commencement of axon decussation in both species reveals that equivalent commissural fascicles are involved in generating the columnar neuroarchitecture of the fan-shaped body. Further, the tract-specific columns in both the grasshopper and Drosophila can be shown to contain axons from identical combinations of central complex lineages, suggesting that this columnar neuroarchitecture is also conserved.


[Effect of colloid gold on physiologic-biochemical processes in Escherichia coli 1257].
The influence of colloid gold on the growth processes, ATP-ase activity and extrusion of protons in Escherichia coli 1257 was studied. The particles of colloid gold exert nonmonotonous influence on these processes with different direction is such a way that small concentration of this metal (5 x 10(-7)-5 x 10(-6) mg/ml) exert stimulative effect, while higher concentrations of colloid gold result in the suppression of biological activity of the bacterial cells. The discovered peculiarities of colloid gold influence of E. coli strain may be determined by specificity of contact interaction of metal particles with the surface of bacterial cells.


Evaluation of gastric emptying time, gastrointestinal transit time, sedation score, and nausea score associated with intravenous constant rate infusion of lidocaine hydrochloride in clinically normal dogs.
OBJECTIVE To quantify nausea and sedation scores, gastric emptying time, and gastrointestinal transit time after IV administration of a lidocaine hydrochloride bolus followed by a constant rate infusion (CRI) in clinically normal dogs. ANIMALS 6 Beagles. PROCEDURES In a crossover study, dogs were fed thirty 1.5-mm barium-impregnated spheres (BIPS) and received a saline (0.9% NaCl) solution bolus (0.05 mL/kg) IV (time 0) followed by a CRI at 10 mL/h, a lidocaine bolus (1 mg/kg) IV followed by a CRI at 25 μg/kg/min, or a lidocaine bolus (1 mg/kg) IV followed by a CRI at 50 μg/kg/min; CRIs were for 12 hours. Nausea and sedation scores were assessed and abdominal radiographs obtained immediately after feeding of BIPS and every hour for 12 hours and again 16 hours after CRI start. Percentage of BIPSs in the small and large intestines, gastric emptying time, and gastrointestinal transit time were assessed. RESULTS Gastric emptying time did not differ significantly among treatments. Significantly more BIPS were in the large intestine 4 to 7 hours after treatment start for the 50-μg/kg/min treatment than for the other 2 treatments. Six hours after treatment start, significantly more BIPS were in the large intestine for the 25-μg/kg/min treatment than for the saline solution treatment. Higher sedation and nausea scores were associated with the 50-μg/kg/min CRI. CONCLUSIONS AND CLINICAL RELEVANCE In clinically normal dogs, lidocaine CRI did not significantly affect gastric emptying. However, gastrointestinal transit time was mildly decreased and sedation and nausea scores increased in dogs administered a lidocaine CRI at clinically used doses.


An Iterative Centroid Approach for Diffeomorphic Online Atlasing.
Online atlasing, i.e., incrementing an atlas with new images as they are acquired, is key when performing studies on very large, or still being gathered, databases. Regular approaches to atlasing however do not focus on this aspect and impose a complete reconstruction of the atlas when adding images. We propose instead a diffeomorphic online atlasing method that allows gradual updates to an atlas. In this iterative centroid approach, we integrate new subjects in the atlas in an iterative manner, gradually moving the centroid of the images towards its final position. This leads to a computationally cheap approach since it only necessitates one additional registration per new subject added. We validate our approach on several experiments with three main goals: 1- to evaluate atlas image quality of the obtained atlases with sharpness and overlap measures, 2- to assess the deviation in terms of transformations with respect to a conventional atlasing method and 3- to compare its computational time with regular approaches of the literature. We demonstrate that the transformations divergence with respect to a state-of-the-art atlas construction method is small and reaches a plateau, that the two construction methods have the same ability to map subject homologous regions onto a common space and produce images of equivalent quality. The computational time of our approach is also drastically reduced for regular updates. Finally, we also present a direct extension of our method to update spatio-temporal atlases, especially useful for developmental studies.


Glycine 100 in the dinitrogenase reductase of Rhodospirillum rubrum is required for nitrogen fixation but not for ADP-ribosylation.
Dinitrogenase reductase (Rr2) is required for reduction of the molybdenum dinitrogenase in the nitrogen fixation reaction and is the target of posttranslational regulation in Rhodospirillum rubrum. This posttranslational regulation involves the ADP-ribosylation of Rr2. To study the structural requirements for these two functions of Rr2, i.e., activity and regulation, two site-directed mutations in nifH, the gene encoding Rr2, were constructed and analyzed. The mutations both affected a region of the protein known to be highly conserved in evolution and to be relevant to both of the above properties. These mutants were both Nif-, but one of the altered Rr2s was a substrate for ADP-ribosylation. This demonstrates that the ability of Rr2 to participate in nitrogen fixation can be separated from its ability to act as a substrate for ADP-ribosylation.


Characterization of photocycle intermediates in crystalline photoactive yellow protein.
The photocycle in photoactive yellow protein (PYP) crystals was studied by single-crystal absorption spectroscopy with experimental setups for low-temperature and time-resolved measurements. Thin and flat PYP crystals, suitable for light absorption studies, were obtained using special crystallization conditions. Illumination of PYP crystals at 100 K led to the formation of a photostationary state, which includes at least one hypsochromic and one bathochromic photoproduct that resemble PYP(H) and PYP(B), respectively. The effect of temperature, light color and light pulse duration on the occupancy of these low-temperature photoproducts was determined and appeared similar to that observed in solution. At room temperature a blueshifted photocycle intermediate was identified that corresponds to the blueshifted state of PYP (pB). Kinetic studies show that the decay of this blueshifted intermediate is biphasic at -12 degrees C and 15-fold faster than that observed in solution at room temperature. These altered pB decay kinetics confirm a model that holds that the photocycle in crystals takes place in a shortcut version. In this version the key structural events of the photocycle, such as photoisomerization and reversible protonation of the chromophore, take place, but large conformational changes in the surrounding protein are limited by constraints imposed by the crystal lattice.


Adapting to changes in molecular biosciences and technologies.
Dental education, like any other educational programme in a research-intensive university environment, must be research led or at least research informed. In this context, as the research and knowledge base of dentistry lies in the biological and physical sciences, dental education must be led by advances in research in both these areas. There is no doubt that biotechnology and nanotechnology have, over the past 25 years, led research in both these areas. It is therefore logical to assume that this has also impacted on dental education. The aim of this paper is twofold; on one hand to examine the effects of biotechnology and nanotechnology and their implications for dental education and on the other to make recommendations for future developments in dental education led by research in biotechnology and nanotechnology. It is now generally accepted that dental education should be socially and culturally relevant and directed to the community it serves. In other words, there can be no universal approach and each dental school or indeed curriculum must apply the outcomes in their own social, cultural and community settings.


Renal clearance of pancreatic and salivary amylase relative to creatinine clearance in patients with renal disease and proteinuria.
To study the charge-selective properties of the glomerular filter in renal disease, we measured the fractional clearance, relative to creatinine clearance (ECC), of the amylase isoenzymes pancreatic amylase and salivary amylase, which have identical size but different charge. In 63 healthy subjects the mean (and SD) fractional excretion of pancreatic amylase, 4.07% (1.24%), was fourfold that of salivary amylase: 1.02% (0.54%). For 29 patients with renal disease and proteinuria, the mean fractional excretion of pancreatic amylase was significantly lower, 3.31% (1.94%), and that of salivary amylase significantly higher, 2.06% (1.41%), than in controls. In these patients, fractional excretions of both these isoenzymes were negatively correlated with urinary excretion of beta 2-microglobulin and ECC. Evidently, differences in clearances of pancreatic and salivary amylase are a consequence of differences in charge-related glomerular filtration. The relative increase of salivary amylase clearance in patients with renal disease and proteinuria is most probably caused by a loss of the charge-selective properties of the glomerular basement membrane.


Clinicians' perceptions of the benefits and harms of prostate and colorectal cancer screening.
Clinicians' perceptions of screening benefits and harms influence their recommendations, which in turn shape patients' screening decisions. We sought to understand clinicians' perceptions of the benefits and harms of cancer screening by comparing 2 screening tests that differ in their balance of potential benefits to harms: colonoscopy, which results in net benefit for many adults, and prostate-specific antigen (PSA) testing, which may do more harm than good. In this cross-sectional study, 126 clinicians at 24 family/internal medicine practices completed surveys in which they listed and rated the magnitude of colonoscopy and PSA testing benefits and harms for a hypothetical 70-year-old male patient and then estimated the likelihood that these tests would cause harm and lengthen the life of 100 similar men in the next 10 years. We tested the hypothesis that the availability heuristic would explain the association of screening test to perceived likelihood of benefit/harm and a competing hypothesis that clinicians' gist of screening tests as good or bad would mediate this association. Clinicians perceived PSA testing to have a greater likelihood of harm and a lower likelihood of lengthening life relative to colonoscopy. Consistent with our gist hypothesis, these associations were mediated by clinicians' gist of screening (balance of perceived benefits to perceived harms). Generalizability beyond academic clinicians remains to be established. Targeting clinicians' gist of screening, for example through graphical displays that allow clinicians to make gist-based relative magnitude comparisons, may influence their risk perception and possibly reduce overrecommendation of screening.


Current Practices for Genetic Testing in Neonatal Extracorporeal Membrane Oxygenation: Findings from a National survey.
Introduction: Comprehensive genetic testing with whole-exome (WES) or whole-genome (WGS) sequencing facilitates diagnosis, can optimize treatment, and may improve outcomes in critically ill neonates, including those requiring extracorporeal membrane oxygenation (ECMO) for respiratory failure. Our objective was to describe practice variation and barriers to the utilization of comprehensive genetic testing for neonates on ECMO.Methods: We performed a cross-sectional survey of Level IV neonatal intensive care units in the United States across the Children's Hospitals Neonatal Consortium (CHNC).Results: Common indications for WES and WGS included concerning phenotype, severity of disease, unexpected postnatal clinical course, and inability to wean from ECMO support. Unexpected severity of disease on ECMO was the most common indication for rapid genetic testing. Cost of utilization was the primary barrier to testing. If rapid WES or WGS were readily available, 63% of centers would consider incorporating universal screening for neonates upon ECMO cannulation.Conclusion: Despite variation in the use of WES and WGS, universal testing may offer earlier diagnosis and influence the treatment course among neonates on ECMO. Cost is the primary barrier to utilization and most centers would consider incorporating universal screening on ECMO if readily available.


Experimental evidences on the potential of prebiotic fructans to reduce the risk of colon cancer.
Inulin is extracted from the chicory root. It is a set of fructans with its monomers linked by means of beta(2-1) bonds. This linkage cannot be hydrolysed by either pancreatic or by brush border digestive enzymes in the upper intestinal tract of humans. As such the carbohydrates arrive in the colon, where they are fermented by bifidobacteria and other lactic acid producing bacteria, thus enhancing their relative populations in the gut. Recent research in experimental animal models revealed that inulin has significant anticarcinogenic properties. It acts chemopreventively by reducing the incidence of azoxymethane (AOM) - induced aberrant crypt foci and tumours in the colon. These effects may be due to the stimulation of bifidobacteria, which themselves have been shown to act as antigenotoxic in the colon and to reduce AOM-induced tumours. Also fermentation products, including the short-chain fatty acid butyrate, could contribute to the protective effects. In this case a mechanism may be the induction of apoptosis of already transformed cells. The experimental evidence from animal studies and from studies elucidating potential mechanisms strongly supports the possibility that inulin will contribute to reducing risks for colon cancer in humans. In order to obtain more insight into this possibility, human dietary intervention studies relating biomarkers of reduced risk to inulin consumption are needed.


Increased vitreous concentrations of MCP-1 and IL-6 after vitrectomy in patients with proliferative diabetic retinopathy: possible association with postoperative macular oedema.
To determine whether vitreal concentrations of MCP-1, IL-6 and IL-8 are altered after vitrectomy in patients with proliferative diabetic retinopathy (PDR) and to investigate whether the altered levels of these cytokines are associated with postoperative macular oedema. Vitreous samples were collected from 36 eyes of 33 patients with PDR before pars plana vitrectomy without intraocular lens (IOL) implantation, and also from the same 36 eyes during IOL implantation surgery approximately 7 months after the initial vitrectomy. Levels of MCP-1, IL-6, IL-8 and vascular endothelial growth factor were measured by flow cytometry using cytometric bead array (CBA) technology. The mean vitreous levels of MCP-1, IL-6 and IL-8 in the samples collected before vitrectomy were significantly higher in patients with PDR than in control patients (p<0.0001). The levels of MCP-1 and IL-6 in the samples collected at the time of IOL implantation were significantly higher than those collected before vitrectomy (p<0.05). In contrast, the level of IL-8 was significantly lower after vitrectomy (p<0.05). The levels of IL-6 and IL-8, but not MCP-1, in the vitreous from eyes with PDR were inversely correlated with the interval between the initial vitrectomy and the time of implantation surgery. Among the vitrectomised patients, the mean vitreous level of MCP-1 in eyes with diabetic macular oedema (DME) was significantly higher than in those without DME (p=0.028). The elevated levels of MCP-1 and IL-6 may indicate prolonged inflammation even after successful vitrectomy, which can cause postoperative DME.


Devazepide attenuates dl-fenfluramine-induced suppression of gastric emptying but not food intake in the 17 h food-deprived rat.
Recently a number of studies have provided evidence which suggests that CCK and 5-HT interact in the control of food intake. The present experiments further examine this mechanism and the possibility that CCK and 5-HT interact in the control of gastric emptying. The selective CCK-A receptor antagonist, devazepide, (0.03-3.0 mg/kg) administered alone had no intrinsic effect on gastric emptying. Devazepide (0.1 and 0.3 mg/kg) blocked dl-fenfluramine-induced (3.0 mg/kg) suppression of gastric emptying. However, devazepide (0.03-3.0 mg/kg) failed to attenuate the anorectic effect of the same dose of dl-fenfluramine. These results suggest that under the present experimental conditions CCK and 5-HT interact in the regulation of gastric emptying but not food intake. Thus the interaction between CCK and 5-HT in the regulation of gastric emptying appears not to affect the control of ingestive behaviour.


Matter-wave interference of particles selected from a molecular library with masses exceeding 10,000 amu.
The quantum superposition principle, a key distinction between quantum physics and classical mechanics, is often perceived as a philosophical challenge to our concepts of reality, locality or space-time since it contrasts with our intuitive expectations with experimental observations on isolated quantum systems. While we are used to associating the notion of localization with massive bodies, quantum physics teaches us that every individual object is associated with a wave function that may eventually delocalize by far more than the body's own extension. Numerous experiments have verified this concept at the microscopic scale but intuition wavers when it comes to delocalization experiments with complex objects. While quantum science is the uncontested ideal of a physical theory, one may ask if the superposition principle can persist on all complexity scales. This motivates matter-wave diffraction and interference studies with large compounds in a three-grating interferometer configuration which also necessitates the preparation of high-mass nanoparticle beams at low velocities. Here we demonstrate how synthetic chemistry allows us to prepare libraries of fluorous porphyrins which can be tailored to exhibit high mass, good thermal stability and relatively low polarizability, which allows us to form slow thermal beams of these high-mass compounds, which can be detected using electron ionization mass spectrometry. We present successful superposition experiments with selected species from these molecular libraries in a quantum interferometer, which utilizes the diffraction of matter-waves at an optical phase grating. We observe high-contrast quantum fringe patterns of molecules exceeding a mass of 10,000 amu and having 810 atoms in a single particle.


[Morphological changes in the follicular epithelium in oogenesis of the Peking duck (Anas boschas domestica) and other poultry].
The morphology of the follicular epithelium during the course of oogenesis in poultry (duck goose, hen, turkey) and at the first stages of oocyte growth in some wild birds (finch, totmit, wood-pecker, pigeon) was studied. The general patterns of the follicular epithelium changings are similar in the both groups of birds. In the process of the oocyte growth the flat follicular epithelial monolayer changes to cubic, prismatic, pseudostratified epithelium. It leads sometimes to the impression of multi-layerness owing to its irregular structure. During the oocyte rapid growth the surface of the oocyte increases causing tension on the epithelium layer. This process again turns the pseudostratified epithelium into primatic, cubic and flat epithelium. Pseudostratified structure of the follilicular epithelium is regarded as adaptation to the necessity of the rapid tension during rapid oocyte growth. Correlations of the follicular epithelium morphology with the oocyte diameter are established. Existance of a temporary multilayer stage is discussed with arguments against the interpretation of this stage as a real multilayer.


Outreach strategies for expanding health insurance coverage in children.
Health insurance has the potential to improve access to health care and protect people from healthcare costs when they are ill. However, coverage is often low, particularly in people most in need of protection. To assess the effectiveness of outreach strategies for expanding insurance coverage of children who are eligible for health insurance schemes. We searched the Cochrane Effective Practice and Organisation of Care Group (EPOC) Specialised Register (The Cochrane Library 2009, Issue 2), PubMed (January 1951 to January 2010), EMBASE (January 1966 to April 2009), PsycINFO (January 1967 to April 2009) and other relevant databases and websites. In addition, we searched the reference lists of included studies and relevant reviews, and carried out a citation search for included studies to find more potentially relevant studies. Randomised controlled trials, controlled clinical trials, controlled before-after studies and interrupted time series which evaluated the effects of outreach strategies on increasing health insurance coverage for children. We defined outreach strategies as measures to improve the implementation of existing health insurance to enrol more eligible populations. This included increasing awareness of schemes, modifying enrolment, improving management and organis ation of insurance schemes, and mixed strategies. Two review authors independently extracted data and assessed the risk of bias . We narratively summari sed the data. We included two studies, both from the United States. One randomised controlled trial study with a low risk of bias showed that community- based case managers who provided health insurance information, application support, and negotiated with the insurer were effective in enrolling and maintaining enrolment of Latino American children into health insurance schemes (n = 257). The second quasi-randomised controlled trial, with an unclear risk of bias (n = 223), indicated that handing out insurance application materials in hospital emergenc y departments can increase enrolment of children into health insurance. The two studies included in this review provide evidence that in the US providing health insurance information and application assistance, and handing out application materials in hospital emergency departments can probably both improve insurance coverage of children. Further studies evaluating the effectiveness of different outreach strategies for expanding health insurance coverage of children in different countries are needed, with careful attention given to study design.


The ameliorative impacts of Moringa oleifera leaf extract against oxidative stress and methotrexate-induced hepato-renal dysfunction.
Moringa Oleifera (MO) is a herbal plant native to South Asia known for its anti-oxidative and anti-inflammatory properties. This study explored the protective effects of MO leaf extract (MOLE) against oxidative stress and hepatic and renal injuries caused by methotrexate (MTX) therapy. Mice received a single intraperitoneal injection of 20 mg/kg body weight MTX to induce hepatic and kidney injuries. They then received 300 mg/kg body weight of MOLE orally for seven days, followed by MTX on day 7 then five more days of MOLE (12 days total). Blood, liver and kidney samples were collected from all groups and the following biochemical parameters were tested: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), catalase, superoxide dismutase (SOD), malondialdehyde (MDA) and total proteins. Quantitative real time PCR (qRT-PCR) was used to examine Nrf2, HO-1, BAX, TIMP, XIAP, and NFkB, which are associated with apoptosis, anti-apoptosis and oxidative stress. Capase-9 and Bcl2 genes underwent immunohistochemical analysis. Pretreatment with MOLE reduced the effect of MTX on ALT, AST and total proteins, and reversed its effect on serum and tissue antioxidants. Nrf2/HO-1, apoptotic and anti-apoptotic gene expression was regulated, and Bax and TIMP were reduced; XIAP expression was increased in both the liver and kidney samples, and immunoreactivity of caspase-9 and Bcl2 was restored in the MOLE-administered experimental group. Overall, the study concluded that MOLE can inhibit the effects of hepato-renal injuries caused by MTX by regulating oxidative stress, apoptosis and anti-apoptotic genes at biochemical, molecular and cellular levels.


Validation of thermography in the diagnosis of reflex sympathetic dystrophy.
To examine the validity of several thermogram-derived indices of autonomic functioning in the diagnosis of reflex sympathetic dystrophy (RSD). A series of chronic pain patients were classified diagnostically based on thermogram results using discriminant function analysis, and validity measures (e.g., sensitivity, specificity) were used to determine the accuracy of computerized thermographic pixel analysis in discriminating RSD from other pathology. The study was conducted at the Rush Pain Center, a multidisciplinary outpatient pain clinic. A series of 46 chronic pain patients referred for suspected sympathetically mediated pain. All patients underwent computerized thermographic examination under a baseline condition after acclimating to a climate-controlled room, immediately after a cold challenge was applied to the contralateral uninvolved extremity (4 degrees C for 90 s) and 20 min after the cold challenge. Temperature during the three experimental periods, degree of temperature asymmetry between affected and nonaffected limbs during the three periods, response to cold challenge, and recovery following cold challenge were measured. Temperature asymmetry accurately discriminated between RSD and non-RSD patients, with the most accurate asymmetry measures obtained at baseline. Responses to cold challenge and actual temperature values did not discriminate between RSD and non-RSD pain patients. Thermography can be a useful component of RSD diagnosis. In situations where sensitivity and specificity are equally important, an asymmetry cutoff of 0.6 degree C appears optimal. If specificity (i.e., accurately ruling out non-RSD cases) is more important, a cutoff of 0.8 degree C or 1.0 degree C may be considered as well.


[Clinical effect and tolerance of paxil (paroxetine) in management of panic disorders].
To determine clinical efficiency and tolerance of paxil (paroxetin) in the treatment of panic disorders. An open, non-comparative 7 week study entered 60 patients (mean age 36.6 +/- 3.22 years) with panic disorders and agoraphobias with panic disorders. Paroxetin was given in a single daily dose 20-60 mg/day in the morning. The results were assessed by Hamilton and Sihan scales, scale of clinical impression, by reduction of panic attacks. In 72.2% of patients panic attacks ceased or occurred less frequently (by 50%). Anxiety relieved by 67 +/- 4.6%. The number of the responders was greater while the effect occurred faster in patients with panic disorders. The drug was well tolerated, side effects occurred in 43.3% of cases. They were mild or moderate. Paroxetin has a prominent anxiolytic and antiphobic action, is well tolerated and is effective in panic disorders and agoraphobia with panic disorders.


Rapid serological test for diagnosis of chlamydial ocular infections.
A rapid serodiagnostic test for the diagnosis of paratrachoma (TRIC ophthalmia neonatorum, inclusion conjunctivitis, TRIC punctate keratoconjunctivitis, and trachoma of sexually transmitted origin) has been developed. The technique is based on using a modified micro-immunofluorescence test for detecting antichlamydial IgG and IgM in the blood and IgG and IgA in tears. The blood samples are collected on cellulose sponges after a finger prick, and tears are collected by introducing small sponges into the lower conjunctival fornix of the eye. The blood and tear samples collected in this way could be sent to the diagnostic laboratory by post without special arrangements for cold storage. In general the presence of antichlamydial IgG at a level of greater than or equal to 1/32 or IgM at a level of greater than or equal to 1/8 in blood and antichlamydial IgG or IgA at a level of greater than or equal to 1/8 in tears was closely associated with ocular paratrachoma. The combined results of the micro-IF test of blood and tears has yielded the highest rate of positivity (90%). In patients with acute untreated paratrachoma the sensitivity of this test was similar to that of irradiated McCoy cells. In patients with a milder infection receiving antibiotics the sensitivity of the serodiagnostic test was superior to that of the cultural test. The high sensitivity and specificity of this rapid, simple and inexpensive serodiagnostic test for the diagnosis of chlamydial ocular infections, coupled with simple and practical methods of collection and transport of blood and tear specimens, offer advantages over cultural tests for routine diagnosis and study of chlamydial ocular infections.


Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers.
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy.Experimental Design: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunologic subtypes of PDAC that were confirmed in the Cancer Genome Atlas dataset. Stromal and metabolic characteristics of PDAC cases were evaluated by histologic analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neoantigens were determined by analysis of whole-exome sequencing data. Random-forest clustering was employed to define multimarker subtypes, with univariate and multivariate analyses interrogating prognostic significance.Results: PDAC cases exhibited distinct stromal phenotypes that were associated with prognosis, glycolytic and hypoxic biomarkers, and immune infiltrate composition. Immune infiltrate was diverse among PDAC cases and enrichment for M2 macrophages and select immune checkpoints regulators were specifically associated with survival. Composite analysis with neoantigen burden, immunologic, and stromal features defined novel subtypes of PDAC that could have bearing on sensitivity to immunologic therapy approaches. In addition, a subtype with low levels of neoantigens and minimal lymphocyte infiltrate was associated with improved overall survival.Conclusions: The mutational burden of PDAC is associated with distinct immunosuppressive mechanisms that are conditioned by the tumor stromal environment. The defined subtypes have significance for utilizing immunotherapy in the treatment of PDAC. Clin Cancer Res; 23(15); 4429-40. ©2017 AACR.


Detecting reactive islands in a system-bath model of isomerization.
In this article, we study the conformational isomerization in a solvent using a system-bath model where the phase space structures relevant for the reaction dynamics are revealed. These phase space structures are an integral part of understanding the reaction mechanism, that is the pathways that reactive trajectories undertake, in the presence of a solvent. Our approach involves detecting the analogs of the reactive islands first discussed in the works by Davis, Marston, De Leon, Berne and coauthors in the system-bath model using Lagrangian descriptors. We first present the structure of the reactive islands for the two degrees of freedom system modelling isomerization in the absence of the bath using direct computation of cylindrical (tube) manifolds and verify the Lagrangian descriptor method for detecting the reactive islands. The hierarchy of the reactive islands as indicated in the recent work by Patra and Keshavamurthy is shown to be related to the temporal features in committor probabilities. Next, we investigate the influence of the solvent on the reactive islands that we previously revealed for the two degrees of freedom system and discuss the use of the Lagrangian descriptor in the high-dimensional phase space of the system-bath model.


Effects of gabapentin on anxiety induced by simulated public speaking.
The effects of gabapentin, 400 mg and 800 mg, on anxiety induced by simulated public speaking (SPS) were investigated. Thirty-two normal male volunteers (aged 17-30 years) had their anxiety and mood evaluated by self-scales [Visual Analogue Mood Scale (VAMS) and Profile of Mood State (POMS)] during the SPS procedure. Physiological measures (heart rate and blood pressure) were taken. Treatment with gabapentin at 800 mg attenuated the anxiety of subjects that had a decrease on the VAMS item calm-excite. In addition, volunteers that received gabapentin at 400 mg and 800 mg showed a decrease in the hostility score in POMS. Our results suggest, in agreement with other studies, an anxiolytic potential to gabapentin.


A biogeographical profile of the sand cockroach Arenivaga floridensis and its bearing on origin hypotheses for Florida scrub biota.
Florida scrub is a xeric ecosystem associated with the peninsula's sand ridges, whose intermittent Pliocene-Pleistocene isolation is considered key to scrub endemism. One scrub origin hypothesis posits endemics were sourced by the Pliocene dispersal of arid-adapted taxa from southwestern North America; a second invokes Pleistocene migration within eastern North America. Only one study to date has explicitly tested these competing hypotheses, supporting an eastern origin for certain scrub angiosperms. For further perspective, we conducted a genetic analysis of an endemic arthropod, the Florida sand cockroach (Arenivaga floridensis), with two aims: (1) to reconstruct the peninsular colonization and residence history of A. floridensis and (2) determine whether its biogeographic profile favors either origin hypothesis. We sequenced the cox2 mitochondrial gene for 237 specimens (65 populations) as well as additional loci (cox1, nuclear H3) for a subset of Florida roaches and congeners. Using Network and Bayesian inference methods, we identified three major lineages whose genetic differentiation and phylogeographical structure correspond with late Pliocene peninsula insularization, indicating Arenivaga was present and broadly distributed in Florida at that time. Stem and crown divergence estimates (6.36 Ma; 2.78 Ma) between A. floridensis and western sister taxa span a period of extensive dispersal by western biota along an arid Gulf Coast corridor. These phylogeographical and phylogenetic results yield a biogeographic profile consistent with the western origin hypothesis. Moreover, age estimates for the roach's peninsular residence complement those of several other endemics, favoring a Pliocene (or earlier) inception of the scrub ecosystem. We argue that eastern versus western hypotheses are not mutually exclusive; rather, a composite history of colonization involving disparate biotas better explains the diverse endemism of Florida scrub.


Gastroprotective effect of the traditional herbal medicine, Sipjeondaebo-tang water extract, against ethanol-induced gastric mucosal injury.
Sipjeondaebo-tang, a traditional herbal medicine, has been reported to activate the immune response. Although, most research has focused on its anticancer activity. The purpose of this study was to determine whether Sipjeondaebo-tang exerts antioxidant activity against ethanol-induced gastric injury. Gastric mucosal injury was induced by the oral administration of absolute ethanol at 5 mL/kg to rats after 18 h fast. Sipjeondaebo-tang water extract (SDTW; 200 mg/kg of body weight) was administered to rats 2 h before the oral administration of absolute ethanol. Gastric mucosal injury was evaluated by measuring the gastric injury, such as extent of lesions, malondialdehyde (MDA) concentration, glutathione (GSH) content and activities of antioxidant enzymes including catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase, and superoxide dismutase in stomach tissue. Oral administration of SDTW markedly decreased the damage by conditioning the gastric mucosa such as hemorrhage, hyperemia. Pretreatment with SDTW significantly reduced MDA concentration and significantly increased GSH content and the activities of antioxidant enzymes. In an acute toxicity study, no adverse effects of SDTW were observed at doses up to 5000 mg/kg/day. SDTW may protect the gastric mucosa against ethanol-induced gastric mucosa injury. These results suggested that SDTW might also play an important role in the gastroprotection based on their antioxidant effect.


A hybrid patient-specific biomechanical model based image registration method for the motion estimation of lungs.
This paper presents a new hybrid biomechanical model-based non-rigid image registration method for lung motion estimation. In the proposed method, a patient-specific biomechanical modelling process captures major physically realistic deformations with explicit physical modelling of sliding motion, whilst a subsequent non-rigid image registration process compensates for small residuals. The proposed algorithm was evaluated with 10 4D CT datasets of lung cancer patients. The target registration error (TRE), defined as the Euclidean distance of landmark pairs, was significantly lower with the proposed method (TRE = 1.37 mm) than with biomechanical modelling (TRE = 3.81 mm) and intensity-based image registration without specific considerations for sliding motion (TRE = 4.57 mm). The proposed method achieved a comparable accuracy as several recently developed intensity-based registration algorithms with sliding handling on the same datasets. A detailed comparison on the distributions of TREs with three non-rigid intensity-based algorithms showed that the proposed method performed especially well on estimating the displacement field of lung surface regions (mean TRE = 1.33 mm, maximum TRE = 5.3 mm). The effects of biomechanical model parameters (such as Poisson's ratio, friction and tissue heterogeneity) on displacement estimation were investigated. The potential of the algorithm in optimising biomechanical models of lungs through analysing the pattern of displacement compensation from the image registration process has also been demonstrated.


Does female feeding motivation affect the response to a food-mimicking male ornament in the swordtail characin Corynopoma riisei?
Female response to various aspects of male trait morphology and the effect of female feeding motivation were investigated in the swordtail characin Corynopoma riisei, a species where males are equipped with a flag-like food-mimicking ornament that grows from the operculum. Unfed females responded more strongly to the male ornament and showed a stronger preference for larger ornaments than did fed females. Females were shown not to discriminate between artificial male ornaments of either undamaged or damaged shape.


Association of Reduced-Intensity Conditioning Regimens With Overall Survival Among Patients With Non-Hodgkin Lymphoma Undergoing Allogeneic Transplant.
Reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimens are frequently used in allogeneic hematopoietic cell transplant (HCT) for non-Hodgkin lymphoma. However, the optimal RIC-NMAC regimen in allogeneic HCT for non-Hodgkin lymphoma is not known. To investigate whether RIC-NMAC regimens at a higher end of the intensity spectrum are associated with increased nonrelapse mortality and lower overall survival compared with RIC-NMAC regimens at the lower end of the intensity spectrum in patients with non-Hodgkin lymphoma undergoing allogeneic HCT. This cohort study used data from 1823 adult patients with non-Hodgkin lymphoma in the Center for International Blood and Marrow Transplant Research registry. Included patients underwent allogeneic HCT using matched related or unrelated donors between January 2008 and December 2016. Statistical analysis was performed from June 1, 2019, to February 10, 2020. Patients received 1 of 4 RIC-NMAC regimens: fludarabine-intravenous busulfan (Flu-Bu), approximately 6.4 mg/kg (n = 458); fludarabine-melphalan (Flu-Mel140), 140 mg/m2 (n = 885); fludarabine-cyclophosphamide (Flu-Cy) (n = 391); or Flu-Cy with 2 Gy total body irradiation (Flu-Cy-2GyTBI) (n = 89). The primary outcome was overall survival. Secondary outcomes were nonrelapse mortality, incidence of relapse, progression-free survival, and the incidence of acute and chronic graft-vs-host disease (GVHD). Of 1823 patients, 1186 (65%) were male, with a mean (SD) age of 54.8 (9.9) years. The 4-year adjusted OS was 58% in the Flu-Bu cohort, 67% in the Flu-Cy-2GyTBI cohort, 49% in the Flu-Mel140 cohort, and 63% in the Flu-Cy cohort (P < .001). After adjustment for age, Karnofsky performance score, HCT comorbidity index, NHL subtype, remission status at HCT, and the use of antithymocyte globulin or alemtuzumab, the regression analysis showed a significantly higher mortality risk associated with Flu-Mel140 compared with Flu-Bu (hazard ratio [HR], 1.34; 95% CI, 1.13-1.59; P < .001). Compared with the Flu-Cy cohort, the Flu-Mel140 cohort had a higher risk of chronic GVHD (HR, 1.38; 95% CI, 1.15-1.65; P < .001). The Flu-Mel140 regimen was associated with a higher nonrelapse mortality risk (HR, 1.78; 95% CI, 1.37-2.31; P < .001) compared with the Flu-Bu regimen. The findings suggest that use of the more intense RIC-NMAC regimen, Flu-Mel140, may have a negative association with overall survival and may be associated with higher nonrelapse mortality. The Flu-Bu and Flu-Cy regimens with or without 2GyTBI regimens appeared to provide comparable overall survival.


Specific Reading Comprehension Disability: Major Problem, Myth, or Misnomer?
The goal of the present study was to test three competing hypotheses about the nature of comprehension problems of students who are poor in reading comprehension. Participants in the study were first, second, and third graders, totaling 9 cohorts and over 425,000 participants in all. The pattern of results was consistent across all cohorts: Less than one percent of first- through third-grade students who scored as poor in reading comprehension were adequate in both decoding and vocabulary. Although poor reading comprehension certainly qualifies as a major problem rather than a myth, the term specific reading comprehension disability is a misnomer: Individuals with problems in reading comprehension that are not attributable to poor word recognition have comprehension problems that are general to language comprehension rather than specific to reading. Implications for assessment and intervention are discussed.


Patient education in the management of diabetes mellitus.
A patient education programme in the management of diabetes mellitus (DM) was piloted in a government polyclinic. This study aimed to evaluate the effectiveness of the education programme in improving knowledge of DM and skills in self-care in order to achieve long term control of DM. The study was carried out on an intervention group of 183 diabetic patients who completed the education programme and a control group of 95 diabetic patients who attended the clinic during the period of the study. The patients were assessed on their knowledge of diabetes and their practice for good control of the disease (dietary practice, compliance, home monitoring) through a questionnaire. Long term control was assessed by their glycosylated haemoglobin levels. The education programme comprised individual counselling using a diabetes education guide, talks, videoshows and food displays. The intervention group showed a significant and greater improvement in the knowledge of the disease and self-care and in the dietary practice (taking more unpolished rice/high fibre food, reducing calories intake and cutting down oily/fatty food) when compared to the control group. Compliance with medication and the mean HbA1c levels were also improved in the intervention group. In this study the educational intervention was observed to have improved the diabetic patients' knowledge of the disease and self-care and the long term control of the disease. Patient education is thus an important component in the management of diabetes mellitus.


Stress-induced analgesia in humans: endogenous opioids and naloxone-reversible depression of pain reflexes.
The cumulative effects of a repetitive stress induced by anticipation of pain (noxious foot shock) were studied on the threshold of a nociceptive flexion reflex of the lower limb. The threshold of the nociceptive reflex progressively increased with the repetition of the stress. This effect was reversed by naloxone, which even produced hyperalgesia, since a rapid and significant decrease in this threshold, below the initial values, was noted. Tha data provide evidence for involvement of endogenous opioids in the phenomenon of stress-induced analgesia in normal man.


European experience with methotrexate treatment in Crohn's disease: a multicenter retrospective analysis.
Methotrexate (MTX) has been utilized for the treatment of Crohn's disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD.The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort. This was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome. Between July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5-18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival. MTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies.


Neoplastic modulation of extracellular matrix: proteoglycan changes in the rabbit mesentery induced by V2 carcinoma cells.
Previous studies have shown that the invasion of V2 carcinoma cells in the rabbit mesentery is associated with marked extracellular matrix synthesis leading eventually to an overall increase in mesenteric mass. The purpose of the present study was to investigate the structural and biochemical composition of the extracellular matrix in tumor-free parts of rabbit mesenteries at various stages after intraperitoneal implantation of V2 carcinoma cells. The overall thickness of the tumor-implanted mesenteries increased progressively and peaked at about Day 14, when it was about 8 times greater than the untreated or liver-implanted controls. This was mainly the result of an accumulation of extracellular matrix components. In particular, there was a marked increase in both collagen fibers and proteoglycan granules, as well as filaments, probably hyaluronic acid, as visualized by ruthenium hexammine trichloride. Stereological analysis showed a 6-fold increase in collagen fibers and a significant increase in the density and average diameter of proteoglycan granules. Biochemical analysis revealed a marked elevation in uronic acid content in the tumor-implanted mesenteries. Specifically, they contained 2.6 and 8.6 times the amount of hyaluronic acid and chondroitin sulfate, respectively, than did controls. Furthermore, the relative percentage of chondroitin sulfate was elevated markedly (26 versus 6% in controls). However, the content of heparan or dermatan sulfate did not vary significantly. Stereological analysis of the fibroblasts showed that their absolute number had doubled and that the cell volume of the individual fibroblast had increased markedly. This suggests that the fibroblasts were responsible for the excessive production of the extracellular matrix. These results support the concept that carcinoma cells can modulate their surrounding extracellular environment by stimulating the synthesis of connective tissue in the host mesenchymal cells.


A role for phosphorylation in the maintenance of resurgent sodium current in cerebellar purkinje neurons.
Cerebellar Purkinje neurons express voltage-gated, tetrodotoxin (TTX)-sensitive sodium channels that not only open and inactivate rapidly during depolarization but also reopen during repolarization, carrying an unusual "resurgent" sodium current. Expression of Na(V)1.6 alpha subunits appears necessary but not sufficient to generate this component of current; Purkinje cells without Na(V)1.6 lack resurgent current, but resurgent current is absent from many other Na(V)1.6-expressing neurons. These observations raise the question of how modulation or modification of the Na(V)1.6 subunit may lead to production of resurgent current. Previous studies have suggested that sodium channels of Purkinje neurons are subject to a rapid, voltage-dependent, open channel block by an endogenous particle whose unbinding allows resurgent current to flow. To investigate the nature of this block, we recorded TTX-sensitive sodium currents in outside-out patches from Purkinje cells acutely isolated from mice. In all patches, step depolarizations evoked transient current, and step repolarizations evoked resurgent current. The amplitudes of the transient and resurgent currents were highly correlated across patches (R(2) > 0.99), suggesting that the blocking agent is closely associated with the channel. Intracellular protease eliminated fast inactivation, indicating that the blocking element, like the fast inactivation gate, may be proteinaceous. Intracellular application of alkaline phosphatase abolished resurgent current and significantly slowed inactivation of transient current. The phosphatase inhibitor vanadate reduced these effects. Together, the results suggest that constitutive phosphorylation of the sodium channel complex of Purkinje neurons is necessary to maintain a functional blocking element and produce resurgent sodium current.


Preparation of boron nitride nanotubes aqueous dispersions for biological applications.
While in the last years applications of carbon nanotubes in the field of biotechnology have been largely proposed, biomedical applications of boron nitride nanotubes (BNNTs) are yet totally unexplored. BNNTs have very interesting physical properties that should be exploited in the biomedical field. At this date, studies on their biocompatibility are completely missing and the first issue behind this investigation is the dispersion of BNNTs in aqueous solutions. In this paper the authors propose, for the first time, a technique for obtaining BNNT stable dispersions suitable for biological applications, based on polyethyleneimine (PEI) water solutions. Based on authors' knowledge, in vitro testing performed on human neuroblastoma cell line (SH-SY5Y) is the first study of interaction between BNNTs and living material. Experimental results showed a satisfactory cell viability up to a concentration of 5.0 microg/ml PEI-BNNTs in the cell culture medium.


Monitoring the response to antiretroviral therapy in resource-poor settings: the Malawi model.
With assistance from the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), Malawi is scaling-up the delivery of antiretroviral (ARV) therapy to HIV-positive eligible patients. The country has developed National ARV Treatment Guidelines, which emphasize a structured and standardized approach for all aspects of ARV delivery, including monitoring and evaluation. Using the successful DOTS model adapted by National TB Control Programmes throughout the world, Malawi has developed a system of quarterly ARV cohort and cumulative ARV quarterly analyses. Thyolo district, in the southern region of Malawi, has been using this system since April 2003. This paper describes the standardized ARV treatment regimens and the treatment outcomes used in Thyolo to assess the impact of treatment, the registration and monitoring systems and how the cohort analyses are carried out. Data are presented for case registration and treatment outcome for the first quarterly cohort (April to June) and the combined cohorts (April to June and July to September). Such quarterly analyses may be useful for districts and Ministries of Health in assessing ARV delivery, although the burden of work involved in calculating the numbers may become large once ARV delivery systems have been established for several years.


Reduced testosterone, 17 beta-oestradiol and sexual hormone binding globulin, and increased insulin-like growth factor-1 concentrations, in healthy nulligravid women aged 19-25 years who were first and/or second degree relatives to breast cancer patients.
Differences in hormonal and constitutional parameters between women with at least one first and/or second degree relative with breast cancer (RBC) and women without such affected relatives were studied in a group of healthy, nulligravid women aged 19-25 years. Present oral contraceptive (OC) users were analysed separately. In women not presently exposed to OCs we found significant correlations between RBC and reduced concentrations of testosterone during both the follicular (P < 0.001) and luteal menstrual cycle phases (P = 0.016). 17 beta-oestradiol was also significantly negatively correlated with RBC in the follicular (P = 0.044) and in the luteal phase (P = 0.027). RBC was significantly correlated with a lower waist/hip ratio (P = 0.044) compared with women without such a history. In multivariate analyses, the results for testosterone but not 17 beta-oestradiol remained significant. In these analyses high IGF-1 (P = 0.05) in the follicular phase and low sexual hormone-binding globulin (SHBG) (P = 0.04) in the luteal phase were also related to RBC. Including all 66 women in a multivariate model that analysed the specific effects from OCs and RBC on plasma testosterone showed that plasma testosterone was significantly lower among present OC users (P = 0.004) and in women with RBC (P = 0.005) during cycle days 5-10, with a significant positive two-way interaction between present OC use and RBC (P = 0.007). During cycle days 18-23 plasma testosterone showed a significant negative relationship with present OC use (P < 0.001) and RBC (P = 0.016) no significant interaction was seen during cycle days 18-23. Factors not significantly related to RBC were height, weight, breast size, age at menarche, p-progesterone and p-prolactin. It is concluded that a family history of breast cancer significantly lowered plasma testosterone concentrations in both cycle phases among healthy, nulligravid women compared with women without such history.


Utilisation of hepatocellular carcinoma screening in Australians at risk of hepatitis B virus-related carcinoma and prescribed anti-viral therapy.
To investigate hepatocellular carcinoma screening utilisation and factors associated with utilisation among patients prescribed hepatitis B virus anti-viral therapy and at risk of hepatocellular carcinoma. The incidence of hepatocellular carcinoma has increased in Australia over the past three decades with chronic hepatitis B virus infection a major contributor. hepatocellular carcinoma surveillance programs aim to detect cancers early enabling curative treatment options, longer survival and longer times to recurrence. Multi-site cross-sectional survey. An online study questionnaire was administered to eligible participants attending three Sydney tertiary hospitals. Data were grouped into six mutually exclusive hepatocellular carcinoma risk factor categories as per American Association for the Study of Liver Diseases guidelines. All analyses were undertaken in STATA. Logistic regression was used to assess the associations between covariates and screening utilisation. Multivariate models described were assessed using the Hosmer-Lemeshow goodness of fit. Of the 177 participants, 137 (77.4%) self-reported that US had been performed in the last six months. Awareness that screening should be performed and knowing the correct frequency of US screening were independently associated with screening utilisation. Participants who knew that screening should be undertaken were three times more likely to have had pretreatment education or were prescribed hepatitis B virus anti-viral treatment for >4 years. Participants reporting a family history of hepatocellular carcinoma were less likely to know that screening should be undertaken every 6 months. While utilisation of hepatocellular carcinoma surveillance programs was higher in this study than in previous reports, strategies to further improve surveillance remain necessary. Findings from this research form the basis for proposing strategies to improve utilisation of hepatocellular carcinoma screening, inform hepatitis B virus-related clinical practice and for the delivery of care and nursing education to people receiving hepatitis B virus anti-viral therapy and at risk of developing hepatocellular carcinoma.


HIV-1 viral load and resistance in genital secretions in patients taking protease-inhibitor-based second-line therapy in Africa.
HIV is transmitted primarily through sexual intercourse, and the objective of this study was therefore to assess whether there is occult viral replication and resistance in genital secretions in patients on protease inhibitor (PI)-based second-line therapy. HIV-infected adults taking ritonavir-boosted lopinavir with either two nucleoside reverse transcriptase inhibitors (NRTIs), raltegravir or as monotherapy for 96 weeks, were enrolled at seven clinical sites in Uganda. Viral load (VL) was measured in cervico-vaginal secretions or semen and in a corresponding plasma sample. Genotypic resistance was assessed in genital secretion samples and plasma samples. Results were compared between compartments and with the plasma resistance profile at first-line failure. Of the 111 participants enrolled (91 female, 20 male), 16 (14%) and 30 (27%) had VL >1,000 and >40 copies/ml, respectively, in plasma; 3 (3%) and 23 (21%) had VL >1,000 copies/ml and >40 copies/ml, respectively, in genital secretions. There was 74% agreement between plasma and genital secretion VL classification above/below 40 copies/ml threshold (kappa-statistic =0.29; P=0.001). RT mutations (both NRTI and non-nucleoside reverse transcriptase inhibitor) were detected in genital secretions in four patients (similar profile to corresponding plasma sample at first-line failure) and PI mutations were detected in two (one polymorphism with no impact on resistance; one with high-level PI resistance). High level (>1,000 copies/ml) viral replication and development of new RT or PI resistance in the genital compartment were rare. The risks of transmission arising from resistance evolution in the genital compartment are likely to be low on PI-based second-line therapy.


Unscrambling the effect of C-terminal tail deletion on the stability of a cold-adapted, organic solvent stable lipase from Staphylococcus epidermidis AT2.
Terminal moieties of most proteins are long known to be disordered and flexible. To unravel the functional role of these regions on the structural stability and biochemical properties of AT2 lipase, four C-terminal end residues, (Ile-Thr-Arg-Lys) which formed a flexible, short tail-like random-coil segment were targeted for mutation. Swapping of the tail-like region had resulted in an improved crystallizability and anti-aggregation property along with a slight shift of the thermostability profile. The lipolytic activity of mutant (M386) retained by 43 % compared to its wild-type with 18 % of the remaining activity at 45 °C. In silico analysis conducted at 25 and 45 °C was found to be in accordance to the experimental findings in which the RMSD values of M386 were more stable throughout the total trajectory in comparison to its wild-type. Terminal moieties were also observed to exhibit large movement and flexibility as denoted by high RMSF values at both dynamics. Variation in organic solvent stability property was detected in M386 where the lipolytic activity was stimulated in the presence of 25 % (v/v) of DMSO, isopropanol, and diethyl ether. This may be worth due to changes in the surface charge residues at the mutation point which probably involve in protein-solvent interaction.