Diagnosis by AMPLICOR PCR of Chlamydia trachomatis infection in urine samples from women and men attending sexually transmitted disease clinics.
Screening of urine specimens from men for Chlamydia trachomatis infection by a commercial PCR assay (AMPLICOR C. trachomatis Test; Roche Diagnostic Systems, Inc., Branchburg, N.J.) is a sensitive and specific noninvasive diagnostic assay. Since screening of women for C. trachomatis infection with the AMPLICOR C. trachomatis Test has been limited to use with endocervical swab specimens, we conducted an evaluation of the AMPLICOR C. trachomatis Test for the detection of C. trachomatis using female urine samples and compared the results of those obtained by in vitro culture and PCR of endocervical swab specimens. For 713 men we compared the performance of AMPLICOR C. trachomatis Test with urine specimens with that of culture of urethral specimens. For specimens that were PCR positive and culture negative, two additional tests were used to resolve the discrepancies: direct fluorescent-antibody assay (DFA) of sediment from a spun endocervical specimen culture vial and major outer membrane protein-based PCR of the sediment from the endocervical specimen culture vial. Of 525 urine specimens from females, 67 (12.8%) were PCR positive, and 41 (7.8%) endocervical specimens from the 525 women were culture positive. After resolution of the discrepancies, the resolved sensitivity of the urine PCR was 93.3%, whereas the sensitivity of endocervical swab specimen culture was 67.3%. Of 468 female endocervical swab specimens, 47 (10.0%) had a positive PCR result and 33 (7.0%) were culture positive. The resolved sensitivity of the endocervical swab specimen PCR was 86%. Of 415 matched female urine and endocervical swab specimens, there were 49 confirmed infections; 30 (61.2%) specimens were positive by culture of the endocervical swab specimen, 40 (81.6%) were positive by confirmed endocervical swab specimen PCR, 43 (87.8%) were positive by confirmed urine PCR, and all 49 (100%) were positive by either endocervical swab specimen PCR or urine PCR. For men, the resolved sensitivity of the urine PCR was 88%, and the sensitivity of culture was only 50.7%. These results indicate that urine PCR is highly sensitive for the detection of C. trachomatis in both women and men and provides a noninvasive technique for routine screening for chlamydial infection.


Malaria on the Thai-Burmese border: treatment of 5192 patients with mefloquine-sulfadoxine-pyrimethamine.
Multidrug-resistant falciparum malaria is a major health problem along the Thai-Burmese border. From July 1985 until December 1986 a total of 5192 patients with falciparum malaria (1734 males, 3458 females) from this area were given supervised treatment with the combination mefloquine-sulfadoxine-pyrimethamine (MSP). The radical cure rate, assessed 21 days after drug administration, was 98.4% for the first 1975 patients, and 98.8% when assessed at 28 days for the remaining 3217 patients. In 3.8% of cases, parasites were still detected in peripheral blood smears on day 7 after treatment but this had fallen to 0.27% by day 9. Adverse reactions among the first 1975 patients were: vertigo (7.5% of patients), vomiting (5.8%), epigastric pain (0.6%), and transient confusional state (one case). MSP is an effective and well-tolerated drug for the treatment of drug-resistant falciparum malaria; however, delayed parasite clearance may give a false impression of RII resistance.


The role of ultrasound as an adjunct to arterial catheterization in critically ill surgical and intensive care unit patients.
To review the evidence behind Ultrasound (US) guided placement of arterial cannulae and its use in the critically ill population. We performed a computer-aided literature search using set search terms and electronic data bases of PubMed and EMBASE from their commencement date through the end of July 2013. Insertion of intra-arterial catheters is a commonly performed invasive procedure in the peri-operative and intensive care setting that facilitates invasive blood pressure and cardiac output monitoring as well as frequent blood sampling. Arterial catheterization can be particularly challenging in critically ill and high-risk surgical patients with circulatory collapse, low cardiac output state and peripheral edema, all of which can limit the ability to successfully palpate and cannulate the artery. There is a convincing body of evidence suggesting a decrease in complication rate and first-pass success rate in US guided central venous catheter (CVC) insertion compared with the landmark technique. While most intensivists and peri-operative physicians are familiar with US guided CVC placement, fewer use US to guide arterial access. Most studies have demonstrated a higher success rate when using US guidance for arterial cannulation. Moreover, the technique permits more rapid access and establishment compared with the conventional palpation technique. However, there is evidence opposing the routine use of US to guide arterial cannula insertion. Further studies are required to ascertain the benefits and cost effectiveness of US guided arterial catheterization in peri-operative and critical care.


Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli.
We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the DeltametR, DeltametI and DeltametN mutant strains suggest that CO has effects on the methionine metabolism of E. coli. CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.


Centrifugation of 2 g does not affect otoconial mineralization in chick embryos.
Chick embryos were grown on a rotating centrifuge for periods of 2 wk to study the effects of increased gravity on the relative growth of their otoliths and femurs. Embryos, 20-21 days of age, centrifuged at 2 g showed no difference in utricular otoconial CaCO3 weights and femur CaPO4 weights compared with stationary control embryos of the same age. In addition, control embryos rotated at the center of the centrifuge had otoconial CaCO3 weights and femur CaPO4 weights not significantly different from stationary controls or from embryos rotated at 2 g. Accordingly these data do not support the hypothesis that the weight of the embryonic otoconial membrane is involved in the feedback regulation of its growth.


Epistaxis related to exercise-induced pulmonary haemorrhage in south African Thoroughbreds.
This study investigated if environmental factors had an effect on the incidence of epistaxis related to exercise-induced pulmonary haemorrhage (EIPH) among racehorses in southern Africa. Data covering the period 1986-2001 and involving 778 532 race runs were analysed. This included the following information: date of race, age, sex, name of breeder, trainer, distance, jockey, state of going, weight carried, racing centre and altitude. Veterinarians employed by the Jockey Club suspended officially entered horses that presented with epistaxis (frank bleeding from the nostrils) after racing. On-course endoscopy is not performed as a standard practice at any southern African racetrack. Epistaxis was identified in 1287 horses (0.165%). More horses presented with EIPH-related epistaxis (a) at sea level, (b) from May to October, (c) when older (> 3 years), (d) after 1995, (e) on Fridays and Sundays, and (f) more in geldings than in mares or entire males. No association could be established between epistaxis and breeder, trainer, distance run, jockey, state of going and weight carried. It is concluded that the frequency of EIPH-related epistaxis is associated with altitude, winter and spring, sex and age. It is suggested that racing at lower altitudes may increase the probability of exercise-induced pulmonary haemorrhage.


Renal tumours in a Tsc2(+/-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin.
Tuberous sclerosis (TSC) is an inherited syndrome in which tumours in multiple organs are characterised by activation of mammalian target of rapamycin complex 1 (mTORC1). Previous work suggests that mTORC1 activation is associated with feedback inhibition of Akt, a substrate of mTORC2. This could limit TSC-associated tumour growth but lead to paradoxical promotion of tumour cell survival upon treatment with mTOR inhibitors. However, Akt/mTOR signalling has not been fully investigated in TSC-associated tumours and it has been uncertain whether mTOR inhibition can prevent TSC-associated renal tumourigenesis. In this study, we investigated Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition could prevent renal tumourigenesis. We found that all renal lesions including cysts, adenomas and carcinomas exhibited activation of both Akt and mTORC1 as evidenced by increased protein expression and phosphorylation of Akt and mTOR and their downstream targets. Protein kinase Cα was also highly expressed and phosphorylated in these lesions, consistent with activation of mTORC2. Surprisingly, IRS proteins were highly expressed, in contrast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one mechanism through which loss of feedback inhibition of Akt may occur in mTORC1 hyperactivated Tsc-associated tumours. Long-term treatment with rapamycin reduced both Akt and mTORC1 activity in normal kidney tissues and blocked the development of all types of renal lesions. In conclusion, in contrast to previous studies, we found that Akt signalling is not inhibited in Tsc-associated renal lesions and that by partially inhibiting the Akt/mTOR pathway, rapamycin is highly effective in preventing Tsc-associated tumours.


Comparative study of nest architecture and colony structure of the fungus-growing ants, Mycocepurus goeldii and M. smithii.
Nest architecture and demography of the non leaf-cutting fungus-growing ant species Mycocepurus goeldii and M. smithii (Attini: Formicidae) were studied in an agroforest habitat near Manaus, Brazil during the excavation of 13 nests. Both species built their nests in two different ways. The first type possessed a "tree-like" architecture, in which a vertical tunnel led downwards and lateral tunnels branched off at 90 degrees angles from the main tunnel, with a chamber at the end of each side branch. Alternatively, other nests displayed a "necklace-like" architecture, where the main tunnel also led down vertically, but entered each chamber from the top and exited it at the bottom, resulting in an architecture where chambers appeared like pearls on a necklace. The nest systems of M. goeldii and M. smithii consisted of 1-21 or 1-15 chambers, respectively. Of 199 excavated chambers, 57 % contained fungus-gardens. Chambers not containing fungus gardens were filled with organic matter from decaying fungus gardens or earthworm feces. Only M. smithii workers deposited loose soil in abandoned chambers during the construction of new nest chambers. Workers of M. smithii constructed significantly smaller chambers than those of M. goeldii. In both species, fungus garden-containing chambers were larger than non-garden chambers and were homogenously distributed in the soil between 17 cm and 105 cm depth. Neither fungus gardens nor abandoned chambers were encountered more frequently in deeper or shallower soil strata indicating that ants of both species did not abandon shallower versus deeper chambers, or move the colony to deeper soil layers with increasing colony age. Fungus gardens were suspended from the ceiling of the subterranean chambers and originated as small mycelial tufts. Through continual addition of organic debris, the tufts first grew vertically to strands before they expanded laterally until most of the chamber volume was filled with fungus garden curtains. New garden chambers were found at depths ranging from 17 to 83 cm, suggesting that new garden chambers were not constructed in deeper soil strata with increasing colony age. The size of M. goeldii and M. smithii colonies was dependent on their age. Worker counts varied between a few individuals in recently founded colonies and 1352 workers in an adult M. goeldii colony. The ratio of worker number per fungus garden chamber was higher in M. goeldii colonies than M. smithii colonies; the M. goeldii colonies were more populous. Both species were oligogynous with a maximum of four and three queens observed in a single chamber of M. goeldii and M. smithii, respectively. The reproductive status of each queen was unknown. In both species the ratio of brood to workers was approximately 2:3. Larvae and pupae were unequally distributed throughout the nest, but were only located in chambers containing a garden. Their location in the chamber was dependent upon the developmental state of the fungus garden.


Understanding the Role of Context-Specific Drinking in Neglectful Parenting Behaviors.
Child neglect is the most common form of child maltreatment, yet little is known about how drinking context may be related to particular subtypes of child neglect. This study examines the relationship between parental drinking in multiple contexts and the use of supervisory and physical neglectful. A sample of 2152 parents of children 12 years or younger in 50 cities in California was obtained using a computer-assisted telephone interview. Past-year prevalence of child neglect was measured using the Multidimensional Neglectful Behavior Scale. Information was collected on past month or past-year frequency of having at least one drink in five contexts, continued drinking measures (e.g. number of drinks after the first drink) and sociodemographics. Data were analyzed using multilevel random effects logit models. Frequency of drinking in various contexts was related to different neglect subtypes. Specifically, frequency of drinking with friends was positively related leaving a child home alone when an adult should be present. Parents who drank more frequently with family were less likely to leave their child home alone in the past year yet more likely to unsafely monitor their child in the past year. Drinking at parties more often was related to being more likely to leave a child alone in a car sometime during the past year. That no single drinking context is universally problematic for supervisory and physical neglect suggests that different social mechanisms may underlie the relationships observed between different drinking contexts and neglect subtypes.


The EPCOR model: a model for promoting the successful implementation of evidence-based nursing in hospital-based settings.
An effective organizational infrastructure is essential to successfully implement and sustain an evidence-based nursing (EBN) practice. Although EBN has been promoted in Taiwan for more than 10 years, variations in the organizational policies and strategies necessary to support EBN among healthcare organizations have prevented effective implementation. Barriers to the implementation of EBN located at the organizational level have also been reported. The need for a model that focuses on the organizational infrastructure to promote EBN in Taiwan has therefore become increasingly apparent. This study aims to develop a model that contains the key contextual elements of organizational infrastructure necessary to effectively promote EBN, especially in hospital settings. A steering committee drafted the components and related strategies of the proposed model. Delphi technique was used to obtain consensus on the proposed model among a group of experts with expertise in EBN. Thirty experts participated in all three rounds of the Delphi survey. To confirm the appropriateness of the proposed model for clinical settings, the model was further reviewed by a focus group composed of experts with experience in implementing EBN or evidence-based medicine in hospitals. The strategies were then further modified based on the suggestions of this focus group, and only those strategies that best fit hospital settings were retained. Five key contextual elements and related strategic processes were identified, including equipment, policy, training courses, outcome indicators, and reward plans. The resultant model was named EPCOR, an acronym composed of the names of each identified element. EPCOR is a comprehensive model of organizational infrastructure and strategic procedures for implementing EBN in hospital-based settings in Taiwan. Organizations may use the EPCOR model to initiate and implement EBN practices and then to evaluate their effectiveness.


Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.
Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy. Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis. Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy. The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.


Availability and Use of HIV Monitoring and Early Infant Diagnosis Technologies in WHO Member States in 2011-2013: Analysis of Annual Surveys at the Facility Level.
The Joint United Nations Programme on HIV and AIDS (UNAIDS) 90-90-90 targets have reinforced the importance of functioning laboratory services to ensure prompt diagnosis and to assess treatment efficacy. We surveyed the availability and utilization of technologies for HIV treatment monitoring and early infant diagnosis (EID) in World Health Organization (WHO) Member States. The survey questionnaire included 14 structured questions focusing on HIV testing, cluster of differentiation 4 (CD4) testing, HIV viral load (VL) testing, and EID and was administered annually from 2012 to 2014 through WHO country offices, with each survey covering the previous 12-mo period. Across 127 targeted countries, survey response rates were 60% in 2012, 67% in 2013, and 78% in 2014. There were encouraging trends towards increased procurement of CD4 and VL/EID instruments in reporting countries. Globally, the capacity of available CD4 instruments was sufficient to meet the demand of all people living with HIV/AIDS (PLWHA), irrespective of treatment status (4.62 theoretical tests per PLWHA in 2013 [median 7.33; interquartile range (IQR) 3.44-17.75; median absolute deviation (MAD) 4.35]). The capacity of VL instruments was inadequate to cover all PLWHA in many reporting countries (0.44 tests per PLWHA in 2013 [median 0.90; IQR 0.30-2.40; MAD 0.74]). Of concern, only 13.7% of existing CD4 capacity (median 4.3%; IQR 1.1%-12.1%; MAD 3.8%) and only 36.5% of existing VL capacity (median 9.4%; IQR 2.3%-28.9%; MAD 8.2%) was being utilized across reporting countries in 2013. By the end of 2013, 7.4% of all CD4 instruments (5.8% CD4 conventional instruments and 11.0% of CD4 point of care [POC]) and 10% of VL/EID instruments were reportedly not in use because of lack of reagents, the equipment not being installed or deployed, maintenance, and staff training requirements. Major limitations of this survey included under-reporting and/or incomplete reporting in some national programmes and noncoverage of the private sector. This is the first attempt to comprehensively gather information on HIV testing technology coverage in WHO Member States. The survey results suggest that major operational changes will need to be implemented, particularly in low- and middle-income countries, if the 90-90-90 targets are to be met.


Survival of encapsulated human primary fibroblasts and erythropoietin expression under xenogeneic conditions.
Allogeneic cells are the most attractive source for cell transplantation, as the use of xenogeneic cells is hampered by safety concerns and the use of autologous cells involves practical difficulties. The immune rejection of allogeneic cells can be overcome by physical immunoprotection provided by polymer encapsulation. To study the variability of cell and donor sources, we compared different primary human cells as candidates for gene therapy-mediated delivery of human erythropoietin (hEpo). DARC-3.1 fibroblasts, MDX-01 fibroblasts, and ARPE-19 retinal pigment epithelial cells were encapsulated into polyethersulfone hollow fibers and implanted for 1 month in nude mice as well as in immunocompetent and FK506-immunosuppressed mice to test their in vivo resistance, with the assumption that xenogeneic conditions constitute a stringent model for human application. DARC-3.1 fibroblasts showed the best survival, prompting us to evaluate cell lineages from the same donor (DARC-3.2) or another donor (DARC-4.3 and DARC-4.4). With the exception of DARC-4.3, the remaining three lineages showed comparable survival in immunocompetent C3H and DBA/2J mice. DARC-3.1 fibroblasts were retrovirally engineered with hEpo cDNA, reaching a secretion level of 170 IU of hEpo per 10(6) cells per day. Encapsulated DARC-3.1-hEpo cells led to significantly increased hematocrits in the various hosts and under various transplantation conditions. The present study shows that encapsulated primary human DARC-3.1 fibroblasts are able to survive under xenogeneic conditions and, once engineered with hEpo cDNA, to increase the hematocrit of transplanted mice.


Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients.
Limitations in methods for the rapid diagnosis of hospital-acquired infections often delay initiation of effective antimicrobial therapy. New diagnostic approaches offer potential clinical and cost-related improvements in the management of these infections. We developed a decision modeling framework to assess the potential cost-effectiveness of a rapid biomarker assay to identify hospital-acquired infection in high-risk patients earlier than standard diagnostic testing. The framework includes parameters representing rates of infection, rates of delayed appropriate therapy, and impact of delayed therapy on mortality, along with assumptions about diagnostic test characteristics and their impact on delayed therapy and length of stay. Parameter estimates were based on contemporary, published studies and supplemented with data from a four-site, observational, clinical study. Extensive sensitivity analyses were performed. The base-case analysis assumed 17.6% of ventilated patients and 11.2% of nonventilated patients develop hospital-acquired infection and that 28.7% of patients with hospital-acquired infection experience delays in appropriate antibiotic therapy with standard care. We assumed this percentage decreased by 50% (to 14.4%) among patients with true-positive results and increased by 50% (to 43.1%) among patients with false-negative results using a hypothetical biomarker assay. Cost of testing was set at $110/d. In the base-case analysis, among ventilated patients, daily diagnostic testing starting on admission reduced inpatient mortality from 12.3 to 11.9% and increased mean costs by $1,640 per patient, resulting in an incremental cost-effectiveness ratio of $21,389 per life-year saved. Among nonventilated patients, inpatient mortality decreased from 7.3 to 7.1% and costs increased by $1,381 with diagnostic testing. The resulting incremental cost-effectiveness ratio was $42,325 per life-year saved. Threshold analyses revealed the probabilities of developing hospital-acquired infection in ventilated and nonventilated patients could be as low as 8.4 and 9.8%, respectively, to maintain incremental cost-effectiveness ratios less than $50,000 per life-year saved. Development and use of serial diagnostic testing that reduces the proportion of patients with delays in appropriate antibiotic therapy for hospital-acquired infections could reduce inpatient mortality. The model presented here offers a cost-effectiveness framework for future test development.


Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes.
MUC16 is a cell surface mucin expressed at high levels by epithelial ovarian tumors. Following proteolytic cleavage, cell surface MUC16 (csMUC16) is shed in the extracellular milieu and is detected in the serum of cancer patients as the tumor marker CA125. csMUC16 acts as an adhesion molecule and facilitates peritoneal metastasis of ovarian tumors. Both sMUC16 and csMUC16 also protect cancer cells from cytotoxic responses of natural killer (NK) cells. In a previous study we demonstrated that sMUC16 binds to specific subset of NK cells. Here, we identify the csMUC16/sMUC16 binding partner expressed on immune cells. Analysis of immune cells from the peripheral blood and peritoneal fluid of ovarian cancer patients indicates that in addition to NK cells, sMUC16 also binds to B cells and monocytes isolated from the peripheral blood and peritoneal fluid. I-type lectin, Siglec-9, is identified as the sMUC16 receptor on these immune cells. Siglec-9 is expressed on approximately 30-40% of CD16pos/CD56dim NK cells, 20-30% of B cells and >95% of monocytes. sMUC16 binds to the majority of the Siglec-9pos NK cells, B cells and monocytes. sMUC16 is released from the immune cells following neuraminidase treatment. Siglec-9 transfected Jurkat cells and monocytes isolated from healthy donors bind to ovarian tumor cells via Siglec-9-csMUC16 interaction. Recent studies indicate that csMUC16 can act as an anti-adhesive agent that blocks tumor-immune cell interactions. Our results demonstrate that similar to other mucins, csMUC16 can also facilitate cell adhesion by interacting with a suitable binding partner such as mesothelin or Siglec-9. Siglec-9 is an inhibitory receptor that attenuates T cell and NK cell function. sMUC16/csMUC16-Siglec-9 binding likely mediates inhibition of anti-tumor immune responses.


Patient dose from 3D rotational neurovascular studies.
The use of image-guided interventional radiological techniques is increasing in prevalence and complexity. Imaging system developments have helped improve the information available to interventionalists to plan and guide procedures. Information on doses to patients resulting from alternative imaging techniques or protocols is useful for both the process of justifying particular procedures and in optimizing the resultant exposures. Such information is not always available, especially for new or developing imaging techniques. We have undertaken a study of doses to patients associated with two alternative imaging methods for pre-intervention assessment of intracranial aneurysms. In the first technique the aneurysm is assessed from a series of digital subtraction angiography (DSA) runs taken at different imaging projections. The second technique involved acquiring images from one single image run while the imaging system rotated 180 degrees around the patient's head. In this technique, the aneurysm was then evaluated from a 3D reconstruction of the projection images. Effective doses were calculated using a computer model to simulate the exposure geometry and parameters. The mean dose from the DSA protocol used at our centre was 3.4 mSv and from the 3D rotational angiography (RA) technique was 0.20 mSv.


Impact of diabetes and early revascularization on the need for late and repeat procedures.
Coronary artery disease often progresses more rapidly in diabetics, but the integrated impact of diabetes and early revascularization status on late or repeat revascularization in the contemporary era is less clear. Coronary angiography was performed in 12,420 patients between the years 2000-2015 and early revascularization status [none, percutaneous coronary intervention (PCI) or bypass surgery (CABG)] was determined. Subsequent revascularization procedures were recorded over a median follow-up of 67 months and its relation to diabetic and baseline revascularization status was studied. Early revascularization status was none in 5391, PCI in 5682 and CABG in 1347 patients. Late revascularization rates were 10, 26 and 11.1% respectively. Diabetes was present in 37%; a stepwise relationship of diabetic status with late revascularization was observed: no diabetes (reference) 14.4%, non-insulin treated diabetes 21% (adjusted HR 1.35, 95% CI 1.23-1.49, p < 0.001) and insulin-treated diabetes 32.8% (adjusted HR 2.20, 95% CI 1.91-2.54, p < 0.001), which was similar in magnitude for each early revascularization state (none, PCI or CABG). Further revascularizations (≥ 2) were also significantly more common in diabetics, in particular if insulin-treated. Glycosylated hemoglobin level was moderately associated with late revascularization in diabetics after early PCI but not following diagnostic catheterization or CABG. Diabetic status graded by treatment, and in particular insulin therapy, is a strong predictor for late or repeat revascularization irrespective of early revascularization status. The high rate of repeat revascularization in diabetics following PCI remains a challenging issue.


Derepression of an NAD-linked dehydrogenase that serves an Escherichia coli mutant for growth on glycerol.
An Escherichia coli mutant using an NAD-linked dehydrogenase instead of an ATP-dependent kinase as the first enzyme for glycerol dissimilation excreted dihydroxyacetone during the initial phase of growth. The intermediate was salvaged as growth of the culture advanced. The transient loss of the intermediate into the medium appeared to be partly determined by variation of the level of glycerol dehydrogenase with growth conditions. With up to 2% casein hydrolysate as the carbon and energy source, the cellular level of the dehydrogenase increased 1 order of magnitude at the end of growth. This increase was probably caused by the depletion of certain metabolites and was prevented by the addition of pyruvate or glucose to the growth medium. The repressive effect of these compounds was not lifted by the addition of cyclic AMP. Diminution of oxygen tension in the culture medium with increased cell density was not directly responsible for the increase of the enzyme level. Thus, neither catabolite repression nor respiratory repression was implicated as an important control mechanism in the synthesis of this enzyme. Since increases in the specific activity of the enzyme in cell extracts reflected increases in the concentration of the enzyme protein, post-translational control was also not involved. A novel kind of regulation of gene expression is indicated.


Adaptive directional lifting-based wavelet transform for image coding.
We present a novel 2-D wavelet transform scheme of adaptive directional lifting (ADL) in image coding. Instead of alternately applying horizontal and vertical lifting, as in present practice, ADL performs lifting-based prediction in local windows in the direction of high pixel correlation. Hence, it adapts far better to the image orientation features in local windows. The ADL transform is achieved by existing 1-D wavelets and is seamlessly integrated into the global wavelet transform. The predicting and updating signals of ADL can be derived even at the fractional pixel precision level to achieve high directional resolution, while still maintaining perfect reconstruction. To enhance the ADL performance, a rate-distortion optimized directional segmentation scheme is also proposed to form and code a hierarchical image partition adapting to local features. Experimental results show that the proposed ADL-based image coding technique outperforms JPEG 2000 in both PSNR and visual quality, with the improvement up to 2.0 dB on images with rich orientation features.


Unintended benefits: the potential economic impact of addressing risk factors to prevent Alzheimer's disease.
Certain chronic conditions appear to be modifiable risk factors of Alzheimer's disease and related dementias. To understand the potential health and economic impacts of addressing those risk factors, we used data on a Medicare cohort to simulate four scenarios: a 10 percent reduction in the prevalence of diabetes, hypertension, cardiovascular diseases, respectively, and a 10 percent reduction in body mass index among beneficiaries who were overweight or obese. Our simulation demonstrated that reducing the prevalence of these conditions may yield "unintended benefits" by lowering the risk, delaying the onset, reducing the duration, and lowering the costs of dementia. More research is needed to clarify the exact relationship between various other chronic diseases and dementia. However, our findings highlight potential health gains and savings opportunities stemming from the better management of other conditions associated with dementia.


Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissues.
Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a 'brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4. The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity. Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target.


Lymphangioleiomyomatosis: a case report and review of diagnosis and treatment.
Lymphangioleiomyomatosis (LAM) is a rare disease that generally affects young women and involves the abnormal proliferation of smooth muscle-like cells (LAM cells) in the lungs (pulmonary LAM) and extrapulmonary sites (extrapulmonary LAM). This disease is rare in males. It is hard to distinguish between lung cancer and pulmonary LAM, especially during early stages. Herein, we present a case of a 66-year-old man with a small nodule in the right upper lobe that was first diagnosed as a lung malignancy using a chest CT scan. After a wedge dissection, a pathologist performed a histologic and immunohistochemical examination, and a diagnosis of pulmonary LAM was made. We further performed a 518-gene panel analysis using next-generation sequencing, and only three genes, BARD1, BLM, and BRCA2, were found to have mutations. We also provide a summary of the diagnosis and treatment of this disease.


Large oscillations of the magnetoresistance in nanopatterned high-temperature superconducting films.
Measurements on nanoscale structures constructed from high-temperature superconductors are expected to shed light on the origin of superconductivity in these materials. To date, loops made from these compounds have had sizes of the order of hundreds of nanometres(8-11). Here, we report the results of measurements on loops of La(1.84)Sr(0.16)CuO(4), a high-temperature superconductor that loses its resistance to electric currents when cooled below approximately 38 K, with dimensions down to tens of nanometres. We observe oscillations in the resistance of the loops as a function of the magnetic flux through the loops. The oscillations have a period of h/2e, and their amplitude is much larger than the amplitude of the resistance oscillations expected from the Little-Parks effect. Moreover, unlike Little-Parks oscillations, which are caused by periodic changes in the superconducting transition temperature, the oscillations we observe are caused by periodic changes in the interaction between thermally excited moving vortices and the oscillating persistent current induced in the loops. However, despite the enhanced amplitude of these oscillations, we have not detected oscillations with a period of h/e, as recently predicted for nanoscale loops of superconductors with d-wave symmetry, or with a period of h/4e, as predicted for superconductors that exhibit stripes.


The impact of Uber and Lyft on vehicle ownership, fuel economy, and transit across U.S. cities.
We estimate the effects of transportation network companies (TNCs) Uber and Lyft on vehicle ownership, fleet average fuel economy, and transit use in U.S. urban areas using a set of difference-in-difference propensity score-weighted regression models that exploit staggered market entry across the U.S. from 2011 to 2017. We find evidence that TNC entry into urban areas causes an average 0.7% increase in vehicle registrations with significant heterogeneity in these effects across urban areas: TNC entry produces larger vehicle ownership increases in urban areas with higher initial ownership (car-dependent cities) and in urban areas with lower population growth (where TNC-induced vehicle adoption outpaces population growth). We also find no statistically significant average effect of TNC entry on fuel economy or transit use but find evidence of heterogeneity in these effects across urban areas, including larger transit ridership reductions after TNC entry in areas with higher income and more childless households.


Surgical treatment and complications of penile fractures.
Paper goal is to determine complications after urgent surgical treatment of patient with penile fractures, by using circumferential-degloving technique (degloving penile skin to root of penis). In period between 1998-2006 year, 23 patients have been treated as urgent cases with clinically proven penis fracture, age between 18 and 35. Patients were treated in 3 medical centers in Bosnia and Herzegovina(Sarajevo, Tuzla and Zenica). All 23 (100%) patients were injured during sexual intercourse. In the case of 20 (86,9%) patients partial rupture of corpus cavernosum was verified. Two (8,6%) patients had a complete rupture of urethra and it was primary sutured. In 22 cases (95,6%) spontaneous erection appeared, and in the case of 2 (8,6%) patients penile curvature was verified. Urgent surgical treatment is the best therapy choice, which enables preservation of erection in great number of cases in patients with penile fracture.


Nuclear cardiology practices and radiation exposure in Africa: results from the IAEA Nuclear Cardiology Protocols Study (INCAPS).
While nuclear myocardial perfusion imaging (MPI) offers many benefits to patients with known or suspected cardiovascular disease, concerns exist regarding radiation-associated health effects. Little is known regarding MPI practice in Africa. We sought to characterise radiation doses and the use of MPI best practices that could minimise radiation in African nuclear cardiology laboratories, and compare these to practice worldwide. Demographics and clinical characteristics were collected for a consecutive sample of 348 patients from 12 laboratories in six African countries over a one-week period from March to April 2013. Radiation effective dose (ED) was estimated for each patient. A quality index (QI) enumerating adherence to eight best practices, identified a priori by an IAEA expert panel, was calculated for each laboratory. We compared these metrics with those from 7 563 patients from 296 laboratories outside Africa. Median (interquartile range) patient ED in Africa was similar to that of the rest of the world [9.1 (5.1-15.6) vs 10.3 mSv (6.8-12.6), p = 0.14], although a larger proportion of African patients received a low ED, ≤ 9 mSv targeted in societal recommendations (49.7 vs 38.2%, p < 0.001). Bestpractice adherence was higher among African laboratories (QI score: 6.3 ± 1.2 vs 5.4 ± 1.3, p = 0.013). However, median ED varied significantly among African laboratories (range: 2.0-16.3 mSv; p < 0.0001) and QI range was 4-8. Patient radiation dose from MPI in Africa was similar to that in the rest of the world, and adherence to best practices was relatively high in African laboratories. Nevertheless there remain opportunities to further reduce radiation exposure to African patients from MPI.


Mapping target site selection for the non-specific nuclease activities of retroviral integrase.
To identify the parts of retroviral integrase that interact with its DNA substrates, we compared the patterns of target site usage by chimeric enzymes and protein fragments in assays that reveal integrase's non-specific nuclease activities. The central region of 12 chimeric proteins between the human immunodeficiency virus type 1 and visna virus integrases was found to be responsible for selecting non-viral target DNA sites when small alcohols provide the attacking nucleophilic OH group during non-specific alcoholysis assays. Testing deletion derivatives of the integrase protein in this assay, which has similarities to the DNA joining reaction that occurs during retroviral integration, defined a smaller central domain that is sufficient for activity. Thus, this core domain likely contains both the host DNA site and the nucleophile site. Surprisingly, the region of integrase responsible for selecting non-viral target DNA sites when the viral DNA end is the attacking nucleophile could not similarly be mapped with the standard oligonucleotide joining assay. We therefore tested the proteins in a more sensitive assay that displays preferred sites of viral DNA insertion in a plasmid DNA target. All 12 chimeras yielded novel patterns compared with the wild-type enzymes in this assay, although local insertion patterns indicated that the central domain plays an important role in target site selection. Together, these data suggest that other protein regions must be involved when the attacking nucleophilic group is provided by viral DNA. Because specific recognition of viral DNA ends was previously mapped to the central domain, two different regions of integrase must interact with retroviral DNA.


Effect of age related macular degeneration on the Eger macular stressometer photostress recovery time.
To assess the repeatability of Eger macular stressometer (EMS) measures of photostress recovery and determine their association with other measures of visual function. EMS photostress recovery time was measured in 90 patients with bilateral exudative age related macular degeneration (AMD), 19 with bilateral atrophic AMD and 47 with both forms of the condition (mean age 79 (SD 13) years). Measurements were made on two occasions separated by 1 year. Intrasession repeatability was assessed by repeating the measures after a 10 minute recovery period at the first visit. Distance visual acuity was measured with a logMAR chart, near visual acuity with a MNRead chart at 25 cm, contrast sensitivity with a Pelli-Robson chart, and the presence of central visual disturbance assessed with an Amsler grid. A questionnaire was used to assess self reported difficulties with glare recovery. The average EMS recovery time was 11.0 (SD 8.9) seconds, decreasing by 1.6 (5.2) seconds on repeated measurement (p<0.05). EMS photostress recovery was not correlated with visual function measures or subjective difficulties with lights (p>0.05). EMS photostress recovery time did not predict those whose vision decreased over the following year compared with those among whom it remained stable. The EMS test is not a useful tool in determining the severity or progression of AMD.


Variations in children's dental service use based on four national health surveys.
To compare estimates of dental service use and delayed dental care across 4 national surveys of children's health. Among children 2 to 17 years of age, prevalence estimates of the use of any dental services, preventive dental services, and delayed dental care in the past year were obtained from the 2003 and 2007 National Survey of Children's Health, the 2003-2004 National Health and Nutrition Examination Survey (NHANES), the 2003 and 2007 National Health Interview Survey, and the 2003 and 2007 Medical Expenditure Panel Survey. Trends in parent-reported dental use, including delayed care, by sociodemographic characteristics were assessed by using logistic regression and odds ratios. Data collection methodologies varied across the 4 surveys, and estimates of dental service use varied accordingly. Surveys differed in the survey items used, recall time frames, and protocols for eliciting visit history. As a result, estimates of any dental use ranged from 52% to 81%, whereas estimates of preventive dental use ranged from 67% to 78%. Rates of delayed dental care were low, ranging from 3% to 8%; however, surveys showed consistent sociodemographic disparities in use of dental services and delayed dental care. Each survey has a unique approach to defining and eliciting parents' reports of children's dental service use, which could result in under- or overestimation of the number and nature of children's dental services. Each survey's methodology must be considered when accepting population-based estimates of dental service use to monitor progress in achieving national oral health goals.


Effects of Syngenta Enogen Feed Corn containing an α-amylase trait on finishing cattle performance and carcass characteristics.
Two experiments evaluated the effects of feeding a new corn hybrid, containing an α-amylase enzyme trait, Syngenta Enogen Feed Corn (SYT-EFC), on feedlot performance and carcass characteristics at two locations. Experiment 1 utilized 300 calffed steers (298.5 ± 16.3 kg of BW) at the University of Nebraska-Lincoln Eastern Nebraska Research and Extension Center Mead, NE. Treatments were designed as a 2 × 2 + 1-factorial arrangement with factors consisting of 1) corn type (SYT-EFC or conventional [CON]) and 2) byproduct type (with or without Sweet Bran [SB]), or a BLEND of STY-EFC and CON without SB. In Exp. 2, 240 crossbred, calf-fed steers (287.6 ± 15.4 kg of BW) were utilized at the University of Nebraska-Lincoln Panhandle Research and Extension Center near Scottsbluff, NE. Steers were fed SYT-EFC, CON, BLEND, or CON with a commercial α-amylase enzyme supplement (CON-E). In Exp. 1, there was an interaction for ADG (P = 0.05) and G:F (P = 0.02). Steers fed SYT-EFC with SB had greater ADG and G:F than CON; however, in diets without SB, SYT-EFC and CON were not different resulting in a 10.1% change in G:F when steers were fed SYT-EFC in SB compared with CON and only 1.6% change between SYT-EFC and CON without SB. Energy values, based on performance data, resulted in a 6.5% and 8.3% change in NEm and NEg, respectively, for steers fed SYT-EFC and CON with SB and 1.6% change for both NEm and NEg for steers fed SYT-EFC and CON without SB. For the main effect of corn trait, steers fed SYT-EFC had greater marbling scores, fat depth, and calculated yield grade compared with CON (P ≤ 0.03). In diets without SB, there was no difference between SYT-EFC, CON, or BLEND for DMI, final BW, ADG, G:F, NEm, or NEg (P ≥ 0.35). In Exp. 2, cattle fed SYT-EFC, BLEND, or CON-E had greater final BW, ADG, and G:F than cattle fed CON (P ≤ 0.03). On average, NEm and NEg were 4.9% and 7.0% greater, respectively, for steers fed amylase enzyme treatments compared with CON (P ≤ 0.01). Hot carcass weights were greater in steers fed α-amylase treatments compared with CON (P < 0.01). Feeding Syngenta Enogen Feed Corn, which contains an α-amylase enzyme trait, at both locations improved feed efficiency in finishing cattle diets containing WDGS or SB.


The ferret as an animal model in cerebrovascular research.
Clinical and pathologic observations have suggested analogies between the developing nervous system of ferrets (Mustela putorius furo) and those of more traditional animal models employed in stroke research. Experimental work has demonstrated advantages of the ferret as a model of visual development. We performed in vivo cerebral angiography and postmortem neurovascular dissection of latex-injected specimens of adult ferrets. The great vessels include a cervical arterial trunk that gives rise to both carotid arteries. The anatomy of the cranial arteries is similar to that of rabbits. No carotid rete mirabile is present. There are no intracranial anastomoses between the external and internal carotid systems. We present in vivo cerebral angiograms with pathologic correlation that demonstrate that ferrets may provide the same anatomic advantages as a rabbit model for the experimental study of cerebrovascular disease, with the additional advantage of a long extracranial cervical segment of the carotid artery, affording easier access to the intracranial vasculature.


Challenges and opportunities for perinatal health services in the COVID-19 pandemic: a qualitative study with perinatal healthcare professionals.
Perinatal healthcare professionals (PHCPs) provide essential support to all parents in the perinatal period, including young parents aged 16-24, who are at an increased risk of morbidity and mortality. Little is known about the impact of COVID-19 restrictions on the provision of perinatal services, and on perinatal healthcare professionals, caring for young parents in the UK. A UK based qualitative study using semi-structured interviews with perinatal healthcare professionals (n = 17). Data were analysed using thematic analysis. Two themes were identified describing perinatal healthcare professionals' perceptions of providing care to young parents during the pandemic. Perinatal healthcare professionals perceived that young parents' needs were amplified by the pandemic and that pandemic-related changes to the service, such as the use of telemedicine to replace face-to-face interactions, did not manage to successfully mitigate the increased feelings of anxiety and isolation experienced by young parents. Concerns were raised by perinatal healthcare professionals that these changes reduced young parent's access to vital support for themselves and their child and may contribute to exacerbating pre-existing inequalities. This study provides insight into the impact of the COVID-19 pandemic on the provision of perinatal care to young parents. Perinatal mental health professionals felt these negative impacts could be overcome by using a blended approach of technology and face-to-face interactions allowing regular contact with young parents and facilitating the exchange of vital information, while maintaining access to opportunities for social interactions with other parents. Findings from this study could be used to future-proof services against further COVID-19 restrictions.


Equal efficacy of endoscopic variceal ligation and propranolol in preventing variceal bleeding in patients with noncirrhotic portal hypertension.
Variceal bleeding increases morbidity and mortality among patients with noncirrhotic portal hypertension (NCPH). Blockers of β-adrenergic receptor signaling and endoscopic variceal ligation (EVL) have been used to prevent recurrence of bleeding, based on data from cirrhotic patients. We compared the efficacy and safety of the β-blocker propranolol with that of EVL in preventing the recurrence of variceal bleeding in patients with NCPH. Consecutive patients with NCPH with a history of variceal bleeding in the past 6 weeks were assigned randomly to groups treated every 3 weeks with EVL (n = 51) or propranolol (until they had a resting heart rate of 55 beats per minute or to a maximum of 320 mg/day; n = 50). Primary end points were recurrence of variceal bleeding or death. Secondary end points were complications of EVL in patients given EVL, variceal eradication after EVL, variceal recurrence after EVL, or a decrease in variceal grade in patients given propranolol. After a median follow-up period of 23 months, rates of recurrence of bleeding were similar between the groups (EVL, 23.5%; propranolol, 18%; P = .625). The actuarial probability of remaining free of bleeding recurrence was similar between the groups. No deaths occurred in either group. Of the patients given propranolol, 47% had a decrease in the grade of varices and none experienced bleeding. Adverse events were minor and comparable between groups (EVL, 12%; propranolol, 18%; P = .635). EVL was not more effective than the β-blocker propranolol for the secondary prophylaxis of variceal bleeding in patients with NCPH.


Perinatal exposure to mixtures of anti-androgenic chemicals causes proliferative lesions in rat prostate.
Elevated levels of endogenous or exogenous estrogens during fetal life can induce permanent disturbances in prostate growth and predispose to precancerous lesions. Recent studies have indicated that also early anti-androgen exposure may affect prostate cancer risk. We examined the influence of perinatal exposure to mixtures of anti-androgenic and estrogenic chemicals on prostate development. Wistar rats were exposed from gestation day 7 to postnatal day 22 to a mixture of 8 anti-androgenic compounds (AAMix), a mixture of four estrogenic compounds (EMix), or paracetamol or a mixture of all 13 compounds (TotalMix) in mixture ratios reflecting human exposure levels. Ventral prostate weights were reduced by the TotalMix and AAMix in pre-pubertal rats. Histological changes in prostate appeared with increasing age and indicated a shift from the normal age-dependent epithelial atrophy towards hyperplasia. These lesions showed similarities to pre-cancerous lesions in humans. Increased proliferation was observed already in pre-puberty and it was hypothesized that this could be associated with reduced ERβ signaling, but no clear conclusions could be made from gene expression studies on ERβ-related pathways. The influences of the estrogenic chemicals and paracetamol on prostate morphology were minor, but in young adulthood the estrogen mixture reduced ventral prostate mRNA levels of Igf1 and paracetamol reduced the mRNA level ofPbpc3. Mixtures of endocrine disrupters relevant for human exposure was found to elicit persistent effects on the rat prostate following perinatal exposure, suggesting that human perinatal exposure to environmental chemicals may increase the risk of prostate cancer later in life.


Development of dual-activity vectors by co-envelopment of adenovirus and SiRNA in artificial lipid bilayers.
Gene therapy with human adenovirus type 5 (Ad5) has been extensively explored for the treatment of diseases resistant to traditional therapies. Intravenous administration leads to rapid clearance from blood circulation and high liver accumulation, which restrict the use of Ad-based vectors in clinical gene therapy protocols that involve systemic administration. We have previously proposed that such limitations can be improved by engineering artificial lipid envelopes around Ad and designed a variety of artificial lipid bilayer envelopes around the viral capsid. In this study, we sought to explore further opportunities that the artificially enveloped virus constructs could offer, by designing a previously unreported gene therapy vector by simultaneous envelopment of Ad and siRNA within the same lipid bilayer. Such a dual-activity vector can offer efficacious therapy for different genetic disorders where both turning on and switching off genes would be needed. Dynamic light scattering, transmission electron microscopy and atomic force microscopy were used to characterize these vectors. Agarose gel electrophoresis, Ribo green and dot blot assays showed that siRNA and Ad virions can be enveloped together within lipid bilayers at high envelopment efficiency. Cellular uptake and in vitro transfection experiments were carried out to show the feasibility of combining siRNA-mediated gene silencing with viral gene transfer using these newly designed dual-activity vectors.


Vitamin D and magnesium absorption in man.
1. The effects of vitamin D and its hydroxylated derivatives on calcium and magnesium absorption have been examined in 47 balance studies on patients with various disorders of calcium or bone metabolism. 2. Vitamin D significantly increased the mean net absorption of calcium and also the calcium balance. The mean net absorption of magnesium was also significantly increased although the rise was much less than that of calcium and the mean magnesium balance was unaffected. 3. It is suggested that the slight effect of vitamin D on magnesium absorption may be incidental to its stimulation of active calcium transport, since the latter system has weak affinities for other alkaline earth ions including strontium, barium and magnesium.


Universal calibration of surgical instruments for spinal stereotaxy.
To describe new software applications and interchangeable instrumentation enabling the use of standard surgical instruments with image-guided systems for stereotactic spinal procedures. The ability to adapt essentially any surgical instrument for stereotactic procedures will improve the safety and accuracy of image-guided spinal surgery. Using universal dynamic registration hardware and software, standard surgical instruments are adapted for real-time image-guided surgery. The Radionics Optical Tracking System (Radionics, Inc., Burlington, MA) has custom software applications and universal hardware adaptation devices for spinal stereotaxy that allows the use of standard instruments for intraoperative guidance. An array of light-emitting diodes can be attached to essentially any rigid instrument with a definable tip and can then be calibrated to the system for intraoperative use. Stereotactic guidance of a drill, tap, and screwdriver may improve screw placement accuracy in spinal surgery because every step of the procedure can be monitored in real time. Most stereotactic systems have only a standard probe or limited instruments for localization, targeting, and tracking a procedure. The surgeon then resumes the operation using standard surgical instruments without the benefit of image guidance for the key steps of the procedure. Because each surgical step for screw placement in the spine has a potential for error, use of multiple instruments that can be interchanged for real-time image-guided spinal surgery may increase the accuracy and safety of spinal instrumentation procedures. These techniques can also be applied to intracranial image-guided surgery.


Cord blood oxidative stress markers correlate with umbilical artery pulsatility in fetal growth restriction.
To compare cord blood oxidative stress markers (OSM) between intrauterine small fetuses with high umbilical artery (UA) Doppler indices and normal indices. Forty women who had oligohydramnios and intrauterine growth-restricted fetuses with abnormal (n = 20, group I) or normal Doppler indices (n = 20, group II) were included. All patients underwent fetal Doppler ultrasound studies. Cord blood was collected at birth and six OSMs (ischemia-modified albumin (IMA), hepatocyte growth factor (HGF), malondialdehyde (MDA)) levels, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were studied. The mean cord blood IMA, MDA, TOS, and OSI values for group I were significantly increased when compared to the group II (p < 0.001 for IMA, MDA, TOS, and OSI). However the mean cord blood HGF and TAS values were statistically significantly decreased in group I, compared with group II (p < 0.001 for HGF, and TAS). A significant positive (for IMA, MDA,TOS levels, and OSI ratio) and negative (for HGF and TAS levels) correlations between UA pulsatility index (PI) and cord blood OSM were found. The correlation between cord blood OSM and Doppler blood flow changes shown in this study may contribute to understanding the underlying oxidative stress-related mechanisms.


Nanostructured chitosan/propolis formulations: characterization and effect on the growth of Aspergillus flavus and production of aflatoxins.
A great diversity of agricultural products is susceptible to contamination caused by Aspergillus flavus. To reduce fungal contamination, the application of natural products has been proposed, including chitosan and propolis, due to its broad and recognized antimicrobial activity on several microorganisms. Currently, the application of nanotechnology allows for a greater activity to be more reactive and efficient. The objectives of this research were to characterize by TEM and Z potential some of the studied nanoparticles and to determine the in vitro antifungal activity of the formulations and the production of aflatoxins of the treated fungus. For this, individual treatments and different nanoformulations were elaborated by varying the percentage of the components such as chitosan solution, chitosan nanoparticles, an extract of propolis, nanoparticles of propolis, glycerol and canola oil. The final concentrations of the formulations were of 20%, 30% and 40% and the control consisted of Czapeck-dox agar medium. TEM micrographies showed a spherical morphology in a range of 2.3-3.0 nm with values of Z potential from 18.5 to 116.2 nm. Compared to the untreated fungus, the highest effect was seen in the parameter of spore germination, since inhibition was of c. a. 97% corresponding to the formulation containing chitosan + propolis nanoparticles + chitosan nanoparticles + propolis extract at the highest concentration of 40%. At this same concentration, the production of aflatoxins was 100% inhibited with the treatment with chitosan at 1%. Since these results are under carefully controlled conditions, further research should be extended to different fruit and vegetables affected by this fungus.


Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation.
Bone mineral density (BMD) decreases 2%-6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss. We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4(+) and 16-week CD4(+) change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)- or tenofovir-containing regimen on 96-week total BMD change. The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4(+) cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4(+) <50 cells/µL lost significantly more BMD compared to those with CD4(+) ≥500 cells/µL. A greater relative, but not absolute, 16-week increase in CD4(+) count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4(+) count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline. Low pretreatment CD4(+) count, but not greater CD4(+) count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4(+) counts may reduce the burden of osteoporosis and fragility fractures.


The Effects of Physical Exercise and Cognitive Training on Memory and Neurotrophic Factors.
This study examined the combined effect of physical exercise and cognitive training on memory and neurotrophic factors in healthy, young adults. Ninety-five participants completed 6 weeks of exercise training, combined exercise and cognitive training, or no training (control). Both the exercise and combined training groups improved performance on a high-interference memory task, whereas the control group did not. In contrast, neither training group improved on general recognition performance, suggesting that exercise training selectively increases high-interference memory that may be linked to hippocampal function. Individuals who experienced greater fitness improvements from the exercise training (i.e., high responders to exercise) also had greater increases in the serum neurotrophic factors brain-derived neurotrophic factor and insulin-like growth factor-1. These high responders to exercise also had better high-interference memory performance as a result of the combined exercise and cognitive training compared with exercise alone, suggesting that potential synergistic effects might depend on the availability of neurotrophic factors. These findings are especially important, as memory benefits accrued from a relatively short intervention in high-functioning young adults.


2004 where do we go from here?--Summary of working group discussions on thyroid function and gestational outcomes.
A workshop entitled, "The Impact of Maternal Thyroid Diseases on the Developing Fetus: Implications for Diagnosis, Treatment, and Screening," was held in Atlanta, Georgia, January 12-13, 2004. This paper reports points of agreement among the attendees based on the scientific rigor of material presented. At the end of the workshop, participants were divided into four smaller groups to discuss and determine areas of agreement on issues associated with thyroid insufficiency, identify research needs and gaps, and recommend research strategies and policy needs. Discussion included: problems for the mother and the pregnancy; neuropsychological/developmental performance in offspring of women with thyroid deficiency; issues of diagnosis and treatment for the pregnant women with overt and subclinical hypothyroidism; the issues involved with screening women who are pregnant or who are planning pregnancy; and the status of Iodine Nutrition in the United States. The group then identified research needs and gaps. The results of these discussions are outlined in the paper with recommended research strategies and public health action.


Eating disorders and pathological gambling in males: can they be differentiated by means of weight history and temperament and character traits?
In the present study, we investigated whether binge/purge eating disorders (ED) and pathological gambling (PG) in males can be differentiated by means of weight history and temperament and character traits. We investigated 43 male ED patients, 46 pathological gamblers and 46 healthy controls (HC) by means of lifetime weight information and the Cloninger's Temperament and Character Inventory-Revised (TCI-R). The MANCOVA results showed that ED patients showed significantly more lifetime weight fluctuations compared with PG and HC after controlling for age. Additionally, both ED and PG patients showed significantly higher scores on Harm Avoidance and lower Self-Directedness compared with HC. Results of a multinomial logistic regression showed that ED versus HC membership was determined by more weight fluctuations and lower Self-Directedness; whereas ED versus PG membership was determined by more weight fluctuations. Finally, PG versus HC membership was characterized by more Harm Avoidance, Novelty Seeking, and Persistence, and less Self-directedness. Given that both patient groups were characterized by low levels of Self-Directedness (i.e., low levels of effortful or executive control), they can benefit from training in self-regulation; and in PG patients special attention needs to be given on the training of behavioral control in the presence of novel and rewarding stimuli.


Ovarian cancer predisposition beyond BRCA1 and BRCA2 genes.
Several genes associated with hereditary ovarian cancer have been discovered as a result of the work done with next generation sequencing. It is estimated that approximately 23% of ovarian carcinomas have a hereditary predisposition. The most common hereditary condition is represented by germline mutations in BRCA1 or BRCA2 genes that account for 20-25% of high grade serous ovarian cancer. A number of other hereditary ovarian cancers are associated with different genes, with a crucial role in the DNA damage response pathway, such as the mismatch repair genes in Lynch syndrome, TP53 in Li-Fraumeni syndrome, STK11 in Peutz-Jeghers syndrome, CHEK2, RAD51, BRIP1, and PALB2. The goal of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to provide a tool that might be useful in discussing risk assessment, genetic testing, prevention strategies, as well as clinical and therapeutic implications for patients with ovarian cancer.


Mycobacterium tuberculosis CarD, an essential global transcriptional regulator forms amyloid-like fibrils.
CarD is an essential global transcription regulator from Mycobacterium tuberculosis (Mtb) that binds RNA polymerase and activates transcription by stabilizing the transcription initiation complex. Available crystal structures have captured two distinct, monomeric and domain-swapped homodimeric, oligomeric states of CarD. However, the actual oligomeric state of CarD in solution and its biological relevance has remained unclear. Here, we confirm the presence of the homodimeric state of CarD in solution by using synchrotron-based small-angle X-ray scattering. Furthermore, by using biochemical and biophysical experiments, in addition to mass-spectrometry, transmission electron microscopy, and confocal imaging, we show that CarD is the first soluble cytosolic protein in Mtb which displays the tendency to form amyloid-like fibrils both in vitro as well as in vivo. We demonstrate that the deletion of the fourteen N-terminal residues involved in domain-swapping hampers amyloid formation, thus, suggesting that domain-swapping is crucial in amyloidogenesis. The discovery of the amyloidogenic property of an essential cytosolic global transcription regulator, CarD, in a pathogenic bacteria will further open up new frontiers in research.


Sudden cardiac death by Commotio cordis: role of mechano-electric feedback.
Moderate pre-cordial mechanical impact can cause sudden cardiac death, even in the absence of morphological damage to the heart. This is the most severe expression of a condition termed, in the 19th century, Commotio cordis. Experimental studies performed in the early 1930s showed that sudden cardiac death after chest impact is brought about by an intrinsic cardiac response to the mechanical stimulus. The precise (sub-)cellular mechanisms of this response are still poorly understood. This article summarises experimental findings on the condition and relates them to the more recently established concept of cardiac mechano-electric feedback. As a result, an explanation of the mechanisms that give rise to sudden cardiac death by Commotio cordis and targets for further research are suggested.


Distribution and expression of CD200 in the rat respiratory system under normal and endotoxin-induced pathological conditions.
In vivo and in vitro studies have clearly demonstrated that signaling mediated by the interaction of CD200 and its cognate receptor, CD200R, results in an attenuation of inflammatory or autoimmune responses through multiple mechanisms. The present results have shown a differential expression of CD200 in the respiratory tract of intact rats. Along the respiratory passage, CD200 was specifically distributed at the bronchiolar epithelia with intense CD200 immunoreactivity localized at the apical surface of some ciliated epithelial cells; only a limited expression was detected on the Clara cells extending into the alveolar duct. In the alveolar septum, double immunofluorescence showed intense CD200 immunolabeling on the capillary endothelia. A moderate CD200 labeling was observed on the alveolar type II epithelial cells. It was, however, absent in the alveolar type I epithelial cells and the alveolar macrophages. Immunoelectron microscopic study has revealed a specific distribution of CD200 on the luminal front of the thin portion of alveolar endothelia. During endotoxemia, the injured lungs showed a dose- and time-dependent decline of CD200 expression accompanied by a vigorous infiltration of immune cells, some of them expressing ionized calcium binding adapter protein 1 or CD200. Ultrastructural examination further showed that the marked reduction of CD200 expression was mainly attributable to the loss of alveolar endothelial CD200. It is therefore suggested that CD200 expressed by different lung cells may play diverse roles in immune homeostasis of normal lung, in particular, the molecules on alveolar endothelia that may control regular recruitment of immune cells via CD200-CD200R interaction. Additionally, it may contribute to intense infiltration of immune cells following the loss or inefficiency of CD200 under pathological conditions.


Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis.
One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na(+),K(+)-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na(+),K(+)-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.


Genetic Variation in the Syntaxin-Binding Protein STXBP5 in Type 1 von Willebrand Disease Patients.
von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, VWF, ABO and STXBP5. Here, we comprehensively screen for STXBP5 variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the STXBP5 gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in STXBP5 was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of STXBP5. The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. STXBP5 showed a high level of linkage disequilibrium and a low overall nucleotide diversity of π = 3.2 × 10-4 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the STXBP5 Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare STXBP5 mutations contribute to type 1 VWD in the Swedish population.


Rising Threat; Bonsai.
In recent years, and especially in the past few months, the number of synthetic cannabinoid (bonsai) users has increased in our country. The aim of this study was to draw attention to the consumption of bonsai among young people and reveal the demographic and basic clinical characteristics of these users. This was a retrospective study conducted at the Ümraniye Training and Research Hospital. All of the adult patients (≥18 year old) with synthetic cannabinoid intoxication who presented to the Emergency Department throughout the two years of the study (July 1(st) 2012-June 30(th) 2014) were enrolled. The frequencies were given as the median and inter-quartile range). 197 patients were included in this study, with 190 male patients (96.4%) and 7 (3.6%) female patients. Two of the four hospitalized patients were exitus, 52 left on their own will and a total of 141 patients were discharged after 6-12 hours of observation in the ED. The use of synthetic cannabinoids (bonsai) in the recent years, especially in the summer months of 2014 was investigated in this study. Although these patients can have a benign clinical course, the process can also be fatal. It should especially be noted that patients with depressed respiration, low GCS scores and high PaCO2 values are at higher risk for mortality and the necessity of early intubation should be kept in mind.


Haemophilia B: from molecular diagnosis to gene therapy.
Thanks to its typical expression, haemophilia can be identified in writings from the second century AD. Haemophilia B, an X-linked recessive bleeding disorder due to factor IX (FIX) deficiency, has an incidence of about 1:30,000 live male births. The factor 9 (F9) gene was mapped in 1984 on Xq27.1. Haemophilia is diagnosed from prothrombin time, activated partial thromboplastin time, and FIX levels. Carrier females are usually asymptomatic and must be identified only with molecular analysis. Linkage analysis of F9 polymorphisms is rapid and inexpensive but limited by non-informative families, recombinant events, and the high incidence of germline mutations; thus, various procedures have been used for the direct scan of F9 mutations. We set up a novel denaturing high performance liquid chromatographic procedure to scan the F9 gene. This rapid, reproducible procedure detected F9 mutations in 100% of a preliminary cohort of 18 haemophilia B patients. Parallel to the development of more efficient diagnostic tools, the life expectancy and reproductive fitness of haemophilic patients have greatly improved and will continue to improve thanks to the use of less immunogenic recombinant FIX. Hopefully, new approaches based on gene therapy now being evaluated in clinical trials will revolutionise haemophilia B treatment.


Dynamic genome-scale cell-specific metabolic models reveal novel inter-cellular and intra-cellular metabolic communications during ovarian follicle development.
The maturation of the female germ cell, the oocyte, requires the synthesis and storing of all the necessary metabolites to support multiple divisions after fertilization. Oocyte maturation is only possible in the presence of surrounding, diverse, and changing layers of somatic cells. Our understanding of metabolic interactions between the oocyte and somatic cells has been limited due to dynamic nature of ovarian follicle development, thus warranting a systems approach. Here, we developed a genome-scale metabolic model of the mouse ovarian follicle. This model was constructed using an updated mouse general metabolic model (Mouse Recon 2) and contains several key ovarian follicle development metabolic pathways. We used this model to characterize the changes in the metabolism of each follicular cell type (i.e., oocyte, granulosa cells, including cumulus and mural cells), during ovarian follicle development in vivo. Using this model, we predicted major metabolic pathways that are differentially active across multiple follicle stages. We identified a set of possible secreted and consumed metabolites that could potentially serve as biomarkers for monitoring follicle development, as well as metabolites for addition to in vitro culture media that support the growth and maturation of primordial follicles. Our systems approach to model follicle metabolism can guide future experimental studies to validate the model results and improve oocyte maturation approaches and support growth of primordial follicles in vitro.


The signal recognition particle in S. cerevisiae.
We have identified the Saccharomyces cerevisiae homolog of the signal recognition particle (SRP) and characterized its function in vivo. S. cerevisiae SRP is a 16S particle that includes a homolog of the signal sequence-binding protein subunit of SRP (SRP54p) and a small cytoplasmic RNA (scR1). Surprisingly, the genes encoding scR1 and SRP54p are not essential for growth, though SRP-deficient cells grow poorly, suggesting that SRP function can be partially by-passed in vivo. Protein translocation across the ER membrane is impaired in SRP-deficient cells, indicating that yeast SRP, like its mammalian counterpart, functions in this process. Unexpectedly, the degree of the translocation defect varies for different proteins. The ability of some proteins to be efficiently targeted in SRP-deficient cells may explain why previous genetic and biochemical analyses in yeast and bacteria did not reveal components of the SRP-dependent protein targeting pathway.


Effect of dexamethasone added to lidocaine in supraclavicular brachial plexus block: A prospective, randomised, double-blind study.
Different additives have been used to prolong brachial plexus block. We performed a prospective, randomised, double-blind study to evaluate the effect of dexamethasone added to lidocaine on the onset and duration of supraclavicular brachial plexus block as this is the most common type of brachial block performed in our institute. Sixty American Society of Anaesthesiologist's physical status I and II patients undergoing elective hand, forearm and elbow surgery under brachial plexus block were randomly allocated to receive either 1.5% lidocaine (7 mg/kg) with adrenaline (1:200,000) and 2 ml of normal saline (group C, n=30) or 1.5% lidocaine (7 mg/kg) with adrenaline (1:200,000) and 2 ml of dexamethasone (8 mg) (group D, n=30). The block was performed using a nerve stimulator. Onset and duration of sensory and motor blockade were assessed. The sensory and motor blockade of radial, median, ulnar and musculocutaneous nerves were evaluated and recorded at 5, 10, 20, 120 min, and at every 30 min thereafter. Two patients were excluded from the study because of block failure. The onset of sensory and motor blockade (13.4±2.8 vs. 16.0±2.3 min and 16.0±2.7 vs. 18.7±2.8 min, respectively) were significantly more rapid in the dexamethasone group than in the control group (P=0.001). The duration of sensory and motor blockade (326±58.6 vs. 159±20.1 and 290.6±52.7 vs. 135.5±20.3 min, respectively) were significantly longer in the dexamethasone group than in the control group (P=0.001). Addition of dexamethasone to 1.5% lidocaine with adrenaline in supraclavicular brachial plexus block speeds the onset and prolongs the duration of sensory and motor blockade.


Algal Bloom Expansion Increases Cyanotoxin Risk in Food.
As advances in global transportation infrastructure make it possible for out of season foods to be available year-round, the need for assessing the risks associated with the food production and expanded distribution are even more important. Risks for foodborne illness are associated with contamination by bacteria, viruses, mold, parasites, natural and synthetic toxins, chemical residues, and conditions that lead to contamination. An increase in the popularity of natural alternatives to pharmaceuticals, herbal remedies and the desire for consuming "super foods" is leading to a change in the dietary patterns of consumers. Similarly, dietary trends are plentiful, with more consumers adopting changes with little medical guidance to dietary plans that are supported by inadequate scientific data. In particular, U.S. consumers are acquiring novel foods that may not be adequately checked for the presence of marine toxins and heat stable toxins in dry or minimally processed foods. Some dry foods cultivated in or processed in regions that may utilize hypoxic agricultural waters high in cyanobacterial or algal contamination. These may perpetuate increased risks for chronic liver, kidney, and neurodegenerative disorders due to intoxication from preventable foodborne agents. Global climate change, which has the effect of potentially expanding the toxic waters into higher latitudes, forecasts an increase in the risk of food contamination with toxins.


Photorefractive adaptive resonance neural network.
We describe a novel adaptive resonance theory (ART) device that is fully optical in the input-output processing path. This device is based on holographic information processing in a photorefractive crystal. This sets up an associative pattern retrieval in a resonating loop that uses angle-multiplexed reference beams for pattern classification. A reset mechanism is used to reject any given beam, permitting an ART search strategy. The design is similar to an existing nonlearning optical associative memory, but ours permits learning and makes use of information that the other device discards. It is a suitable response to the challenges of connectivity, learning, and reset presented by ART architectures. Furthermore, the design includes an efficient mechanism for area normalization of templates. It also permits the user to capitalize on the ability of ART networks to process large patterns. This new device is expected to offer higher information storage density than alternative ART implementations.


[Aedes albopictus seasonality in a protected area in the city of São Paulo, Brazil].
The study had the objective of assessing the seasonality of Aedes albopictus and the impact of environmental factors on breeding sites in a protected urban area. Immature individuals were collected through fluid aspiration from nine tree holes, in the Ecological Park of Tietê in the city of São Paulo, Southern Brazil, from 2001 to 2002. The index of positivity and number of individuals results were as follows: positivity x precipitation (rho=0.69, p<0.001), positivity x temperature (rho=0.35, p<0.001), number of individuals x precipitation (rho=0.29, p<0.001) and number of individuals x temperature (rho=0.13, p<0.05). These correlations suggest rainfalls had greater impact than temperature.


Selective sweeps in the presence of interference among partially linked loci.
Recurrent directional selection on a partially recombining chromosome may cause a substantial reduction of standing genetic variation in natural populations. Previous studies of this effect, commonly called selective sweeps, assumed that at most one beneficial allele is on the way to fixation at a given time. However, for a high rate of selected substitutions and a low recombination rate, this assumption can easily be violated. We investigated this problem using full-forward simulations and analytical approximations. We found that interference between linked beneficial alleles causes a reduction of their fixation probabilities. The hitchhiking effect on linked neutral variation for a given substitution also slightly decreases due to interference. As a result, the strength of recurrent selective sweeps is weakened. However, this effect is significant only in chromosomal regions of relatively low recombination rates where the level of variation is greatly reduced. Therefore, previous results on recurrent selective sweeps although derived for a restricted parameter range are still valid. Analytical approximations are obtained for the case of complete linkage for which interference between competing beneficial alleles is maximal.


Breeding racehorses: what price good genes?
Horse racing is a multi-million pound industry, in which genetic information is increasingly used to optimize breeding programmes. To maximize the probability of producing a successful offspring, the owner of a mare should mate her with a high-quality stallion. However, stallions with big reputations command higher stud fees and paying these is only a sensible strategy if, (i) there is a genetic variation for success on the racecourse and (ii) stud fees are an honest signal of a stallion's genetic quality. Using data on thoroughbred racehorses, and lifetime earnings from prize money (LE) as a measure of success, we performed quantitative genetic analyses within an animal model framework to test these two conditions. Although LE is heritable (VA=0.299+/-0.108, Pr=0.002), there is no genetic variance for stud fee and the genetic correlation between traits is therefore zero. This result is supported by an absence of any relationship between stud fees for currently active stallions and the predicted LE for their (hypothetical) offspring. Thus, while there are good genes to be bought, a stallion's fees are not an honest signal of his genetic quality and are a poor predictor of a foal's prize winning potential.


Mumps and ovarian cancer: modern interpretation of an historic association.
Epidemiologic studies found childhood mumps might protect against ovarian cancer. To explain this association, we investigated whether mumps might engender immunity to ovarian cancer through antibodies against the cancer-associated antigen MUC1 abnormally expressed in the inflamed parotid gland. Through various health agencies, we obtained sera from 161 cases with mumps parotitis. Sera were obtained from 194 healthy controls. We used an ELISA to measure anti-MUC1 antibodies and electro-chemiluminescence assays to measure MUC1 and CA 125. Log-transformed measurements were analyzed by t-tests, generalized linear models, and Pearson or Spearman correlations. We also conducted a meta-analysis of all published studies regarding mumps and ovarian cancer. Adjusting for assay batch, age, and sex, the level of anti-MUC1 antibodies was significantly higher in mumps cases compared to controls (p = 0.002). Free circulating levels of CA 125, but not MUC1, were also higher in cases (p = 0.02). From the meta-analysis, the pooled odds ratio estimate (and 95% CI) for the mumps and ovarian cancer association was 0.81 (0.68-0.96) (p = 0.01). Mumps parotitis may lead to expression and immune recognition of a tumor-associated form of MUC1 and create effective immune surveillance of ovarian cancer cells that express this form of MUC1.


Clozapine Augmentation With Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials.
To meta-analyze randomized controlled trials (RCTs) for the efficacy and safety of adjunctive antiepileptic drugs (AEDs) to augment clozapine therapy for treatment-resistant schizophrenia. The search included databases in English (PubMed, PsycINFO, Embase, and Cochrane Library databases and the Cochrane Controlled Trials Register) and in Chinese (China Journal Net [CJN], WanFang, and China Biology Medicine [CBM]) and references from retrieved articles. The databases were searched using dates inclusive from their onset until January 1, 2016, for terms reflecting (a) schizophrenia, (b) clozapine, and (c) adjunctive drugs. From 1,969 potentially relevant articles, 21 articles describing 22 RCTs were selected. Two independent investigators extracted data for a random-effects meta-analysis and assessed the quality of the studies using risk of bias and the Jadad scale. Standard mean difference, risk ratio (RR) ± 95% confidence intervals (CIs), and the number needed to harm (NNH) were used. A total of 22 RCTs (N = 1,227) with 4 AEDs (topiramate [5 RCTs, n = 270], lamotrigine [8 RCTs, n = 299], sodium valproate [6 RCTs, n = 430], and magnesium valproate [3 RCTs, n = 228]) were analyzed. The means weighted by sample size were 12.1 weeks for treatment duration, 36.2 years for age, and 61% for male frequency. Significant superiority in total psychopathology was observed for topiramate (P < .0001), lamotrigine (P = .05), and sodium valproate (P = .002), compared to clozapine monotherapy. After removing outliers, the positive effect of sodium valproate remained, but the positive effect of lamotrigine disappeared (P = .40). Significantly improved efficacy in positive and general symptom severity was observed for topiramate (P = .04 and P = .02, respectively) and sodium valproate (P = .009 and P = .003, respectively). There were no significant differences regarding adverse drug reactions and all-cause discontinuations except for topiramate, which was associated with more all-cause discontinuations (RR = 1.99; 95% CI, 1.16 to 3.39; P = .01; I² = 0%; NNH = 7). Sodium valproate augmentation was efficacious and safe. Topiramate augmentation had a too-high discontinuation rate. High-quality RCTs are needed to inform clinical recommendations.


Poincaré plots and tachograms reveal beat patterning in sick sinus syndrome with supraventricular tachycardia and varying AV nodal block.
Using 24-h ambulatory electrocardiography, the RR intervals of all beats were determined in a West Highland white terrier with sick sinus syndrome characterized by long sinus pauses, bradycardia, supraventricular tachycardia (SVT) and varying degrees of atrioventricular (AV) heart block. Distinctive patterns of bradycardia and 1:1, 2:1, 3:1, 4:1 and 5:1 AV block associated with SVT were evident in the tachogram (RR interval distribution over time) and Poincaré plots (short-term heart rate variability plots of RRn versus RRn+1). These patterns differed from those of abrupt alteration in cycle length during long sinus pauses or bursts of supraventricular tachycardia. Recognition of such patterns may direct attention to time points for which close attention to the cardiac rhythm should be evaluated in the full-disclosure of the 24-h ECG recording.