Effects of Aqueous Film-Forming Foams (AFFFs) on Trichloroethene (TCE) Dechlorination by a Dehalococcoides mccartyi-Containing Microbial Community.
The application of aqueous film-forming foams (AFFFs) to extinguish chlorinated solvent-fueled fires has led to the co-contamination of poly- and perfluoroalkyl substances (PFASs) and trichloroethene (TCE) in groundwater and soil. Although reductive dechlorination of TCE by Dehalococcoides mccartyi is a frequently used remediation strategy, the effects of AFFF and PFASs on TCE dechlorination are not well-understood. Various AFFF formulations, PFASs, and ethylene glycols were amended to the growth medium of a D. mccartyi-containing enrichment culture to determine the impact on dechlorination, fermentation, and methanogenesis. The community was capable of fermenting organics (e.g., diethylene glycol butyl ether) in all AFFF formulations to hydrogen and acetate, but the product concentrations varied significantly according to formulation. TCE was dechlorinated in the presence of an AFFF formulation manufactured by 3M but was not dechlorinated in the presence of formulations from two other manufacturers. Experiments amended with AFFF-derived PFASs and perfluoroalkyl acids (PFAAs) indicated that dechlorination could be inhibited by PFASs but that the inhibition depends on surfactant concentration and structure. This study revealed that the fermentable components of AFFF can stimulate TCE dechlorination, while some of the fluorinated compounds in certain AFFF formulations can inhibit dechlorination.


U3-1402, a Novel HER3-Targeting Antibody-Drug Conjugate, for the Treatment of Colorectal Cancer.
HER3 is overexpressed in several cancers, including colorectal cancer. Although therapies with anti-HER3 antibodies have been investigated, significant clinical benefits have not been reported. U3-1402 is a novel HER3-antibody-drug conjugate (ADC) composed of the HER3 antibody patritumab and a novel topoisomerase I inhibitor, DX-8951 derivative (DXd). The sensitivity of DXd was evaluated by a growth inhibition assay. The antitumor activity of U3-1402 was evaluated in a murine xenograft model in which its effects on cells, with a range of HER3 expression levels, were compared with those of patritumab alone, irinotecan, control-ADC, and saline. In the growth inhibition assay, all colorectal cancer cell lines were sensitive to DXd. In the tumor xenograft model, significant tumor regression with U3-1402 was observed both in the DiFi cell line (high HER3 expression; KRAS wild type) and in SW620 (high HER3 expression; KRAS mutation), but no treatment effect was observed in Colo320DM (low HER3 expression). Notably, SW620 tumor growth was significantly suppressed with U3-1402 compared with the saline-treated group (P < 0.001) and showed greater activity compared with the irinotecan group. By contrast, patritumab alone, control-ADC, and saline did not significantly differ in tumor growth inhibition. The antitumor activity of U3-1402 was dependent on HER3 expression level, but not on KRAS mutation status. These results support further investigation of development strategies for U3-1402 in patients with HER3-expressing colorectal cancer.


Comparative study of three tests (dye test, indirect haemagglutination test, latex agglutination test) for the detection of antibodies to Toxoplasma gondii in human sera.
An evaluation has been made of a commercial latex agglutination test, Toxotest-MT (TMT) (Eiken, Japan), for the detection of antibodies to Toxoplasma gondii in human sera. In qualitative studies, 878 sera were examined in both the TMT and dye test (DT) and 96.6% agreement was found, In quantitative studies 339 sera were titrated in the TMT and DT, with 337 of these sera also titrated in the indirect haemagglutination test (IHAT). Agreement between the DT and TMT was best, 78% of the sera showing titres within +/- 1 dilution in the two tests. The IHAT and TMT gave 66% agreement, while the DT and IHAT showed least agreement, 40.9%. The results suggest that the pattern of antigenic determinants to which antibody levels are measured are different in the three test systems. The TMT is a better substitute for the DT than the IHAT.


Endocrine toxicity of cancer immunotherapy: clinical challenges.
Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune-related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors. We review the presentation and management of the common endocrine immune-related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.


An Oxalyl-CoA Synthetase Is Involved in Oxalate Degradation and Aluminum Tolerance.
Acyl Activating Enzyme3 (AAE3) was identified to be involved in the catabolism of oxalate, which is critical for seed development and defense against fungal pathogens. However, the role of AAE3 protein in abiotic stress responses is unknown. Here, we investigated the role of rice bean (Vigna umbellata) VuAAE3 in Al tolerance. Recombinant VuAAE3 protein has specific activity against oxalate, with Km = 121 ± 8.2 µm and Vmax of 7.7 ± 0.88 µmol min-1 mg-1 protein, indicating it functions as an oxalyl-CoA synthetase. VuAAE3-GFP localization suggested that this enzyme is a soluble protein with no specific subcellular localization. Quantitative reverse transcription-PCR and VuAAE3 promoter-GUS reporter analysis showed that the expression induction of VuAAE3 is mainly confined to rice bean root tips. Accumulation of oxalate was induced rapidly by Al stress in rice bean root tips, and exogenous application of oxalate resulted in the inhibition of root elongation and VuAAE3 expression induction, suggesting that oxalate accumulation is involved in Al-induced root growth inhibition. Furthermore, overexpression of VuAAE3 in tobacco (Nicotiana tabacum) resulted in the increase of Al tolerance, which was associated with the decrease of oxalate accumulation. In addition, NtMATE and NtALS3 expression showed no difference between transgenic lines and wild-type plants. Taken together, our results suggest that VuAAE3-dependent turnover of oxalate plays a critical role in Al tolerance mechanisms.


Physical aggressive resident behavior during hygienic care.
Management of aggressive behavior has been identified as a concern for nursing staff who provide institutional care for cognitively impaired elderly. The Omnibus Reconciliation Act (OBRA '87) mandates a trial reduction in the use of chemical and physical restraints, and the development of nursing interventions for the management of behavioral disorders of institutionalized cognitively impaired elderly. Most skilled nursing facilities, however, are limited in their ability to provide environmental and behavioral programs to manage aggressive patient behavior. For the purposes of this study, physically aggressive behavior was identified as threatened or actual aggressive patient contact which has taken place between a patient and a member of the nursing staff. This study explored the nursing staff's responses to patient physical aggression and the effects that physical aggression had on them and on nursing practice from the perspective of the nursing staff. Nursing staff employed on one Dementia Special Care Unit (DSCU) were invited to participate. Interviews with nursing staff were analyzed using qualitative descriptive methods described by Miles and Huberman (1994). Nursing staff reported that they were subjected to aggressive patient behaviors ranging from verbal threats to actual physical violence. Nursing staff reported that showering a resident was the activity of daily living most likely to provoke patient to staff physical aggression. The findings revealed geropsychiatric nursing practices for the management of physically aggressive residents, and offered recommendations for improving the safety of nursing staff and residents on a secured DSCU.


Isolation-free measurement of single urinary extracellular vesicles by imaging flow cytometry.
Urinary extracellular vesicles (uEVs) are promising biomarkers for various diseases. However, many tools measuring uEVs rely on time-consuming uEV isolation methods, which could induce sample bias. This study demonstrates the detection of single uEVs without isolation using imaging flow cytometry (IFCM). Unstained urine samples contained auto-fluorescent (A-F) particles when characterized with IFCM. Centrifugation successfully removed A-F particles from the unprocessed urine. Based on the disappearance of A-F particles, a gate was defined to distinguish uEVs from A-F particles. The final readouts of IFCM were verified as single EVs based on detergent treatment and serial dilutions. When developing this protocol to measure urine samples with abnormally high protein levels, 25 mg/mL dithiothreitol (DTT) showed improved uEV recovery over 200 mg/mL DTT. This study provides an isolation-free protocol using IFCM to quantify and phenotype single uEVs, eliminating the hindrance and influence of A-F particles, protein aggregates, and coincidence events.


Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. A retrospective postmortem immunocytochemical and histofluorescent study.
Diabetics have impaired cognitive performance relative to age-matched control subjects, but the pathologic basis for this impairment is unknown. Because Alzheimer-type lesions, including both senile plaques and neurofibrillary tangles, contain glycated proteins and glycation is known to be increased in diabetes, we hypothesized that cognitive impairment in diabetes may be due in part to increased Alzheimer-type pathology. We measured the amount of Alzheimer-type pathology in postmortem brains of diabetic and age-matched control subjects with sensitive and specific histofluorescent and immunocytochemical methods. As expected, there were strong correlations between severity of senile plaques and neurofibrillary degeneration and age and also a strong correlation between severity of senile plaques and neurofibrillary degeneration and age and also a strong correlation between the pathologic measures. On the other hand, there was no significant difference between diabetics and control subjects with respect to severity of Alzheimer-type pathology, on average, or with respect to age. This finding was true for diabetics with and without insulin dependence. The results confirm reports showing that diabetes is not a risk factor for Alzheimer-type pathology and suggest that factors other than Alzheimer's disease are responsible for cognitive impairment in diabetics.


Dynamic response of high-entropy alloys to ballistic impact.
High-entropy alloys (HEAs) are promising to provide effective antiballistic capability because of their superior mechanical properties. However, the twinning-active Cantor alloy is found less ballistic resistant, compared with its Mn-free companion. It is unclear how the HEAs resist ballistic impact and why Mn does not benefit the ballistic resistance. Here, we used molecular dynamics simulations to investigate the ballistic resistances of CrMnFeCoNi and CrFeCoNi and elucidate underlying mechanisms. It is shown that the alloys' ballistic resistances dominantly benefit from active dislocations generated at higher strain rates. Stronger atomic bonding and higher dislocation densities make the CrFeCoNi easier to be strain hardened with elevated toughness to resist high-speed deformation, while weaker atomic bonding and easier occurrence of dislocation tangling make CrMnFeCoNi less resistant to failure under ballistic impact. This work helps better understand the antiballistic behavior of HEAs and guide the design of armor and energy-absorption materials.


The experience of patients with acute myeloid leukemia in remission post-transplant.
The symptoms of acute myeloid leukemia (AML) and its treatment can negatively impact patient functioning and quality of life. Through concept elicitation interviews, we sought to evaluate the experience of patients with AML in remission following hematopoietic stem cell transplant (HSCT). Thirty patients with AML in remission post-HSCT, and eight clinicians with experience treating such patients, were asked to identify symptoms and impacts associated with AML and/or its treatment. The findings were used to develop an AML conceptual disease model to reflect the experience of these patients. We identified five symptoms and six impacts that were salient to patients with AML in remission post-HSCT. Although clinician and patient perspectives largely aligned, emotional and cognitive impacts were most important to patients, whereas clinicians focused on physical impacts. This model could be used to ensure patient-reported outcome measures included in clinical trials are reflective of the post-HSCT AML patient experience.


Growth of In x Ga1-x Sb alloy semiconductor at the International Space Station (ISS) and comparison with terrestrial experiments.
In x Ga1-x Sb is an important material that has tunable properties in the infrared (IR) region and is suitable for IR-device applications. Since the quality of crystals relies on growth conditions, the growth process of alloy semiconductors can be examined better under microgravity (μG) conditions where convection is suppressed. To investigate the dissolution and growth process of In x Ga1-x Sb alloy semiconductors via a sandwiched structure of GaSb(seed)/InSb/GaSb(feed) under normal and μG conditions. In x Ga1-x Sb crystals were grown at the International Space Station (ISS) under μG conditions, and a similar experiment was conducted under terrestrial conditions (1G) using the vertical gradient freezing (VGF) method. The grown crystals were cut along the growth direction and its growth properties were studied. The indium composition and growth rate of grown crystals were calculated. The shape of the growth interface was nearly flat under μG, whereas under 1G, it was highly concave with the initial seed interface being nearly flat and having facets at the peripheries. The quality of the μG crystals was better than that of the 1G samples, as the etch pit density was low in the μG sample. The growth rate was higher under μG compared with 1G. Moreover, the growth started at the peripheries under 1G, whereas it started throughout the seed interface under μG. Kinetics played a dominant role under 1G. The suppressed convection under μG affected the dissolution and growth process of the In x Ga1-x Sb alloy semiconductor.


Summed-score linking using item response theory: application to depression measurement.
An item response theory (IRT) approach to test linking based on summed scores is presented and demonstrated by calibrating a modified 23-item version of the Center for Epidemiologic Studies Depression Scale (CES-D) to the standard 20-item CES-D. Data are from the Depression Patient Outcomes Research Team, II, which used a modified CES-D to measure risk for depression. Responses (N = 1,120) to items on both the original and modified versions were calibrated simultaneously using F. Samejima's (1969, 1997) graded IRT model. The 2 scales were linked on the basis of derived summed-score-to-IRT-score translation tables. The established cut score of 16 on the standard CES-D corresponded most closely to a summed score of 20 on the modified version. The IRT summed-score approach to test linking is a straightforward, valid, and practical method that can be applied in a variety of situations.


Container system for enabling commercial production of cryopreserved cell therapy products.
The expansion of cellular therapeutics will require large-scale manufacturing processes to expand and package cell products, which may not be feasible with current blood-banking bag technology. This study investigated the potential for freezing, storing and shipping cell therapy products using novel pharmaceutical-grade Crystal Zenith((R)) (CZ) plastic vials. CZ vials (0.5, 5 and 30 ml volume) with several closure systems were filled with mesenchymal stem cells and stored at either -85 or -196 degrees C for 6 months. Vials were tested for their ability to maintain cell viability, proliferative and differentiation capacity, as well as durability and integrity utilizing a 1-m drop test. As controls, 2 ml polypropylene vials were investigated under the same conditions. Post-thaw viability utilizing a dye exclusion assay was over 95% in all samples. Stored cells exhibited rapid recovery 2 h post-thaw and cultures were approximately 70% confluent within 5-7 days, consistent with nonfrozen controls and indicative of functional recovery. Doubling times were consistent over all vials. The doubling rate for cells from CZ vials were 2.14 + or - 0.83 days (1 week), 1.84 + or - 0.68 days (1 month) and 1.79 + or - 0.71 days (6 months), which were not significantly different compared with frozen and fresh controls. Cells recovered from the vials exhibited trilineage differentiation consistent with controls. As part of vial integrity via drop testing, no evidence of external damage was found on vial surfaces or on closure systems. Furthermore, the filled vials stored for 6 months were tested for container closure integrity. Vials removed from freezer conditions were transported to the test laboratory on dry ice and tested using pharmaceutical packaging tests, including dye ingress and microbial challenge. The results of all stoppered vials indicated container closure integrity with no failures. Pharmaceutical-grade plastic CZ vials, which are commercially used to package pharmaceutical products, are suitable for low-temperature storage and transport of mesenchymal stem cells, and are a scalable container system for commercial manufacturing and fill-finish operation of cell therapy products.


Prehospital use of magnesium sulfate as neuroprotection in acute stroke.
Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents. We randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability). Among the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (±SD) age was 69±13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7±1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran-Mantel-Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events. Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG ClinicalTrials.gov number, NCT00059332.).


Integrating sexual and reproductive health into health system strengthening in humanitarian settings: a planning workshop toolkit to transition from minimum to comprehensive services in the Democratic Republic of Congo, Bangladesh, and Yemen.
Planning to transition from the Minimum Initial Service Package for Sexual and Reproductive Health (SRH) toward comprehensive SRH services has been a challenge in humanitarian settings. To bridge this gap, a workshop toolkit for SRH coordinators was designed to support effective planning. This article aims to describe the toolkit design, piloting, and final product. Anchored in the Health System Building Blocks Framework of the World Health Organization, the design entailed two complementary and participatory strategies. First, a collaborative design phase with iterative feedback loops involved global partners with extensive operational experience in the initial toolkit conception. The second phase engaged stakeholders from three major humanitarian crises to participate in pilot workshops to contextualize, evaluate, validate, and improve the toolkit using qualitative interviews and end-of-workshop evaluations. The aim of this two-phase design process was to finalize a planning toolkit that can be utilized in and adapted to diverse humanitarian contexts, and efficiently and effectively meet its objectives. Pilots occurred in the Democratic Republic of Congo for the Kasai region crisis, Bangladesh for the Rohingya humanitarian response in Cox's Bazar, and Yemen for selected Governorates. Results suggest that the toolkit enabled facilitators to foster a systematic, participatory, interactive, and inclusive planning process among participants over a two-day workshop. The approach was reportedly effective and time-efficient in producing a joint work plan. The main planning priorities cutting across settings included improving comprehensive SRH services in general, healthcare workforce strengthening, such as midwifery capacity development, increasing community mobilization and engagement, focusing on adolescent SRH, and enhancing maternal and newborn health services in terms of quality, coverage, and referral pathways. Recommendations for improvement included a dedicated and adequately anticipated pre-workshop preparation to gather relevant data, encouraging participants to undertake preliminary study to equalize knowledge to partake fully in the workshop, and enlisting participants from marginalized and underserved populations. Collaborative design and piloting efforts resulted in a workshop toolkit that could support a systematic and efficient identification of priority activities and services related to comprehensive SRH. Such priorities could help meet the SRH needs of communities emerging from acute humanitarian situations while strengthening the overall health system.


Circulating immune complexes in sarcoidosis, a clinical role for the Raji assay?
Many immunological abnormalities, including circulating immune complexes (CICs), have been described in patients with sarcoidosis. The relationship of these abnormalities to clinical states is uncertain. In 31 proven cases of sarcoidosis we used the Raji assay in the investigation of the relationship between disease activity and the presence of CICs. Circulating immune complexes (greater than 49 micrograms.ml-1) were found in 11 of 14 patients with evidence of recent significant disease deterioration, whereas only one of 17 patients with chronic stable sarcoidosis demonstrated CICs (p less than 0.001). At follow-up, it was found that eight of the 11 cases with active disease and detectable CICs had resolved clinically. Resolution was accompanied by normalization of CICs in seven and persistence in one. The remaining three patients did not improve clinically and continued to demonstrate CICs. Measurements of complement levels did not demonstrate any significant difference between the two groups of patients. It is concluded that elevated levels of CICs, as detected by the Raji assay, are commonly found in association with significantly deteriorating sarcoidosis, often normalize following disease improvement and, consequently, may have a useful clinical role as a marker of activity.


Nationwide surveillance of antimicrobial resistance among Enterobacteriaceae in intensive care units in Taiwan.
To determine the antimicrobial resistance profiles among clinical isolates of Enterobacteriaceae in Taiwanese intensive care units (ICUs), a national surveillance of antibiotic resistance among important Enterobacteriaceae was conducted from September 2005 through November 2005 at the ICUs of ten major teaching hospitals in Taiwan. A total of 574 Enterobacteriaceae isolates recovered from various clinical samples of our ICU patients were submitted for in vitro test. Minimum inhibitory concentrations (MICs) of these isolates to 18 antimicrobial agents were determined by the broth microdilution method. The prevalences of Enterobacteriaceae isolates with phenotypic extended-spectrum beta-lactamase (ESBL) production were 26% in Klebsiella pneumoniae, 16% in Serratia marcescens, 14% in Escherichia coli, and 13% in Proteus mirabilis, in which a significantly rising prevalence of ESBL production among K. pneumoniae was noted (p = 0.002) when compared with a previous Taiwanese survey in 2000. Heterogeneous resistance to various fluoroquinolones was found among our Enterobacteriaceae isolates, except for Enterobacter cloacae. Emergence of ertapenem-resistant isolates of E. coli, K. pneumoniae, E. cloacae, and S. marcescens was noted. Gradually increasing rates of drug-resistant Enterobacteriaceae were noted in Taiwanese ICUs. Periodic surveillance of the evolutionary trend of antimicrobial resistance among ICU isolates is crucial for starting appropriately empirical antimicrobial therapy in the future.


The role of veterinarians in equestrian sport: a comparative review of ethical issues surrounding human and equine sports medicine.
Veterinarians have a key role in providing medical care for sports horses during and between competitions, but the standard client:veterinarian relationship that exists in companion and production animal medicine is distorted by the involvement of third parties in sports medicine, resulting in distinct ethical dilemmas which warrant focused academic attention. By comparing the existing literature on human sports medicine, this article reviews the ethical dilemmas which face veterinarians treating equine athletes, and the role of regulators in contributing to or resolving those dilemmas. Major ethical dilemmas occur both between and during competitions. These include conflicts of responsibility, conflicts between the need for client confidentiality and the need to share information in order to maximise animal welfare, and the need for an evidence base for treatment. Although many of the ethical problems faced in human and equine sports medicine are similar, the duty conferred upon a veterinarian by the licensing authority to ensure the welfare of animals committed to his or her care requires different obligations to those of a human sports medicine doctor. Suggested improvements to current practice which would help to address ethical dilemmas in equine sports medicine include an enhanced system for recording equine injuries, the use of professional Codes of Conduct and Codes of Ethics to establish acceptable responses to common ethical problems, and insistence that treatment of equine athletes is evidence-based (so far as possible) rather than economics-driven.


Assessment of cardiovascular autonomic function in patients with polycystic ovary syndrome.
The study was conducted to assess the sympathovagal balance in patients with polycystic ovary syndrome (PCOS) using short-term heart rate variability (HRV) analysis and conventional autonomic function tests (CAFT). Thirty-one newly diagnosed patients with PCOS and 30 age-matched controls were recruited. Body mass index (BMI), waist : hip ratio (WHR), cardiovascular parameters such as basal heart rate (BHR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and rate-pressure product (RPP), and fasting blood glucose (FBG) were measured in both groups. Cardiovascular autonomic functions assessed were spectral analysis of HRV, heart rate and blood pressure response to standing (30:15 ratio), deep breathing (E:I ratio) and isometric handgrip (ΔDBP(ihg)). The cases had significantly increased BMI, WHR, BHR, SBP, DBP and RPP. Ratio of low-frequency to high-frequency power of HRV (LF-HF ratio), the marker of sympathovagal balance was significantly increased in cases compared to controls. Time-domain indices of HRV and E:I ratio were decreased, and 30:15 ratio, ΔDBP(ihg) and FBG were increased in cases. Though there was a significant correlation of LF-HF ratio with BMI, WHR, BHR, RPP and FBG, only BHR and RPP had independent contribution to LF-HF ratio. We conclude that PCOS patients have altered autonomic modulation in the form of increased sympathetic and decreased parasympathetic reactivity and HRV. The sympathovagal imbalance exposes them to cardiovascular morbidities.


Sexual patterning and condom use among a group of HIV vulnerable men in Thika, Kenya.
A composite sample of 37 peer educators and 215 members of self help groups of male informal sector workers in Thika, Kenya, targeting HIV/AIDS prevention, were interviewed about their sexual behaviour, using a customised template, as part of a broader survey on gender attitudes and peer pressure. Details on each sexual partner reported by each man over a 12 month recall period included type of partner, months during which sexual relations took place, and condom use. The men reported 471 sexual partners over the recall period, with a range of 0-16 partners, and an average of just under two partners. 8% of men had had no sexual partner, half were monogamous, and 3% had multiple partners with whom they used condoms exclusively, leaving 39% at varying degrees of risk. Condom use increased significantly with reduced intimacy of partner. 16% of men reported having at least one liaison with a female sex worker and two thirds of such liaisons were exclusively protected by condom use. Younger, single men had significantly more partners, but were more likely to use condoms. Duration of membership in self help groups was strongly associated with exclusive use of condoms with casual or FSW partners. Recorded attitudes corresponded somewhat with practice, but the data showed large gaps between the two, and low levels of gender sensitivity. There is some evidence that group membership has resulted in increased condom use and partner reduction, but there are doubts as to the extent to which the "ABC" strategy can be successful in stemming the HIV/AIDS epidemic. It may be necessary for interventions to target contextual issues, particularly gender relations, if the approach is to be more successful.


Emerging drugs for pneumococcal pneumonia.
Nowadays, despite excellent antibiotics being available, mortality of pneumococcal pneumonia remains high. The excellent antipneumococcal activity and the large amount of clinical data available with β-lactams and fluorquinolones will probably delay the need for new antibiotics. However, concerns about the evolution of antibiotic resistance justify the review of new indications for known antibiotics and the development of new products. In this review, the authors focus on the actual situation of pneumococcal antibiotic resistance, the different antimicrobial therapies available and future therapeutic options as well as novel therapeutic strategies. An extensive literature review of manuscripts published in the last 10 years has been performed. This is a review of all antimicrobials for the treatment of pneumococcal pneumonia. Both actual antibiotics available and new antibiotics that may have a role in the treatment of pneumococcal pneumonia are extensively reviewed. The utility of combination therapy with β-lactams and macrolides is discussed. β-Lactams continue to be the drugs of choice for pneumococcal pneumonia. Fluorquinolones constitute an excellent alternative therapy. Patients with shock or severe sepsis should probably receive combination therapy with β-lactams plus a macrolide due to its immunomodulatory effect.


Evidence for a promoter-like activity in the short non-coding region of human papillomaviruses.
A short non-coding region (SNR) commonly exists between the E5 and L2 open reading frames of human papillomaviruses (HPVs). Except for the poly(A) signal for early gene transcripts, no biological functions have been discovered for the SNR. To test a possible promoter-like activity of the SNR, we carried out CAT reporter assays using constructs containing the SNRs from HPV-16, -18 and -33 linked to a promoterless CAT gene. We reproducibly observed enhanced expression of CAT gene by the SNRs. Co-expression of a transcriptional activator (LAP/NF-IL6) or deletion of the poly(A) signal augmented the promoter-like activity of the SNRs. RNase protection assays revealed a LAP-inducible CAT mRNA properly initiated from the HPV-16 SNR. These results may suggest that the SNR has a promoter activity that is regulated by keratinocyte differentiation.


Clinical and hormonal effects of the new angiotensin II receptor antagonist LRB081.
The renin-angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. Antagonizing angiotensin (Ang) II at the receptor site may produce fewer side effects than inhibition of the promiscuous converting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT1-receptor antagonist, on the pressor action of exogenous Ang II. At the same time, plasma hormones and drug levels were monitored. At 1-week intervals and in a double-blind randomized fashion, 8 male volunteers received three doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP) was measured at a finger by photoplethysmograph. The peak BP response to intravenous injection of a standard dose of Ang II was determined before and for < or = 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood BP response to Ang II was expressed in percent of the response before drug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by high-performance liquid chromatography) were monitored. After LRB081 administration, a dose dependent inhibition of the BP response to Ang II was observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB081, respectively. The time to peak was 3 h for 6 subjects and 4 and 6 h for 2 others. Preliminary plasma half-life (t1/2) was calculated at 2 h. With the highest dose, the inhibition remained significant for 24 h (31 +/- 5%, p < 0.05). Maximal BP-blocking effect and maximal plasma drug level coincided, suggesting that the unmetabolized LRB081 is responsible for the antagonistic effect. PRA and Ang II increased dose dependently after LRB081 intake. Aldosterone, epinephrine, and norepinephrine concentrations remained unchanged. No clinically significant adverse reaction was observed during the study. LRB081 is a well-tolerated, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has been shown to be responsible for the main effects.


Differential expression of aquaporin 8 in human colonic epithelial cells and colorectal tumors.
The gene expression pattern in tumor cells differs from that in corresponding normal cells. In order to identify differentially expressed genes in colorectal tumors and normal colorectal epithelium, a differential display experiment was used to compare RNA expression in normal and tumor tissue samples. One gene fragment was expressed only in normal tissue and not, or to a much lesser extent, in the adenomas, carcinomas and cancer cell lines. The isolated gene fragment was identical to Aquaporin 8 (AQP8), a water channel protein. In situ hybridization demonstrated that AQP8 was expressed in the cells facing the lumen in the normal colonic epithelium. Our result suggests that the expression of AQP8 is a marker of normal proliferating colonic epithelial cells and suggest these cells to be involved in fluid transport in the colon.


Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies.
The presence of donor human leukocyte antigen (HLA)-specific antibodies (DSA) increases engraftment failure risk in partially HLA-mismatched, or HLA-haploidentical, allogeneic marrow (alloBMT) transplantation. As pre-existing sensitization to HLA antigens is not well characterized among candidates for HLA-haploidentical alloBMT, we retrospectively evaluated both the incidence and relative strength of DSA in this patient population. Based on correlations of solid-phase antibody assays on the Luminex (Luminex, Austin, TX) platform with actual crossmatch tests, DSA were characterized as weak for results that were consistent with negative flow cytometric crossmatch results or as moderate-to-strong for results consistent with positive flow cytometric or cytotoxicity crossmatches. We evaluated 296 alloBMT candidates; 111 (37.5%) were female. DSA were detected in 43 (14.5%) candidates, mostly among female candidates (42.9% female versus 12.5% male). Moderate-to-strong DSA strength was more frequently encountered when directed against haploidentical donors as compared with mismatched unrelated donors. DSA were most commonly detected in female patients directed against their children. Because the presence of DSA has been considered prohibitive for HLA-mismatched alloBMT, we additionally report a desensitization methodology used to reduce DSA to negative or weak levels, ie, levels well below those detectable in a flow cytometric crossmatch. Nine patients without other available donors underwent desensitization. Eight who reduced their DSA to negative or weak levels proceeded to alloBMT and achieved full donor engraftment. These data support routine DSA evaluation in all patients considered for mismatched alloBMT; however, for patients with no other viable options, desensitization to weak or negative DSA levels may afford the opportunity for successful transplantation.


Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome.
Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels. In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥ 2-fold elevation posttreatment) occurred in ≥ 25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P ≤ 0.05). Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. See related commentary by Hellstrom and Hellstrom, p. 3581.


Hyperthermia as an adjunctive treatment for soft-tissue sarcoma.
The treatment for high-risk soft-tissue sarcomas (STSs) in adults remains a challenge for the multidisciplinary approach. Despite aggressive local treatment, high-risk STSs have a tendency for hematogenous spread, which is related, for each histologically distinct sarcoma, to risk factors, such as pathologic grade, size and location. The multimodality approach focuses on the combination of radiochemotherapy in a neoadjuvant or adjuvant setting, surgery being considered the mainstay of local treatment. Therefore, current clinical research aims include preoperative treatment to control systemic microscopic disease and to downsize the primary tumor mass. Within the past 20 years, the application of hyperthermia has been integrated in multimodal treatment strategies in several forms of advanced malignant tumors, as well as in STSs. Hyperthermia is of clinical interest in the temperature range of 40-43 degrees C. Higher temperatures of 44-46 degrees C are not clinically realistic. The rationale for the combination of cytotoxic drugs with regional hyperthermia in the treatment of STS is based upon experimental and clinical evidence that heat increases the killing of tumor cells by direct thermal toxicity and enhances the efficacy of some drugs, such as alkylating agents and platinum analogs. Moreover, recent results show that hyperthermia may be able to modulate the immune system by inducing the expression of heat-shock proteins. The approach of multimodality treatment in STS has used regional hyperthermia with systemic chemotherapy within a preoperative and postoperative strategy. The synergistic effect of hyperthermia with chemotherapy is also used in locoregional treatments, such as isolated limb perfusion and intraperitoneal chemotherapy.


Therapy options in imatinib failures.
Chronic myelogenous leukemia (CML) is defined by the presence of the constitutively active tyrosine kinase breakpoint cluster region/Abelson (Bcr-Abl), which activates numerous signal transduction pathways leading to uncontrolled cell proliferation. The development of the Bcr-Abl-targeted imatinib represents a paradigm shift in the treatment of CML, because treatment with imatinib resulted in significantly better patient outcome, response rates, and overall survival compared with previous standards. Despite this advance, not all patients benefit from imatinib because of resistance and intolerance. Resistance to imatinib can develop from a number of mechanisms that can be defined as Bcr-Abl-dependent (e.g., most commonly resulting from point mutations in the Abl kinase domain) and Bcr-Abl-independent mechanisms (including the constitutive activation of downstream signaling molecules, e.g., Src family kinases), which could result in the activation of the pathway regardless of Bcr-Abl inhibition. Clearly, new treatment approaches are required for patients resistant to or intolerant of imatinib, which can be dose escalated in patients who demonstrate resistance. This does not result in long-term responses. Hematopoietic stem cell transplantation is limited by the availability of matched donors and the potential for morbidity. Dasatinib, a dual Bcr-Abl/Src kinase inhibitor, has shown efficacy against all imatinib-resistant Bcr-Abl mutations except for T315I. A large trial program showed that dasatinib is effective in patients previously exposed to imatinib and has a manageable safety profile in all phases of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, resulting in its approval. Nilotinib, an analogue of imatinib, also has demonstrated activity in a similar patient population. These agents and less clinically advanced strategies are discussed in this review.


Potential role of pyrin, the protein mutated in familial Mediterranean fever, during inflammatory cell migration.
Familial Mediterranean fever (FMF), the most common of the systemic autoinflammatory disorders, is caused by mutations in the MEFV (Mediterranean Fever) gene, which encodes the protein pyrin. Neutrophils, one of the major components during inflammation, are the main cell type that expresses pyrin. In response to an inflammatory stimulus, neutrophils migration to their main active site. To date, several pyrin-interacting proteins have been demonstrated to co-localise with the cytoskeletal protein actin, which is important in the process of neutrophil migration and raises the question of whether pyrin plays a role in the actin cytoskeletal network during inflammatory cell migration. In this study, we examined the possible role of pyrin during inflammatory cell migration in neutrophils. We generated a cell migration assay with neutrophils and primary neutrophils from patients. We also knocked down pyrin expression using siRNA and then performed cell migration assay. We showed co-localisation of pyrin and F-actin at the leading edge during inflammatory cell migration. In pyrin knocked down cells, we identified a significant decrease in neutrophil migration. In addition, we demonstrated a dramatic increase in migration in the neutrophils of FMF patients compared with a healthy control group. These data together provide new insight into the cellular function of pyrin and demonstrate an important link between pyrin and polymerising actin in the process of inflammatory cell migration.


Transactions between Problem Behaviors and Academic Performance in Early Childhood.
This study aimed to further the understanding of transactional relationships that exist between problem behaviors and academic performance in early childhood. Early academic and behavior difficulties increase the risk of school disengagement, academic failure, and dropout. Although children's academic and behavioral difficulties have been shown to be intercorrelated, little research has focused on how the relationship reciprocates and progresses in early childhood. This study investigated how problem behaviors (i.e., externalizing and internalizing) influence and are influenced by academic performance (i.e., poor reading and math) from kindergarten to third grade. Participants included 18,135 students (51.22% boys) derived from a nationally representative sample in the Early Childhood Longitudinal Study, Kindergarten Class of 2011 (ECLS-K: 2011). Teacher ratings of children's internalizing (low self-esteem, anxiety, loneliness, or sadness) and externalizing (fighting, arguing, showing anger, impulsively acting, and disruptive behaviors) problem behaviors, as well as direct assessments of children's academic performance (reading and math), were collected yearly. Cross-lagged panel modeling (CLPM) was employed to examine reciprocal relationships between problem behaviors and academic performance over time from kindergarten to third grade. The results supported the transactional relationships in early childhood, with higher externalizing as well as internalizing problem behaviors predicting lower academic performance and lower academic performance predicting higher externalizing and internalizing problem behaviors. The implications for research, prevention, and early intervention regarding the progression of academic and behavioral problems are discussed.


Comparing pooled peptides with intact protein for accessing cross-presentation pathways for protective CD8+ and CD4+ T cells.
To better understand the mechanisms of intracellular trafficking and presentation of exogenous peptides by antigen-presenting cells (APC), we compared the handling of overlapping 24-mer peptides from HIV Nef either mixed or covalently linked in tandem in one protein. Once internalized, peptides trafficked not only to endosomes but also to cytosol, and activated CD8(+) and CD4(+) T cells. In contrast, whole protein was found to traffic only to the endosomal compartments, and primarily activated CD4(+) T cells. Finally, with adjuvant, overlapping peptides were capable of protecting against lethal viral challenge, whereas the intact protein was less protective. These data suggest that overlapping long peptides are cross-presented through more varied intracellular routes and are more efficient in priming protective immunity than the whole protein.


School performance in children with type 1 diabetes--a population-based register study.
We examined the school marks of diabetic children in Sweden at the time of leaving compulsory education. Marks were examined in comparison with non-diabetic children and with special regard to age at onset of diabetes. The study involved 5,159 children who developed diabetes between 1 July 1977 and 1 July 2000, and 1,330,968 non-diabetic children. We linked the nationwide Swedish Childhood Diabetes Register to the Swedish School-Mark Register, which contains school marks for all children in Sweden at the time of leaving compulsory education (usually at 16 years old). Adjustment was made for potential confounders such as year of birth, maternal age, parity and educational level. The mean of all numerical school marks for diabetic children was slightly but statistically significantly lower than those of the referent children (3.15 +/- 0.01 [mean + SD] vs 3.23, p < 0.001). The lowest mean score was among children with diabetes diagnosis before the age of 2 years (2.97 +/- 0.09 vs 3.08-3.17 in the older age groups, p = 0.10). When individual subjects were studied (sports, mathematics, English and Swedish), a more complex picture emerged. In four subjects (mathematics, English, Swedish and sports) the risk of a diabetic child not getting a school mark or not passing was increased; in sports and English the diabetic children had significantly reduced odds of getting a high mark. Despite a well-developed diabetes care system, we have not succeeded in preventing the disease from affecting school achievements. Among children with a young age at onset and therefore longer duration, the negative effects tend to be greater.


Functional aerobic capacity and body size.
An endurance treadmill exercise test protocol of two minute stages of increasing speed and gradient has been designed and evaluated for children under 10 years of age. There was a significant relation between test protocol time and oxygen uptake measured in ml/kg/min in tests performed on 20 subjects. One hundred and sixty exercise tests performed in a semi longitudinal study of healthy primary schoolchildren were used to assess the relation of functional aerobic capacity with age and size. In boys functional aerobic capacity measured by predicting maximal oxygen uptake from endurance time in the treadmill test increased from 33.8 ml/kg/min at age 5 to 50.5 ml/kg/min at age 9.5 and was most closely related to age. The variables of size were not significant in predicting functional aerobic capacity for boys. In girls functional aerobic capacity increased from 34.9 to 43.5 ml/kg/min at the same ages and was related positively to lean body mass and age but negatively to weight. For girls lean body mass contributed 53.9% to the variance of functional aerobic capacity in stepwise multiple regression, weight 7.7%, and age 3.5%. A significant difference between the sexes was found.


Go big and go home: A bulky extension makes promiscuous ligands settle down.
Synthetic ligands often show undesired polypharmacology, affecting the function of multiple targets. In this issue of Structure, Huber et al. developed a PXR-specific agonist based on a promiscuous ligand. Their structure-guided approach exploited the malleability of the PXR ligand-binding pocket, which unlike other nuclear receptors could accommodate bulkier ligands.


Polaron delocalization in ladder macromolecular systems.
Organic macromolecules with conjugated building blocks have been the focus of extensive research that is motivated, in part, by the potential to create optical and electronic devices. We have shown that palladium-catalyzed amination can assemble triarylamine ladder materials with extended structures. Two ladder macromolecules have been prepared in high yields by a series of twelve or sixteen C-N coupling reactions. Studies of the electronic and optical properties of neutral and oxidized forms of the ladder structures were conducted. The optical and electronic properties of the ladder systems are compared to those of the linear tetra-phenyl-p-phenylenediamine as well as the tetra-p-anisyl-p-tetraazacyclophane. The electrochemistry of the ladder systems consists of a multiwave voltammogram with a relatively low first oxidation potential. Electron paramagnetic resonance spectroscopy of the ladder systems suggests the presence of a large density of delocalized polarons. Linear absorption measurements of the chemically oxidized ladders revealed both polaron and intervalence absorption bands. Steady-state and time-resolved fluorescence measurements were also carried out to characterize the dynamics in these novel systems.


A silent slip event on the deeper Cascadia subduction interface.
Continuous Global Positioning System sites in southwestern British Columbia, Canada, and northwestern Washington state, USA, have been moving landward as a result of the locked state of the Cascadia subduction fault offshore. In the summer of 1999, a cluster of seven sites briefly reversed their direction of motion. No seismicity was associated with this event. The sudden displacements are best explained by approximately 2 centimeters of aseismic slip over a 50-kilometer-by-300-kilometer area on the subduction interface downdip from the seismogenic zone, a rupture equivalent to an earthquake of moment magnitude 6.7. This provides evidence that slip of the hotter, plastic part of the subduction interface, and hence stress loading of the megathrust earthquake zone, can occur in discrete pulses.


The state of DNA methylation in the promoter and exon 1 regions of the human gene for the interleukin-2 receptor alpha chain (IL-2R alpha) in various cell types.
The gene for the human interleukin-2 receptor alpha chain (IL-2R alpha) is expressed only in stimulated, not in resting, human T lymphocytes. This gene, in conjunction with others, plays a pivotal role in eliciting the T cell-mediated immune response. We have investigated the promoter and exon 1 region, the nucleotide -300 to +300 region of this gene relative to the position of transcriptional initiation at nucleotide +1, particularly with respect to the extent of DNA methylation at the 5'-CG-3' sequences and its changes upon induction. By using RNA transfer analyses and the in vivo footprinting technique, we have confirmed the previously reported finding that, upon stimulation of lymphocytes by phytohemagglutinin (PHA) plus interleukin-2 (IL-2), the IL-2R alpha gene can be induced to be transcribed. The region of the IL-2R alpha gene analyzed for 5'-CG-3' methylation by the genomic sequencing method or a polymerase chain reaction-based method subsequent to HpaII or HhaI cleavage of the DNA does not seem to be significantly methylated in most cell types tested, except for the cytidine residue in position +198 which is partly methylated. In the DNA of cells from a chronic B cell lymphatic leukemia 5'-CCGG-3' sequences in the exon 1 region are almost completely unmethylated. These results suggest that the promoter of a gene that is crucial in promoting the immune response and may have to be activated momentarily, will not be silenced by a long-term mechanism like DNA methylation. It is striking that the absence of DNA methylation in this promoter and exon 1 segment also extends to cell types not directly associated with the immune response and even to continuous cell lines.


Maternal behavioural determinants and livestock ownership are associated with animal source food consumption among young children during fasting in rural Ethiopia.
Religious fasting often involves abstention from animal source foods (ASFs). Although children are exempt, their diets are influenced by the widespread fasting practices. This study investigated the factors influencing ASF consumption among young children during the Lent fasting period in western Amhara, Ethiopia. We used baseline survey data from households with children 6-23 months of age (n = 2,646). We conducted regression analysis to examine the maternal and household factors associated with ASF consumption and path analysis to examine the direct and indirect effects of maternal knowledge, beliefs, social norms, and livestock ownership on ASF consumption. Only 24% of children consumed any ASF in the previous day-18% dairy products, 5% eggs, and 2% flesh foods. Mothers with high knowledge, beliefs, and social norms about feeding children ASFs during fasting had higher odds (odds ratio: 1.3-1.4) of children who consumed them. Compared with households with no ASFs, those with ASFs available were 4.8 times more likely to have children who consumed them. Most of the association between knowledge, beliefs and social norms, and ASF consumption was explained by pathways operating through ASF availability (approximately 9, 12, and 8 pp higher availability, respectively), which in turn were associated with higher consumption. Cow ownership was directly and indirectly associated with ASF consumption, whereas having chickens was indirectly associated with consumption via the availability pathway. Our findings corroborate the importance of maternal behavioural determinants related to feeding ASFs to children during fasting on ASF consumption via household availability and the positive influence of livestock ownership.


Viewing movie smoking undermines antismoking parenting practices.
To test the hypothesis that viewing depictions of smoking in movies makes adolescents less responsive to parenting factors that prevent smoking. Cross-sectional survey of 4807 students (grades 5-8) through which we ascertained exposure to smoking in movies, parent smoking, and adolescents' perception of parental responsiveness (support), and parental demandingness (behavioral control). Adolescents attending randomly selected middle schools in the Northeastern U.S. ever tried smoking a cigarette. Exposure to movie smoking was ascertained by counting occurrences of tobacco use in 601 recent popular motion pictures; surveying students to identify films they had seen from a random subset of 50 films; and summing tobacco use occurrences for the films each adolescent reported seeing. We also measured adolescents' perceptions of parent smoking, parental responsiveness and demandingness. The overall prevalence of adolescent smoking was 17.4 percent. The prevalence of smoking increased with exposure to movie smoking (low vs. high exposure 8.8 vs. 25.8%, p < 0.0001). Parenting factors associated with lower rates of adolescent smoking were parent non smoking status (11.0% vs. 27.7% for parents who smoke, p < 0.0001), higher levels of demandingness (13.7% vs. 20.7% for low demandingness, p < 0.0001) and higher levels of parental responsiveness (12.4% vs. 23.1% for low parental responsiveness, p < 0.0001). Parenting factors were not strongly associated with exposure to movie smoking. For adolescents with low exposure to movie smoking the adjusted odds (95% confidence interval) of smoking were 0.31 (0.23, 0.42) if parents did not smoke, 0.57 (0.42, 0.78) if parents exerted high demandingness, and 0.52 (0.38, 0.71) if parents were highly responsive. Parents had significantly less influence for adolescents with high exposure to movie smoking, for whom the adjusted odds of smoking were only 0.50 if parents did not smoke (p = 0.014 for the interaction effect), 0.97 if parents exerted high demandingness (p = 0.007 for the interaction effect) and 0.73 if parents were highly responsive (p = 0.045 for the interaction effect). Viewing smoking in movies not only has a direct association with adolescent smoking, it may also undermine parental attempts to prevent this behavior.


The Treatment of Hepatic Fibrosis: Reversal of the Underlying Disease Process.
Cirrhosis is considered an irreversible end stage of all liver diseases. Current knowledge indicates that fibrosis is part of the liver repair process, which is dynamic. Understanding this repair process will provide better approaches to halt, ameliorate, or reverse fibrosis. The diagnosis of cirrhosis is currently established by liver biopsy and in most advanced cases can be confirmed by imaging. Liver biopsy remains the gold standard but has several limitations: sampling error, size of the biopsy, and both inter- and intra-observer inconsistencies. Hence, many patients can be inaccurately staged for the degree of fibrosis on their initial biopsy, as well as on subsequent re-examination. Although a decrease of 1 stage between consecutive biopsies may be a result of sampling error, the reduction from cirrhosis by at least 2 stages more likely represents a reversal of cirrhosis. There are several cases of reversal of cirrhosis reported in association with different liver diseases. The resolution of fibrosis in the majority of these diseases is related to successful treatment of the underlying etiology (eg, hepatitis B, hepatitis C, iron overload, Wilson disease, alcohol abstinence, metabolic syndrome in fatty liver disease, and decompression of biliary obstruction). The other important feature of reversal of cirrhosis is the successful control of inflammation (eg, autoimmune hepatitis, primary biliary cirrhosis, hepatitis B, C, and D).


Impaired adaptation to renal mass reduction in the polycystic rat.
Autosomal dominant polycystic kidney disease (ADPKD) is a serious cause of renal failure. In many renal-disease models, surgical renal mass reduction accelerates disease progression. We explored whether surgical renal mass reduction and the method of renal mass reduction accelerate the course of ADPKD. Studies were conducted in male heterozygous cystic Han:SPRD rats and unaffected littermate controls. Control and cystic rats were subjected to 50% renal mass reduction by uninephrectomy, 50% renal mass reduction by infarction of half of each kidney, or sham operation. Most groups were followed up to the age of 20 weeks, with serial measurements of blood pressure and proteinuria. At 20 weeks, glomerular filtration rate (GFR) and renal plasma flow (RPF) rate were measured. Similar studies to 12 weeks of age were performed in additional groups of control and cystic rats with either sham operation or 50% renal infarction. In noncystic rats, uninephrectomy led to minimal effects on blood pressure and proteinuria and to substantial compensatory renal hypertrophy, hyperfiltration, and hyperperfusion. Similar renal mass reduction by segmental infarction led to greater values for blood pressure and proteinuria and significant compensatory hyperfiltration. In contrast, the cystic rats showed a significant reduction in baseline renal blood flow, more profound increases in blood pressure and proteinuria, and no compensatory increases in GFR and RPF after reduction of renal mass. These studies suggest that the ability of cystic kidneys to respond to acquired loss of nephrons is impaired and that these kidneys are at greater risk when additional renal injury is superimposed.


Coupling between human brain activity and body movements: Insights from non-invasive electromagnetic recordings.
Electroencephalographic and magnetoencephalographic data have characterized two types of brain-body interactions observed during various types of motor actions, "corticokinematic" and "corticomuscular" coupling. Here, we review the literature on these interactions in healthy individuals, discuss several open debates, and outline current limitations and directions for future research. Corticokinematic coupling (commonly referred to as corticokinematic coherence) probes the relationship between activity of sensorimotor network nodes and various movement-related signals (e.g., speed, velocity, acceleration). It is mainly driven by movement rhythmicity during active, passive, and observed dynamic motor actions. It typically predominates at the primary sensorimotor cortex contralateral to the moving limb, occurs at movement frequency and its harmonics, and predominantly reflects the cortical processing of proprioceptive feedback driven by movement rhythmicity in a broad range of dynamic motor actions. Corticomuscular coupling (commonly referred to as corticomuscular coherence) probes the interaction between sensorimotor cortical rhythms and electromyographic (EMG) activity that mainly occurs during steady isometric muscle contraction. We will here focus on the ~20-Hz coupling that is observed during weak isometric contraction and is linked to the modulation of the descending motor command by the ~20-Hz sensorimotor rhythm. This review argues that corticokinematic and corticomuscular couplings have different neural bases. Corticokinematic coupling is mainly driven by afferent signals, while corticomuscular coupling is mainly (but not solely) driven by efferent signals. This distinction should be considered when investigating interactions between brain and body movements.


Effects of the estrous cycle on local humoral immune responses and protection of intranasally immunized female mice against herpes simplex virus type 2 infection in the genital tract.
This study demonstrates that the levels of gB-specific IgG and IgA in vaginal washes of mice immunized intranasally (i.n.) with a recombinant adenovirus vector expressing herpes simplex virus (HSV) glycoprotein B (AdgB8) vary inversely with each other and are dependent on the stage of the estrous cycle. Anti-gB IgA titers in vaginal washes were significantly higher during estrus than diestrus or proestrus, whereas specific IgG titers were significantly higher during diestrus than estrus. This was further demonstrated in hormone-treated mice, where progesterone administration induced a diestrus-like state that resulted in elevated specific IgG-to-IgA ratios. Interestingly, unimmunized mice were only susceptible to intravaginal (ivag) infection with HSV-2 during diestrus. Mice immunized i.n. with AdgB8 and given progesterone were protected from a lethal intravaginal HSV-2 challenge, despite the fact that virus replication was present for 4 days postchallenge. Further, high numbers of gB-specific IgA and IgG antibody-secreting cells were present in both the genital tracts and the draining iliac lymph nodes of i.n.-immunized, but not unimmunized, mice 6 days following ivag HSV-2 challenge. These results demonstrate that the levels of specific antibodies in the female genital tract are dependent on the stage of the estrous cycle. Furthermore, i.n. AdgB8 immunization provided a significant level of protection and specific IgA and IgG antibody-secreting cells in the genital tissues during resolution of an ivag infection with HSV-2.


Tumor immunobiological differences in prostate cancer between African-American and European-American men.
The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared with European-American men. We tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical variables. We also evaluated 18 nontumor prostate tissues from seven African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed a significant number of genes, e.g., 162 transcripts at a false-discovery rate of <or=5% to be differently expressed between African-American and European-American patients. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differently expressed genes clustering in immune response, stress response, cytokine signaling, and chemotaxis pathways. Several known metastasis-promoting genes, including autocrine mobility factor receptor, chemokine (C-X-C motif) receptor 4, and matrix metalloproteinase 9, were more highly expressed in tumors from African-Americans than European-Americans. Furthermore, a two-gene tumor signature that accurately differentiated between African-American and European-American patients was identified. This finding was confirmed in a blinded analysis of a second sample set. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups.


Efficacy of percutaneous transluminal coronary angioplasty: technique, patient selection, salutary results, limitations and complications.
Percutaneous transluminal coronary angioplasty (PTCA) was performed in 25 patients and 29 vessels during a 12-month period. In six additional patients scheduled for PTCA, the procedure was cancelled when repeat angiography identified progression to occlusion, coronary spasm, or other adverse factors not previously apparent. PTCA was successful in 14 of 25 patients (56%) and in 18 or 29 vessels (62%); success was associated with clinical improvement in all patients by symptomatology, exercise testing and/or myocardial radionuclide imaging. Beneficial results were particularly achieved with left anterior descending artery lesions and with stenoses showing less than 90% narrowing. One peripheral arterial complication occurred and no patients required emergency surgery. While coronary dissection was detected angiographically in four patients and evidence of coronary spasm was present in three patients post-PTCA, neither was accompanied by untoward early clinical events. Multivessel dilatation in three patients was initially successful but symptoms returned in two during follow-up. Restenosis developed in 3 of 14 patients (21%) after 3 months. Our experience indicates (1) that the specific vessel attempted and lesion severity particularly influence the liklihood of success, (2) the not infrequently induced coronary dissection or spasm does not necessarily represent a serious complication, and (3) angiography repeated in preparation for PTCA identifies a significant minority of patients rwho are no longer candidates.


Stable isotope peptide mass spectrometry to decipher amino acid metabolism in Dehalococcoides strain CBDB1.
Dehalococcoides species are key players in the anaerobic transformation of halogenated solvents at contaminated sites. Here, we analyze isotopologue distributions in amino acid pools from peptides of Dehalococcoides strain CBDB1 after incubation with (13)C-labeled acetate or bicarbonate as a carbon source. The resulting data were interpreted with regard to genome annotations to identify amino acid biosynthesis pathways. In addition to using gas chromatography-mass spectrometry (GC-MS) for analyzing derivatized amino acids after protein hydrolysis, we introduce a second, much milder method, in which we directly analyze peptide masses after tryptic digest and peptide fragments by nano-liquid chromatography-electrospray ionization-tandem mass spectrometry (nano-LC-ESI-MS/MS). With this method, we identify isotope incorporation patterns for 17 proteinaceous amino acids, including proline, cysteine, lysine, and arginine, which escaped previous analyses in Dehalococcoides. Our results confirmed lysine biosynthesis via the α-aminoadipate pathway, precluding lysine formation from aspartate. Similarly, the isotopologue pattern obtained for arginine provided biochemical evidence of its synthesis from glutamate. Direct peptide MS/MS analysis of the labeling patterns of glutamine and asparagine, which were converted to glutamate and aspartate during protein hydrolysis, gave biochemical evidence of their precursors and confirmed glutamate biosynthesis via a Re-specific citrate synthase. By addition of unlabeled free amino acids to labeled cells, we show that in strain CBDB1 none of the 17 tested amino acids was incorporated into cell mass, indicating that they are all synthesized de novo. Our approach is widely applicable and provides a means to analyze amino acid metabolism by studying specific proteins even in mixed consortia.


Treatment of early-stage Hodgkin's disease with four cycles of ABVD followed by adjuvant radio-therapy: analysis of efficacy and long-term toxicity.
The use of combined modality therapy in early-stage Hodgkin's disease can spare staging laparotomy and reduces the risk of relapse compared to radiation alone. This paper reports on the efficacy and long-term events of a combined modality approach consisting of a brief course of chemotherapy followed by adjuvant radiotherapy, without laparotomy, in early-stage Hodgkin's disease. This study included 78 patients with Hodgkin's disease (20 in stage I and 58 in stage II); 60% had mediastinal enlargement (12% had bulky disease) and 5% had subdiaphragmatic disease. Their median age was 33 years (range: 15-64) and median follow-up 60 months. The treatment program consisted of four cycles of ABVD followed by adjuvant radiation to involved sites (43 patients) or involved and contiguous sites of disease (35 patients); radiation doses ranged from 30 to 36 Gy to uninvolved and involved sites, respectively; bulky disease received up to 44 Gy. Gonadal function in women was assessed by hormonal tests and evaluation of menses; young men were given the opportunity to have their semen cryopreserved. The treatment program was completed in a median of 6.2 months (range: 5-10). The complete remission rate was 88% after 4 courses of ABVD and 98.7% after adjunctive RT. The 5-year relapse-free survival was 97% and overall survival 98%; three patients died, one of disease progression and two of small cell lung carcinoma. Long-term events included three cases of pulmonary fibrosis with symptomatic interstitial disease, one case of dilated cardiomyopathy with cardiac failure (all had received mediastinal radiation) and four cases of dysthyroidism. Fertility was preserved in young women, with three subsequent normal pregnancies. Second neoplasms included two small cell lung carcinomas and one breast carcinoma. In early-stage Hodgkin's disease, four cycles of ABVD followed by adjuvant radiotherapy produced a 5-year overall survival of 98%. Prolonged monitoring for therapy-related long term complications is mandatory in these potentially curable patients.


Galectin-8 induces functional disease markers in human osteoarthritis and cooperates with galectins-1 and -3.
The reading of glycan-encoded signals by tissue lectins is considered a major route of the flow of biological information in many (patho)physiological processes. The arising challenge for current research is to proceed from work on a distinct protein to family-wide testing of lectin function. Having previously identified homodimeric galectin-1 and chimera-type galectin-3 as molecular switches in osteoarthritis progression, we here provide proof-of-principle evidence for an intra-network cooperation of galectins with three types of modular architecture. We show that the presence of tandem-repeat-type galectin-8 significantly correlated with cartilage degeneration and that it is secreted by osteoarthritic chondrocytes. Glycan-inhibitable surface binding of galectin-8 to these cells increased gene transcription and the secretion of functional disease markers. The natural variant galectin-8 (F19Y) was less active than the prevalent form. Genome-wide array analysis revealed induction of a pro-degradative/inflammatory gene signature, largely under control of NF-κB signaling. This signature overlapped with respective gene-expression patterns elicited by galectins-1 and -3, but also presented supplementary features. Functional assays with mixtures of galectins that mimic the pathophysiological status unveiled cooperation between the three galectins. Our findings shape the novel concept to consider individual galectins as part of a so far not realized teamwork in osteoarthritis pathogenesis, with relevance beyond this disease.


Intensity modulated radiation therapy after extra-pleural pneumonectomy for malignant pleural mesothelioma is feasible without fatal pulmonary toxicity and provides good survival.
To analyze patterns of failure, toxicity, relapse-free survival (RFS), and overall survival (OS) in malignant pleural mesothelioma (MPM) patients treated with intensity-modulated radiation therapy following extrapleural pneumonectomy (EPP). We reviewed 18 charts of patients with MPM from 2005 to 2014 who underwent EPP followed by hemithoracic intensity-modulated radiation therapy. Intensity-modulated radiation therapy dose delivery adhered to published lung dose constraints. Kaplan-Meier curves were used to assess the RFS and OS. Median survival times are reported for both RFS and OS. Median age was 65 years (range: 40-76 years). Chemotherapy was administered in four neo-adjuvant and seven adjuvant patients. Pathological American Joint Committee on Cancer stages II, III, IV, surgical margin, lympho-vascular space, pericardium, and chest wall involvement were seen in 3, 12, 3, 9, 7, 12 and 3 patients, respectively. The majority of the patients received 45 Gy in 25 fractions. The mean lung dose was 7.14 Gy (range: 5 Gy-9.3 Gy). The mean V20 was 2.23%. At a median follow-up of 3 years, eight patients were alive (44%); 10 experienced relapse (56%). Median RFS and OS were 24.4 months (95% CI: >16.3 months) and 38.2 months (95% CI: 17.4-78.1 months), respectively. Acute toxicities were fatigue, dermatitis, nausea, esophagitis/dysphagia, cough, and dyspnea on exertion. No grade III, IV, or fatal pulmonary toxicities were observed. Intensity-modulated radiation therapy following EPP for MPM resulted in RFS and OS comparable to the published literature without significant toxicity.


Magnetization transfer imaging diagnosis of intracranial tuberculomas.
Tuberculomas (TB) can mimic brain tumors and abscesses. We performed prospective magnetization transfer ratio (MTR) analysis on 60 patients with 52 intracranial TB, 13 pyogenic abscesses and 65 tumors to determine the efficacy of magnetization transfer (MT) imaging in the differential diagnosis of brain tumors and infection. The nonenhancing cores of TB had significantly higher (P=.026) MTR (0.14+/-0.29) than necrotic components of high-grade gliomas (-0.19+/-0.22). The MTR of cores of TB were also higher than those of the cystic areas of low-grade gliomas (-0.53+/-0.32), benign (-0.09+/-0.21) and malignant (-0.07+/-0.25) tumors, and abscesses (-0.03+/-0.13), but the differences were not significant because of the small number of tumors and abscesses. There was also no significant difference between the MTR of abscesses, malignant and benign tumors. Using the criteria of MTR of necrotic center > 0.14 (mean MTR of TB) for diagnosing TB, MTR <-0.03 (mean MTR of abscesses) for diagnosing tumors and MTR between these values for diagnosing abscesses, MTI had diagnostic sensitivity of 68.42%, specificity of 80.49%, and accuracy of 76.67%. The improved diagnostic accuracy of MRI with the addition of MTR analysis from 86.67% to 91.67% and from 85.71% to 87.50% for both radiologists respectively was not significant. MTR analysis helped us to differentiate solitary TB or abscess from low-grade glioma in five patients and to diagnose multiple TB, abscesses, and metastases in four.


The de Morton Mobility Index (DEMMI): an essential health index for an ageing world.
Existing instruments for measuring mobility are inadequate for accurately assessing older people across the broad spectrum of abilities. Like other indices that monitor critical aspects of health such as blood pressure tests, a mobility test for all older acute medical patients provides essential health data. We have developed and validated an instrument that captures essential information about the mobility status of older acute medical patients. Items suitable for a new mobility instrument were generated from existing scales, patient interviews and focus groups with experts. 51 items were pilot tested on older acute medical inpatients. An interval-level unidimensional mobility measure was constructed using Rasch analysis. The final item set required minimal equipment and was quick and simple to administer. The de Morton Mobility Index (DEMMI) was validated on an independent sample of older acute medical inpatients and its clinimetric properties confirmed. The DEMMI is a 15 item unidimensional measure of mobility. Reliability (MDC(90)), validity and the minimally clinically important difference (MCID) of the DEMMI were consistent across independent samples. The MDC(90) and MCID were 9 and 10 points respectively (on the 100 point Rasch converted interval DEMMI scale). The DEMMI provides clinicians and researchers with a valid interval-level method for accurately measuring and monitoring mobility levels of older acute medical patients. DEMMI validation studies are underway in other clinical settings and in the community. Given the ageing population and the importance of mobility for health and community participation, there has never been a greater need for this instrument.


A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency.
Danon disease is a genetic deficiency in lysosome-associated membrane protein 2 (LAMP-2), a highly glycosylated constituent of the lysosomal membrane and characterized by a cardiomyopathy, skeletal muscle myopathy, and cognitive impairment. Patients, however, often manifest hepatic abnormalities, but liver function has not been well evaluated and the syndrome is relatively uncommon. Hence, we have taken advantage of a rat that has been deleted of LAMP-2 to study the relative role of LAMP-2 on liver function. Interestingly, rats deficient in LAMP-2 develop a striking increase in serum alkaline phosphatase (ALP) and a decrease in bile flow compared with wild-type littermates. Importantly and by ultrastructural analysis, deficient rats manifest dilated canaliculi that lack microvilli with evidence of bile-containing bodies. Moreover, following bile duct ligation, LAMP-2-deficient rats develop rapid and severe evidence of advanced cholestasis, with an increase in serum bilirubin, as early as 6 h later. In wild-type control rats, multidrug resistance-associated protein 2 (Mrp2) normally concentrates at the bile canalicular membranes to secrete conjugated bilirubin into bile. However, in LAMP-2y/- rats, Mrp2 was detected in hepatocytes compared with other canalicular proteins including P-glycoproteins, dipeptidyl peptidase IV (CD26), and aminopeptidase (CD13). Our data further suggest that LAMP-2 interacts with the membrane cytoskeletal proteins radixin and F-actin in determining the localization of integral membrane proteins.


Enterocytozoon bieneusi genotypes in people with gastrointestinal disorders in Queensland and Western Australia.
Enterocytozoon bieneusi is the commonest pathogenic microsporidian found in humans and animals in many countries, but there is scant information on this pathogen in Australia. Here, we conducted the first molecular epidemiological investigation of E. bieneusi in humans with gastrointestinal disorders in Queensland and Western Australia. Genomic DNAs derived from 605 individual faecal samples from children (n = 279) and adults (n = 326) were extracted, and then subjected to nested PCR-based sequencing of the internal transcribed spacer (ITS) of nuclear ribosomal DNA to detect and characterise E. bieneusi. Enterocytozoon bieneusi was detected in eight of 605 human faecal samples (1.3%), including five children (≤3 years of age) and one adult (58 years) in Queensland, and two children (≤3 years) in Western Australia. Analysis of ITS sequence data revealed two known zoonotic (ALP1 and Ind4) and three novel (Hum_q1-3) genotypes of E. bieneusi. Genotype ALP1 identified here in humans has been found previously in farmed alpacas in Australia. Phylogenetic analysis showed that genotypes ALP1, Hum_q1-2 and Ind4 belonged to E. bieneusi Group 1 (with zoonotic potential), whereas genotype Hum_q3 clustered within E. bieneusi Group 10, suggesting that some genotypes within Group 10 might have zoonotic potential. Further investigations of humans, alpacas, marsupials and other animals in Australia will be significant to understand the epidemiology of E. bieneusi in Australia, to identify possible reservoirs of human infection, and to assist in the prevention and control of human microsporidiosis.


Characterization and adaptive optical correction of aberrations during in vivo imaging in the mouse cortex.
The signal and resolution during in vivo imaging of the mouse brain is limited by sample-induced optical aberrations. We find that, although the optical aberrations can vary across the sample and increase in magnitude with depth, they remain stable for hours. As a result, two-photon adaptive optics can recover diffraction-limited performance to depths of 450 μm and improve imaging quality over fields of view of hundreds of microns. Adaptive optical correction yielded fivefold signal enhancement for small neuronal structures and a threefold increase in axial resolution. The corrections allowed us to detect smaller neuronal structures at greater contrast and also improve the signal-to-noise ratio during functional Ca(2+) imaging in single neurons.


[Nucleic acid synthesis in the cells of some ascites tumors induced by change in ionic homeostasis].
The DNA and RNA synthesis was studied in the cells of Ehrlich ascite tumour, lymphoma NK/Ly and carcinoma T.O. was studied under conditions when the Na+/K+ ratio was changed by preincubation in salt media at low temperatures. The incorporation of [3H]thymidine was inhibited at a decrease of the Na+/K+ ratio. The high rate of synthesis was observed only when the cells interacted with K+-free media. Under these conditions some cells which had not incorporated the label induced DNA synthesis. RNA synthesis in lymphoma NK/Ly cells was repressed by about 70% at an increase in K+ concentration (cK) up to 30 mM, followed by a further increase and a subsequent decrease at cK greater than 90 mM. In Ehrlich tumour cells the RNA synthesis was increased 2-fold at an increase in cK from 0 to 30 mM and decreased 3-fold within the concentration range of 30-50 mM. At cK of 50-80 mM it remained constant and showed a further decrease at cK greater than 90 mM. As in the case of DNA synthesis this effect was reversible, i. e. when the cells were transferred to a Na+-rich medium the incorporation of the label rapidly increased and reached its maximum after 30-35 min. Ouabain (2 mM) did not prevent the activation. Actinomycin D (0.05 mkg/ml) inhibited the incorporation of [3H]uridine at any values of Na+/K+. Electrophoresis of RNA isolated from the nuclei and cytoplasm of Ehrlich tumour cells showed that the changes in ionic homeostasis result in the synthesis of new forms of RNA. It is concluded that the distribution of Na+ and K+ in intact cell nuclei is uneven and that monovalent cations can control transcription via the tertiary structure of deoxyribonucleoprotein.


Dealing with interference: Chimpanzees respond to conflicting cues in a food-choice memory task.
Interference effects emerge when responding on the basis of task-relevant features is directly pitted against task-irrelevant cues that could lead to errors. To study potential interference effects in a food-choice memory test, 3 chimpanzees were presented with conflicting information in a magnitude judgment task. In Experiment 1, chimpanzees were presented with an ordinal series of colored containers that they sequenced on the basis of relative preference for the different foods that were consistently hidden under the containers. Chimpanzees also were presented with a relative quantity judgment task in which they saw identical containers cover different amounts of a consistent food type. Then, the ordinal and quantity tasks were combined such that the colored containers from the ordinal task were used as covers for the consistent food type from the quantity task. This created instances of congruency (e.g., a highly preferred colored container placed over the largest food quantity) and incongruency (e.g., a highly preferred colored container placed over a small food quantity) between task-relevant and task-irrelevant features. Interference effects were evident when chimpanzees responded on the basis of task-irrelevant features (i.e., container value) rather than task-relevant features (i.e., food quantity), sometimes leading to suboptimal responses in incongruent trial types. Chimpanzees also demonstrated some evidence of the cognitive control needed to inhibit responding based solely on the learned values of the containers. (PsycINFO Database Record


The stress-induced virulence protein InlH controls interleukin-6 production during murine listeriosis.
The genome of the pathogenic bacterium Listeria monocytogenes contains a family of genes encoding proteins with a leucine-rich repeat domain. One of these genes, inlH, is a sigma(B)-dependent virulence gene of unknown function. Previously, inlH was proposed to be coexpressed with two adjacent internalin genes, inlG and inlE. Using tiling arrays, we showed that inlH expression is monocistronic and specifically induced in stationary phase as well as in the intestinal lumen of mice, independent of inlG and inlE expression. Consistent with inlH sigma(B)-dependent regulation, surface expression of the InlH protein is induced when bacteria are subjected to thermal, acidic, osmotic, or oxidative stress. Disruption of inlH increases the amount of the invasion protein InlA without changing inlA transcript level, suggesting that there is a link between inlH expression and inlA posttranscriptional regulation. However, in contrast to InlA, InlH does not contribute to bacterial invasion of cultured cells in vitro or of intestinal cells in vivo. Strikingly, the reduced virulence of inlH-deficient L. monocytogenes strains is accompanied by enhanced production of interleukin-6 (IL-6) in infected tissues during the systemic phase of murine listeriosis but not by enhanced production of any other inflammatory cytokine tested. Since InlH does not modulate IL-6 secretion in macrophages at least in vitro, it may play a role in other immune cells or contribute to a pathway that modulates survival or activation of IL-6-secreting cells. These results strongly suggest that InlH is a stress-induced surface protein that facilitates pathogen survival in tissues by tempering the inflammatory response.


Controls for lung dendritic cell maturation and migration during respiratory viral infection.
Dendritic cells are ideally suited to orchestrate the innate and adaptive immune responses to infection, but we know little about how these cells respond to infection with common respiratory viruses. Paramyxoviral infections are the most frequent cause of serious respiratory illness in childhood and are associated with an increased risk of asthma. We therefore used a high-fidelity mouse model of paramyxoviral respiratory infection triggered by Sendai virus to examine the response of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) in the lung. We found that pDCs are scarce at baseline but become the predominant population of lung dendritic cells during infection. This recruitment allows for a source of IFN-alpha locally at the site of infection. In contrast, cDCs rapidly differentiate into myeloid cDCs and begin to migrate from the lung to draining lymph nodes within 2 h after viral inoculation. These events cause the number of lung cDCs to decrease rapidly and remain decreased at the site of viral infection. Maturation and migration of lung cDCs depends on Ccl5 and Ccr5 signals because these events are significantly impaired in Ccl5(-/-) and Ccr5(-/-) mice. cDCs failure to migrate to draining lymph nodes in Ccl5(-/-) or Ccr5(-/-) mice is associated with impaired up-regulation of CCR7 that would normally direct this process. Our results indicate that pDCs and cDCs respond distinctly to respiratory paramyxoviral infection with patterns of movement that should serve to coordinate the innate and adaptive immune responses, respectively.


Reno-protective effect of Rheum turkestanicum against gentamicin-induced nephrotoxicity.
Gentamicin belongs to the family of aminoglycoside antibiotics and is a preferred drug in developing countries because of its low cost, availability, and potent effects against bacterial. However, gentamicin can induce nephrotoxicity. In this research, hydroalcoholic extract of Rheum turkestanicum was used against gentamicin- induced nephrotoxicity and its effect against gentamicin-induced nephrotoxicity in rats has been investigated. The rats were placed into one of these groups: saline group, gentamicin group that received gentamicin 80 mg/kg/day for six days, and two treatment groups that received R. turkestanicum intraperitoneally at doses of 100 and 200 mg/kg body weight, respectively, 1 hr before gentamicin injections. Urine samples were collected at 24 hr to measure glucose and protein concentration. Blood samples were collected to determine serum urea and creatinine. One kidney was homogenized to measure malondialdehyde and thiol, and the other kidney was kept for pathological studies. Gentamicin increased the level of urinary glucose and protein, and increased malondialdehyde while it decreased thiol in kidney tissue, and increased the concentration of urea and creatinine in the serum. Histopathological pathology revealed renal damage following gentamicin usage; however, the extract was able to improve gentamicin toxicity. R. turkestanicum has positive effects in the attenuation of gentamicin-induced nephrotoxicity.


Postmortem Findings in a Young Man With Congenital Generalized Lipodystrophy, Type 4 Due to CAVIN1 Mutations.
Congenital generalized lipodystrophy, type 4 (CGL4) is a rare autosomal recessive disorder caused by mutations in caveolae-associated protein 1. Patients with CGL4 also have myopathy and cardiomyopathy with a predisposition for sudden death due to ventricular arrhythmias. However, the underlying pathology for these morbidities remains unknown. Therefore, we report on an autopsy of a Hispanic boy with CGL4. Our patient had early-onset generalized lipodystrophy, feeding difficulties, myopathy, atlanto-axial dislocation, and learning disabilities. He was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) at age 8 years, had poor compliance with medications, and died suddenly at age 15.3 years. Autopsy showed marked loss of subcutaneous and omental fat with no inflammatory cells in adipose tissue and normal adipocytes in the parathyroid glands. There were adipocytes interdigitating cardiac muscle fibers, with fibro-fatty infiltration in the right ventricle, near coronary sinus, and atrioventricular node. There was no evidence of coronary heart disease. The quadriceps femoris muscle did not show adipocyte infiltration, inflammation, or fibrosis. The muscularis mucosa layer was thickened in the esophagus and at the gastro-duodenal junction, and the esophagus had prominent, large nerves in the subserosa. The liver weighed 3000 g, with minimal chronic inflammation and steatosis in 40% of parenchyma, primarily in zones 2 and 3. There was no spermatogenesis in the spermatic tubules. Our data suggest that fibro-fatty infiltration of the right ventricle may contribute to CPVT in patients with CGL4. Thick muscularis mucosa and large nerves in the esophagus likely contributed to dysphagia and dysmotility. A lack of spermatids suggests infertility in affected male patients.


Prevalence and diversity of enterotoxigenic Escherichia coli strains in fresh produce.
Analysis of fresh produce showed that enterotoxigenic Escherichia coli (ETEC) strains are most often found in cilantro and parsley, with prevalence rates of approximately 0.3%. Some ETEC strains also carried Shiga toxigenic E. coli (STEC) genes but had no STEC adherence factors, which are essential to cause severe human illness. Most ETEC strains in produce carried stable toxin and/or labile toxin genes but belonged to unremarkable serotypes that have not been reported to have caused human illnesses.


[Asthenic syndrome in patients with burnout syndrome].
The authors present the results of a survey of 103 patients aged 25 to 45 years with burnout syndrom. The results showed that most patients with the syndrome of burnout have clinical manifestations of asthenia, varying degrees of severity. According to psychological and psychophysiological examination in this group of patients were found attention and memory dysfunction. This study evaluated the efficacy of memoplant in the treatment of this pathology. The high efficiency of memoplant (improvement in 69.7% of cases) was detected, confirmed by the data of the clinical, psychological and neuropsychological research.