Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer.
Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castration-resistant prostate cancer. Eligible men had castration-resistant prostate cancer treated with one prior chemotherapy. Subjects were treated with 6 mg/kg CNTO328 i.v. every 2 weeks for 12 cycles. Response was assessed after every three cycles. Primary end point was prostate-specific antigen (PSA) response rate defined as a 50% reduction. Accrual was planned in two stages, with 20 eligible patients in the first stage and 40 overall. Plasma cytokines and growth factors were measured by Luminex. Fifty-three eligible subjects had all received prior taxane therapy. Two (3.8%; 95% CI, 0.5-13.0%) had PSA response. None of the 31 patients with measurable disease had a RECIST (Response Evaluation Criteria in Solid Tumors) response but 7 (23%) had stable disease. With median follow-up of 14.8 months, median progression-free survival was 1.6 months (95% CI, 1.6-1.7) and median overall survival was 11.6 months (95% CI, 7.5-19.0). Grade 3/4 toxicities included disseminated intravascular coagulation (1), central nervous system ischemia (1), elevated aspartate aminotransferase (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leukopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (interquartile range, 2.5-41.5). Patients with IL-6 >12.5 pg/mL had worse survival than those with levels <12.5 pg/mL (53% versus 94%; P = 0.02). After treatment, IL-6 levels were >250-fold higher. Thirty-two of 38 patients had a decline in C-reactive protein plasma levels at 6 weeks. CNTO328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Declining C-reactive protein levels during treatment may reflect biological activity. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis.


Examination of food waste co-digestion to manage the peak in energy demand at wastewater treatment plants.
Many digesters in Germany are not operated at full capacity; this offers the opportunity for co-digestion. Within this research the potentials and limits of a flexible and adapted sludge treatment are examined with a focus on the digestion process with added food waste as co-substrate. In parallel, energy data from a municipal wastewater treatment plant (WWTP) are analysed and lab-scale semi-continuous and batch digestion tests are conducted. Within the digestion tests, the ratio of sewage sludge to co-substrate was varied. The final methane yields show the high potential of food waste: the higher the amount of food waste the higher the final yield. However, the conversion rates directly after charging demonstrate better results by charging 10% food waste instead of 20%. Finally, these results are merged with the energy data from the WWTP. As an illustration, the load required to cover base loads as well as peak loads for typical daily variations of the plant's energy demand are calculated. It was found that 735 m³ raw sludge and 73 m³ of a mixture of raw sludge and food waste is required to cover 100% of the base load and 95% of the peak load.


PAR-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease.
To assess the effect of vorapaxar on global thrombotic and thrombolytic status. The propensity for thrombus formation is determined by the balance between prothrombotic factors and endogenous thrombolysis. Impaired thrombolytic status increases cardiovascular risk. Vorapaxar is a novel, oral, protease-activated receptor-1 antagonist that inhibits thrombin-induced platelet activation. In the TRACER and TRA 2°P-TIMI 50 studies, patients with acute coronary syndromes and established atherosclerosis were randomized to vorapaxar 2.5 mg daily or placebo, in addition to standard care. In 57 patients enrolled in a single center, blood was tested with the point-of-care global thrombosis test, on and off treatment. This automated test employs non-anticoagulated blood to assess thrombotic and thrombolytic status, measuring the time required to form a shear-induced thrombus under physiological conditions (occlusion time, OT), and subsequently, the time to achieve endogenous lysis of the thrombus (lysis time, LT). Patients on vorapaxar exhibited longer OT on vs. off treatment [median 561 s (interquartile range 422-654) vs. 372 s(338-454), P = 0.003] and shorter LT on treatment than off [1,158 s(746-1,492) vs. 1,733 s(1,388-2,230), P = 0.016]. Patients on placebo showed no difference in OT [419 s(343-514) vs. 411 s(346-535), P = 0.658] or LT [1,236 s(985-1,594) vs. 1,400 s(1,092-1,686), P = 0.524] on and off treatment. During treatment, OT was longer in patients taking vorapaxar [561 s(422-654) vs. 419 s(343-514), P = 0.009], but LT was similar in vorapaxar and placebo arms [1,158 s(746-1,492) vs. 1,236 s(985-1,594), P = 0.277]. Vorapaxar prolongs OT and shortens LT, with favorable effects on thrombotic and thrombolytic status. In addition to its antiplatelet effect, vorapaxar may enhance endogenous thrombolysis, which is frequently impaired in coronary disease.


The use of neoadjuvant platinum-based chemotherapy in locally advanced breast cancer that is triple negative: retrospective analysis of 144 patients.
Triple-negative breast cancers comprise about 20 % of breast cancers. They have poor prognosis and have no standard therapy. The aim of this study was to evaluate pathologic complete response (pCR), progression-free survival (PFS), and overall survival (OS) in patients with TNBC treated with neoadjuvant platinum-based chemotherapy. This is a retrospective study of one hundred and forty-four women with TNBC treated with neoadjuvant platinum-containing chemotherapy for locally advanced breast cancer at the University of Miami between January 1, 1999, and January 1, 2011. The medical record was reviewed to obtain data on clinical characteristics, including ethnicity, race, age, clinical stage, treatment regimen, and vital status. This study was approved by the University of Miami IRB. All patients had locally advanced breast cancer with at least one of the following features at presentation: T3, T4, N2, and N3. The mean tumor size by palpation was 9.4 cm. The clinical T-stage at presentation was 1.4 % T1, 8.3 % T2, 52.8 % T3, and 37.5 % T4 (19.4 % T4d). The nodal status by physical exam at presentation was 23 % N0, 37.5 % N1, 34 % N2, and 5.5 % N3. pCR in breast and axilla was seen in 31 %. PFS and OS were 55 and 59 %, respectively, at 7 years. Cisplatin offered a survival advantage over carboplatin in both PFS (P = 0.007) and OS (P = 0.018). Node positivity was the most important predictor of survival. Cisplatin/docetaxel neoadjuvant therapy was well tolerated and an effective therapy in locally advanced TNB.


Impact of age at first childbirth on primary open-angle glaucoma.
No studies have addressed the relationship between the timing of first childbirth and primary open-angle glaucoma (POAG). The aim of the study was to identify the relationship between age at first childbirth and POAG and to examine the contribution of parity to the age at first childbirth-POAG relationship in postmenopausal women. The study population comprised postmenopausal women aged 50 or above in the cross-sectional Korea National Health and Nutrition Examination Survey from 2010 to 2012. Participants were grouped into quintiles by age at first childbirth for analysis. This study used logistic regression and mediation analyses with accommodations for the complex sampling structure of the survey. Of the 4,057 women in the study population, the mean age at first childbirth was 23.7 years, and POAG prevalence was 3.4%. Prevalence of POAG was lowest in women whose first childbirth was between the ages of 27 and 44 (1.8%). Their risk for POAG (odds ratio [OR], 0.25; 95% CI, 0.10-0.65) was significantly lower than in those whose first childbirth was between the ages of 13 and 20, after adjustments for covariates. Late first delivery (≥27 y) was directly (OR, 0.57) and totally (OR, 0.85) associated with the decreased risk of POAG; decreased parity in women who delivered their first child at an older age attenuated the age at first childbirth-POAG relationship (OR of indirect effect, 1.50). First childbirth at the age of 27 years or above decreases the risk of POAG in postmenopausal women. Decreased parity, caused by late first childbirth, attenuated the magnitude of the total effects of age at first childbirth on POAG.


Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted. We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety. The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001). Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).


[Golgi's documents about the history of malaria].
Camillo Golgi played a key role in the studies of malaria infection. Among his outstanding contributions to the topic are the description of the intraerythrocytic cycle of the malaria parasite Plasmodium, responsible for the quartan and tertian fever, and the discovery of the temporal relationship between the recurrent attacks of fever and parasite's multiplication in human blood. Moreover, Golgi was also actively involved in the campaigns against malaria performed in the first ten years of this century by his pupil Adelchi Negri. Golgi's archive at the Museum for the History of the Pavia University keeps important materials on the role of this scientist in the history of malariology. Here we summarize and report some brief extracts of the documents (mainly letters from the nineteenth century biologists to Golgi) relevant to the history of human malaria.


The acute care nurse practitioner role in Canada.
The acute care nurse practitioner (ACNP) role was developed in Canada in the late 1980s to offset rapidly increasing physician workloads in acute care settings and to address the lack of continuity of care for seriously ill patients and increased complexity of care delivery. These challenges provided an opportunity to develop an advanced practice nursing role to care for critically ill patients with the intent of improving continuity of care and patient outcomes. For this paper, we drew on the ACNP-related findings of a scoping review of the literature and key informant interviews conducted for a decision support synthesis on advanced practice nursing. The synthesis revealed that ACNPs are working in a range of clinical settings. While ACNPs are trained at the master's level, there is a gap in specialty education for ACNPs. Important barriers to the full integration of ACNP roles into the Canadian healthcare system include lack of full utilization of role components, limitations to scope of practice, inconsistent team acceptance and funding issues. Facilitators to ACNP role implementation include clear communication about the role, with messages tailored to the specific information needs of various stakeholder groups; supportive leadership of healthcare managers; and stable and predictable funding. The status of ACNP roles continues to evolve across Canada. Ongoing leadership and continuing research are required to enhance the integration of these roles into our healthcare system.


A qualitative investigation of changes in the belief systems of families of children with autism or Down syndrome.
There have been few reports of the world views, values and priorities of families of children with autism or Down syndrome, despite the fact that family belief systems are considered to be among the most important factors affecting the adaptation and resilience of families. Transcripts from three focus groups involving 19 key informants (15 parents of children with autism or Down syndrome, and 4 service providers) were analysed using qualitative methods. The themes indicated that raising a child with a disability can be a life-changing experience that spurs families to examine their belief systems. Parents can come to gain a sense of coherence and control through changes in their world views, values and priorities that involve different ways of thinking about their child, their parenting role, and the role of the family. Although parents may grapple with lost dreams, over time positive adaptations can occur in the form of changed world views concerning life and disability, and an appreciation of the positive contributions made by children to family members and society as a whole. Parents' experiences indicate the importance of hope and of seeing possibilities that lie ahead. The information from this study may be used to provide families with an advance understanding of the changes in beliefs that they might undergo, and assists service providers in providing individualized and family-centred services and supports to families.


Profiling of the tetraspanin CD151 web and conspiracy of CD151/integrin β1 complex in the progression of hepatocellular carcinoma.
Tetraspanin CD151 has been implicated in metastasis through forming complexes with different molecular partners. In this study, we mapped tetraspanin web proteins centered on CD151, in order to explore the role of CD151 complexes in the progression of hepatocellular carcinoma (HCC). Immunoprecipitation was used to isolate tetraspanin complexes from HCCLM3 cells using a CD151 antibody, and associated proteins were identified by mass spectrometry. The interaction of CD151 and its molecular partners, and their roles in invasiveness and metastasis of HCC cells were assayed through disruption of the CD151 network. Finally, the clinical implication of CD151 complexes in HCC patients was also examined. In this study, we identified 58 proteins, characterized the tetraspanin CD151 web, and chose integrin β1 as a main partner to further investigate. When the CD151/integrin β1 complex in HCC cells was disrupted, migration, invasiveness, secretion of matrix metalloproteinase 9, and metastasis were markedly influenced. However, both CD151 and integrin β1 expression were untouched. HCC patients with high expression of CD151/integrin β1 complex had the poorest prognosis of the whole cohort of patients. Together, our data show that CD151 acts as an important player in the progression of HCC in an integrin β1-dependent manner.


ParkIndex: Using Key Informant Interviews to Inform the Development of a New Park Access Evaluation Tool.
The relationship between park availability, physical activity, and positive health outcomes has been documented across the globe. However, studying how people access parks and why they use the parks is difficult due to a lack of consensus with respect to measurement approaches and assessment of park environments. Establishing a parsimonious method and tool for quantifying both park availability and park quality represents a major step that could advance park and physical activity research and practice. This paper describes phase one of the effort to develop such a measurement tool, known as ParkIndex. ParkIndex is a two-year National Institutes of Health (NIH)-funded study to create an evidence-based tool that will assist citizens and professionals in understanding and using information regarding community park access and use. Phase one consisted of key informant interviews conducted with research and practice leaders to inform development and provide insight on the essential foundations of ParkIndex. Twelve professionals from practice and academia, including parks and recreation, landscape design, and public health sectors, were interviewed in fall 2016. Key informants were interviewed on four topics concerning the content, value, feasibility, and dissemination of ParkIndex. Trained research assistants employed double, emergent, open, and axial coding methods to develop key themes and concepts to guide phase 2 and further development of ParkIndex. Key themes throughout the interviews included measures for park use, including distance, safety, neighborhood characteristics, route and travel mode to park, and overall park characteristics. Park elements discussed included quality of, and availability of, amenities, activity spaces, programming, and park management, as well as the context of the park and the engagement of the local community. Respondents determined that ParkIndex could benefit park planning and community development and provide for a standardized method for evaluating park access. Interviews and themes offer parks and public health practitioners and researchers-and this specific ParkIndex development team-the opportunity to refine and evaluate measures to be included in a comprehensive park access and use tool. Key informants repeatedly referenced the need, especially within parks and recreation management, for consistent, reliable, and valid measures of park access and use, such as ParkIndex seeks to provide. We believe a well-conceived, integrated index will at the very least allow for greater comparison between parks and park systems and at best will facilitate the many park stakeholders to best design, maintain, program, research, and advocate for their local parks.


Polycentric spatial focus of time-reversal electromagnetic field in rectangular conductor cavity.
Polycentric focus effect of time-reversal (TR) electromagnetic field is found in a rectangular resonant cavity. Theoretical deduction shows that the effect is due to the mirror symmetry of the cavity and the maximum number of focus points is 27 including 1 main focus point and 26 secondary focus points. A case of 6 focus points is calculated, in which the numerical results are consistent with the theoretical predictions, and particularly the 5 secondary focus points have directly resulted in inaccurate imaging and pulse signal interception.


Proteomic profiling reveals that EhPC4 transcription factor induces cell migration through up-regulation of the 16-kDa actin-binding protein EhABP16 in Entamoeba histolytica.
Actin cytoskeleton is an essential structure involved in cell migration and invasion in parasites. In Entamoeba histolytica, the protozoan parasite causing human amoebiasis, the mechanisms underlying the expression of migration-related genes are poorly understood. Here, we investigated the biological effects of ectopic overexpression of EhPC4 (positive coactivator 4) in cell migration of E. histolytica trophozoites. Using differential in gel two-dimensional electrophoresis, 33 modulated proteins were detected in EhPC4-overexpressing cells. By electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis, 16 of these proteins were identified. Interestingly, four up-regulated proteins involved in cytoskeleton organization and cell migration were identified. Particularly, we found the up-regulation of a 16-kDa actin-binding protein (EhABP16) which is a putative member of the cofilin/tropomyosin family involved in actin polymerization. EhPC4 overexpression induced a significant increase in migration of trophozoites and in the destruction of human SW480 colon cells. Consistently, silencing of gene expression by RNA interference of EhABP16 significantly impairs cell migration. These changes were associated to alterations in the organization of actin cytoskeleton, and suppression of uropod-like structure formation in EhABP16-deficient cells. In summary, we have uncovered novel proteins modulated by EhPC4, including EhABP16, with a potential role in cell migration, cytopathogenicity and virulence in E. histolytica. The human pathogen Entamoeba histolytica infects around 50million people worldwide resulting in 40,000-100,000 deaths annually. Cell motility is a complex trait that is critical for parasites adaptation, spread and invasion processes into host tissues; it has been associated with virulence. In this study, we used a differential proteomic approach to demonstrate that E. histolytica EhPC4 induces changes in the expression of actin cytoskeleton proteins, including EhABP16, promoting a significant increase in cell motility and destruction of intestinal human cells. Particularly, we demonstrated for the first time that abrogation of EhABP16 impairs cell migration by altering the actin cytoskeleton dynamics and uropod-like structure formation in trophozoites. These data contribute to the understanding of molecular mechanisms that regulate virulence properties in this neglected protozoan parasite.


Polarization-dependent GaN surface grating reflector for short wavelength applications.
This study proposes a one-dimensional sub-wavelength grating structure on GaN surface which behaves as a reflector for transverse-electric polarized light in the blue wavelength range. The rigorous coupled-wave analysis method was used to analyze the effects of various structural parameters on the reflectance spectra of the grating. Based on the optimal design, a GaN surface grating reflector (SGR) was fabricated using holographic lithography and dry etching processes. It showed reflectance that exceeded 90% over a 60-nm bandwidth. The obtained experimental results were in good agreement with simulated ones. The SGR has an advantage of structural simplicity, which should greatly facilitate the fabrication and integration of high reflectors on GaN-based short-wavelength photonic devices.


Piscivore-prey fish interactions: mechanisms behind diurnal patterns in prey selectivity in brown and clear water.
Environmental change may affect predator-prey interactions in lakes through deterioration of visual conditions affecting foraging success of visually oriented predators. Environmental change in lakes includes an increase in humic matter causing browner water and reduced visibility, affecting the behavioural performance of both piscivores and prey. We studied diurnal patterns of prey selection in piscivorous pikeperch (Sander lucioperca) in both field and laboratory investigations. In the field we estimated prey selectivity and prey availability during day and night in a clear and a brown water lake. Further, prey selectivity during day and night conditions was studied in the laboratory where we manipulated optical conditions (humic matter content) of the water. Here, we also studied the behaviours of piscivores and prey, focusing on foraging-cycle stages such as number of interests and attacks by the pikeperch as well as the escape distance of the prey fish species. Analyses of gut contents from the field study showed that pikeperch selected perch (Perca fluviatilis) over roach (Rutilus rutilus) prey in both lakes during the day, but changed selectivity towards roach in both lakes at night. These results were corroborated in the selectivity experiments along a brown-water gradient in day and night light conditions. However, a change in selectivity from perch to roach was observed when the optical condition was heavily degraded, from either brown-stained water or light intensity. At longer visual ranges, roach initiated escape at distances greater than pikeperch attack distances, whereas perch stayed inactive making pikeperch approach and attack at the closest range possible. Roach anti-predatory behaviour decreased in deteriorated visual conditions, altering selectivity patterns. Our results highlight the importance of investigating both predator and prey responses to visibility conditions in order to understand the effects of degrading optical conditions on piscivore-prey interaction strength and thereby ecosystem responses to brownification of waters.


Distal pancreatectomy: indications and outcomes in 235 patients.
Distal pancreatectomy is performed for a variety of benign and malignant conditions. In recent years, significant improvements in perioperative results have been observed at high-volume centers after pancreaticoduodenectomy. Little data, however, are available concerning the current indications and outcomes after distal pancreatectomy. This single-institution experience reviews the recent indications, complications, and outcomes after distal pancreatectomy. A retrospective analysis was performed of the hospital records of all patients undergoing distal pancreatectomy between January 1994 and December 1997, inclusive. The patient population (n = 235) had a mean age of 51 years, (range 1 month to 82 years); 43% were male and 84% white. The final diagnoses included chronic pancreatitis (24%), benign pancreatic cystadenoma (22%), pancreatic adenocarcinoma (18%), neuroendocrine tumor (14%), pancreatic pseudocyst (6%), cystadenocarcinoma (3%), and miscellaneous (13%). The level of resection was at or to the left of the superior mesenteric vein in 96% of patients. A splenectomy was performed in 84% and a cholecystectomy in 15% of patients. The median intraoperative blood loss was 450 ml, the median number of red blood cell units transfused was zero, and the median operative time was 4.3 hours. Two deaths occurred in the hospital or within 30 days of surgery for a perioperative mortality rate of 0.9%. The overall postoperative complication rate was 31%; the most common complications were new-onset insulin-dependent diabetes (8%), pancreatic fistula (5%), intraabdominal abscess (4%), small bowel obstruction (4%), and postoperative hemorrhage (4%). Fourteen patients (6%) required a second surgical procedure; the most common indication was postoperative bleeding. The median length of postoperative hospital stay was 10 days. Patients who underwent a distal pancreatectomy with splenectomy (n = 198) had a similar complication rate (30% vs. 29%), operative time (4.6 vs. 5.1 hours), and intraoperative blood loss (500 vs. 350 ml) and a shorter postoperative length of stay (13 vs. 21 days) than the patients who had splenic preservation (n = 37). This series represents the largest single-institution experience with distal pancreatectomy. These data demonstrate that elective distal pancreatectomy is associated with a mortality rate of <1%. These results demonstrate that, as with pancreaticoduodenectomy, distal pancreatectomy can be performed with minimal perioperative mortality and acceptable morbidity.


['Nothing' or 'just a bit'? 'Much' or 'too much'? Impulsivity traits as markers of severity transitions within non-problematic and problematic ranges of alcohol and Internet use].
This study aims to explore the relationship between impulsivity traits and perceived negative consequences of alcohol consumption and Internet use. More specifically, impulsivity traits - positive and negative urgency, sensation seeking, lack of premeditation, and lack of perseverance - in (1) the occurrence of initial negative consequences linked to use, and (2) the transition from consequences possibly indicating a problematic behavior to consequences very likely indicating a clinical problem. For this, 709 first-year college students were assessed using the UPPS-P impulsive behavior scale, and the Multicage CAD-4 scale for addictive behaviors. Logistic regressions were used to discriminate (a) between individuals with a 0-score and individuals with a 1-score in the Multicage scales (low severity range), and (b) between individuals with a 2-score and individuals with 3/4-score (high severity range), separately for alcohol and Internet use. For alcohol use, positive urgency and lack of premeditation marked the transition from 0 to 1 scores, whereas negative urgency marked the transition from 2 to 3/4 scores. For Internet use, however, none of the UPPS-P dimensions significantly marked the transition from 0 to 1 (occurrence of initial negative consequences), and positive urgency marked the transition from 2 to 3/4 (from possible to very likely problematic behavior). Negative urgency arises as a pathologization marker for alcohol abuse, whereas changes in non-clinical levels are linked to impulsivity elicited by appetitive emotions. Impulsivity does not seem to play any role in low severity levels of Internet use, and positive urgency marks the transition between high severity scores. These differential patterns are indicative of different etiological paths for excessive Internet use and substance abuse.


Is complementary and alternative medicine effective in job satisfaction among dentists with musculoskeletal disorders? A cross sectional study.
Musculoskeletal disorders have serious impact on the profession of dentistry. There is common occurrence of pain due to incorrect posture in dental professionals. Complementary and alternative medicine (CAM) therapies may cast a new light on preventing and intercepting musculoskeletal disorders (MSD). An epidemiological study was conducted in an effort to contribute to the prevention of musculoskeletal disorders in dentistry. The purpose of this study was to determine the prevalence of MSD at dentists using CAM as a treatment and preventive modality for MSD and to compare job/career satisfaction between dentists who use CAM and conventional therapy (CT). Dentists registered in Uttrakhand state, India, under the Dental Council of India and registered members of the Indian Dental Association, Uttrakhand branch (N = 1496) were surveyed. Statistical analysis was conducted using SPSS 17. A response rate of 84% (N = 1257) was obtained, revealing that 90% (N = 1131) had the problem of MSD. Seventy three percentage (N = 826) of dentists with MSD reported the use of CAM and CT. Complementary and alternative medicine users reported greater overall health (72.7% vs. 51%, p < 0.001), job satisfaction (61.2% vs. 35%, p < 0.001) and work efficiency compared to CT users. Complementary and alternative medicine therapies may improve quality of life, reduce work interruption and enhance job satisfaction for dentists who suffers from MSD. Through the course of their studies, dentists should be equipped with knowledge on ergonomics and CAM therapies, such as yoga and others, to help them prevent musculoskeletal disorders more effectively.


The Investigation of Protein Diffusion via H-Cell Microfluidics.
In this study, we developed a microfluidics method, using a so-called H-cell microfluidics device, for the determination of protein diffusion coefficients at different concentrations, pHs, ionic strengths, and solvent viscosities. Protein transfer takes place in the H-cell channels between two laminarly flowing streams with each containing a different initial protein concentration. The protein diffusion coefficients are calculated based on the measured protein mass transfer, the channel dimensions, and the contact time between the two streams. The diffusion rates of lysozyme, cytochrome c, myoglobin, ovalbumin, bovine serum albumin, and etanercept were investigated. The accuracy of the presented methodology was demonstrated by comparing the measured diffusion coefficients with literature values measured under similar solvent conditions using other techniques. At low pH and ionic strength, the measured lysozyme diffusion coefficient increased with the protein concentration gradient, suggesting stronger and more frequent intermolecular interactions. At comparable concentration gradients, the measured lysozyme diffusion coefficient decreased drastically as a function of increasing ionic strength (from zero onwards) and increasing medium viscosity. Additionally, a particle tracing numerical simulation was performed to achieve a better understanding of the macromolecular displacement in the H-cell microchannels. It was found that particle transfer between the two channels tends to speed up at low ionic strength and high concentration gradient. This confirms the corresponding experimental observation of protein diffusion measured via the H-cell microfluidics.


Hand position alters vision by modulating the time course of spatial frequency use.
The nervous system gives preferential treatment to objects near the hands that are candidates for action. It is not yet understood how this process is achieved. Here we show evidence for the mechanism that underlies this process having used an experimental technique that maps the use of spatial frequencies (SFs) during object recognition across time. We used this technique to replicate and characterize with greater precision the coarse-to-fine SF sampling observed in previous studies. Then we show that the visual processing of real-world objects near an observer's hands is biased toward the use of low-SF information, around 288 ms. Conversely, high-SF information presented around 113 ms impaired object recognition when objects were presented near the hands. Notably, both of these effects happened relatively late during object recognition and suggest that the modulation of SF use by hand position is at least partly attentional in nature. (PsycINFO Database Record


The cultural evolution of prosocial religions.
We develop a cultural evolutionary theory of the origins of prosocial religions and apply it to resolve two puzzles in human psychology and cultural history: (1) the rise of large-scale cooperation among strangers and, simultaneously, (2) the spread of prosocial religions in the last 10-12 millennia. We argue that these two developments were importantly linked and mutually energizing. We explain how a package of culturally evolved religious beliefs and practices characterized by increasingly potent, moralizing, supernatural agents, credible displays of faith, and other psychologically active elements conducive to social solidarity promoted high fertility rates and large-scale cooperation with co-religionists, often contributing to success in intergroup competition and conflict. In turn, prosocial religious beliefs and practices spread and aggregated as these successful groups expanded, or were copied by less successful groups. This synthesis is grounded in the idea that although religious beliefs and practices originally arose as nonadaptive by-products of innate cognitive functions, particular cultural variants were then selected for their prosocial effects in a long-term, cultural evolutionary process. This framework (1) reconciles key aspects of the adaptationist and by-product approaches to the origins of religion, (2) explains a variety of empirical observations that have not received adequate attention, and (3) generates novel predictions. Converging lines of evidence drawn from diverse disciplines provide empirical support while at the same time encouraging new research directions and opening up new questions for exploration and debate.


Polymorphism H558R in the human cardiac sodium channel SCN5A gene is associated with atrial fibrillation.
Atrial fibrillation (AF) is one of the most common sustained cardiac arrhythmias and its prevalence is increasing worldwide in line with the growing elderly population. Many single nucleotide polymorphisms and mutations are associated with AF, including the common loss-of-function histidine-558-to-arginine (H558R) polymorphism of the human cardiac sodium channel, voltage-gated, type V, α subunit (encoded by the SCN5A gene). The H558R polymorphism results from the T-C transition in the SCN5A gene. This study recruited 135 patients with AF and 296 healthy controls to scan for and perform targeted genotyping of the H558R polymorphism of the SCN5A gene. Logistic regression analysis showed that the TC and CC genotypes (i.e. genotypes that result in the R558 polymorphism) were significantly associated with an increased risk of developing AF. The R558 polymorphism conferred an odds ratio for AF of 3.451 (95% confidence interval 1.718, 6.931). In conclusion, this study provided evidence for the role of the H558R polymorphism of the SCN5A gene in increasing the susceptibility to AF.


Compromised vascular endothelial cell SK(Ca) activity: a fundamental aspect of hypertension?
Smooth muscle hyperpolarization originating in the endothelium and commonly referred to as the EDHF (endothelium-derived hyperpolarizing factor) response provides a very significant drive to vasodilatation particularly in small resistance arteries. Together with other endothelium-dependent dilator pathways 'EDHF' hyperpolarization is compromised by cardiovascular disease, including hypertension. However, although attenuated vascular hyperpolarization has been described in animal models of hypertension, the underlying mechanisms are not fully understood. In the current issue of the British Journal of Pharmacology, Weston et al. combine classic pharmacological approaches with electrophysiological and molecular techniques to suggest that attenuated endothelium-dependent hyperpolarization (and as a consequence vasodilatation) reflects major disruption of pathways associated with the activation of endothelial small conductance Ca(2+)-activated K-channels (SK(Ca)) in mesenteric arteries from spontaneously hypertensive rats. In addition to reductions in SK(Ca) and K(IR) proteins, changes in caveolin-1 isomers were also detected, possibly indicating channel realignment within plasmalemmal structures.


Multiplex PCR strategy for rapid identification of structural types and variants of the mec element in methicillin-resistant Staphylococcus aureus.
Full characterization of methicillin-resistant Staphylococcus aureus (MRSA) requires definition of not only the bacterial genetic background but also the structure of the complex and heterologous mec element these bacteria carry, which is associated with drug resistance determinant mecA. We report the development, validation, and application of a multiplex PCR strategy that allows quick presumptive characterization of the mec element types based on the structural features that were shown to be typical of mec elements carried by several MRSA clones. The strategy was validated by using a representative collection of pandemic MRSA clones in which the full structure of the associated mec elements was previously determined by hybridization and PCR screenings and also by DNA sequencing. The method was tested together with multilocus sequence typing and other typing methods for the characterization of 18 isolates representative of the MRSA clones recovered during a hospital outbreak in Barcelona, Spain. The multiplex PCR was shown to be rapid, robust, and capable in a single assay of identifying five structural types of the mec element among these strains, three major and two minor variants, each one of which has been already been seen among MRSA characterized earlier. This technique should be a useful addition to the armamentarium of molecular typing tools for the characterization of MRSA clonal types and for the rapid tentative identification of structural variants of the mec element.


Bupropion for smoking cessation in African American light smokers: a randomized controlled trial.
Previous research demonstrated the efficacy of sustained release bupropion (bupropion SR) for smoking cessation in whites as well as moderate to heavy (≥10 cigarettes per day [CPD]) African American smokers. We evaluated whether bupropion SR was effective for smoking cessation among African American light smokers (≤10 CPD). A randomized, double-blind placebo-controlled trial was conducted from December 27, 2007, to May 13, 2010. All participants were African American light smokers (≤10 CPD), aged 18 years or older. Participants were randomly assigned to receive 300 mg bupropion SR (150 mg once daily for 3 days and then 150 mg twice daily) (n = 270 participants) or placebo (n = 270 participants) for 7 weeks, and up to six sessions of health education counseling. Serum cotinine was measured at baseline (week 0). The primary outcome was salivary cotinine-verified 7-day point prevalence smoking abstinence at week 26; a cut point of 15 ng/mL differentiated smokers from nonsmokers. Salivary cotinine-verified smoking abstinence at end of medication treatment at week 7 was also examined. Odds ratios (OR) for smoking abstinence and 95% confidence intervals (CIs) were calculated using logistic regression models. All statistical tests were two-sided. Participants at baseline visit (week 0) smoked an average of 8.0 CPD and had a mean serum cotinine level of 275.8 ng/mL (SD = 155.8 ng/mL); most used menthol cigarettes (83.7%) and smoked within 30 minutes of waking (72.2%). After imputing those lost to follow-up as smokers, no statistically significant difference in long-term smoking abstinence rates at week 26 was observed between bupropion SR and placebo groups (13.3% vs 10.0%, OR = 1.39, 95% CI = 0.82 to 2.35, P = .23). Cotinine-verified smoking abstinence rate at end of medication week 7 was higher in the bupropion SR vs placebo group (23.7% vs 9.6%, OR = 2.92, 95% CI = 1.78 to 4.77, P < .001). Bupropion SR was effective in promoting smoking cessation during the medication phase of treatment but showed no effect on long-term smoking cessation among African American light smokers. More research is needed to identify strategies for sustaining abstinence among African American light smokers.


Analytical approximations in multiple scattering of electromagnetic waves by aligned dielectric spheroids.
In a dense medium, the failure to properly take into account multiple-scattering effects could lead to significant errors. This has been demonstrated in the past from extensive theoretical, numerical, and experimental studies of electromagnetic wave scattering by densely packed dielectric spheres. Here, electromagnetic wave scattering by densely packed dielectric spheroids with aligned orientation is studied analytically through quasicrystalline approximation (QCA) and QCA with coherent potential (QCA-CP). We assume that the spheroids are electrically small so that single-particle scattering is simple. Low-frequency QCA and QCA-CP solutions are obtained for the average Green's function and the effective permittivity tensor. For QCA-CP, the low-frequency expansion of the uniaxial dyadic Green's function is required. The real parts of the effective permittivities from QCA and QCA-CP are compared with the Maxwell-Garnett mixing formula. QCA gives results identical to those with the mixing formula, while QCA-CP gives slightly higher values. The extinction coefficients from QCA and QCA-CP are compared with results from Monte Carlo simulations. Both QCA and QCA-CP agree well with simulations, although qualitative disagreement is evident at higher fractional volumes.


Experimental transmission of Pasteurella multocida 6:B in goats.
Haemorrhagic septicaemia (HS) is an acute disease of cattle and buffaloes caused by Pasteurella multocida 6:B. Outbreaks of the disease have been closely associated with carrier animals that transmit the organism to susceptible animals during stressful condition. This study was conducted to determine whether goats exposed intranasally to P. multocida 6:B can transmit the organism to contact goats. Thirty-six healthy local Katjang goats were divided into four groups and goats of groups 1 and 3 were each inoculated intranasally with a 1-ml inoculum that contained 1 x 10(9) CFU/ml of live P. multocida 6:B. Following the exposure, all goats of groups 3 and 4 were injected with dexamethasone at the rate of 1 mg/kg for three consecutive days. At the end of the dexamethasone treatment, goats of groups 1 and 2 were commingled but kept separate from goats of groups 3 and 4, which were commingled in another pen. Three surviving goats from each group were killed on days 7, 14 and 21 post-exposure for postmortem examination. Naso-pharyngeal mucus and heart blood were collected on swabs. Tissues from lungs, lymph nodes and tonsils were collected for bacteriological isolation and identification. Only one goat of group 3 died 6 days post-exposure showing clinical signs and lesions typical of HS. Other goats showed mild signs of upper respiratory tract infection. Goats of all groups developed acute mild pneumonic lesions, however, those treated with dexamethasone had significantly (P < 0.05) more extensive lesion scoring based on the lesion scoring system. P. multocida 6:B was isolated from the nasal mucosa and lung lesions of exposed and contact goats not treated with dexamethasone. Exposed and contact goats treated with dexamethasone carried the organism for 21 days. P. multocida isolation from heart blood was made only from exposed and contact goats treated with dexamethasone. P. multocida was isolated from the lymph node of the goat that died during the experiment.


3D surface-imaging for volumetric measurement in people with obesity.
Current methods for tracking the progress of people with obesity towards a weight loss goal appear simple and potentially misleading. A technique to quantify change in body shape whilst visualising areas of the body where weight loss occurs would be advantageous, and has the potential to be used as a motivational tool. Three-dimensional (3D) surface-imaging would serve as a good basis for such a technique, however current systems are prohibitively expensive. Highlight the use of a cheaper alternative 3D surface-imaging system for volumetric measurement in people with obesity. A recently developed low-cost 3D surface-imaging system was used, having previously being validated in a healthy population. A total of 61 people with obesity, enrolled on a weight-loss programme, were surface-imaged using the system. The findings suggest the low-cost system can obtain 3D surface-images of an obese human body, from which numerical parameters could be calculated and further analysis conducted. Further studies will focus on the validity and reliability of such analyses and the potential of the system to be considered as a long-term instalment in primary healthcare settings as a weight loss aid.


Erythrocytes are essential for development of cerebral vasculopathy resulting from subarachnoid hemorrhage in cats.
In an effort to determine which blood elements play a critical role in the development of cerebral vasospasm, adult cats were subjected to prepontine injection of either autogenous whole blood or erythrocyte-free blood containing latex beads as a substitute morphologic marker. Seven or 10 days later the cats were anesthetized and perfused with fixative, and the basilar arteries were prepared for light and electron microscopy. Successful clot deposition was confirmed by the presence of numerous erythrocytes or latex beads within the adventitia of vessels. In agreement with previous studies, instillation of whole blood produced luminal narrowing associated with profound ultrastructural changes in all layers of the vascular wall. No significant alterations, however, occurred in arteries bathed in erythrocyte-free blood. These findings suggest first, that erythrocytes are essential for the development of the vasculopathy associated with chronic cerebral vasospasm, and second, that the role, if any, of other blood elements is not autonomous.


Hidden progress: broadband plasmonic invisibility.
One of the key challenges in current research into electromagnetic cloaking is to achieve invisibility at optical frequencies and over an extended bandwidth. There has been significant progress towards this using the idea of cloaking by sweeping under the carpet of Li and Pendry. Here, we show that we can harness surface plasmon polaritons at a metal surface structured with a dielectric material to obtain a unique control of their propagation. We exploit this control to demonstrate both theoretically and experimentally cloaking over an unprecedented bandwidth (650-900 nm). Our non-resonant plasmonic metamaterial is designed using transformational optics extended to plasmonics and allows a curved reflector to mimic a flat mirror. Our theoretical predictions are validated by experiments mapping the surface light intensity at a wavelength of 800 nm.


Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation.
Human mesenchymal stem cells (hMSC) aid in tissue maintenance and repair by differentiating into specialized cell types. Due to this ability, hMSC are currently being evaluated for cell-based therapies of tissue injury and degenerative diseases. However, extensive expansion ex vivo is a prerequisite to obtain the cell numbers required for human cell-based therapy protocols. Recent studies indicate that hMSC may contribute to cancer development and progression either by acting as cancer-initiating cells or through interactions with stromal elements. If spontaneous transformation ex vivo occurs, this may jeopardize the use of hMSC as therapeutic tools. Whereas murine MSC readily undergo spontaneous transformation, there are conflicting reports about spontaneous transformation of hMSC. We have addressed this controversy in a two-center study by growing bone marrow-derived hMSC in long-term cultures (5-106 weeks). We report for the first time spontaneous malignant transformation to occur in 45.8% (11 of 24) of these cultures. In comparison with hMSC, the transformed mesenchymal cells (TMC) showed a significantly increased proliferation rate and altered morphology and phenotype. In contrast to hMSC, TMC grew well in soft agar assays and were unable to undergo complete differentiation. Importantly, TMC were highly tumorigenic, causing multiple fast-growing lung deposits when injected into immunodeficient mice. We conclude that spontaneous malignant transformation may represent a biohazard in long-term ex vivo expansion of hMSC. On the other hand, this spontaneous transformation process may represent a unique model for studying molecular pathways initiating malignant transformation of hMSC.


Expression of mRNA transcripts of the Na+/H+ and Cl-/HCO3- exchanger isoforms in human nasal mucosa.
Electrolyte transport by nasal epithelia has been suggested to be important for controlling the quantity and composition of the nasal fluid and may play an important role in the development of nasal polyps. One of a number of mechanisms involving translocation of Na+ and Cl- across cell membranes includes electroneutral processes, such as Na+/H+ exchange (NHE) and Cl-/HCO3- exchange (AE). The present study evaluated the presence of mRNAs for various members of the human NHE and AE gene families in human inferior turbinate mucosa and nasal polyp using reverse transcriptase polymerase chain reaction and in situ hybridization. The mRNA for NHE1 was detected in human turbinate mucosa and nasal polyp while the mRNAs for NHE2 and NHE3 could not be detected in any of the samples examined. Of the AE isoforms, AE2 mRNA was expressed in inferior turbinate mucosa but not in nasal polyp. In situ hybridization revealed that NHE1 mRNA in the turbinate mucosa and nasal polyp was localized in the epithelial layer and submucosal glands. AE2 mRNA was also expressed in the epithelial layer and submucosal glands of inferior turbinate mucosa. Taken together, these results indicate that the expression of AE2 mRNA is altered in nasal polyp compared with inferior turbinate mucosa, suggesting that the altered expression of these genes in nasal polyp may cause impaired electrolyte and water transport across the epithelial cells.


Quartz crystal microbalance based nanosensor for lysozyme detection with lysozyme imprinted nanoparticles.
The aim of this study is to prepare quartz crystal microbalance (QCM) nanosensor for the real-time detection of lysozyme. In the first part, the lysozyme imprinted (MIP) nanoparticles were prepared by mini-emulsion polymerization. The MIP nanoparticles were characterized by TEM, zeta-sizer and FTIR-ATR measurements. Particle size was found around 50 nm. The MIP nanoparticles were attached by dropping of nanoparticle solution to gold surface and then, dried at 37°C for 6h. QCM nanosensor was characterized with AFM and ellipsometer. The observations indicated that the nanoparticle film was almost monolayer. The detection limit was found as 1.2 ng/mL. The specificity of the QCM nanosensor was shown by using albumin as a competitor molecule. The results show that the QCM nanosensor has high selectivity and sensitivity with a wide range of lysozyme concentrations in both aqueous solutions (0.2-1500 μg/mL) and natural sources (egg white) (460-1500 ng/mL).


Urban-rural differences explain the association between serum 25-hydroxyvitamin D level and insulin resistance in Korea.
An increasing number of studies report associations between low serum 25-hydroxyvitamin D [25(OH)D] level and insulin resistance; however, whether low vitamin D levels directly contribute to increased insulin resistance is unclear. We investigated the impact of residential area on the association between 25(OH)D and insulin resistance in elderly Koreans. Using data from the Korean Urban Rural Elderly study, we conducted cross-sectional analyses in 1628 participants (505 men and 1123 women). Serum 25(OH)D was analyzed as both continuous and categorized variables. Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated using fasting blood glucose and insulin levels. In men, 25(OH)D level was inversely associated with HOMA-IR (standardized β = -0.133, p < 0.001) after adjustment for age, body mass index, waist circumference, smoking, alcohol intake, exercise, and study year. However, we noted significant urban-rural differences in 25(OH)D level (43.4 versus 65.6 nmol/L; p < 0.001) and HOMA-IR (1.2 versus 0.8 mmol · pmol/L2; p < 0.001). When we additionally adjusted for residential area, the association between 25(OH)D and HOMA-IR was attenuated (standardized β = -0.063, p = 0.115). In women, the association between 25(OH)D and HOMA-IR was not significant before or after adjustment for residential area. Environmental or lifestyle differences in urban and rural areas may largely explain the inverse association between serum 25(OH)D and insulin resistance.


Quantitative analysis of estimated scattering coefficient and phase retardation for ovarian tissue characterization.
In this report, optical scattering coefficient and phase retardation quantitatively estimated from polarization-sensitive OCT (PSOCT) were used for ovarian tissue characterization. A total of 33 ex vivo ovaries (normal: n = 26, malignant: n = 7) obtained from 18 patients were investigated. A specificity of 100% and a sensitivity of 86% were achieved by using estimated scattering coefficient alone; and a specificity of 100% and a sensitivity of 43% were obtained by using phase retardation alone. However, a superior specificity of 100% and sensitivity of 100% were achieved if these two parameters were used together for classifying normal and malignant ovaries. Quantitative measurement of collagen content obtained from Sirius red histology sections shows that it correlates with estimated scattering coefficient and phase retardation. Our initial results demonstrate that quantitative analysis of PSOCT could be a potentially valuable method for distinguishing normal from malignant ovarian tissues during minimally invasive surgery and help guide surgical intervention.


Mortality of elderly individuals with TBI in the first 5 years following injury.
Although there has been a decline in the incidence of TBI in the general population, the rate of TBI in older adults has increased. Increased age has been long recognized as a predictor of worse outcomes after TBI. Despite the growing number of TBI in the elderly, our understanding of the long-term consequences of TBI is quite limited. Chart review; individuals 55 years and older, who completed inpatient acute rehabilitation during the period 2003-2009 and who died one to four years after injury, were compared to matched patients who did not die. There were a significantly higher proportion of deceased subjects with a diagnosis of Abnormality of Gait (53%), respiratory medications at admission (32%) and discharge (17%). Deceased participants were more likely to be prescribed diabetes medication at discharge (35%) while controls were more likely to be prescribed cholesterol-lowering medications (27%) at admission. Deceased patients were discharged with significantly more medications, The results suggest the need for medical and lifestyle interventions for selected elderly TBI patients. The factors related to death following TBI in the elderly are in need of more research.


* CRISPR-Based Epigenome Editing of Cytokine Receptors for the Promotion of Cell Survival and Tissue Deposition in Inflammatory Environments.
Musculoskeletal diseases have been associated with inflammatory cytokine action, particularly action by TNF-α and IL-1β. These inflammatory cytokines promote apoptosis and senescence of cells in diseased tissue and extracellular matrix breakdown. Stem cell-based therapies are being considered for the treatment of musculoskeletal diseases, but the presence of these inflammatory cytokines will have similar deleterious action on therapeutic cells delivered to these environments. Methods that prevent inflammatory-induced apoptosis and proinflammatory signaling, in cell and pathway-specific manners are needed. In this study we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing to alter cell response to inflammatory environments by repressing inflammatory cytokine cell receptors, specifically TNFR1 and IL1R1. We targeted CRISPR/Cas9-based repressors to TNFR1 and IL1R1 gene regulatory elements in human adipose-derived stem cells (hADSCs) and investigated the functional outcomes of repression of these genes. Efficient signaling regulation was demonstrated in engineered hADSCs, as activity of the downstream transcription factor NF-κB was significantly reduced or maintained at baseline levels in the presence of TNF-α or IL-1β. Pellet culture of undifferentiated hADSCs demonstrated improved survival in engineered hADSCs treated with TNF-α or IL-1β, while having little effect on their immunomodulatory properties. Furthermore, engineered hADSCs demonstrated improved chondrogenic differentiation capacity in the presence of TNF-α or IL-1β, as shown by superior production of glycosaminglycans in this inflammatory environment. Overall this work demonstrates a novel method for modulating cell response to inflammatory signaling that has applications in engineering cells delivered to inflammatory environments, and as a direct gene therapy to protect endogenous cells exposed to chronic inflammation, as observed in a broad spectrum of degenerative musculoskeletal pathology.


Sodium sulfite is a potential hypoxia inducer that mimics hypoxic stress in Caenorhabditis elegans.
Physical and chemical hypoxia have been widely used in the study of hypoxic injury; however, both of these hypoxia models have their own limitations. Physical hypoxia is usually difficult to control and maintain. Chemical hypoxia, which is usually induced by chemical hypoxia-mimicking agents, such as CoCl(2), may result in heavy metal toxicity or impose security threats. To develop a more suitable hypoxia model, we focused on sodium sulfite (Na(2)SO(3)) and evaluated its ability to remove dissolved oxygen in aqueous solutions. Our results showed that sodium sulfite successfully induced hypoxic conditions. The degree of hypoxia and the guarantee period of the sodium sulfite solution could be easily controlled by the concentration of soluble sodium sulfite. In addition, we used sodium sulfite to create a hypoxia model in Caenorhabditis elegans. Similar to physical hypoxia, the sodium sulfite solutions induced hypoxia-related death in the worms and led to morphologic cell defects and C. elegans hypoxia inducible factor 1 stabilization. Taken together, our data show that sodium sulfite is a potential hypoxia inducer that mimics hypoxic stress in C. elegans.


The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical Bacillus Calmette-Guérin therapy.
Molecular markers reliably predicting failure or success of Bacillus Calmette-Guérin (BCG) in the treatment of nonmuscle-invasive urothelial bladder cancer (NMIBC) are lacking. The aim of our study was to evaluate the value of cytology and chromosomal aberrations detected by fluorescence in situ hybridization (FISH) in predicting failure to BCG therapy. Sixty-eight patients with NMIBC were prospectively recruited. Bladder washings collected before and after BCG instillation were analyzed by conventional cytology and by multitarget FISH assay (UroVysion, Abbott/Vysis, Des Plaines, IL) for aberrations of chromosomes 3, 7, 17 and 9p21. Persistent and recurrent bladder cancers were defined as positive events during follow-up. Twenty-six of 68 (38%) NMIBC failed to BCG. Both positive post-BCG cytology and positive post-BCG FISH were significantly associated with failure of BCG (hazard ratio (HR)= 5.1 and HR= 5.6, respectively; p < 0.001 each) when compared to those with negative results. In the subgroup of nondefinitive cytology (all except those with unequivocally positive cytology), FISH was superior to cytology as a marker of relapse (HR= 6.2 and 1.4, respectively). Cytology and FISH in post-BCG bladder washings are highly interrelated and a positive result predicts failure to BCG therapy in patients with NMIBC equally well. FISH is most useful in the diagnostically less certain cytology categories but does not provide additional information in clearly malignant cytology.


Could CO(2)-induced land-cover feedbacks alter near-shore upwelling regimes?
The response of marine and terrestrial environments to global changes in atmospheric carbon dioxide (CO(2)) concentrations will likely be governed by both responses to direct environmental forcing and responses to Earth-system feedbacks induced by that forcing. It has been proposed that anthropogenic greenhouse forcing will intensify coastal upwelling in eastern boundary current regions [Bakun, A. (1990) Science 247, 198-201]. Focusing on the California Current, we show that biophysical land-cover-atmosphere feedbacks induced by CO(2) radiative forcing enhance the radiative effects of CO(2) on land-sea thermal contrast, resulting in changes in eastern boundary current total seasonal upwelling and upwelling seasonality. Specifically, relative to CO(2) radiative forcing, land-cover-atmosphere feedbacks lead to a stronger increase in peak- and late-season near-shore upwelling in the northern limb of the California Current and a stronger decrease in peak- and late-season near-shore upwelling in the southern limb. Such changes will impact both marine and terrestrial communities [Bakun, A. (1990) Science 247, 198-201; Soto, C. G. (2001) Rev. Fish Biol. Fish. 11, 181-195; and Agostini, V. N. & Bakun, A. (2002) Fish. Oceanogr. 11, 129-142], and these and other Earth-system feedbacks should be expected to play a substantial role in shaping the response of eastern boundary current regions to CO(2) radiative forcing.


Uremia modulates the phenotype of aortic smooth muscle cells.
Chronic kidney disease leads to uremia and markedly accelerates atherosclerosis. Phenotypic modulation of smooth muscle cells (SMCs) in the arterial media plays a key role in accelerating atherogenesis. The aim of this study was to investigate whether uremia per se modulates the phenotype of aortic SMCs in vivo. Moderate uremia was induced by 5/6 nephrectomy in apolipoprotein E knockout (ApoE-/-) and wildtype C57Bl/6 mice. Plasma analysis, gene expression, histology, and myography were used to determine uremia-mediated changes in the arterial wall. Induction of moderate uremia in ApoE-/- mice increased atherosclerosis in the aortic arch en face 1.6 fold (p = 0.04) and induced systemic inflammation. Based on histological analyses of aortic root sections, uremia increased the medial area, while there was no difference in the content of elastic fibers or collagen in the aortic media. In the aortic arch, mRNA and miRNA expression patterns were consistent with a uremia-mediated phenotypic modulation of SMCs; e.g. downregulation of myocardin, α-smooth muscle actin, and transgelin; and upregulation of miR146a. Notably, these expression patterns were observed after acute (2 weeks) and chronic (19 and 30 weeks) uremia, both under normo- and hypercholesterolemic settings. Functionally, aortic constriction was decreased in uremic as compared to non-uremic aorta segments, as measured by myography. Uremia modulates the phenotype of aortic SMCs as determined by mRNA/miRNA expression, an increased medial area, and decreased aortic contractility. We propose that this phenotypic modulation of SMCs precedes the acceleration of atherosclerosis observed in uremic mice.


Demographic effects of extreme weather events: snow storms, breeding success, and population growth rate in a long-lived Antarctic seabird.
Weather extremes are one important element of ongoing climate change, but their impacts are poorly understood because they are, by definition, rare events. If the frequency and severity of extreme weather events increase, there is an urgent need to understand and predict the ecological consequences of such events. In this study, we aimed to quantify the effects of snow storms on nest survival in Antarctic petrels and assess whether snow storms are an important driver of annual breeding success and population growth rate. We used detailed data on daily individual nest survival in a year with frequent and heavy snow storms, and long term data on petrel productivity (i.e., number of chicks produced) at the colony level. Our results indicated that snow storms are an important determinant of nest survival and overall productivity. Snow storm events explained 30% of the daily nest survival within the 2011/2012 season and nearly 30% of the interannual variation in colony productivity in period 1985-2014. Snow storms are a key driver of Antarctic petrel breeding success, and potentially population dynamics. We also found state-dependent effects of snow storms and chicks in poor condition were more likely to die during a snow storm than chicks in good condition. This stresses the importance of considering interactions between individual heterogeneity and extreme weather events to understand both individual and population responses to climate change.


A novel acropectoral syndrome maps to chromosome 7q36.
F syndrome (acropectorovertebral syndrome) is a dominantly inherited skeletal dysplasia affecting the hands, feet, sternum, and lumbosacral spine, which has previously been described in only two families. Here we report a six generation Turkish family with a related but distinct dominantly inherited acropectoral syndrome. All 22 affected subjects have soft tissue syndactyly of all fingers and all toes and 14 also have preaxial polydactyly of the hands and/or feet. In addition, 14 have a prominent upper sternum and/or a blind ending, inverted U shaped sinus in the anterior chest wall. Linkage studies and haplotype analysis carried out in 16 affected and nine unaffected members of this family showed that the underlying locus maps to a 6.4 cM interval on chromosome 7q36, between EN2 and D7S2423, a region to which a locus for preaxial polydactyly and triphalangeal thumb-polysyndactyly has previously been mapped. Our findings expand the range of phenotypes associated with this locus to include total soft tissue syndactyly and sternal deformity, and suggest that F syndrome may be another manifestation of the same genetic entity. In mice, ectopic expression of the gene Sonic hedgehog (Shh) in limb buds and lateral plate mesoderm during development causes preaxial polydactyly and sternal defects respectively, suggesting that misregulation of SHH may underlie the unusual combination of abnormalities in this family. A recently proposed candidate gene for 7q36 linked preaxial polydactyly is LMBR1, encoding a novel transmembrane receptor which may be an upstream regulator of SHH.


The Ranger First Responder Program and Tactical Emergency Casualty Care Implementation: A Whole-Community Approach to Reducing Mortality From Active Violent Incidents.
Active violent incidents are dynamic and challenging situations that can produce a significant amount of preventable deaths. Lessons learned from the military?s experience in Afghanistan and Iraq through the Committee on Tactical Combat Casualty Care and the 75th Ranger Regiment?s Ranger First Responder Program have helped create the Committee for Tactical Emergency Casualty Care (C-TECC) to address the uniqueness of similar wounding patterns and to end preventable deaths. We propose a whole-community approach to active violent incidents, using the C-TECC Trauma Chain of Survival and a tiered approach for training and responsibilities: the first care provider, nonmedical professional first responders, medical first responders, and physicians and trauma surgeons. The different tiers are critical early links in the Chain of Survival and this approach will have a significant impact on active violent incidents.


Microfluidic flow cytometer for quantifying photobleaching of fluorescent proteins in cells.
Traditional flow cytometers are capable of rapid cellular assays on the basis of fluorescence intensity and light scatter. Microfluidic flow cytometers have largely followed the same path of technological development as their traditional counterparts; however, the significantly smaller transport distance and resulting lower cell speeds in microchannels provides for the opportunity to detect novel spectroscopic signatures based on multiple, nontemporally coincident excitation beams. Here, we characterize the design and operation of a cytometer with a three-beam, probe/bleach/probe geometry, employing HeLa suspension cells expressing fluorescent proteins. The data collection rate exceeds 20 cells/s under a range of beam intensities (5 kW to 179 kW/cm(2)). The measured percent photobleaching (ratio of fluorescence intensities excited by the first and third beams: S(beam3)/S(beam1)) partially resolves a mixture of four red fluorescent proteins in mixed samples. Photokinetic simulations are presented and demonstrate that the percent photobleaching reflects a combination of the reversible and irreversible photobleaching kinetics. By introducing a photobleaching optical signature, which complements traditional fluorescence intensity-based detection, this method adds another dimension to multichannel fluorescence cytometry and provides a means for flow-cytometry-based screening of directed libraries of fluorescent protein photobleaching.


ASD-DiagNet: A Hybrid Learning Approach for Detection of Autism Spectrum Disorder Using fMRI Data.
Heterogeneous mental disorders such as Autism Spectrum Disorder (ASD) are notoriously difficult to diagnose, especially in children. The current psychiatric diagnostic process is based purely on the behavioral observation of symptomology (DSM-5/ICD-10) and may be prone to misdiagnosis. In order to move the field toward more quantitative diagnosis, we need advanced and scalable machine learning infrastructure that will allow us to identify reliable biomarkers of mental health disorders. In this paper, we propose a framework called ASD-DiagNet for classifying subjects with ASD from healthy subjects by using only fMRI data. We designed and implemented a joint learning procedure using an autoencoder and a single layer perceptron (SLP) which results in improved quality of extracted features and optimized parameters for the model. Further, we designed and implemented a data augmentation strategy, based on linear interpolation on available feature vectors, that allows us to produce synthetic datasets needed for training of machine learning models. The proposed approach is evaluated on a public dataset provided by Autism Brain Imaging Data Exchange including 1, 035 subjects coming from 17 different brain imaging centers. Our machine learning model outperforms other state of the art methods from 10 imaging centers with increase in classification accuracy up to 28% with maximum accuracy of 82%. The machine learning technique presented in this paper, in addition to yielding better quality, gives enormous advantages in terms of execution time (40 min vs. 7 h on other methods). The implemented code is available as GPL license on GitHub portal of our lab (https://github.com/pcdslab/ASD-DiagNet).


Prazosin in the treatment of hypertension.
1. Prazosin decreases blood pressure in normotensive, renal hypertensive and spontaneous hypertensive rats. The effect is greatest in the last-named. 2. In spontaneously hypertensive rats the decrease in pressure is associated with a decrease in heart rate. 3. In hypertensive patients prazosin decreases blood pressure by decreasing total peripheral resistance with minor effects on cardiac output. 4. Prazosin is effective in the long-term therapy of hypertensive patients, alone and in combination with a diuretic. The effect on blood pressure is the same in the supine and standing position.


Diablo ubiquitination analysis by sandwich immunoassay.
Ubiquitin plays an essential role in modulating protein function, and deregulation of the ubiquitin system leads to the development of a variety of human diseases. E3 Ubiquitin ligases that mediate ubiquitination and degradation of caspases prevent apoptosis, and as such belong to the family of inhibitors of apoptosis proteins (IAPs). Diablo is a substrate of IAPs but also a negative regulator of IAPs in apoptotic pathway as it blocks the interaction between IAPs and caspases. In efforts to identify IAP inhibitors, we developed sandwich immunoassays in conjunction with an electrochemical luminescence (ECL) platform for quantitation of total Diablo, ubiquitinated Diablo, and ubiquitinated Diablo with K48-specific linkage. The assay panel detects Diablo ubiquitination level changes in the presence of IAP inhibitor or proteasome inhibitor, demonstrating its potential as a cost-efficient high-throughput method for drug discovery involving IAP ubiquitination cascade. The ECL based sandwich assay panel performance was subsequently evaluated for precision, linearity, and limit of quantification.


Impact of limiting erythropoiesis-stimulating agent use for chemotherapy-induced anemia on the United States blood supply margin.
Recently, the Centers for Medicare and Medicaid Services issued a national coverage determination that limited erythropoiesis-stimulating agents (ESAs) utilization in patients with chemotherapy-induced anemia (CIA). This study evaluated the impact of limiting the use of ESAs for CIA on the US blood supply margin. A modeling simulation was employed to compare the number of red blood cell (RBC) units transfused in CIA patients treated with ESAs to the number of RBC units that would be transfused if ESAs were limited or discontinued. The excess number of RBC units that would be required with limited ESA treatment was contrasted with the available marginal blood supply from 2004 and 2008. Model inputs were obtained from published literature or empirical evidence when published information was unavailable. The model predicted that up to 18 and 15 percent of the respective 2004 and 2008 marginal US blood supply would be required to cover the incremental demand for blood that would arise from a 25 percent decrease in ESA use. For ESA use reductions of 50 and 75 percent, the model predicted 17 to 21 percent (134,667 units) and 26 to 31 percent (202,001 units) of the 2008 and 2004 marginal US blood supply would be required, respectively. This study showed that limiting ESA use in CIA patients would impose considerable pressure on the available blood supply margin given the small margin between usable blood and transfusion demand. The public health consequences of such an outcome should be taken into account when revisions to ESA use are being considered.


Activation of Rap1 promotes prostate cancer metastasis.
Elucidating the mechanisms of prostate cancer (CaP) survival and metastasis are critical to the discovery of novel therapeutic targets. The monomeric G protein Rap1 has been implicated in cancer tumorigenesis. Rap1 signals to pathways involved in cell adhesion, migration, and survival, suggesting Rap1 may promote several processes associated with cancer cell metastasis. Examination of CaP cell lines revealed cells with a high metastatic ability exhibited increased Rap1 activity and reduced expression of the negative regulator Rap1GAP. Rap1 can be further stimulated in these cells by stromal-derived factor (SDF-1), an agonist known to regulate tumor cell metastasis and tropism to bone. Activation of Rap1 increased CaP cell migration and invasion, and inhibition of Rap1A activity via RNAi-mediated knockdown or ectopic expression of Rap1GAP markedly impaired CaP cell migration and invasion. Additional studies implicate integrins alpha4, beta3, and alphavbeta3 in the mechanism of Rap1-mediated CaP migration and invasion. Extending the effect of Rap1 activity in CaP metastasis in vivo, introduction of activated Rap1 into CaP cells dramatically enhanced the rate and incidence of CaP metastasis in a xenograft mouse model. These studies provide compelling evidence to support a role for aberrant Rap1 activation in CaP progression, and suggest that targeting Rap1 signaling could provide a means to control metastatic progression of this cancer.


Background ventilatory stimulus as a determinant of load compensation.
Compensation for inspiratory flow-resistive loading was compared during progressive hypercapnia and incremental exercise to determine the effect of changing the background ventilatory stimulus and to assess the influence of the interindividual variability of the unloaded CO2 response on evaluation of load compensation in normal subjects. During progressive hypercapnia, ventilatory response was incompletely defended with loading (mean unloaded delta VE/delta PCO2 = 3.02 +/- 2.29, loaded = 1.60 +/- 0.67 1.min-1.Torr-1 CO2, where VE is minute ventilation and PCO2 is CO2 partial pressure; P less than 0.01). Furthermore the degree of defense of ventilation with loading was inversely correlated with the magnitude of the unloaded CO2 response. During exercise, loading produced no depression in ventilatory response (mean delta VE/delta VCO2 unloaded = 20.5 +/- 1.9, loaded = 19.2 +/- 2.5 l.min-1.l-1.min-1 CO2 where VCO is CO2 production; P = NS), and no relationship was demonstrated between degree of defense of the exercise ventilatory response and the unloaded CO2 response. Differences in load compensation during CO2 rebreathing and exercise suggest the presence of independent ventilatory control mechanisms in these states. The type of background ventilatory stimulus should therefore be considered in load compensation assessment.


The effects of dairy processes and storage on insulin-like growth factor-I (IGF-I) content in milk and in model IGF-I-fortified dairy products.
The effects of several dairy processes on insulin-like growth factor-I (IGF-I) concentrations in milk and the storage stability of IGF-I-fortified dairy products were examined. The IGF-I content in raw milk determined by radioimmunoassay was significantly changed by the strength of heat treatments. In commercial manufacture of whole milk dry powder, IGF-I concentration was not significantly changed. A significant reduction in IGF-I content was found as the result of fermentation with a commercial starter culture. The IGF-I content in fortified milk and dried milk powder exhibited no significant changes over the tested storage periods (12 d for milk, 4 wk for dried milk powder), but the IGF-I content in the yogurt decreased significantly during storage. The use of IGF-I was varied by lactic strains and was apparent in the viable cells. When IGF-I was encapsulated using the surface-reforming process, the remaining IGF-I content after fermentation was significantly higher compared with that of the untreated control. Therefore, enteric coating of IGF-I before fermentation might be an effective method for the prevention of IGF-I degradation during fermentation.


Urban habituation, ecological connectivity and epidemic dampening: the emergence of Hendra virus from flying foxes (Pteropus spp.).
Anthropogenic environmental change is often implicated in the emergence of new zoonoses from wildlife; however, there is little mechanistic understanding of these causal links. Here, we examine the transmission dynamics of an emerging zoonotic paramyxovirus, Hendra virus (HeV), in its endemic host, Australian Pteropus bats (fruit bats or flying foxes). HeV is a biosecurity level 4 (BSL-4) pathogen, with a high case-fatality rate in humans and horses. With models parametrized from field and laboratory data, we explore a set of probable contributory mechanisms that explain the spatial and temporal pattern of HeV emergence; including urban habituation and decreased migration-two widely observed changes in flying fox ecology that result from anthropogenic transformation of bat habitat in Australia. Urban habituation increases the number of flying foxes in contact with human and domestic animal populations, and our models suggest that, in addition, decreased bat migratory behaviour could lead to a decline in population immunity, giving rise to more intense outbreaks after local viral reintroduction. Ten of the 14 known HeV outbreaks occurred near urbanized or sedentary flying fox populations, supporting these predictions. We also demonstrate that by incorporating waning maternal immunity into our models, the peak modelled prevalence coincides with the peak annual spill-over hazard for HeV. These results provide the first detailed mechanistic framework for understanding the sporadic temporal pattern of HeV emergence, and of the urban/peri-urban distribution of HeV outbreaks in horses and people.


Identification of diagnostic upper gastrointestinal cancer tissue type-specific urinary biomarkers.
Several potential urinary biomarkers exhibiting an association with upper gastrointestinal tumour growth have been previously identified, of which S100A6, S100A9, rabenosyn-5 and programmed cell death 6-interacting protein (PDCD6IP) were further validated and found to be upregulated in malignant tumours. The cancer cohort from our previous study was subclassified to assess whether distinct molecular markers can be identified for each individual cancer type using a similar approach. Urine samples from patients with cancers of the stomach, oesophagus, oesophagogastric junction or pancreas were analysed by surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry using both CM10 and IMAC30 (Cu2+-complexed) chip types and LC-MS/MS-based mass spectrometry after chromatographic enrichment. This was followed by protein identification, pattern matching and validation by western blotting. We found 8 m/z peaks with statistical significance for the four cancer types investigated, of which m/z 2447 and 2577 were identified by pattern matching as fragments of cathepsin-B (CTSB) and cystatin-B (CSTB); both molecules are indicative of pancreatic cancer. Additionally, we observed a potential association of upregulated α-1-antichymotrypsin with pancreatic and gastric cancers, of PDCD6IP, vitelline membrane outer layer protein 1 homolog (VMO1) and triosephosphate isomerase (TPI1) with oesophagogastric junctional cancers, and of complement C4-A, prostatic acid phosphatase, azurocidin and histone-H1 with oesophageal cancer. Furthermore, the potential pancreatic cancer biomarkers CSTB and CTSB were validated independently by western blotting. Therefore, the present study identified two new potential urinary biomarkers that appear to be associated with pancreatic cancer. This may provide a simple, non-invasive screening test for use in the clinical setting.


Factors affecting the evolution of oncology nursing care.
Oncology nursing has evolved in response to population growth and changing demographics, changing regulatory requirements, decreasing lengths of inpatient hospital stays, and ongoing advances in cancer treatment, information, and biotechnology. Changes in societal perceptions of cancer and increased access to information have enabled patients to seek out knowledgeable and skilled oncology nurses. Nurses also play an ever-increasing role in rehabilitation as patients live longer with the effects of cancer and treatment. Significant outcomes achieved through nursing research include increased access to care and patient education; improved patient satisfaction, cost-effectiveness of health care, and treatment adherence; fewer hospital admissions; decreased lengths of stay; lower readmission rates; fewer emergency room visits; and lower healthcare costs. Oncology nurse researchers also have studied the economic burden of cancer treatment, limited employment options, and survivorship issues. The progress in professional oncology nursing parallels the progress in surgical, radiologic, biologic, medical, and genetic approaches to cancer treatment. The role and practice of the oncology nurse will continue to evolve in the coming decades as population demographics and healthcare systems change and new scientific and technologic discoveries are integrated into cancer care.


Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice.
Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.


P2X7 receptor-mediated killing of an intracellular parasite, Toxoplasma gondii, by human and murine macrophages.
The P2X7R is highly expressed on the macrophage cell surface, and activation of infected cells by extracellular ATP has been shown to kill intracellular bacteria and parasites. Furthermore, single nucleotide polymorphisms that decrease receptor function reduce the ability of human macrophages to kill Mycobacterium tuberculosis and are associated with extrapulmonary tuberculosis. In this study, we show that macrophages from people with the 1513C (rs3751143, NM_002562.4:c.1487A>C) loss-of-function P2X7R single nucleotide polymorphism are less effective in killing intracellular Toxoplasma gondii after exposure to ATP compared with macrophages from people with the 1513A wild-type allele. Supporting a P2X7R-specific effect on T. gondii, macrophages from P2X7R knockout mice (P2X7R-/-) are unable to kill T. gondii as effectively as macrophages from wild-type mice. We show that P2X7R-mediated T. gondii killing occurs in parallel with host cell apoptosis and is independent of NO production.


Influences on Decision Making Identified by Parents of Children Receiving Pediatric Palliative Care.
Parental decision making is a critical component in the provision of palliative and end-of-life care, yet factors that parents perceive as influencing this process, when they are making decisions for their children, have not been well characterized. As part of a mixed-methods cohort study, we interviewed 73 parents of 50 pediatric patients who were referred to the hospital's pediatric palliative care service. The semistructured interviews focused on "decision making for your child"; the interviews were recorded and transcribed. A random sample (n = 13) was first coded and analyzed for core themes, and these themes were then cross-validated with a second random sample (n = 3) of interviews. Four dominant interrelated themes permeated parents' discussions about the decisions they were making for their children and the process of decision making. First, Orientation and Direction (including the subthemes of Goals and Hopes, Spirituality and Meaning, and Purposeful Effort) connotes the parents' effort to establish and clarify the broad context of decision making. Second, Defining What Is Good for the Child (including the subthemes of Quality of Life and Suffering, and Normalcy and Normalization) conveys how the parents posed questions and pondered what decisions would be in the child's best interests. Third, the entwined theme of Relationships, Communication, and Support reflects how parents reported the social and interactive nature of decision making. Fourth, the theme of Feelings and Personal Accountability focuses inward as parents report efforts to deal with their emotional responses and self-judgments. Parents report grappling with several influences upon their decision-making processes that extend well beyond the standard discussions of medical information exchanges and the evaluation of risks and benefits. Decision support for these parents should account for these diverse influences.


Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist.
The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.


Synaptic refinement during development and its effect on slow-wave activity: a computational study.
Recent evidence suggests that synaptic refinement, the reorganization of synapses and connections without significant change in their number or strength, is important for the development of the visual system of juvenile rodents. Other evidence in rodents and humans shows that there is a marked drop in sleep slow-wave activity (SWA) during adolescence. Slow waves reflect synchronous transitions of neuronal populations between active and inactive states, and the amount of SWA is influenced by the connection strength and organization of cortical neurons. In this study, we investigated whether synaptic refinement could account for the observed developmental drop in SWA. To this end, we employed a large-scale neural model of primary visual cortex and sections of the thalamus, capable of producing realistic slow waves. In this model, we reorganized intralaminar connections according to experimental data on synaptic refinement: during prerefinement, local connections between neurons were homogenous, whereas in postrefinement, neurons connected preferentially to neurons with similar receptive fields and preferred orientations. Synaptic refinement led to a drop in SWA and to changes in slow-wave morphology, consistent with experimental data. To test whether learning can induce synaptic refinement, intralaminar connections were equipped with spike timing-dependent plasticity. Oriented stimuli were presented during a learning period, followed by homeostatic synaptic renormalization. This led to activity-dependent refinement accompanied again by a decline in SWA. Together, these modeling results show that synaptic refinement can account for developmental changes in SWA. Thus sleep SWA may be used to track noninvasively the reorganization of cortical connections during development.


Characterization and mechanisms of H2O2-induced contractions of pulmonary arteries.
We studied H2O2-induced contractions of isolated rabbit intrapulmonary arteries mounted in standard tissue baths. All vessels were pretreated with a thromboxane A2/prostaglandin H2 receptor antagonist, SQ 29,548, to block immediate transient contractions to H2O2 and to isolate slowly developing sustained contractions. When exposed to H2O2 (0.1, 0.2, 0.3, 0.6, and 1.0 mM) for 30 min, vessels contracted in (0.1, 0.2, 0.3, 0.6, and 1.0 mM) for 30 min, vessels contracted in a concentration-dependent fashion between 0.1 and 0.3 mM H2O2; contractions at 0.6 and 1.0 mM H2O2 were not significantly different from those at 0.3 mM H2O2. During recovery (90 min) from H2O2 exposures, baseline tension was significantly greater, but active tension (10 microM phenylephrine) was significantly less for vessels previously exposed to 0.6 and 1.0 mM H2O2. Contractions to 0.3 mM H2O2 were not blunted by the following interventions: 1) endothelium rubbing, 2) incubation in Ca(2+)-free 100 microM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) Krebs-Ringer solution, 3) incubation in the Ca(2+)-free solution and depletion of ryanodine (20 microM)-sensitive Ca(2+) stores, or 4) pretreatment with the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-3-methyl-piperazine (20 microM). However, contractions were depressed by approximately 50% when vessels were pretreated with the phospholipase C/serine esterase inhibitor 2-nitro-4-carboxy-phenyl-N,N-diphenylcarbamate (50 microM). These results suggest that slow-developing contractions to H2O2 are concentration dependent and may result, in part, from activation of a serine esterase(s) and/or phospholipase C.


Sensitivity enhancement of multidimensional NMR experiments by paramagnetic relaxation effects.
One of the main goals of NMR method development is to increase the sensitivity of multidimensional NMR experiments or reduce the required acquisition time. In these experiments, more than 80% of the NMR instrument time is spent on the recycle delay, where the instrument idles to wait for the recovery of proton magnetization. In this study, we report a method of using paramagnetic relaxation effects to shorten the recycle delays required in multidimensional NMR experiments of biological macromolecules. This approach significantly reduces the NMR instrument time required. Ni(2+) ion, complexed with the chelating molecule DO2A, is used to decrease the proton T(1) relaxation time of biological macromolecules without the significant line-broadening effects that are associated with most paramagnetic ions. The Ni(DO2A) also significantly decreases the T(1) relaxation time of water, thus providing additional sensitivity gain by eliminating the saturation of labile amide resonances.


Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS.
Chronic HIV-1 infection commonly affects behavioral, cognitive, and motor functions in the infected human host and is commonly referred to as HIV-1-associated neurocognitive disorders (HAND). This occurs, in measure, as a consequence of ingress of leukocytes into brain perivascular regions. Such cells facilitate viral infection and disease by eliciting blood-brain barrier and neuronal network dysfunctions. Previous works demonstrated that the endocannabinoid system modulates neuroimmunity and as such neuronal and glial functions. Herein, we investigated CB2R receptor expression in murine HIV-1 encephalitis (HIVE) and the abilities of a highly selective CB2R agonist, Gp1a, to modulate disease. HIV-1-infected human monocyte-derived macrophages were injected into the caudate and putamen of immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL/HIVE). Brains of hu-PBL/HIVE mice showed microglial activation and increased expression of CB2R, but not CB1R or GPR55. Gp1a substantively reduced infiltration of human cells into the mouse brain and reduced HLA DQ activation. Gp1a down modulated CCR5 expression on human cells in the spleen with an increase in Fas ligand expression. Our results support the notion that CB2 receptor agonists may be a viable therapeutic candidate for HAND.