Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis.
Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis. Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit's uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort. uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort. uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.


MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs.
Piwi-interacting RNAs (piRNAs) comprise a broad class of small noncoding RNAs that function as an endogenous defense system against transposable elements. Here we show that the putative DExD-box helicase MOV10-like-1 (MOV10L1) is essential for silencing retrotransposons in the mouse male germline. Mov10l1 is specifically expressed in germ cells with increasing expression from gonocytes/type A spermatogonia to pachytene spermatocytes. Primary spermatocytes of Mov10l1(-/-) mice show activation of LTR and LINE-1 retrotransposons, followed by cell death, causing male infertility and a complete block of spermatogenesis at early prophase of meiosis I. Despite the early expression of Mov10l1, germline stem cell maintenance appears unaffected in Mov10l1(-/-) mice. MOV10L1 interacts with the Piwi proteins MILI and MIWI. MOV10L1 also interacts with heat shock 70-kDa protein 2 (HSPA2), a testis-enriched chaperone expressed in pachytene spermatocytes and also essential for male fertility. These studies reveal a crucial role of MOV10L1 in male fertility and piRNA-directed retrotransposon silencing in male germ cells and suggest that MOV10L1 functions as a key component of a safeguard mechanism for the genetic information in male germ cells of mammals.


Vaccinating health care workers during an influenza pandemic.
In response to the 2009 H1N1 influenza pandemic, health care workers (HCWs) were offered immunization with H1N1 vaccine in addition to seasonal flu vaccine. Previously, low rates of influenza vaccine uptake in HCWs have been attributed to concerns about vaccine clinical effectiveness, side effects and access difficulties. To explore H1N1 influenza vaccination of HCWs in London during 2009-10 and examine reasons for vaccine refusal. An online questionnaire survey of doctors and nurses working in two primary care trust (PCT) areas and one acute trust area was carried out in London. Only 59% of the 221 respondents had been immunized with H1N1 influenza vaccine and 43% with seasonal influenza vaccine. The commonest reasons for remaining unvaccinated were 'side effects', 'swine flu not severe' and 'concerns about clinical effectiveness of the vaccine'. Respondents who had been vaccinated that season gave positive feedback on their experience. While uptake among HCWs was greater for the pandemic vaccine than is usually seen with seasonal influenza vaccine, this survey suggests that in this area of London during the 2009 pandemic, HCWs refused H1N1 vaccination due to concerns about clinical effectiveness, side effects and perceptions that H1N1 infection was not generally severe. We found no evidence to suggest poor access was a barrier to H1N1 vaccination of HCWs. If good access is maintained, the key barrier to improving seasonal flu vaccine uptake lies with informing the personal risk assessment made by the HCW.


Preconceptional paternal exposure to depleted uranium: transmission of genetic damage to offspring.
Depleted uranium (DU) is an alpha particle emitter and radioactive heavy metal used in military applications. Due to internalization of DU during military operations and the ensuing chronic internal exposure to DU, there are concerns regarding its potential health effects. Preconceptional paternal irradiation has been implicated as a causal factor in childhood cancer and it has been suggested that this paternal exposure to radiation may play a role in the occurrence of leukemia and other cancers to offspring. Similarly, in vivo heavy metal studies have demonstrated that carcinogenic effects can occur in unexposed offspring. Using a transgenic mouse system employing a lambda shuttle vector allowing mutations (in the lacI gene) to be analyzed in vitro, we have investigated the possibility that chronic preconceptional paternal DU exposure can lead to transgenerational transmission of genomic instability. The mutation frequencies in vector recovered from the bone marrow cells of the F1 offspring of male parents exposed to low, medium, and high doses of internalized DU for 7 mo were evaluated and compared to control, tantalum, nickel, and gamma radiation F1 samples. Results demonstrate that as paternal DU-dose increased there was a trend towards higher mutation frequency in vector recovered from the DNA obtained from bone marrow of F1 progeny; medium and high dose DU exposure to P1 fathers resulted in a significant increase in mutation frequency in F1 offspring (3.57 +or - 0.37 and 4.81 + or - 0.43 x 10; p < 0.001) in comparison to control (2.28 + or - 0.31 x 10). The mutation frequencies from F1 offspring of low dose DU, Ta- or Ni-implanted fathers (2. 71 + or - 0.35, 2.38 + or - 0.35, and 2.93 + or - 0.39 x 10, respectively) were not significantly different than control levels (2.28 + or - 0.31 x 10). Offspring from Co (4 Gy) irradiated fathers did demonstrate an increased lacI mutation frequency (4.69 + or - 0.48 x 10) as had been shown previously. To evaluate the role of radiation involved in the observed DU effects, males were exposed to equal concentrations (50 mg U L) of either enriched uranium or DU in their drinking water for 2 mo prior to breeding. A comparison of these offspring indicated that there was a specific-activity dependent increase in offspring bone marrow mutation frequency. Taken together these uranyl nitrate data support earlier results in other model systems showing that radiation can play a role in DU-induced biological effects in vitro. However, since the lacI mutation model measures point mutations and cannot measure large deletions that are characteristic of radiation damage, the role of DU chemical effects in the observed offspring mutation frequency increase may also be significant. Regardless of the question of DU-radiation vs. DU-chemical effects, the data indicate that there exists a route for transgenerational transmission of factor(s) leading to genomic instability in F1 progeny from DU-exposed fathers.


Socioeconomic burden of influenza in the Republic of Korea, 2007-2010.
Although the socioeconomic burden of 2009 pandemic influenza A (H1N1) was considerable, no reliable estimates have been reported. Our aim was to compared medical costs and socioeconomic burden resulting from pandemic influenza A (H1N1) 2009 with that of previous seasonal influenza. We estimated the medical costs and socioeconomic burden of influenza from May 2007 to April 2010. We used representative national data sources(data from the Health Insurance Review Agency, the National Health Insurance Corporation, the Korea Centers for Disease Control and Prevention, and the Korean National Statistics Office) including medical utilization, prescription of antivirals, and vaccination. Uncertainty of data was explored through sensitivity analysis using Monte Carlo simulation. Compared with the seasonal influenza, total medical costs (US$291.7 million) associated with pandemic (H1N1) 2009 increased more than 37-fold. Compared with the 2007-2008 season, outpatient diagnostic costs (US$135.3 million) were 773 times higher in the 2009-2010 season, and the mean diagnostic cost per outpatient visit was 58.8 times higher. Total socioeconomic burden of pandemic (H1N1) 2009 was estimated at US$1581.3 million (10%-90%: US$1436.0-1808.3 million) and those of seasonal influenza was estimated at US$44.7 million (10%-90%: US$32.4-57.9 million) in 2007-2008 season and US$42.3 million (10%-90%: US$31.5-53.8 million) in 2008-2009 season. Indirect costs accounted for 56.0% of total costs in pandemic (H1N1) 2009, and 66.48-68.09% in seasonal influenza. The largest contributors to total burden were productivity losses of caregiver in pandemic (H1N1) 2009, and productivity losses due to morbidity of outpatient in seasonal influenza. In the Republic of Korea, socioeconomic burden of pandemic (H1N1) 2009 were considerably higher than burden of the previous two influenza seasons, primarily because of high diagnostic costs and longer sick leave.


The effect of a 9-week physical activity programme on bone and body composition of children aged 10-11 years: an exploratory trial.
A high-impact exercise and a lifestyle intervention were implemented over a 9-week period; changes in bone and body composition were compared to controls. Sixty-one children volunteered from three randomly selected schools. Each school was randomly assigned to either a structured exercise (STEX) intervention, a lifestyle intervention (PASS) or control (CONT). Bone mineral content (BMC) and density (BMD) of total body, femoral neck and lumbar spine were measured as well as fat and lean mass at baseline and post-intervention by dual-energy X-ray absorptiometry. The STEX intervention resulted in an additional mean increase in total body BMC of 63.3 g (p = 0.019) and an additional increase of 0.011 g . cm (-2) (p = 0.018) for BMD over increases observed by controls. Bone mineral increases observed for the PASS intervention were not significant compared to the control group (p > 0.05). Neither intervention produced significant increases in bone mineral at femoral neck or lumbar spine sites (p > 0.05) compared with the controls. No significant changes were found in fat mass index (p > 0.05), lean mass index (p > 0.05) or percent body fat (p = 0.09) in any groups. Structured impact exercise promoted significant and clinically relevant increases in bone measures, without significant changes to body composition. A larger, definitive randomised trial is needed to confirm the present results.


Teaching medical students a clinical approach to altered mental status: simulation enhances traditional curriculum.
Simulation-based medical education (SBME) is increasingly being utilized for teaching clinical skills in undergraduate medical education. Studies have evaluated the impact of adding SBME to third- and fourth-year curriculum; however, very little research has assessed its efficacy for teaching clinical skills in pre-clerkship coursework. To measure the impact of a simulation exercise during a pre-clinical curriculum, a simulation session was added to a pre-clerkship course at our medical school where the clinical approach to altered mental status (AMS) is traditionally taught using a lecture and an interactive case-based session in a small group format. The objective was to measure simulation's impact on students' knowledge acquisition, comfort, and perceived competence with regards to the AMS patient. AMS simulation exercises were added to the lecture and small group case sessions in June 2010 and 2011. Simulation sessions consisted of two clinical cases using a high-fidelity full-body simulator followed by a faculty debriefing after each case. Student participation in a simulation session was voluntary. Students who did and did not participate in a simulation session completed a post-test to assess knowledge and a survey to understand comfort and perceived competence in their approach to AMS. A total of 154 students completed the post-test and survey and 65 (42%) attended a simulation session. Post-test scores were higher in students who attended a simulation session compared to those who did not (p<0.001). Students who participated in a simulation session were more comfortable in their overall approach to treating AMS patients (p=0.05). They were also more likely to state that they could articulate a differential diagnosis (p=0.03), know what initial diagnostic tests are needed (p=0.01), and understand what interventions are useful in the first few minutes (p=0.003). Students who participated in a simulation session were more likely to find the overall AMS curriculum useful (p<0.001). Students who participated in a simulation exercise performed better on a knowledge-based test and reported increased comfort and perceived competence in their clinical approach to AMS. SBME shows significant promise for teaching clinical skills to medical students during pre-clinical curriculum.


Expression of nitric oxide synthase by motor neurones in the spinal cord of the mutant mouse wobbler.
The expression of nitric oxide synthase (NOS) has been studied in the spinal cord of the mutant mouse wobbler, a recessive mutation in which there is motor neurone degeneration, using nicotinamide dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Abnormal NOS positive large neuronal profiles could be found in the ventral born of affected mutant animals but not their unaffected littermate controls. The number of abnormal profiles observed was dependent upon the age of the animal. A small number of these NOS positive large neuronal profiles were seen at the onset of the disease at 3-4 weeks of age, larger numbers were found in animals aged 5-8 weeks coincident with the main period of motor neurone death, whilst in the spinal cords of older animals aged 9-12 months, when motor neurone death is minimal, none were found. These NOS positive profiles seen in younger wobbler mouse ventral horn had a morphology and size similar to that of degenerating motor neurones seen in Nissl stained preparations. It was concluded that these NOS positive profiles were degenerating motor neurones. These observations provide further evidence that induction of nitric oxide synthase expression may play a role in motor neurone death. Though no NOS positive motor neurones were found in the spinal cords of older wobblers increased numbers of NOS positive varicose axons were observed in the ventral horn often forming tangled accumulations on the border of the grey and white matter.


Shared paramyxoviral glycoprotein architecture is adapted for diverse attachment strategies.
Members within the paramyxovirus subfamily Paramyxovirinae constitute a large number of highly virulent human and animal pathogens. The glycoproteins present on these viruses are responsible for mediating host cell attachment and fusion and are key targets for the design of antiviral entry inhibitors. In the present review, we discuss recent structural studies which have led to a better understanding of the various mechanisms by which different paramyxoviruses use their attachment glycoproteins to hijack specific protein and glycan cell-surface receptors to facilitate viral entry. It is observed that the paramyxovirus attachment glycoprotein consists of a conserved overall structure which includes an N-terminal six-bladed β-propeller domain which is responsible for cell receptor binding. Crystal structures of this domain from different biomedically important paramyxoviruses, including measles, Nipah, Hendra, Newcastle disease and parainfluenza viruses, alone and in complex with their functional cell-surface receptors, demonstrate three contrasting mechanisms of receptor engagement that paramyxoviruses have evolved to confer discreet protein- and glycan-receptor specificity. This structural information highlights the adaptability of the paramyxovirus attachment glycoprotein surface and the potential for the emergence of new and potentially harmful viruses in human hosts.


Evidence for optimal semantic search throughout adulthood.
As people age, they learn and store new knowledge in their semantic memory. Despite learning a tremendous amount of information, people can still recall information relevant to the current situation with ease. To accomplish this, the mind must efficiently organize and search a vast store of information. It also must continue to retrieve information effectively despite changes in cognitive mechanisms due to healthy aging, including a general slowing in information processing and a decline in executive functioning. How effectively does the mind of an individual adjust its search to account for changes due to aging? We tested 746 people ages 25 through 69 on a semantic fluency task (free listing animals) and found that, on average, retrieval follows an optimal path through semantic memory. Participants tended to list a sequence of semantically related animals (e.g., lion, tiger, puma) before switching to a semantically unrelated animal (e.g., whale). We found that the timing of these transitions to semantically unrelated animals was remarkably consistent with an optimal strategy for maximizing the overall rate of retrieval (i.e., the number of animals listed per unit time). Age did not affect an individual's deviation from the optimal strategy given their general performance, suggesting that people adapt and continue to search memory optimally throughout their lives. We argue that this result is more likely due to compensating for a general slowing than a decline in executive functioning.


Tryptophan degradation and serum neopterin concentrations in intensive care unit patients.
Alterations in neopterin concentrations and tryptophan degradation accompany the activation of cellular immune systems. Accordingly, in a variety of diseases, mainly in infections, elevated neopterin levels and tryptophan degradation have been observed. This study aimed to assess serum neopterin levels and tryptophan degradation in intensive care unit (ICU) patients with systemic inflammatory response syndrome (SIRS, n = 9), sepsis (n = 8), septic shock (n = 10), and multiple organ dysfunction syndrome (MODS, n = 7) at the first day of ICU hospitalization. The kynurenine-to-tryptophan (kyn/trp) ratio was used in order to evaluate the degree of tryptophan degradation. The results of each patient group were compared with the control group (n = 30). The differences among the ICU groups and the correlations between APACHE II scores and neopterin concentrations or tryptophan degradation were investigated. All patient groups presented statistically higher kyn/trp and neopterin levels than the controls. The sepsis, septic shock, and MODS group had markedly higher neopterin levels than the SIRS group (all P < 0.05). Additionally, it was found that the survivor group had significantly lower neopterin levels compared with non-survivors (P < 0.05) and lower kyn/trp, but the latter difference was not significant. Neopterin levels and kyn/trp were both correlated with APACHE II score (both P < 0.05). The results indicate that serum neopterin levels and tryptophan degradation correlate well with the severity of the disease in ICU patients, and this was true even at the first day of hospitalization in the unit.


The Availability of Echinococcus IgG ELISA for Diagnosing Pulmonary Hydatid Cysts.
In this study, we researched the availability of Echinococcus IgG ELISA in pulmonary hydatid cysts. Between January 2008 and December 2015, 93 successive cases, which were studied in preoperative Echinococcus IgG and histopathologically found to have pulmonary hydatid cysts, were retrospectively analyzed. Age and sex of the cases and the cyst's location, number, size, spread to other organs outside the lungs, and its condition as intact or ruptured were reviewed. Forty-seven (50.5%) patients were male and 46 (49.5%) patients were female; the mean age was 27.7±19.6 years. While in 56 (60.2%) cases, only lung cysts were detected, 32 (34.4%) cases presented with both lung and liver cysts. While lung cysts were single in 71 (76.3%), they were multiple in 22 (23.6%) cases (between 2 and 20 pieces). In 48 (51.6%) cases, cysts were in the right lung, and in 32 (34.4%) cases, they were in the left. In 13 (14%) cases, cysts presented in both the right and left lungs. The mean diameter of the pulmonary cysts was 6.4 cm (ranging from 2 to 19 cm). In 53 (57%) cases, hydatid cysts were ruptured, whereas in 40 (43%) cases, the cysts were intact. While general Echinococcus IgG was found to be positive in 53 (57%) cases, it was negative in 40 (43%) cases. There were 53 ruptured cases, and 48 (90.6%) of them were test-positive; however, the test was positive in only 5 (12.5%) out of the 40 cases where the cysts were intact (p<0.001). A statistically significant correlation has not been found between IgG and patient age, gender, cyst location, number of cysts, cyst diameter, and extrapulmonary involvement. Our study demonstrated that the most important factor that affects the positivity of Echinococcus IgG is the rupture of cysts. When ruptured cysts become confusing, Echinococcus IgG can contribute toward a diagnosis.


An evaluation of the effectiveness of an educational and experiential intervention on nursing students' attitudes towards older people.
Objectives. This paper reports the results of a study that aimed to evaluate the effectiveness of an educational and experiential intervention on nursing students' attitudes towards older people. Background. With repeated exposure to very sick older people in hospitals or nursing homes, nursing students are at risk of adopting stereotypical views about this section of the population as frail and dependent. Design. A pre- and post-test design was used to conduct the study. Methods. Using Kogan's Attitudes Towards Old People Scale, the attitudes of nursing students were tested at the beginning of a degree programme in Adult Nursing (n = 130) and one year later (n = 94) following a series of visits to a well-older person in the community. Results. Nursing students reported positive attitudes towards older people and these were retained throughout the first year of their nurse training. No statistically significant differences were found associated with any of the five independent variables in either pre- or postintervention students. Conclusions. The attitudes of nursing students towards older people remained positive. While it is possible that the experiential and educational interventions utilized in this study may have contributed to the retention of positive attitudes, further research is required to test this hypothesis. Relevance to clinical practice. Nurses have a major role to play in responding to the health and social care needs of older people and their families. The cultivation of positive attitudes is a key factor in enabling practising nurses to respond to this challenge.


1,25-Dihydroxyvitamin D3 activates MMP13 gene expression in chondrocytes through p38 MARK pathway.
Osteoarthritis (OA) is the most prevalent degenerative joint disease. The highly regulated balance of matrix synthesis and degradation is disrupted in OA, leading to progressive breakdown of articular cartilage. The molecular events and pathways involved in chondrocyte disfunction of cartilage in OA are not fully understood. It is known that 1,25-dihydroxyvitamin D₃(1,25-(OH)2D3) is synthesized by macrophages derived from synovial fluid of patients with inflammatory arthritis. Vitmain D receptor is expressed in chondrocytes within osteoarthritic cartilage, suggesting a contributory role of 1,25-(OH)2D3 in the aberrant behavior of chondrocytes in OA. However, the physiological function of 1,25-(OH)2D3 on chondrocytes in OA remains obscure. Effect of 1,25-(OH)2D3 on gene expression in chondrocytes was investigated in this study. We found that 1,25-(OH)2D3 activated MMP13 expression in a dose-dependent and time-dependent manner, a major enzyme that targets cartilage for degradation. Interestingly, a specific mitogen-activated protein kinase p38 inhibitor SB203580, but not JNK kinase inhibitor SP600125, abrogated 1,25-(OH)2D3 activation of MMP13 expression. 1,25-(OH)2D3-induced increase in MMP13 protein level was in parallel with the phosphorylation of p38 in chondrocytes. To further address the effect of 1,25-(OH)2D3 on MMP13 expression, transfection assays were used to show that 1,25-(OH)2D3 activated the MMP13 promoter reporter expression. MMP13 is known to target type II collagen and aggrecan for degradation, two major components of cartilage matrix. We observed that the treatment of 1,25-(OH)2D3 in chondrocytes results in downregulation of both type II collagen and aggrecan while MMP13 was upregulated. Taken together, we provide the first evidence to demonstrate that 1,25-(OH)2D3 activates MMP13 expression through p38 pathway in chondrocytes. Since MMP13 plays a major role in cartilage degradation in OA, we speculate that the ability of 1,25-(OH)2D3 to potentiate MMP13 expression might facilitate cartilage erosion at the site of inflammatory arthritis.


Identification of Interleukin-1β-Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal-Onset Multisystem Inflammatory Disease.
Spontaneous inflammatory responses initiated by NLRP3 mutations promote inflammasome-mediated interleukin-1β (IL-1β) processing and release and can induce rapid necrotic cell death. The cells that produce IL-1β in neonatal-onset multisystem inflammatory disease (NOMID) have not been clearly identified, nor have the mechanisms mediating IL-1β release and cell death been completely elucidated. Whole blood cells were stimulated with lipopolysaccharide (LPS) in the presence of cathepsin B and caspase 1 inhibitors, followed by ATP treatment. Supernatants were collected and incubated with IL-1β-capturing beads. Cells were fixed, permeabilized, and stained for a combination of cell surface and intracellular markers, and a novel flow cytometry bead-based assay was used to measure secreted IL-1β. LPS-stimulated cells were also evaluated using immunofluorescence microscopy. Monocytes characterized by CD14(high) -CD16(low) expression and intracellular CD83 were increased in NOMID patients and were responsible for the majority of IL-1β production in response to LPS stimulation. This population of monocytes also underwent a rapid death response with LPS alone that is temporally associated with IL-1β and ASC release and has characteristic features of pyronecrotic but not pyroptotic cell death. Inhibition of cell death reduced IL-1β production from NOMID patient cells. In addition, IL-1 triggered cell death in monocytes from NOMID patients. Our findings indicate that monocytes are the predominant IL-1β-producing cell population in the peripheral blood of NOMID patients. Furthermore, they suggest that IL-1 receptor blockade may work in part by preventing pyronecrotic cell death, which may be an important target in NOMID and other forms of cryopyrin-associated periodic syndromes.


Folding and unfolding of light-triggered β-hairpin model peptides.
Ultrafast spectroscopy in the visible and mid-infrared is used to study the reaction dynamics of two light-triggered model peptides containing an azobenzene derivative as a switching element. One model peptide, the AzoTrpZip2, forms a β-hairpin structure in the cis form of the chromophore. This peptide is compared to the core structure consisting of the chromophore and the two flanking amino acid residues, used as a minimal model. This combination of experiments performed in different spectral ranges on peptides of different sizes allows for improved insight into light triggered reaction dynamics. The kinetics observed for the core structure are directly connected to the switching process of the chromophore and are finished on the 10 ps time scale. The trans-to-cis reaction of AzoTrpZip2, leading to the formation of the β-hairpin structure involves ultrafast processes on the 100 ps time scale, which are directly related to the relaxation of the strain between the isomerized molecular switch and the two peptide strands. IR-signatures characteristic for changes in interstrand interactions are absent on the <1 ns time scale. Thus folding into the β-hairpin structure occurs on a much longer time scale. In the cis-to-trans unfolding reaction, all IR signatures related to changes in interstrand interactions occur within 1 ns, in a time range where visible spectroscopy reveals the final decay of the intramolecular strain. Apparently unfolding of AzoTrpZip2 is to a large extent a fast, driven process.


Suspensory Versus Interference Tibial Fixation of Hamstring Tendon Autografts in Anterior Cruciate Ligament Reconstruction: Results From the New Zealand ACL Registry.
The hamstring tendon is frequently used to reconstruct the anterior cruciate ligament (ACL), but there is a lack of consensus on the optimal method of fixation. Registry studies have shown that the type of femoral fixation device can influence the risk of revision ACL reconstruction (ACLR), but it is unclear whether the type of tibial fixation has an effect. In New Zealand, over 95% of hamstring tendon grafts are fixed with an adjustable loop suspensory device on the femoral side, with variable usage between suspensory and interference devices, with or without a sheath, on the tibial side. To investigate the association between the type of tibial fixation device and the risk of revision ACLR. Cohort Study; Level of evidence, 2. Prospective data recorded in the New Zealand ACL Registry were analyzed. Only primary ACLRs performed with a hamstring tendon autograft fixed with a suspensory device on the femoral side were included. A Cox regression survival analysis with adjustment for patient factors was performed to analyze the effects of the type of tibial fixation device, the number of graft strands, and graft diameter on the risk of revision. A total of 6145 primary ACLRs performed between 2014 and 2019 were analyzed. A total of 59.6% of hamstring tendon autografts were fixed with a suspensory device on the tibial side (n = 3662), 17.6% with an interference screw with a sheath (n = 1079), and 22.8% with an interference screw without a sheath (n = 1404). When compared with suspensory devices, a higher revision risk was observed when using an interference screw with a sheath (adjusted hazard ratio [HR], 2.05; P = .009) and without a sheath (adjusted HR, 1.81; P = .044). The number of graft strands and a graft diameter of ≥8 mm were associated with the rate of revision on the univariate analysis; however, after adjusting for confounding variables on the multivariate analysis, they did not significantly influence the risk of revision. In this study of hamstring tendon autografts fixed with an adjustable loop suspensory device on the femoral side during primary ACLR, the use of an interference screw, with or without a sheath, on the tibial side resulted in a higher revision rate when compared with a suspensory device.


Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy.
Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority. Following completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction [PCR] for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint. The demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the MDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group. Following standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors. NCT00031486.


Inhibitory effects of (-)-epigallocatechin-3-gallate from green tea on the growth of Babesia parasites.
(-)-Epigallocatechin-3-gallate (EGCG) is the major tea catechin and accounts for 50-80% of the total catechin in green tea. (-)-Epigallocatechin-3-gallate has antioxidant, anti-inflammatory, anti-microbial, anti-cancer, and anti-trypanocidal activities. This report describes the inhibitory effect of (-)-Epigallocatechin-3-gallate on the in vitro growth of bovine Babesia parasites and the in vivo growth of the mouse-adapted rodent babesia B. microti. The in vitro growth of the Babesia species was significantly (P<0.05) inhibited in the presence of micromolar concentrations of EGCG (IC50 values=18 and 25 microM for B. bovis, and B. bigemina, respectively). The parasites showed no re-growth at 25 microM for B. bovis and B. bigemina in the subsequent viability test. The drug significantly (P<0.05) inhibited the growth of B. microti at doses of 5 and 10 mg/kg body weight, and the parasites completely cleared on day 14 and 16 post-inoculation in the 5 and 10 mg/kg treated groups, respectively. These findings highlight the potentiality of (-)-Epigallocatechin-3-gallate as a chemotherapeutic drug for the treatment of babesiosis.


svmPRAT: SVM-based protein residue annotation toolkit.
Over the last decade several prediction methods have been developed for determining the structural and functional properties of individual protein residues using sequence and sequence-derived information. Most of these methods are based on support vector machines as they provide accurate and generalizable prediction models. We present a general purpose protein residue annotation toolkit (svmPRAT) to allow biologists to formulate residue-wise prediction problems. svmPRAT formulates the annotation problem as a classification or regression problem using support vector machines. One of the key features of svmPRAT is its ease of use in incorporating any user-provided information in the form of feature matrices. For every residue svmPRAT captures local information around the reside to create fixed length feature vectors. svmPRAT implements accurate and fast kernel functions, and also introduces a flexible window-based encoding scheme that accurately captures signals and pattern for training effective predictive models. In this work we evaluate svmPRAT on several classification and regression problems including disorder prediction, residue-wise contact order estimation, DNA-binding site prediction, and local structure alphabet prediction. svmPRAT has also been used for the development of state-of-the-art transmembrane helix prediction method called TOPTMH, and secondary structure prediction method called YASSPP. This toolkit developed provides practitioners an efficient and easy-to-use tool for a wide variety of annotation problems. http://www.cs.gmu.edu/~mlbio/svmprat.


Cancer, stress and personality: a correlational investigation of life-events, repression-sensitization and locus of control.
This study investigated the hypothesis that stress-inducing life experiences and the personality factors of external locus of control and tendency to repress emotion are relevant in the aetiology of cancer. Fifty cancer patients scored higher than 50 matched controls on a life-events scale (especially negative events), but were found to be lower on repression of emotion. There was no difference between groups on locus of control.


Extended perioperative thromboprophylaxis in patients with cancer. A systematic review.
We systematically reviewed the literature to compare the relative efficacy and safety of extended versus limited duration heparin for perioperative thromboprophylaxis in patients with cancer. We followed the Cochrane Collaboration systematic review methodology and searched MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL. The outcomes of interest included mortality, symptomatic deep venous thrombosis (DVT), pulmonary embolism, and bleeding. We evaluated the quality of evidence by outcome using the GRADE approach. Of 3,986 identified citations, we included three randomized clinical trials using low-molecular-weight heparin (LMWH). The quality of evidence for mortality, DVT, and major bleeding was low. There was no significant difference between extended (4 weeks) and limited duration thromboprophylaxis in terms of death at three months (relative risk [RR] = 0.49; 95% confidence interval [CI] 0.12-1.94), or major bleeding at four weeks (RR = 2.94; 95% CI 0.12-71.85). An extended regimen was associated with a significantly lower risk of asymptomatic DVT (RR = 0.21; 95% CI 0.05-0.94). No data was available for symptomatic DVT. In conclusion, there is limited and low-quality evidence that extended duration LMWH for perioperative thromboprophylaxis reduces DVT in patients with cancer undergoing major abdominal or pelvic surgery. More and better quality evidence is needed to justify extended regimens.


Adapting to social and political transitions - the influence of history on health policy formation in the Republic of the Union of Myanmar (Burma).
The Republic of the Union of Myanmar (Burma) has a long and complex history characterized by internal conflict and tense international relations. Post-independence, the health sector has gradually evolved, but with health service development and indicators lagging well behind regional expectations. In recent years, the country has initiated political reforms and a reorientation of development policy towards social sector investment. In this study, from a systems and historical perspective, we used publicly available data sources and grey literature to describe and analyze links between health policy and history from the post-independence period up until 2012. Three major periods are discernable in post war health system development and political history in Myanmar. The first post-independence period was associated with the development of the primary health care system extending up to the 1988 political events. The second period is from 1988 to 2005, when the country launched a free market economic model and was arguably experiencing its highest levels of international isolation as well as very low levels of national health investment. The third period (2005-2012) represents the first attempts at health reform and recovery, linked to emerging trends in national political reform and international politics. Based on the most recent period of macro-political reform, the central state is set to transition from a direct implementer of a command and control management system, towards stewardship of a significantly more complex and decentralized administrative order. Historical analysis demonstrates the extent to which these periodic shifts in the macro-political and economic order acts to reset the parameters for health policy making. This case demonstrates important lessons for other countries in transition by highlighting the extent to which analysis of political history can be instructive for determination of more feasible boundaries for future health policy action.


Modeling dynamic functional relationship networks and application to ex vivo human erythroid differentiation.
Functional relationship networks, which summarize the probability of co-functionality between any two genes in the genome, could complement the reductionist focus of modern biology for understanding diverse biological processes in an organism. One major limitation of the current networks is that they are static, while one might expect functional relationships to consistently reprogram during the differentiation of a cell lineage. To address this potential limitation, we developed a novel algorithm that leverages both differentiation stage-specific expression data and large-scale heterogeneous functional genomic data to model such dynamic changes. We then applied this algorithm to the time-course RNA-Seq data we collected for ex vivo human erythroid cell differentiation. Through computational cross-validation and literature validation, we show that the resulting networks correctly predict the (de)-activated functional connections between genes during erythropoiesis. We identified known critical genes, such as HBD and GATA1, and functional connections during erythropoiesis using these dynamic networks, while the traditional static network was not able to provide such information. Furthermore, by comparing the static and the dynamic networks, we identified novel genes (such as OSBP2 and PDZK1IP1) that are potential drivers of erythroid cell differentiation. This novel method of modeling dynamic networks is applicable to other differentiation processes where time-course genome-scale expression data are available, and should assist in generating greater understanding of the functional dynamics at play across the genome during development. The network described in this article is available at http://guanlab.ccmb.med.umich.edu/stageSpecificNetwork.


Registered Replication Report: Study 1 From Finkel, Rusbult, Kumashiro, & Hannon (2002).
Finkel, Rusbult, Kumashiro, and Hannon (2002, Study 1) demonstrated a causal link between subjective commitment to a relationship and how people responded to hypothetical betrayals of that relationship. Participants primed to think about their commitment to their partner (high commitment) reacted to the betrayals with reduced exit and neglect responses relative to those primed to think about their independence from their partner (low commitment). The priming manipulation did not affect constructive voice and loyalty responses. Although other studies have demonstrated a correlation between subjective commitment and responses to betrayal, this study provides the only experimental evidence that inducing changes to subjective commitment can causally affect forgiveness responses. This Registered Replication Report (RRR) meta-analytically combines the results of 16 new direct replications of the original study, all of which followed a standardized, vetted, and preregistered protocol. The results showed little effect of the priming manipulation on the forgiveness outcome measures, but it also did not observe an effect of priming on subjective commitment, so the manipulation did not work as it had in the original study. We discuss possible explanations for the discrepancy between the findings from this RRR and the original study.


Presepsin: A new marker of catheter related blood stream infections in pediatric patients.
Catheter related blood stream infections (CRBSI) are mostly preventable hospital-acquired conditions. We aimed to investigate the value of presepsin in detection of CRBSI in hospitalized children. Hospitalized pediatric patients who had clinical suspicion of CRBSI were followed. Results of peripheral blood cultures and blood cultures from central venous catheters, procalcitonin (PCT), C-reactive protein (CRP), total white blood cell (WBC) counts were recorded. Serum samples for presepsin were studied at the same time with the samples of healthy controls. The patients with positive blood cultures were defined as proven CRBSI and with negative cultures as suspected CRBSI. Fifty-eight patients and 80 healthy controls were included in the study. Proven CRBSI group consisted of 36 patients (62%) with positive blood cultures and compared with the suspected CRBSI group (n = 22, 36%) with negative culture results. There was no difference between proven and suspected CRBSI groups concerning WBC, PCT, CRP and presepsin. Presepsin was significantly higher in patient groups when compared with healthy controls. The receiver operating characteristic curve area under the curve was 0.98 (%95 CI: 0.97-1) and best cut-off value was 990 pg/ml. In hospitalized pediatric patients with CRBSI, presepsin may be a helpful rapid marker in early diagnosis.


Context-aware visual tracking.
Enormous uncertainties in unconstrained environments lead to a fundamental dilemma that many tracking algorithms have to face in practice: Tracking has to be computationally efficient, but verifying whether or not the tracker is following the true target tends to be demanding, especially when the background is cluttered and/or when occlusion occurs. Due to the lack of a good solution to this problem, many existing methods tend to be either effective but computationally intensive by using sophisticated image observation models or efficient but vulnerable to false alarms. This greatly challenges long-duration robust tracking. This paper presents a novel solution to this dilemma by considering the context of the tracking scene. Specifically, we integrate into the tracking process a set of auxiliary objects that are automatically discovered in the video on the fly by data mining. Auxiliary objects have three properties, at least in a short time interval: 1) persistent co-occurrence with the target, 2) consistent motion correlation to the target, and 3) easy to track. Regarding these auxiliary objects as the context of the target, the collaborative tracking of these auxiliary objects leads to efficient computation as well as strong verification. Our extensive experiments have exhibited exciting performance in very challenging real-world testing cases.


An amphioxus homeobox gene: sequence conservation, spatial expression during development and insights into vertebrate evolution.
The embryology of amphioxus has much in common with vertebrate embryology, reflecting a close phylogenetic relationship between the two groups. Amphioxus embryology is simpler in several key respects, however, including a lack of pronounced craniofacial morphogenesis. To gain an insight into the molecular changes that accompanied the evolution of vertebrate embryology, and into the relationship between the amphioxus and vertebrate body plans, we have undertaken the first molecular level investigation of amphioxus embryonic development. We report the cloning, complete DNA sequence determination, sequence analysis and expression analysis of an amphioxus homeobox gene, AmphiHox3, evolutionarily homologous to the third-most 3' paralogous group of mammalian Hox genes. Sequence comparison to a mammalian homologue, mouse Hox-2.7 (HoxB3), reveals several stretches of amino acid conservation within the deduced protein sequences. Whole mount in situ hybridization reveals localized expression of AmphiHox3 in the posterior mesoderm (but not in the somites), and region-specific expression in the dorsal nerve cord, of amphioxus neurulae, later embryos and larvae. The anterior limit to expression in the nerve cord is at the level of the four/five somite boundary at the neurula stage, and stabilises to just anterior to the first nerve cord pigment spot to form. Comparison to the anterior expression boundary of mouse Hox-2.7 (HoxB3) and related genes suggests that the vertebrate brain is homologous to an extensive region of the amphioxus nerve cord that contains the cerebral vesicle (a region at the extreme rostral tip) and extends posterior to somite four.(ABSTRACT TRUNCATED AT 250 WORDS)


Double-stranded RNA upregulates the expression of inflammatory mediators in human aortic valve cells through the TLR3-TRIF-noncanonical NF-κB pathway.
Calcific aortic valve disease is a chronic inflammatory condition, and the inflammatory responses of aortic valve interstitial cells (AVICs) play a critical role in the disease progression. Double-stranded RNA (dsRNA) released from damaged or stressed cells is proinflammatory and may contribute to the mechanism of chronic inflammation observed in diseased aortic valves. The objective of this study is to determine the effect of dsRNA on AVIC inflammatory responses and the underlying mechanism. AVICs from normal human aortic valves were stimulated with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of dsRNA. Poly(I:C) increased the production of IL-6, IL-8, monocyte chemoattractant protein-1, and ICAM-1. Poly(I:C) also induced robust activation of ERK1/2 and NF-κB. Knockdown of Toll-like receptor 3 (TLR3) or Toll-IL-1 receptor domain-containing adapter-inducing IFN-β (TRIF) suppressed ERK1/2 and NF-κB p65 phosphorylation and reduced inflammatory mediator production induced by poly(I:C). Inhibition of NF-κB, not ERK1/2, reduced inflammatory mediator production in AVICs exposed to poly(I:C). Interestingly, inhibition of NF-κB by prevention of p50 migration failed to suppress inflammatory mediator production. NF-κB p65 intranuclear translocation induced by the TLR4 agonist was reduced by inhibition of p50 migration; however, poly(I:C)-induced p65 translocation was not, although the p65/p50 heterodimer is present in AVICs. Poly(I:C) upregulates the production of multiple inflammatory mediators through the TLR3-TRIF-NF-κB pathway in human AVICs. The NF-κB activated by dsRNA appears not to be the canonical p65/p50 heterodimers.


Influence of sodium fumarate addition on rumen fermentation in vitro.
The influence of sodium fumarate on rumen fermentation was investigated in vitro using batch and semi-continuous cultures of mixed rumen micro-organisms taken from three sheep receiving a basal diet of hay, barley, molasses, fish meal and a mineral-vitamin supplement (500, 299.5, 100, 91 and 9.5 g/kg DM respectively). Batch cultures consisted of 10 ml strained rumen fluid in 40 ml anaerobic buffer containing 200 mg of the same feed given to the sheep. Sodium fumarate was added to achieve a final concentration of 0, 5 or 10 mmol/l, as a result of the addition of 0, 250 or 500 mumol, equivalent to 0, 200 and 400 g/kg feed. CH4 production at 24 h (360 mumol in the control cultures) fell (P < 0.05) by 18 and 22 mumol respectively (SED 7.5). Total gas production was increased by the addition of fumarate without significant accumulation of H2. Substantial increases in acetate production (92 and 194 mumol; SED 26.7, P < 0.01) were accompanied by increases in propionate formation (212 and 396 mumol; SED 13.0, P < 0.001). Longer-term effects of fumarate supplementation on ruminal fermentation and CH4 production were investigated using the rumen simulation technique (Rusitec). Eight vessels were given 20 g basal diet/d, and half of them received a supplement of fumarate (disodium salt) over a period of 19 d. The response to the daily addition of 6.25 mmol sodium fumarate was a decrease in CH4 production of 1.2 mmol (SED 0.39, P < 0.05), equivalent to the consumption of 4.8 mmol H2, and an increase in propionate production of 4.9 mmol (from 10.4 to 15.3 (SED 1.05) mmol/d, P < 0.01). The inhibition of CH4 production did not decline during the period of time that fumarate was added to the vessels. Thus, the decrease in CH4 corresponded well to the fraction of the fumarate that was converted to propionate. Fumarate had no significant (P > 0.05) effect on total bacterial numbers or on the number of methanogenic archaea, but numbers of cellulolytic bacteria were increased (8.8 v. 23.9 (SED 2.49) x 10(5) per ml, P < 0.01). Fumarate also increased DM digestibility of the basal diet after 48 h incubation (0.476 v. 0.508 (SED 0.0123), P < 0.05). Thus, it was concluded that sodium fumarate may be a useful dietary additive for ruminants, because it diverts some H2 from CH4 production and because it is able to stimulate proliferation of cellulolytic bacteria and digestion of fibre.


Hippocampal granule cells opt for early retirement.
Increased excitability and plasticity of adult-generated hippocampal granule cells during a critical period suggests that they may "orthogonalize" memories according to time. One version of this "temporal tag" hypothesis suggests that young granule cells are particularly responsive during a specific time period after their genesis, allowing them to play a significant role in sculpting CA3 representations, after which they become much less responsive to any input. An alternative possibility is that the granule cells active during their window of increased plasticity, and excitability become selectively tuned to events that occurred during that time and participate in later reinstatement of those experiences, to the exclusion of other cells. To discriminate between these possibilities, rats were exposed to different environments at different times over many weeks, and cell activation was subsequently assessed during a single session in which all environments were revisited. Dispersing the initial experiences in time did not lead to the increase in total recruitment at reinstatement time predicted by the selective tuning hypothesis. The data indicate that, during a given time frame, only a very small number of granule cells participate in many experiences, with most not participating significantly in any. Based on these and previous data, the small excitable population of granule cells probably correspond to the most recently generated cells. It appears that, rather than contributing to the recollection of long past events, most granule cells, possibly 90-95%, are effectively "retired." If granule cells indeed sculpt CA3 representations (which remains to be shown), then a possible consequence of having a new set of granule cells participate when old memories are reinstated is that new representations of these experiences might be generated in CA3. Whatever the case, the present data may be interpreted to undermine the standard "orthogonalizer" theory of the role of the dentate gyrus in memory.


Structure of Electronically Reduced N-Donor Bidentate Ligands and Their Heteroleptic Four-Coordinate Zinc Complexes: A Survey of Density Functional Theory Results.
The role of Hartree-Fock exchange in describing the structural changes occurring upon reduction of bipyridine-based ligands and their complexes is investigated within the framework of density functional theory (DFT) calculations. A set of four free ligands in their neutral and radical anionic forms, and two of their zinc complexes in their dicationic and monocationic radical forms, is used to compare a large panel of pure, conventional, and long-range corrected hybrid DFT functionals; coupled cluster single and double calculations are used alongside experimental results as benchmarks. Particular attention has been devoted to the magnitude of the change, upon reduction, of the Δ-parameter, which measures the difference between the Cpy-Cpy and the C-N bond lengths in bipyridine ligand and is known to experimentally correlate with the charge of the ligands. Our results indicate that the structural changes significantly depend on the amount of exact exchange included in the functional. A progressive evolution is observed for the free ligands, whereas two distinct sets of results are obtained for the complexes. Functionals with a small degree of HF exchange, e.g., B3LYP, do not adequately describe geometric changes for the considered species, and, quite surprisingly, the same holds for the CC2 method. The best agreement to experimental and CCSD values is obtained with functionals that include a significant but not excessive part of exact exchange, e.g., CAM-B3LYP, M06-2X, and ωB97X-D. The calculated localization of the added electron after reduction, which depends on the self-interaction error, is used to rationalize these outcomes. Static correlation is also shown to play a role in the accurate description of the electronic structure.


Primary empathy deficits in frontotemporal dementia.
Loss of empathy is an early central symptom and diagnostic criterion of the behavioral variant frontotemporal dementia (bvFTD). Although changes in empathy are evident and strongly affect the social functioning of bvFTD patients, few studies have directly investigated this issue by means of experimental paradigms. The current study assessed multiple components of empathy (affective, cognitive and moral) in bvFTD patients. We also explored whether the loss of empathy constitutes a primary deficit of bvFTD or whether it is explained by impairments in executive functions (EF) or other social cognition domains. Thirty-seven bvFTD patients with early/mild stages of the disease and 30 healthy control participants were assessed with a task that involves the perception of intentional and accidental harm. Participants were also evaluated on emotion recognition, theory of mind (ToM), social norms knowledge and several EF domains. BvFTD patients presented deficits in affective, cognitive and moral aspects of empathy. However, empathic concern was the only aspect primarily affected in bvFTD that was neither related nor explained by deficits in EF or other social cognition domains. Deficits in the cognitive and moral aspects of empathy seem to depend on EF, emotion recognition and ToM. Our findings highlight the importance of using tasks depicting real-life social scenarios because of their greater sensitivity in the assessment of bvFTD. Moreover, our results contribute to the understanding of primary and intrinsic empathy deficits of bvFTD and have important theoretical and clinical implications.


Options for national parks and reserves for adapting to climate change.
Past and present climate has shaped the valued ecosystems currently protected in parks and reserves, but future climate change will redefine these conditions. Continued conservation as climate changes will require thinking differently about resource management than we have in the past; we present some logical steps and tools for doing so. Three critical tenets underpin future management plans and activities: (1) climate patterns of the past will not be the climate patterns of the future; (2) climate defines the environment and influences future trajectories of the distributions of species and their habitats; (3) specific management actions may help increase the resilience of some natural resources, but fundamental changes in species and their environment may be inevitable. Science-based management will be necessary because past experience may not serve as a guide for novel future conditions. Identifying resources and processes at risk, defining thresholds and reference conditions, and establishing monitoring and assessment programs are among the types of scientific practices needed to support a broadened portfolio of management activities. In addition to the control and hedging management strategies commonly in use today, we recommend adaptive management wherever possible. Adaptive management increases our ability to address the multiple scales at which species and processes function, and increases the speed of knowledge transfer among scientists and managers. Scenario planning provides a broad forward-thinking framework from which the most appropriate management tools can be chosen. The scope of climate change effects will require a shared vision among regional partners. Preparing for and adapting to climate change is as much a cultural and intellectual challenge as an ecological challenge.


Low dose rate brachytherapy (LDR-BT) as monotherapy for early stage prostate cancer in Italy: practice and outcome analysis in a series of 2237 patients from 11 institutions.
Low-dose-rate brachytherapy (LDR-BT) in localized prostate cancer is available since 15 years in Italy. We realized the first national multicentre and multidisciplinary data collection to evaluate LDR-BT practice, given as monotherapy, and outcome in terms of biochemical failure. Between May 1998 and December 2011, 2237 patients with early-stage prostate cancer from 11 Italian community and academic hospitals were treated with iodine-125 ((125)I) or palladium-103 LDR-BT as monotherapy and followed up for at least 2 years. (125)I seeds were implanted in 97.7% of the patients: the mean dose received by 90% of target volume was 145 Gy; the mean target volume receiving 100% of prescribed dose (V100) was 91.1%. Biochemical failure-free survival (BFFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method. Log-rank test and multivariable Cox regression were used to evaluate the relationship of covariates with outcomes. Median follow-up time was 65 months. 5- and 7-year DSS, OS and BFFS were 99 and 98%, 94 and 89%, and 92 and 88%, respectively. At multivariate analysis, the National Comprehensive Cancer Network score (p < 0.0001) and V100 (p = 0.09) were correlated with BFFS, with V100 effect significantly different between patients at low risk and those at intermediate/high risk (p = 0.04). Short follow-up and lack of toxicity data represent the main limitations for a global evaluation of LDR-BT. This first multicentre Italian report confirms LDR-BT as an excellent curative modality for low-/intermediate-risk prostate cancer. Multidisciplinary teams may help to select adequately patients to be treated with brachytherapy, with a direct impact on the implant quality and, possibly, on outcome.


Endogenous creatinine clearance as a clinical measure of glomerular filtration rate.
Endogenous creatinine clearance was assessed by inulin in 91 simultaneous studies in 41 patients and proved an accurate measurement of glomerular filtration rate. For filtration rates <20 ml/min the creatinine clearance may slightly overestimate the glomerular filtration rate. Successive determinations of filtration rate by either method may vary by 20% even though the methods agree with each other. Glomerular filtration rate itself is variable, and in its clinical usage this should be recognized.


Application of Biocatalysis to on-DNA Carbohydrate Library Synthesis.
DNA-encoded libraries are increasingly used for the discovery of bioactive lead compounds in high-throughput screening programs against specific biological targets. Although a number of libraries are now available, they cover limited chemical space due to bias in ease of synthesis and the lack of chemical reactions that are compatible with DNA tagging. For example, compound libraries rarely contain complex biomolecules such as carbohydrates with high levels of functionality, stereochemistry, and hydrophilicity. By using biocatalysis in combination with chemical methods, we aimed to significantly expand chemical space and generate generic libraries with potentially better biocompatibility. For DNA-encoded libraries, biocatalysis is particularly advantageous, as it is highly selective and can be performed in aqueous environments, which is an essential feature for this split-and-mix library technology. In this work, we demonstrated the application of biocatalysis for the on-DNA synthesis of carbohydrate-based libraries by using enzymatic oxidation and glycosylation in combination with traditional organic chemistry.


Welfare of pigs on farm.
This scientific opinion focuses on the welfare of pigs on farm, and is based on literature and expert opinion. All pig categories were assessed: gilts and dry sows, farrowing and lactating sows, suckling piglets, weaners, rearing pigs and boars. The most relevant husbandry systems used in Europe are described. For each system, highly relevant welfare consequences were identified, as well as related animal-based measures (ABMs), and hazards leading to the welfare consequences. Moreover, measures to prevent or correct the hazards and/or mitigate the welfare consequences are recommended. Recommendations are also provided on quantitative or qualitative criteria to answer specific questions on the welfare of pigs related to tail biting and related to the European Citizen's Initiative 'End the Cage Age'. For example, the AHAW Panel recommends how to mitigate group stress when dry sows and gilts are grouped immediately after weaning or in early pregnancy. Results of a comparative qualitative assessment suggested that long-stemmed or long-cut straw, hay or haylage is the most suitable material for nest-building. A period of time will be needed for staff and animals to adapt to housing lactating sows and their piglets in farrowing pens (as opposed to crates) before achieving stable welfare outcomes. The panel recommends a minimum available space to the lactating sow to ensure piglet welfare (measured by live-born piglet mortality). Among the main risk factors for tail biting are space allowance, types of flooring, air quality, health status and diet composition, while weaning age was not associated directly with tail biting in later life. The relationship between the availability of space and growth rate, lying behaviour and tail biting in rearing pigs is quantified and presented. Finally, the panel suggests a set of ABMs to use at slaughter for monitoring on-farm welfare of cull sows and rearing pigs.


Enhanced inflammation with high carbohydrate intake during recovery from eccentric exercise.
Inflammation associated with adipose tissue is modulated by macronutrient availability. For example, glucose increases inflammation in obese but not lean individuals. Little is known about how macronutrient intake influences inflammation associated with muscle. The aim of this study was to determine the impact of macronutrient intake differences during recovery from eccentric exercise on the inflammatory response. The study was a cross-over design in which young men and women (n = 12) completed high and low carbohydrate (CHO) conditions. Both conditions consisted of six sets of ten maximal high-force eccentric contractions of the elbow flexors and extensors followed by a controlled diet for the first 8 h post-exercise. Glucose, insulin, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and C-reactive protein were measured from blood samples pre-exercise, 1.5, 4, 8, and 24 h post-exercise. Perceived muscle soreness, strength loss, and serum CK activity were measured through 120 h post-exercise. Perceived soreness was elevated (P < 0.001) at all time points post-exercise in both conditions and was higher (P < 0.05) in the high compared to the low CHO condition. IL-1beta increased (P = 0.05) 24 h post-exercise in the high compared to the low CHO condition. There was a trend (P = 0.06) for IL-6 to be elevated in the high compared to the low CHO condition. We conclude that inflammation induced by high-force eccentric exercise in skeletal muscle is greater when a high CHO compared to a low CHO diet is consumed during recovery.


Quantitative neuropathology by high resolution magic angle spinning proton magnetic resonance spectroscopy.
We describe a method that directly relates tissue neuropathological analysis to medical imaging. Presently, only indirect and often tenuous relationships are made between imaging (such as MRI or x-ray computed tomography) and neuropathology. We present a biochemistry-based, quantitative neuropathological method that can help to precisely quantify information provided by in vivo proton magnetic resonance spectroscopy (1HMRS), an emerging medical imaging technique. This method, high resolution magic angle spinning (HRMAS) 1HMRS, is rapid and requires only small amounts of unprocessed samples. Unlike chemical extraction or other forms of tissue processing, this method analyzes tissue directly, thus minimizing artifacts. We demonstrate the utility of this method by assessing neuronal damage using multiple tissue samples from differently affected brain regions in a case of Pick disease, a human neurodegenerative disorder. Among different regions, we found an excellent correlation between neuronal loss shown by traditional neurohistopathology and decrease of the neuronal marker N-acetylaspartate measured by HRMAS 1HMRS. This result demonstrates for the first time, to our knowledge, a direct, quantitative link between a decrease in N-acetylaspartate and neuronal loss in a human neurodegenerative disease. As a quantitative method, HRMAS 1HMRS has potential applications in experimental and clinical neuropathologic investigations. It should also provide a rational basis for the interpretation of in vivo 1HMRS studies of human neurological disorders.


Trends in the Family Income Distribution by Race/Ethnicity and Income Source, 1988-2009.
The recent dramatic rise in U.S. income inequality has prompted a great deal of research on trends in overall family income and changes in sources of family income, especially among the highest income earners. However, less is known about changes in sources of income among the bottom 99% or about racial/ethnic differences in those trends. The present research contributes to the literatures on income trends and racial economic inequality by using family-level data from the 1988-2009 Current Population Survey to examine changes in overall family income and the proportion of income coming from employment, property/assets, and transfers across five different levels of family income for white-, black, and Hispanic-headed families. We find that at all income levels above the 25th percentile, employment income is by far the largest contributor to family income for all racial/ethnic groups. Employment income trended upward over the period in both real dollars and as a percentage of total family income. In this respect, white, black and Hispanic families are remarkably similar. The racial gap in total family income has remained fairly stable over the period, but this trend conceals a narrowing of racial differences in property income, mostly as a function of the decline in property income among whites, a widening of racial differences in transfer income among the bottom 25%, and a widening of racial differences in employment income, particularly at the top of the family income distribution. Income accrued from wealth is a very small component of overall family income for all three racial groups, even for the highest-income families (top 1%).


Teaching anatomy with surgeons' tools: use of the laparoscope in clinical anatomy.
The purpose of this study was to establish the feasibility of laparoscopy in embalmed cadavers to teach abdominal gross anatomy. One cadaver was selected based on body habitus and absence of previous abdominal operations. A standard trocar was used to enter the abdomen at the umbilicus. Two trocars were placed in the left upper quadrant. Pneumoperitoneum was achieved with continuous CO(2) pressure. Liver retraction was achieved percutaneously, exposing the porta hepatis and the gallbladder. The dissection was done with four first-year medical students using standard laparoscopic equipment. Following this, the demonstration was projected over multiple monitors so that all students could participate. Laparoscopic dissection in an embalmed cadaver is feasible and an excellent educational tool for both the medical student and the dissector. The dissector has the opportunity to manipulate laparoscopic tools in a human model closely paralleling operative experience, and the students have an opportunity to learn abdominal anatomy from a clinical perspective. Laparoscopic examination and dissection of fresh cadavers has been used for training surgeons on new procedures such as colon resection, antireflux procedures, and cholecystectomy. There is no report of this same technology used in embalmed cadavers to teach basic anatomy. This approach allows first-year medical students to learn the anatomy while exposing them to the technology currently used in surgical practice, and it affords surgical residents and students additional opportunities to practice laparoscopic skills.


Obesity and obstetric anaesthesia.
The prevalence of obesity continues to increase despite preventive strategies. Obese parturients are at increased risk of having either concurrent medical problems or superimposed antenatal diseases such as pre-eclampsia and gestational diabetes. Moreover, they have a tendency to labour abnormally contributing to increased instrumental delivery and Caesarean section. Obesity is a risk factor for anaesthesia related maternal mortality. Morbidly obese women must be considered as high-risk and deserve an anaesthetic consultation during their antenatal care. The significant difficulty in administering epidural analgesia should not preclude their use in labour. A more liberalised use of regional techniques may be a means to further reduce anaesthesia-related maternal mortality in the obese population. The mother's life should not be jeopardised to save a compromised fetus. Prophylactic placement of an epidural catheter when not contraindicated in labouring morbidly obese women would potentially decrease anaesthetic and perinatal complications associated with attempts at emergency provision of regional or general anaesthesia. Early mobilisation, aggressive chest physiotherapy and adequate pain control are essential components of effective postoperative care.


Intraspecific variability of natural populations of Phlebotomus sergenti, the main vector of Leishmania tropica.
An intraspecific study of Phlebotomus sergenti was performed on populations from Turkey, Syria, Israel, and Uzbekistan by four different approaches: geometric morphometrics, RAPD analysis, internal transcribed spacer 2 (ITS2) sequencing (nuclear marker), and cytochrome B sequencing (mitochondrial marker). In RAPD analysis, distinct clades were formed in accordance with the geographical origin of the specimens. There was no distinct grouping according to place of origin within the Turkish samples from various localities in south-eastern Anatolia, which suggests a gene flow between populations separated spatially by the Amanos mountains, a mountain range of a considerable altitude. The results of ITS2 rDNA sequencing complied with the previously published intraspecific division of P. sergenti into two branches, northeastern and southwestern. However, mtDNA haplotypes formed three lineages with specimens from Turkey and Israel, sharing a common clade. A previously postulated hypothesis about a complex of sibling species within P. sergenti is therefore questionable. Cytochrome B seems to be a more discriminative marker for intraspecific variability assessment.


Scale and state dependence of the relationship between personality and dispersal in a great tit population.
1. Dispersal is a key process in population biology and ecology. Although the general ecological conditions that lead to dispersal have been well studied, the causes of individual variation in dispersal are less well understood. A number of recent studies suggest that heritable temperament - or personality - traits are correlated with dispersal in the wild but the extent to which these 'personality-dispersal syndromes' are general, how they depend on an individual's state and on spatial scale and whether they are temporally stable, both within and across individuals, remains unclear. 2. Here, we examine the relationship between exploration behaviour - an axis of personality that appears to be important in animals generally - and a variety of dispersal processes over 6 years in a population of the great tit Parus major. 3. Exploration behaviour was higher in immigrant than in locally born juveniles, but the difference was much larger for individuals with a small body mass, though independent of sex, representing one of the first examples of a state-dependent effect in a personality-dispersal syndrome. 4. Despite a temporal trend in exploration behaviour at the population level, the difference between immigrants and locally born birds remained stable over time, both across and within individuals. This suggests that the personality difference between immigrants and locally born birds is established early in development, but that the process of immigration interacts with both personality and state. 5. We found that the number of immigrant parents a locally born bird had did not influence exploration behaviour, suggesting either the difference between immigrants and residents was environmental or that the effect is overridden by local environmental sources of variation. 6. In contrast to previous work, we found no evidence for links between personality and natal dispersal distance within the population, either in terms of an individual's own exploration behaviour or that of its parents. 7. Our results suggest that there are links between individual differences in personality and dispersal, but that these can be dependent on differences in state among individuals and on the scale over which dispersal is measured. Future work should aim to understand the differences between dispersal within and between populations and the ways in which personality and state interact to determine the outcome of these processes.


Oral contraceptives, depression, and libido.
Depression, headaches, and libido were rated in 272 women before starting a contraceptive method and at intervals during the first year of use-54 were fitted with an intrauterine device (I.U.D.) and 218 used one of three oral contraceptives. Side effects caused 25% of the oral contraceptive group and 13% of the I.U.D. group to stop the method. Depression, headaches, and loss of libido were the most common reasons for stopping oral contraceptives and breakthrough bleeding was the most common reason for stopping the I.U.D.The group of women who stopped or changed their oral contraceptives during the survey were compared with the group who remained on the same oral contraceptive throughout. The former had higher mean depression and neuroticism scores at the first clinic visit and contained more women with a history of premenstrual weepiness, depression during pregnancy, outpatient psychiatric treatment, and treatment with antidepressants. Changes in the depression, headache, and libido ratings throughout the survey are presented.


Pictorial cigarette pack warnings: a meta-analysis of experimental studies.
To inform international research and policy, we conducted a meta-analysis of the experimental literature on pictorial cigarette pack warnings. We systematically searched 7 computerised databases in April 2013 using several search terms. We also searched reference lists of relevant articles. We included studies that used an experimental protocol to test cigarette pack warnings and reported data on both pictorial and text-only conditions. 37 studies with data on 48 independent samples (N=33,613) met criteria. Two independent coders coded all study characteristics. Effect sizes were computed from data extracted from study reports and were combined using random effects meta-analytic procedures. Pictorial warnings were more effective than text-only warnings for 12 of 17 effectiveness outcomes (all p<0.05). Relative to text-only warnings, pictorial warnings (1) attracted and held attention better; (2) garnered stronger cognitive and emotional reactions; (3) elicited more negative pack attitudes and negative smoking attitudes and (4) more effectively increased intentions to not start smoking and to quit smoking. Participants also perceived pictorial warnings as being more effective than text-only warnings across all 8 perceived effectiveness outcomes. The evidence from this international body of literature supports pictorial cigarette pack warnings as more effective than text-only warnings. Gaps in the literature include a lack of assessment of smoking behaviour and a dearth of theory-based research on how warnings exert their effects.


Pre-surgical depression and anxiety and recovery following coronary artery bypass graft surgery.
We aimed to explore the combined contribution of pre-surgical depression and anxiety symptoms for recovery following coronary artery bypass graft (CABG) using data from 251 participants. Participants were assessed prior to surgery for depression and anxiety symptoms and followed up at 12 months to assess pain and physical symptoms, while hospital emergency admissions and death/major adverse cardiac events (MACE) were monitored on average 2.68 years after CABG. After controlling for covariates, baseline anxiety symptoms, but not depression, were associated with greater pain (β = 0.231, p = 0.014) and greater physical symptoms (β = 0.194, p = 0.034) 12 months after surgery. On the other hand, after controlling for covariates, baseline depression symptoms, but not anxiety, were associated with greater odds of having an emergency admission (OR 1.088, CI 1.010-1.171, p = 0.027) and greater hazard of death/MACE (HR 1.137, CI 1.042-1.240, p = 0.004). These findings point to different pathways linking mood symptoms with recovery after CABG surgery.


Evolutionary optimization of classifiers and features for single-trial EEG discrimination.
State-of-the-art signal processing methods are known to detect information in single-trial event-related EEG data, a crucial aspect in development of real-time applications such as brain computer interfaces. This paper investigates one such novel approach, evaluating how individual classifier and feature subset tailoring affects classification of single-trial EEG finger movements. The discrete wavelet transform was used to extract signal features that were classified using linear regression and non-linear neural network models, which were trained and architecturally optimized with evolutionary algorithms. The input feature subsets were also allowed to evolve, thus performing feature selection in a wrapper fashion. Filter approaches were implemented as well by limiting the degree of optimization. Using only 10 features and 100 patterns, the non-linear wrapper approach achieved the highest validation classification accuracy (subject mean 75%), closely followed by the linear wrapper method (73.5%). The optimal features differed much between subjects, yet some physiologically plausible patterns were observed. High degrees of classifier parameter, structure and feature subset tailoring on individual levels substantially increase single-trial EEG classification rates, an important consideration in areas where highly accurate detection rates are essential. Also, the presented method provides insight into the spatial characteristics of finger movement EEG patterns.


Targeted protein degradation: expanding the toolbox.
Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.


Up-frameshift protein 1 (UPF1): multitalented entertainer in RNA decay.
Up-frameshift protein 1 (UPF1) is an evolutionarily conserved protein with RNA/DNA-dependent ATPase and RNA helicase activity. The protein is well known for its central role in nonsense-mediated mRNA decay (NMD), which eliminates aberrant mRNAs harboring premature termination codon (PTC), preventing the accumulation of nonfunctional or potentially harmful truncated proteins. NMD is also involved in the regulation of the state-levels of many normal physiological mRNAs. Moreover UPF1 is not only a key player in NMD but is also involved in non-NMD RNA degradation, such as staufen1 (STAU1)-mediated mRNA decay (SMD) and replication-dependent histone mRNA decay. Thus, UPF1 is an important factor for the RNA quality control system and the regulation of physiological gene expression. Further, recent studies have clarified that UPF1 contributes to DNA replication, DNA repair, telomere metabolism, and stabilization of HIV-1 genomic RNA. In the review, we summarize numerous functions of UPF1.


Fabrication of phase-change Ge2Sb2Te5 nano-rings.
Phase-change material Ge2Sb2Te5 rings with nanometer-scale thickness have been fabricated using the photo-thermal effect of a focused laser beam followed by differential chemical etching. Laser irradiation conditions and etching process parameters are varied to control the geometric characteristics of the rings. We demonstrate the possibility of arranging the rings in specific geometric patterns, and also their release from the original substrate.


When more is less: Emergent suppressive interactions in three-drug combinations.
In drug-drug interactions, there are surprising cases in which the growth inhibition of bacteria by a single antibiotic decreases when a second antibiotic is added. These interactions are termed suppressive and have been argued to have the potential to limit the evolution of resistance. Nevertheless, little attention has been given to suppressive interactions because clinical studies typically search for increases in killing efficiency and because suppressive interactions are believed to be rare based on pairwise studies. Here, we quantify the effects of single-, double-, and triple-drug combinations from a set of 14 antibiotics and 3 bacteria strains, totaling 364 unique three-drug combinations per bacteria strain. We find that increasing the number of drugs can increase the prevalence of suppressive interactions: 17% of three-drug combinations are suppressive compared to 5% of two-drug combinations in this study. Most cases of suppression we find (97%) are "hidden" cases for which the triple-drug bacterial growth is less than the single-drug treatments but exceeds that of a pairwise combination. We find a surprising number of suppressive interactions in higher-order drug combinations. Without examining lower-order (pairwise) bacterial growth, emergent suppressive effects would be missed, potentially affecting our understanding of evolution of resistance and treatment strategies for resistant pathogens. These findings suggest that careful examination of the full factorial of drug combinations is needed to uncover suppressive interactions in higher-order combinations.


Does Tobacco Abstinence Decrease Reward Sensitivity? A Human Laboratory Test.
Animal studies report abstinence from nicotine makes rewards less rewarding; however, the results of human tests of the effects of cessation on reward sensitivity are mixed. The current study tested reward sensitivity in abstinent smokers using more rigorous methods than most prior studies. A human laboratory study compared outcomes for 1 week prior to quitting to those during 4 weeks postquit. The study used smokers trying to quit, objective and subjective measures, multiple measures during smoking and abstinence, and monetary rewards to increase the prevalence of abstinence. Current daily smokers (n = 211) who were trying to quit completed an operant measure of reward sensitivity and a survey of pleasure from various rewards as well as self-reports of anhedonia, delay discounting, positive affect, and tobacco withdrawal twice each week. A comparison group of long-term former smokers (n = 67) also completed the tasks weekly for 4 weeks. Primary analyses were based on the 61 current smokers who abstained for all 4 weeks. Stopping smoking decreased self-reported pleasure from rewards but did not decrease reward sensitivity on the operant task. Abstinence also decreased self-reported reward frequency and increased the two anhedonia measures. However, the changes with abstinence were small for all outcomes (6%-14%) and most lasted less than a week. Abstinence from tobacco decreased most self-report measures of reward sensitivity; however, it did not change the objective measure. The self-report effects were small. Animal research suggests that nicotine withdrawal decreases reward sensitivity. Replication tests of this in humans have produced inconsistent results. We report what we believe is a more rigorous test. We found smoking abstinence slightly decreases self-reports of reward sensitivity but does not do so for a behavioral measure of reward sensitivity.


Acute and chronic diseases as part of multimorbidity in acutely hospitalized older patients.
To describe the prevalence of multimorbidity and to study the association between acute and chronic diseases in acutely hospitalized older patients Prospective cohort study conducted between 2006 and 2008 in three teaching hospitals in the Netherlands. 639 patients aged 65 years and older, hospitalized for >48 h were included. Two physicians scored diseases, using ICD-9 codes. Chronic multimorbidity was defined as the presence of ≥2 chronic diseases, and acute multimorbidity as ≥1 acute diseases upon pre-existent chronic diseases. Logistic regression analyses were conducted to analyse cluster associations between a chronic index disease and the concurrent chronic or acute disease, corrected for age and sex. The mean age of patients was 78 years, over 50% had ADL impairments. Prevalence of chronic multimorbidity was 69%, and acute multimorbidity was present in 88%. Hypertension (OR 1.16; 95% CI 1.08-1.24), diabetes (type I or type 2) (OR 1.12; 95% CI 1.04-1.21), heart failure (OR 1.25; 95% CI 1.14-1.38) and COPD (OR 1.19; 95% CI 1.05-1.34) were associated with acute renal failure. Hypertension (OR 1.10; 95% CI 1.04-1.17) and atrial fibrillation (OR 1.17; 95% CI 1.08-1.27) were associated with an adverse drug event. Gastro-intestinal bleeding was clustered with atrial fibrillation (OR 1.11; 95% CI 1.04-1.19) and gastric ulcer (OR 1.16; 95% CI 1.07-1.25). Both acute and chronic multimorbidity was frequently present in hospitalized older patients. We identified specific associations between acute and chronic diseases. There is a need for strategies addressing multimorbidity during the exacerbation of chronic diseases.


Treatment of clinical hypothyroidism with thyroxine and triiodothyronine: a literature review and metaanalysis.
Thyroxine is the standard replacement therapy for patients with clinical hypothyroidism. However, there has been recent interest in examining the potential advantages of combined thyroxine and triiodothyronine treatment for the treatment of hypothyroidism. The authors review the nine studies to-date and conclude that the variability and limitations in study design make definitive and clinically useful recommendations difficult. They therefore conducted a metaanalysis of the nine controlled studies examining the impact of combined thyroxine-plus-triiodothyronine versus thyroxine alone, with measures of psychiatric symptoms as the primary outcome. Their analysis reveals no significant difference in treatment effect on psychiatric symptoms in the nine controlled studies to date.


Reviving managed care with health savings accounts.
Although health savings accounts (HSAs) and managed care are often seen as antithetical, they can be integrated in fruitful ways. Moreover, combining these approaches would serve policy objectives by clarifying the payment responsibilities of patients, health plans, and premium payers, thus altering important perceptions about health care decision making. The availability in HSAs of funds that patients can use to pay for services not covered under insurance contracts should help to relegitimize the predetermination of benefits and enable the public and the legal system to take a more benign view of corporate health plans as agents of their subscribers.


Low-cost improvements in prehospital trauma care in a Latin American city.
Prehospital care is a critical component of efforts to lower trauma mortality. In less-developed countries, scarce resources dictate that any improvements in prehospital care must be low in cost. In one Latin American city, recent efforts to improve prehospital care have included an increase in the number of sites of ambulance dispatch from two to four and introduction of the Prehospital Trauma Life Support (PHTLS) course. The effect of increased dispatch sites was evaluated by comparing response times before and after completion of the change. The effect of PHTLS was evaluated by comparing prehospital treatment for the 3 months before initiation of the course (n = 361 trauma patients) and the 6 months after (n = 505). Response time decreased from a mean of 15.5 +/- 5.1 minutes, when there were two sites of dispatch, to 9.5 +/- 2.7 minutes, when there were four sites. Prehospital trauma care improved after initiation of the PHTLS course. For all trauma patients, use of cervical immobilization increased from 39 to 67%. For patients in respiratory distress, there were increases in the use of oropharyngeal airways (16-39%), in the use of suction (10-38%), and in the administration of oxygen (64-87%). For hypotensive patients, there was an increase in use of large-bore intravenous lines from 26 to 58%. The improved prehospital treatment did not increase the mean scene time (5.7 +/- 4.4 minutes before vs. 5.9 +/- 6.8 minutes after). The percent of patients transported who died in route decreased from 8.2% before the course to 4.7% after. These improvements required a minimal increase (16%) in the ambulance service budget. Increase in sites of dispatch and increased training in the form of the PHTLS course improved the process of pre-hospital care in this Latin American city and resulted in a decrease in prehospital deaths. These improvements were low cost and should be considered for use in other less developed countries.


Photosynthesis and circadian rhythms regulate the buoyancy of marimo lake balls.
Marimo are unusual, attractive and endangered spherical aggregations of the filamentous green macroalga Aegagropila linnaei (Figure 1A-E) [1]. Globally rare, marimo populations persist in cold freshwater lakes in Japan, Iceland and Ukraine. Marimo occupy both the lake bed and rise to the lake surface [2,3]. Here, we show that marimo buoyancy is conferred by bubbles arising from photosynthesis. We find that light-induced acquisition of buoyancy by marimo is circadian-regulated. We identify that there are circadian rhythms of photosynthesis in marimo, which might explain the circadian rhythm of buoyancy in response to light. This identifies a circadian-regulated buoyancy response in an intriguing and little-studied plant.


Molecular dynamics simulation study on the molecular structures of the amylin fibril models.
The structural characterization of amyloid fibers is one of the most investigated areas in structural biology. Recently, protofibril models for amylin, i.e., the 37-residue human islet amyloid polypeptide or hIAPP were suggested by two groups based on NMR (Biochemistry 2007, 46, 13505-13522) and X-ray (Protein Sci. 2008, 17, 1467-1474) techniques. However, there are significant differences in the two models which maybe originate from the polymorphic nature of amylin fibrils. To obtain further insights into the packing and stability features of the different models, we performed a series of molecular dynamics simulations on them. Our analysis showed that even pairs of β-sheets composed of a limited number of β-strands are stable in the 100-ns simulations, which suggests that steric zipper interactions at a β-sheet-β-sheet interface strongly contribute to the stability of these amyloid aggregates. For both models, outer strands are more flexible, which might coincide with the dynamical requirement that outer strands act as growing sites facilitating conformational changes of new incoming chains. Moreover, simulation results showed that the X-ray models are structurally more compact than the NMR models and have more intimate patterns, which lead to more rigid amyloid models. As a result, the X-ray models are energetically more stable than the NMR models. Further modeling analyses verify the most likely amylin fibril model among both NMR and X-ray models. Upon further study of the force-induced dissociation of a single chain from the protofibrils, the binding energy and the mechanical stability of the fibril models are revealed. On these bases, it is possible to reconcile the crystallographic and the NMR data on the basic amylin fiber unit.