First serial optical coherence tomography assessment at baseline, 12 and 24 months in STEMI patients treated with the second-generation Absorb bioresorbable vascular scaffold.
The aim of the study was to assess the vascular healing response after Absorb bioresorbable vascular scaffold (BVS) implantation in patients with ST-segment elevation myocardial infarction (STEMI) utilising truly serial optical coherence tomography (OCT) examination at baseline, 12 and 24 months. This was a single-centre, prospective, longitudinal study with baseline, 12- and 24-month OCT evaluation of 18 STEMI patients treated with 22 Absorb BVS. The healing pattern was evaluated based upon lumen area, neointimal hyperplasia, strut coverage and apposition. The lumen area decreased at 12 months compared to baseline (8.52±1.69 mm² vs. 7.0±1.70 mm², p<0.01), but it did not change from that point onwards up to 24 months (7.0±1.70 mm² vs. 6.94±1.65 mm², p=0.92). At 12 months after the index procedure, the mean neointimal thickness was 217±69 μm and further neointimal hyperplasia was observed between 12 and 24 months though less pronounced (Δ62±44 μm, p<0.0001). Full circumferential coverage of the vessel wall by neointima was observed in 92% of frames at 24 months. The low number of malapposed struts at the index procedure (<5%) further decreased over the observation period and was found in only one patient at 12 and 24 months. The ratio of uncovered struts was low at both 12 and 24 months. This serial OCT analysis of the second-generation everolimus-eluting BVS in a STEMI population confirmed a favourable healing pattern as expressed by moderate neointimal growth, preserved lumen area and no late acquired malapposition.


Insights into the concept of fish welfare.
Fish welfare issues are predicated on understanding whether fish are sentient beings. Therefore, we analyzed the logic of the methodologies used for studying this attribute. We conclude that empirical science is unable to prove or to disprove that fish are sentient beings. Thus, we propose a combined ethical-scientific approach for considering fish as sentient beings. The most difficult ongoing question is to determine which conditions fish prefer. Approaches to assess fish preferences should be rigorously and cautiously employed. In light of these considerations, attempts to establish physiological standards for fish welfare are discouraged, and a preference-based definition of fish welfare is proposed.


Psychiatrists injured by patient attack.
The seven staff psychiatrists injured by patient attack in a large forensic hospital in five years were compared with the 47 who were not injured by attack. Thirteen percent of the psychiatrists were injured by patient attack (2.6 percent per year); 5.5 injuries per 100 person-years occurred. This rate is comparable to the rate of injury from patient attack noted among ward nursing staff during the same period. Younger psychiatrists, and psychiatrists more recently out of residency, were more likely to be injured. Male psychiatrists were injured at a rate approximately 50 percent higher than female psychiatrists, and graduates of university-affiliated residencies were three times as likely to be injured as graduates of public-sector residencies, though these differences did not reach statistical significance. A slightly higher rate of injury was noted among graduates from non-North American medical schools. Board-certification and length of service in the hospital were not related to being injured.


Effects of keratinocyte growth factor in the endometrium of rhesus macaques during the luteal-follicular transition.
We previously reported that keratinocyte growth factor (KGF) is up-regulated by the action of progesterone (P) in the primate endometrium, and we suggested that this protein is a likely mediator of P-dependent stromal-epithelial paracrine interactions in this tissue. At the end of the menstrual cycle, P levels fall, and the abundance of endometrial KGF transcripts decreases approximately 9-fold. In macaques, withdrawal of P induces the luteal-follicular transition (LFT), marked by menstrual sloughing of the functionalis zone and apoptotic regression of the basalis zone. Because KGF levels fall so dramatically during the LFT, we hypothesized that replacement with exogenous KGF during the LFT would prevent some of the endometrial changes seen after P withdrawal. Here we describe two studies of the effects of exogenously administered KGF during the LFT in rhesus macaques. In one experiment we administered KGF systemically to ovariectomized, juvenile rhesus macaques during an LFT induced by hormonal manipulations. KGF had dramatic proliferative effects on the bladder and salivary glands, known targets of KGF, but did not affect cell proliferation in the endometrium or block menstrual sloughing and bleeding. However, KGF strongly inhibited apoptosis in the basalis zone, increased glandular sacculation and folding in this zone, and had a marked trophic effect on the spiral arteries. In the second experiment we installed oviductal catheters in ovariectomized adult rhesus macaques and infused KGF directly into the uterine lumen during a hormonally induced LFT. Again, arteriotrophic, antiapoptotic, and basalis gland sacculation effects were observed in the absence of any effect on cell proliferation. We concluded that although KGF is mitogenic for many epithelial cell types, it does not play this role in the primate endometrium. Its most important roles may be to stimulate spiral artery growth and inhibit glandular apoptosis during the nonfertile menstrual cycle. Because its expression rises coincident with the time of implantation and because spiral arteries are essential to successful establishment of pregnancy, the role of KGF in the fertile menstrual cycle deserves further study.


Cardiac standstill for cerebral aneurysms in 103 patients: an update on the experience at the Barrow Neurological Institute. Clinical article.
The aim of this study was to clarify the surgical indications, risks, and long-term clinical outcomes associated with the use of deep hypothermic circulatory arrest for the surgical treatment of intracranial aneurysms. The authors retrospectively reviewed 105 deep hypothermic circulatory arrest procedures performed in 103 patients (64 females and 39 males, with a mean age of 44.8 years) to treat 104 separate aneurysms. Patients' clinical histories, radiographs, and operative reports were evaluated. There were 97 posterior circulation aneurysms: at the basilar apex in 60 patients, midbasilar artery in 21, vertebrobasilar junction in 11, superior cerebellar artery in 4, and posterior cerebral artery in 1. Seven patients harbored anterior circulation aneurysms. Two additional patients harbored nonaneurysmal lesions. Perioperatively, 14 patients (14%) died. Five patients (5%) were lost to late follow-up. At a mean long-term follow-up of 9.7 years, 65 patients (63%) had the same or a better status after surgical intervention, 10 (10%) were worse, and 9 (9%) had died. There were 19 cases (18%) of permanent or severe complications. The combined rate of permanent treatment-related morbidity and mortality was 32%. The mean late follow-up Glasgow Outcome Scale score was 4, and the annual hemorrhage rate after microsurgical clipping during cardiac standstill was 0.5%/year. Ninety-two percent of patients required no further treatment of their aneurysm at the long-term follow-up. Cardiac standstill remains an important treatment option for a small subset of complex and giant posterior circulation aneurysms. Compared with the natural history of the disease, the risk associated with this procedure is acceptable.


Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.
Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.


From bit to it: how a complex metabolic network transforms information into living matter.
Organisms live and die by the amount of information they acquire about their environment. The systems analysis of complex metabolic networks allows us to ask how such information translates into fitness. A metabolic network transforms nutrients into biomass. The better it uses information on available nutrient availability, the faster it will allow a cell to divide. I here use metabolic flux balance analysis to show that the accuracy I (in bits) with which a yeast cell can sense a limiting nutrient's availability relates logarithmically to fitness as indicated by biomass yield and cell division rate. For microbes like yeast, natural selection can resolve fitness differences of genetic variants smaller than 10-6, meaning that cells would need to estimate nutrient concentrations to very high accuracy (greater than 22 bits) to ensure optimal growth. I argue that such accuracies are not achievable in practice. Natural selection may thus face fundamental limitations in maximizing the information processing capacity of cells. The analysis of metabolic networks opens a door to understanding cellular biology from a quantitative, information-theoretic perspective.


Analysis of LGR4 receptor distribution in human and mouse tissues.
LGR4 is an R-spondin receptor with strong positive effect on Wnt signaling. It plays a critical role in development as its ablation in the mouse led to total embryonic/neonatal lethality with profound defects in multiple organs. Haplotype insufficiency of LGR4 in human was associated with several diseases, including increased risk of squamous cell carcinoma of the skin, reduced birth weights, electrolyte imbalance, and decreased levels of testosterone, which are similar to the phenotypes of LGR4-hypomorphic mice. Tissue distribution of LGR4 was extensively analyzed in the mouse using gene-trap reporter enzyme alleles. However, its expression pattern in human tissues remained largely unknown. We have developed LGR4-specific monoclonal antibodies and used them to examine the expression of LGR4 in selected adult human and mouse tissues by immunohistochemical analysis. Intense LGR4-like immunoreactivity was observed in the epidermis and hair follicle of the skin, pancreatic islet cells, and epithelial cells in both the male and female reproductive organs. Of particular interest is that LGR4 is highly expressed in germ cells and pancreatic islet cells, which have important implications given the role of R-spondin-LGR4 signaling in the survival of adult stem cells. In addition, the majority of colon tumors showed elevated levels of LGR4 receptor. Overall, the expression pattern of LGR4 in human tissues mapped by this IHC analysis is similar to that in the mouse as revealed from gene trap alleles. Importantly, the pattern lends strong support to the important role of LGR4 in the development and maintenance of skin, kidney, reproductive systems, and other organs.


A distinct and active bacterial community in cold oxygenated fluids circulating beneath the western flank of the Mid-Atlantic ridge.
The rock-hosted, oceanic crustal aquifer is one of the largest ecosystems on Earth, yet little is known about its indigenous microorganisms. Here we provide the first phylogenetic and functional description of an active microbial community residing in the cold oxic crustal aquifer. Using subseafloor observatories, we recovered crustal fluids and found that the geochemical composition is similar to bottom seawater, as are cell abundances. However, based on relative abundances and functional potential of key bacterial groups, the crustal fluid microbial community is heterogeneous and markedly distinct from seawater. Potential rates of autotrophy and heterotrophy in the crust exceeded those of seawater, especially at elevated temperatures (25 °C) and deeper in the crust. Together, these results reveal an active, distinct, and diverse bacterial community engaged in both heterotrophy and autotrophy in the oxygenated crustal aquifer, providing key insight into the role of microbial communities in the ubiquitous cold dark subseafloor biosphere.


How to attract health students to remote areas in Indonesia: a discrete choice experiment.
Remote areas of Indonesia lack sufficient health workers to meet the health-care needs of the population. There is an urgent need for evidence regarding interventions to attract health workers and specifically health students to serve in remote areas. The aim of this research was to analyze the job preferences of health students to develop effective policies to improve the recruitment and retention of health students in remote areas. A discrete choice experiment was conducted to investigate health students' preferences regarding job characteristics. This study was conducted in three different regions of Indonesia, with a total included 400 health students. Mixed logit models were used to explore the stated preferences for each attribute. Data were collected from 150 medical, 150 nursing and 100 midwifery students. Medical students gave the highest preference for receiving study assistance, while nursing students viewed salary as the most important. Midwifery students valued advanced quality facilities as an important attribute. This study confirmed the importance of combination interventions in attracting and retaining health workers in remote areas of Indonesia. Money is not the only factor affecting student preferences to take up a rural post; good management and better facilities were viewed as important by all health students. Addressing health student preferences, which are the candidate of future health workforce, would help the nation solve the recruitment and retention issues. Copyright © 2015 John Wiley & Sons, Ltd.


Complete protection by alpha-crystallin of lens sorbitol dehydrogenase undergoing thermal stress.
Sorbitol dehydrogenase (l-iditol:NAD(+) 2-oxidoreductase, E.C. 1.1.1. 14) (SDH) was significantly protected from thermally induced inactivation and aggregation by bovine lens alpha-crystallin. An alpha-crystallin/SDH ratio as low as 1:2 in weight was sufficient to preserve the transparency of the enzyme solution kept for at least 2 h at 55 degrees C. Moreover, an alpha-crystallin/SDH ratio of 5:1 (w/w) was sufficient to preserve the enzyme activity fully at 55 degrees C for at least 40 min. The protection by alpha-crystallin of SDH activity was essentially unaffected by high ionic strength (i.e. 0.5 m NaCl). On the other hand, the transparency of the protein solution was lost at a high salt concentration because of the precipitation of the alpha-crystallin/SDH adduct. Magnesium and calcium ions present at millimolar concentrations antagonized the protective action exerted by alpha-crystallin against the thermally induced inactivation and aggregation of SDH. The lack of protection of alpha-crystallin against the inactivation of SDH induced at 55 degrees C by thiol blocking agents or EDTA together with the additive effect of NADH in stabilizing the enzyme in the presence of alpha-crystallin suggest that functional groups involved in catalysis are freely accessible in SDH while interacting with alpha-crystallin. Two different adducts between alpha-crystallin and SDH were isolated by gel filtration chromatography. One adduct was characterized by a high M(r) of approximately 800,000 and carried exclusively inactive SDH. A second adduct, carrying active SDH, had a size consistent with an interaction of the enzyme with monomers or low M(r) aggregates of alpha-crystallin. Even though it had a reduced efficiency with respect to alpha-crystallin, bovine serum albumin was shown to mimic the chaperone-like activity of alpha-crystallin in protecting SDH from thermal denaturation. These findings suggest that the multimeric structural organization of alpha-crystallin may not be a necessary requirement for the stabilization of the enzyme activity.


Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations.
IFIT1 (IFN-induced protein with tetratricopeptide repeats-1) is an effector of the host innate immune antiviral response that prevents propagation of virus infection by selectively inhibiting translation of viral mRNA. It relies on its ability to compete with the translation initiation factor eIF4F to specifically recognize foreign capped mRNAs, while remaining inactive against host mRNAs marked by ribose 2'-O methylation at the first cap-proximal nucleotide (N1). We report here several crystal structures of RNA-bound human IFIT1, including a 1.6-Å complex with capped RNA. IFIT1 forms a water-filled, positively charged RNA-binding tunnel with a separate hydrophobic extension that unexpectedly engages the cap in multiple conformations (syn and anti) giving rise to a relatively plastic and nonspecific mode of binding, in stark contrast to eIF4E. Cap-proximal nucleotides encircled by the tunnel provide affinity to compete with eIF4F while allowing IFIT1 to select against N1 methylated mRNA. Gel-shift binding assays confirm that N1 methylation interferes with IFIT1 binding, but in an RNA-dependent manner, whereas translation assays reveal that N1 methylation alone is not sufficient to prevent mRNA recognition at high IFIT1 concentrations. Structural and functional analysis show that 2'-O methylation at N2, another abundant mRNA modification, is also detrimental for RNA binding, thus revealing a potentially synergistic role for it in self- versus nonself-mRNA discernment. Finally, structure-guided mutational analysis confirms the importance of RNA binding for IFIT1 restriction of a human coronavirus mutant lacking viral N1 methylation. Our structural and biochemical analysis sheds new light on the molecular basis for IFIT1 translational inhibition of capped viral RNA.


Functional analysis of BMP4 mutations identified in pediatric CAKUT patients.
Human congenital anomalies of the kidney and urinary tract (CAKUT) represent the major causes of chronic renal failure (CRF) in children. This set of disorders comprises renal agenesis, hypoplasia, dysplastic or double kidneys, and/or malformations of the ureter. It has recently been shown that mutations in several genes, among them BMP4, are associated with hereditary renal developmental diseases. In BMP4, we formerly identified three missense mutations (S91C, T116S, N150K) in five pediatric CAKUT patients. These BMP4 mutations were subsequently studied in a cellular expression system, and here we present functional data demonstrating a lower level of messenger RNA (mRNA) abundance in Bmp4 mutants that indicates a possible negative feedback of the mutants on their own mRNA expression and/or stability. Furthermore, we describe the formation of alternative protein complexes induced by the S91C-BMP4 mutation, which results in perinuclear endoplasmic reticulum (ER) accumulation and enhanced lysosomal degradation of Bmp4. This work further supports the role of mutations in BMP4 for abnormalities of human kidney development.


Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study.
Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0-14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0-14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies.


Opportunities for control of meningococcal disease in the United States.
The United States currently has relatively low rates of meningococcal disease caused by Neisseria meningitidis. Serogroups Y, C, and B are most common. Although most cases are sporadic, a minority are associated with outbreaks. Pediatric populations have disproportionately higher rates of disease, but nearly two thirds of all cases occur in persons aged 15 years and older. The major challenge to control of domestic meningococcal disease is the absence of a vaccine to prevent sporadic cases spanning many age groups. The quadrivalent A/C/Y/W-135 meningococcal polysaccharide vaccine is licensed in the United States, but because of its limited efficacy in children under two years of age, it is recommended for high-risk groups and outbreak response rather than routine childhood immunization. New conjugate meningococcal vaccines have successfully reduced endemic disease in the United Kingdom, and similar vaccines promise to have a dramatic impact on the burden of meningococcal disease in the United States.


Static magnetic fields for treatment of fibromyalgia: a randomized controlled trial.
To test effectiveness of static magnetic fields of two different configurations, produced by magnetic sleep pads, as adjunctive therapies in decreasing patient pain perception and improving functional status in individuals with fibromyalgia. Randomized, placebo-controlled, 6-month trial conducted from November 1997 through December 1998. Adults who met the 1990 American College of Rheumatology criteria for fibromyalgia were recruited through clinical referral and media announcements and evaluated at a university-based clinic. Subjects in Functional Pad A group used a pad for 6 months that provided whole-body exposure to a low, uniform static magnetic field of negative polarity. Subjects in the Functional Pad B group used a pad for 6 months that exposed them to a low static magnetic field that varied spatially and in polarity. Subjects in two Sham groups used pads that were identical in appearance and texture to the functional pads but contained inactive magnets; these groups were combined for analysis. Subjects in the Usual Care group continued with their established treatment regimens. Primary outcomes were the change scores at 6 months in the following measures: functional status (Fibromyalgia Impact Questionnaire), pain intensity ratings, tender point count, and a tender point pain intensity score. There was a significant difference among groups in pain intensity ratings (p = 0.03), with Functional Pad A group showing the greatest reduction from baseline at 6 months. All four groups showed a decline in number of tender points, but differences among the groups were not significant (p = 0.72). The functional pad groups showed the largest decline in total tender point pain intensity, but overall differences were not significant (p = 0.25). Improvement in functional status was greatest in the functional pad groups, but differences among groups were not significant (p = 0.23). Although the functional pad groups showed improvements in functional status, pain intensity level, tender point count, and tender point intensity after 6 months of treatment, with the exception of pain intensity level these improvements did not differ significantly from changes in the Sham group or in the Usual Care group.


How Do Hearing Aid Owners Respond to Hearing Aid Problems?
Although hearing aids can improve hearing and communication, problems that arise following the acquisition of hearing aids can result in their disuse. This study aimed to gather perspectives of hearing aid owners and hearing health care clinicians about how hearing aid owners respond to problems that arise following hearing aid fitting, and then use these perspectives to generate a conceptual framework to better understand these responses. Seventeen hearing aid owners and 21 hearing health care clinicians generated, sorted, and rated statements regarding how hearing aid owners respond to problems associated with hearing aid use. Concept mapping was used to identify key themes and to develop a conceptual framework. Participants identified four concepts regarding how hearing aid owners respond to problems associated with hearing aids: (1) Seeking External Help; (2) Problem Solving; (3) Putting Up with Problems; and (4) Negative Emotional Response. Participants described behaviors of the clinician and significant others that influenced their decision to seek help for hearing aid problems. Participants recognized that these behaviors could either have a helpful or unhelpful impact. Despite the ongoing support offered to clients after they acquire hearing aids, they are hesitant to seek help from their clinician and instead engage in a myriad of helpful and unhelpful behaviors in response to problems that arise with their hearing aid. Previous positive or negative experiences with the clinic, clinician, or significant other influenced these actions, highlighting the influential role of these individuals' in the success of the rehabilitation program. The data generated from this study suggests that clinicians could improve hearing aid problem resolution by providing technical and emotional support, including to significant others, and promoting client empowerment and self-management.


Extracorporeal liver support in severe alcoholic hepatitis.
The severity of alcoholic hepatitis (AH) which may coexist with cirrhosis varies greatly, from asymptomatic forms which are detected in alcoholic patients without any sign of liver disease, except laboratory abnormalities, to severe forms characterised by deep jaundice, ascites, hepatic encephalopathy and low prothrombin index. In hospitalized patients the mortality could be as high as 75%. The elevated number of therapeutic proposals reported for more than forty years reveals the lack of efficacy of a particular modality. Even in the most favorable trials, the survival is already very poor and in some cases related to the development of renal failure or hepatorenal syndrome. There are some motivating reports concerning albumin dialysis as a support treatment in patients with severe AH, either alone or in combination with other pharmacological therapies. The favorable effects of albumin dialysis in patients with severe AH suggest that the procedure used alone or in combination with other therapies may have a role in this clinical condition. This will be particularly relevant to offer an alternative therapy in these patients, thus being a potential bridge to recovery or to be listed for liver transplantation.


Pulmonary function and exercise capacity after lung resection.
The influence of pulmonary resection on functional capacity can be assessed in different ways. The aim of this study was to compare the effect of lobectomy and pneumonectomy on pulmonary function tests (PFT), exercise capacity and perception of symptoms. Sixty eight patients underwent functional assessment with PFT and exercise testing before (Preop), and 3 and 6 months after lung resection. In 50 (36 males and 14 females; mean age 61 yrs) a lobectomy was performed and in 18 (13 males and 5 females; mean age 59 yrs) a pneumonectomy was performed. Three months after lobectomy, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), total lung capacity (TLC), transfer factor of the lungs for carbon monoxide (TL,CO) and maximal oxygen uptake (V'O2,max) were significantly lower than Preop values, increasing significantly from 3 to 6 months after resection. Three months after pneumonectomy, all parameters were significantly lower than Preop values and significantly lower than postlobectomy values and did not recover from 3 to 6 months after resection. At 6 months after resection significant deficits persisted in comparison with Preop: for FVC 7% and 36%, FEV1 9% and 34%, TLC 10% and 33% for lobectomy and pneumonectomy, respectively; and V'O2,max 20% after pneumonectomy only. Exercise was limited by leg muscle fatigue in 53% of all patients at Preop. This was not altered by lobectomy, but there was a switch to dyspnoea as the limiting factor after pneumonectomy (61% of patients at 3 months and 50% at 6 months after resection). Furthermore, pneumonectomy compared to lobectomy led to a significantly smaller breathing reserve (mean +/- SD) (28 +/- 13 vs 37 +/- 16% at 3 months; and 24 +/- 11% vs 33 +/- 12% at 6 months post resection) and lower arterial oxygen tension at peak exercise 10.1 +/- 1.5 vs 11.5 +/- 1.6 kPa (76 +/- 11 vs 86 +/- 12 mmHg) at 3 months; 10.1 +/- 1.3 vs 11.3 +/- 1.6 kPa (76 +/- 10 vs 85 +/- 12 mmHg) at 6 months postresection. We conclude that measurements of conventional pulmonary function tests alone overestimate the decrease in functional capacity after lung resection. Exercise capacity after lobectomy is unchanged, whereas pneumonectomy leads to a 20% decrease, probably due to the reduced area of gas exchange.


Hydraulic residence time and iron removal in a wetland receiving ferruginous mine water over a 4 year period from commissioning.
Analysis of residence time distribution (RTD) has been conducted for the UK Coal Authority's mine water treatment wetland at Lambley, Northumberland, to determine the hydraulic performance of the wetland over a period of approximately 4 years since site commissioning. The wetland RTD was evaluated in accordance with moment analysis and modelled based on a tanks-in-series (TIS) model to yield the hydraulic characteristics of system performance. Greater hydraulic performance was seen during the second site monitoring after 21 months of site operation i.e. longer hydraulic residence time to reflect overall system hydraulic efficiency, compared to wetland performance during its early operation. Further monitoring of residence time during the third year of wetland operation indicated a slight reduction in hydraulic residence time, thus a lower system hydraulic efficiency. In contrast, performance during the fourth year of wetland operation exhibited an improved overall system hydraulic efficiency, suggesting the influence of reed growth over the lifetime of such systems on hydraulic performance. Interestingly, the same pattern was found for iron (which is the primary pollutant of concern in ferruginous mine waters) removal efficiency of the wetland system from the second to fourth year of wetland operation. This may therefore, reflect the maturity of reeds for maintaining efficient flow distribution across the wetland to retain a longer residence time and significant fractions of water involved to enhance the extent of treatment received for iron attenuation. Further monitoring will be conducted to establish whether such performance is maintained, or whether efficiency decreases over time due to accumulation of dead plant material within the wetland cells.


Impact of Cognitive Dysfunction in the Middle East Depressed Patients: The ICMED Study.
Major depressive disorder is a common condition with a high rate of recurrence, chronicity, and affecting economic burden, including disability in the workplace, which leads to negative consequences on both individuals and society. This study aimed to estimate the impact of cognitive dysfunction, as declared by the patient, on performing daily tasks/activities among patients with major depression disorder (MDD). This investigation is based on multinational cross-sectional survey of 499 workers recruited from the Kingdom of Saudi Arabia (KSA) and United Arab Emirates (UAE). We assessed the severity of depression by Hamilton Depression Rating Scale (HDRS). Impact of Depression in the Workplace in Europe Audit (IDEA) survey and trial making test (TMT) parts A and B were used to assess the impact of cognitive dysfunction on performing daily tasks/activities in adult patients presented with MDD. A total of 499 persons were included in this study, aged 18-66 years, current workers and managers. Of them, 17.8% were normal (remitted), 22.4% were mildly depressed, 23.4% were moderately depressed, 8.6% were severely depressed, and 27.7% were very severely depressed at the time of the study according to HDRS. Common symptoms attributable to depression were low mode or sadness (89.8%), followed by insomnia (75.2%) and crying (70.9%). Of them, low mode or sadness was the most common factor affecting the work performance (90.2%). About 66.3% of participants diagnosed with depression by a doctor/medical professional. Awareness of the disease was recognizable by patients' managers in only 31.9% of the cases. Furthermore, 45.3% of cases had taken off work due to depression with mean duration of 38.7 (95% CI 37.7 to 39.7) days. The mean TMT parts A and B score were 69.2 (95% CI 66.3 to 72.2) and 126.6 (95% CI 121 to 132), respectively. Lastly, a significant positive correlation between the mean score for HDRS and TMT-A and B scores was observed. Depression affects work productivity and work environment with negative consequences to countries' economy. Awareness of depression in the workplace in KSA and UAE is still suboptimal. The personal and societal burden of this issue cannot be neglected when we become aware of the proportion of affected people.


Oxidative defense enzyme activity and mRNA levels in lenses of diabetic rats.
This study examines the mRNA expression and enzyme activity of oxidative defense enzymes during the course of streptozotocin-induced hyperglycemic cataract development. Diabetes was produced in 5-wk-old male Sprague-Dawley rats by administering streptozotocin ip and mRNA expression and enzyme activity were monitored on d 4, 8, 12, 16, 20, 40, 60, and 80; concomitantly, the onset and progress of cataract was followed by digital image analysis. Peak enzyme activity and mRNA expression were attained between d 20 and 40. Although catalase and glutathione peroxidase maintained high levels of mRNA expression through d 60, induction of CuZu-superoxide dismutase was transient, with the activity and mRNA levels returning to baseline values by d 40. There was a pronounced increase in aldose reductase activity, which gradually declined to basal levels by d 60; however, the mRNA levels remained unaltered. Other changes included a progressive loss of lenticular transparency, which declined to 40% of control by d 80. The role of antioxidant defense enzymes and, more interestingly, aldose reductase in combating oxidative stress in diabetic cataractogenesis is discussed.


Contact allergens in oral antihistamines.
Excipients in various formulations of active drugs occasionally include known contact allergens. Their ingestion may trigger dermatitis or cause it to become widespread or refractory to therapy. The aim of this study was to investigate the prevalence of common contact allergens among the excipients of oral antihistamines available in this country. We gathered the complete ingredient lists of 2119 different preparations of 12 oral antihistamines from the National Library of Medicine data bank and entered them into an electronic database for analysis. More than half the formulations (55.0%) contained at least 1 member of the 10 allergen families assessed. Most brompheniramine and doxepin preparations included potentially allergenic excipients, whereas fexofenadine was most often free of them. Sorbitan group members, azo dyes, and propylene glycol were the allergens found most frequently in the antihistamines, each present in over 25% of the products. Elixirs, liquids, solutions, suspensions, and syrups were more likely than nonchewable caplets, capsules, and tablets to contain the allergens tabulated (100% vs 39.3%, respectively). Chewable pills frequently contained azo dyes. Ingestion of antihistamines could precipitate a systemic contact dermatitis in a patient sensitized to an allergen present as an excipient in the medicine.


Health impact assessment of the UK soft drinks industry levy: a comparative risk assessment modelling study.
In March, 2016, the UK Government proposed a tiered levy on sugar-sweetened beverages (SSBs; high tax for drinks with >8 g of sugar per 100 mL, moderate tax for 5-8 g, and no tax for <5 g). We estimate the effect of possible industry responses to the levy on obesity, diabetes, and dental caries. We modelled three possible industry responses: reformulation to reduce sugar concentration, an increase of product price, and a change of the market share of high-sugar, mid-sugar, and low-sugar drinks. For each response, we defined a better-case and worse-case health scenario. We developed a comparative risk assessment model to estimate the UK health impact of each scenario on prevalence of obesity and incidence of dental caries and type 2 diabetes. The model combined data for sales and consumption of SSBs, disease incidence and prevalence, price elasticity estimates, and estimates of the association between SSB consumption and disease outcomes. We drew the disease association parameters from a meta-analysis of experimental studies (SSBs and weight change), a meta-analysis of prospective cohort studies (type 2 diabetes), and a prospective cohort study (dental caries). The best modelled scenario for health is SSB reformulation, resulting in a reduction of 144 383 (95% uncertainty interval 5102-306 743; 0·9%) of 15 470 813 adults and children with obesity in the UK, 19 094 (6920-32 678; incidence reduction of 31·1 per 100 000 person-years) fewer incident cases of type 2 diabetes per year, and 269 375 (82 211-470 928; incidence reduction of 4·4 per 1000 person-years) fewer decayed, missing, or filled teeth annually. An increase in the price of SSBs in the better-case scenario would result in 81 594 (3588-182 669; 0·5%) fewer adults and children with obesity, 10 861 (3899-18 964; 17·7) fewer incident cases of diabetes per year, and 149 378 (45 231-262 013; 2·4) fewer decayed, missing, or filled teeth annually. Changes to market share to increase the proportion of low-sugar drinks sold in the better-case scenario would result in 91 042 (4289-204 903; 0·6%) fewer adults and children with diabetes, 1528 (4414-21 785; 19·7) fewer incident cases of diabetes per year, and 172 718 (47 919-294 499; 2·8) fewer decayed, missing, or filled teeth annually. The greatest benefit for obesity and oral health would be among individuals aged younger than 18 years, with people aged older than 65 years having the largest absolute decreases in diabetes incidence. The health impact of the soft drinks levy is dependent on its implementation by industry. Uncertainty exists as to how industry will react and about estimation of health outcomes. Health gains could be maximised by substantial product reformulation, with additional benefits possible if the levy is passed on to purchasers through raising of the price of high-sugar and mid-sugar drinks and activities to increase the market share of low-sugar products. None.


Cue weighting in auditory categorization: implications for first and second language acquisition.
The ability to integrate and weight information across dimensions is central to perception and is particularly important for speech categorization. The present experiments investigate cue weighting by training participants to categorize sounds drawn from a two-dimensional acoustic space defined by the center frequency (CF) and modulation frequency (MF) of frequency-modulated sine waves. These dimensions were psychophysically matched to be equally discriminable and, in the first experiment, were equally informative for accurate categorization. Nevertheless, listeners' category responses reflected a bias for use of CF. This bias remained even when the informativeness of CF was decreased by shifting distributions to create more overlap in CF. A reversal of weighting (MF over CF) was obtained when distribution variance was increased for CF. These results demonstrate that even when equally informative and discriminable, acoustic cues are not necessarily equally weighted in categorization; listeners exhibit biases when integrating multiple acoustic dimensions. Moreover, changes in weighting strategies can be affected by changes in input distribution parameters. This methodology provides potential insights into acquisition of speech sound categories, particularly second language categories. One implication is that ineffective cue weighting strategies for phonetic categories may be alleviated by manipulating variance of uninformative dimensions in training stimuli.


Comparison between instrumental variable and mediation-based methods for reconstructing causal gene networks in yeast.
Causal gene networks model the flow of information within a cell. Reconstructing causal networks from omics data is challenging because correlation does not imply causation. When genomics and transcriptomics data from a segregating population are combined, genomic variants can be used to orient the direction of causality between gene expression traits. Instrumental variable methods use a local expression quantitative trait locus (eQTL) as a randomized instrument for a gene's expression level, and assign target genes based on distal eQTL associations. Mediation-based methods additionally require that distal eQTL associations are mediated by the source gene. A detailed comparison between these methods has not yet been conducted, due to the lack of a standardized implementation of different methods, the limited sample size of most multi-omics datasets, and the absence of ground-truth networks for most organisms. Here we used Findr, a software package providing uniform implementations of instrumental variable, mediation, and coexpression-based methods, a recent dataset of 1012 segregants from a cross between two budding yeast strains, and the Yeastract database of known transcriptional interactions to compare causal gene network inference methods. We found that causal inference methods result in a significant overlap with the ground-truth, whereas coexpression did not perform better than random. A subsampling analysis revealed that the performance of mediation saturates at large sample sizes, due to a loss of sensitivity when residual correlations become significant. Instrumental variable methods on the other hand contain false positive predictions, due to genomic linkage between eQTL instruments. Instrumental variable and mediation-based methods also have complementary roles for identifying causal genes underlying transcriptional hotspots. Instrumental variable methods correctly predicted STB5 targets for a hotspot centred on the transcription factor STB5, whereas mediation failed due to Stb5p auto-regulating its own expression. Mediation suggests a new candidate gene, DNM1, for a hotspot on Chr XII, whereas instrumental variable methods could not distinguish between multiple genes located within the hotspot. In conclusion, causal inference from genomics and transcriptomics data is a powerful approach for reconstructing causal gene networks, which could be further improved by the development of methods to control for residual correlations in mediation analyses, and for genomic linkage and pleiotropic effects from transcriptional hotspots in instrumental variable analyses.


Minilaparoscopy vs. standard laparoscopic donor nephrectomy: comparison of safety, efficacy and cosmetic outcomes in a randomized clinical trial.
This study was conducted to compare safety, efficacy and cosmetic outcome between standard laparoscopic live donor nephrectomy (sLDN) and mini-laparoscopic donor nephrectomy (mLDN) in a randomized clinical trial. From March 2012 to June 2013, 100 consecutive kidney donors were randomly assigned to two equal groups for laparoscopic donor nephrectomy. mLDN: Six to eight centimeters Pfannenstiel incision was made slightly above pubis symphysis and 11 millimeters trocar was fixed through exposed fascia using open technique. Five mm port was placed under direct vision at the umbilicus for camera insertion and two 3.5 mm ports were placed in subxiphoid and paraumbilical area. sLDN: Ten mm port was placed at umbilicus using open access technique for camera insertion. Five mm trocar for grasping and 11 mm trocar for vascular clipping were placed at subxiphoid and paraumbilical areas under direct vision, respectively. The second 5 mm trocar was placed in suprapubic area. Cosmetic appearance was assessed three months after surgery by using the Patient Scar Assessment Questionnaire (PSAQ). Demographic data of the patients was not significantly different between two groups. Total operative time and ischemic time was nearly similar in both groups (104 ± 21 vs. 114 ± 24 min; P = .327 and 4.03 vs. 4.07 min; P = .592). There were no cases of conversion to open surgery. Mean hospital stay was similar between the two groups [2.1 (2-5) vs. 2.4 (2-5) days; P = .346]. Kidney graft function assessed by serum creatinine values (mg/dL) of recipients, was equivalent in both groups (1.58 vs. 1.86: P = .206). Mean appearance score (34 vs. 29) and consciousness score (22 vs. 18) in PSAQ showed significantly better results in the mLDN group. Our experience in this study revealed that peri- and post-operative findings were comparable between sLDN and mLDN, but mLDN has significant better cosmetic appearance than standard laparoscopic approach.


Tracking occupational hearing loss across global industries: a comparative analysis of metrics.
Occupational hearing loss is one of the most prevalent occupational conditions; yet, there is no acknowledged international metric to allow comparisons of risk between different industries and regions. In order to make recommendations for an international standard of occupational hearing loss, members of an international industry group (the International Aluminium Association) submitted details of different hearing loss metrics currently in use by members. We compared the performance of these metrics using an audiometric data set for over 6000 individuals working in 10 locations of one member company. We calculated rates for each metric at each location from 2002 to 2006. For comparison, we calculated the difference of observed-expected (for age) binaural high-frequency hearing loss (in dB/year) for each location over the same time period. We performed linear regression to determine the correlation between each metric and the observed-expected rate of hearing loss. The different metrics produced discrepant results, with annual rates ranging from 0.0% for a less-sensitive metric to more than 10% for a highly sensitive metric. At least two metrics, a 10dB age-corrected threshold shift from baseline and a 15dB nonage-corrected shift metric, correlated well with the difference of observed-expected high-frequency hearing loss. This study suggests that it is feasible to develop an international standard for tracking occupational hearing loss in industrial working populations.


Challenges in assessing the process-outcome link in practice.
The expanded use of clinical process-of-care measures to assess the quality of health care in the context of public reporting and pay-for-performance applications has led to a desire to demonstrate the value of such efforts in terms of improved patient outcomes. The inability to observe associations between improved delivery of clinical processes and improved clinical outcomes in practice has raised concerns about the value of holding providers accountable for delivery of clinical processes of care. Analyses that attempt to investigate this relationship are fraught with many challenges, including selection of an appropriate outcome, the proximity of the outcome to the receipt of the clinical process, limited power to detect an effect, small expected effect sizes in practice, potential bias due to unmeasured confounding factors, and difficulties due to changes in measure specification over time. To avoid potentially misleading conclusions about an observed or lack of observed association between a clinical process of care and an outcome in the context of observational studies, individuals conducting and interpreting such studies should carefully consider, evaluate, and acknowledge these types of challenges.


The effect of zirconia sintering temperature on flexural strength, grain size, and contrast ratio.
This study investigated the effect of sintering temperatures on flexural strength, contrast ratio, and grain size of zirconia. Zirconia specimens (Ceramill ZI, Amann Girrbach) were prepared in partially sintered state. Subsequently, the specimens were randomly divided into nine groups and sintered with different final sintering temperatures: 1,300°C, 1,350°C, 1,400°C, 1,450°C, 1,500°C, 1,550°C, 1,600°C, 1,650°C, or 1,700°C with 120 min holding time. Three-point flexural strength (N = 198; n = 22 per group) was measured according to ISO 6872: 2008. The contrast ratio (N = 90; n = 10 per group) was measured according to ISO 2471: 2008. Grain sizes and microstructure of different groups were investigated (N = 9, n = 1 per group) with scanning electron microscope. Data were analyzed using one-way ANOVA with Scheffé test and Weibull statistics (p < 0.05). Pearson correlation coefficient was calculated between either flexural strength or contrast ratio and sintering temperatures. The highest flexural strength was observed in groups sintered between 1,400°C and 1,550°C. The highest Weibull moduli were obtained for zirconia sintered at 1,400°C and the lowest at 1,700°C. The contrast ratio and the grain size were higher with the higher sintering temperature. The microstructure of the specimens sintered above 1,650°C exhibited defects. Sintering temperatures showed a significant negative correlation with both the flexural strength (r = -0.313, p < 0.001) and the contrast ratio values (r = -0.96, p < 0.001). The results of this study showed that the increase in sintering temperature increased the contrast ratio, but led to a negative impact on the flexural strength. Considering the flexural strength values and Weibull moduli, the sintering temperature for the zirconia tested in this study should not exceed 1,550°C.


Buddha philosophy and western psychology.
Four noble truths as preached by Buddha are that the life is full of suffering (Duhkha), that there is a cause of this suffering (Duhkha-samudaya), it is possible to stop suffering (Duhkha-nirodha), and there is a way to extinguish suffering (Duhkha-nirodha-marga). Eight fold Path (astangika-marga) as advocated by Buddha as a way to extinguish the sufferings are right views, right resolve/aspiration, right speech, right action/conduct, right livelihood, right effort right mindfulness and right concentration. Mid-twentieth century saw the collaborations between many psychoanalysts and Buddhist scholars as a meeting between "two of the most powerful forces" operating in the Western mind. Buddhism and Western Psychology overlap in theory and in practice. Over the last century, experts have written on many commonalities between Buddhism and various branches of modern western psychology like phenomenological psychology, psychoanalytical psychotherapy, humanistic psychology, cognitive psychology and existential psychology. Orientalist Alan Watts wrote 'if we look deeply into such ways of life as Buddhism, we do not find either philosophy or religion as these are understood in the West. We find something more nearly resembling psychotherapy'. Buddha was a unique psychotherapist. His therapeutic methods helped millions of people throughout the centuries. This essay is just an expression of what little the current author has understood on Buddha philosophy and an opportunity to offer his deep tribute to one of the greatest psychotherapists the world has ever produced!


Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.
Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.


Disentangling Fun and Enjoyment in Exergames Using an Expanded Design, Play, Experience Framework: A Narrative Review.
With exergames (as with physical activity in general), more intense and longer-duration game play should accrue more health benefits. Exergames, however, appear to be played for relatively short durations, often at medium or lower intensities. Ostensibly games are played for fun or enjoyment. Enhancing the fun or enjoyment experienced during exergame play should enhance the intensity and duration of physical activity, and thereby the health benefits. Research, reviewed herein, indicates fun and/or enjoyment in games are inherently laden with psychosocial, physiological, and embodiment substrates. Physical activity may also have separate or closely related psychosocial, physiological, and embodiment enjoyment substrates. Research is needed to integrate these levels of experience and to identify the game mechanics that enhance, and even maximize, the fun or enjoyment experienced in exergames, to thereby increase the health benefit.


Cold-induced aldimine bond cleavage by Tris in Bacillus subtilis alanine racemase.
Pyridoxal 5'-phosphate (PLP) is a versatile cofactor involved in a large variety of enzymatic processes. Most of PLP-catalysed reactions, such as those of alanine racemases (AlaRs), present a common resting state in which the PLP is covalently bound to an active-site lysine to form an internal aldimine. The crystal structure of BsAlaR grown in the presence of Tris lacks this covalent linkage and the PLP cofactor appears deformylated. However, loss of activity in a Tris buffer only occurred after the solution was frozen prior to carrying out the enzymatic assay. This evidence strongly suggests that Tris can access the active site at subzero temperatures and behave as an alternate racemase substrate leading to mechanism-based enzyme inactivation, a hypothesis that is supported by additional X-ray structures and theoretical results from QM/MM calculations. Taken together, our findings highlight a possibly underappreciated role for a common buffer component widely used in biochemical and biophysical experiments.


Re-examination of the natural history of high-grade T1 bladder cancer using a large contemporary cohort.
High-grade T1 (HGT1) bladder cancer represents a clinical challenge in that the urologist must balance the risk of disease progression against the morbidity and potential mortality of early radical cystectomy and urinary diversion. Using two non-muscle invasive bladder cancer (NMIBC) databases, we re-examined the rate of progression of HG T1 bladder cancer in our bladder cancer populations. We queried the NMIBC databases that have been established independently at the Atlanta Veterans Affairs Medical Center (AVAMC) and the University of Pennsylvania to identify patients initially diagnosed with HGT1 bladder cancer. Demographic, clinical, and pathologic variables were examined as well as rates of recurrence and progression. A total of 222 patients were identified; 198 (89.1%) and 199 (89.6%) of whom were male and non-African American, respectively. Mean patient age was 66.5 years. 191 (86.0%) of the patients presented with isolated HG T1 disease while 31 (14.0%) patients presented with HGT1 disease and CIS. Induction BCG was utilized in 175 (78.8%) patients. Recurrence occurred in 112 (50.5%) patients with progression occurring in only 19 (8.6%) patients. At a mean follow-up of 51 months, overall survival was 76.6%. Fifty two patients died, of whom only 13 (25%) patient deaths were bladder cancer related. In our large cohort of patients, we found that the risk of progression at approximately four years was only 8.6%. While limited by its retrospective nature, this study could potentially serve as a starting point in re-examining the treatment algorithm for patients with HG T1 bladder cancer.


Attenuation of TNT in seawater microcosms.
The ability of two differing marine sediments (one clayey, the other sandy) to attenuate the explosive 2,4,6-trinitrotoluene (TNT), dissolved in intertidal seawater from the eastern English coast of the North Sea, was examined using aerobic microcosms. Analysis of the seawater from the microcosms revealed an initial sharp decline in TNT concentration with clayey sediment in both sterilized (to prevent microbial activity) and unsterilized microcosms. This effect did not occur to such a marked extent in similar sterile and non-sterile sandy sediment microcosms and was attributed mainly to sorption of TNT to the fine clay particles of the clayey sediment. As time progressed, the attenuation of TNT in microcosms containing either type of sediment was found to be less in those that had been sterilized compared with those where microbial action proceeded unhindered. Feeding the microcosms, (i.e. supplying extra carbon sources for the microbial communities), appeared to have a small, but perceptible, enhancing effect upon TNT dissipation. The attenuation of TNT was also measured in large microcosms containing 2.5 L of seawater and no sediment. Analysis of the seawater revealed a gradual decline in TNT concentration in non-sterile and fed microcosms compared to their sterile counterpart. Overall, this laboratory study showed that the attenuation of TNT is slow (half-life in seawater ca.1900 days; half-life sand sediment <700 days; half life in clay sediment 130 days) under conditions commonly encountered in coastal waters of the North Sea.


Interactions of human osteoprogenitors with porous ceramic following diffusion chamber implantation in a xenogeneic host.
Porous calcium phosphate ceramics are useful bone graft substitutes on account of their osteoconductive properties and lack of toxicity, but they lack osteogenicity and are brittle in nature. Osteogenic properties, and increased biomechanical properties, could be induced by combining them with human bone-forming cell populations. Progress has been hampered both by the lack of a suitable experimental assay of in vivo human bone formation and a suitable in vivo test system with which to study such cells in association with biomaterials. Here, trabecular bone-derived cells and marrow stromal fibroblastic cells from four human donors aged between 14 and 27 y have been cultured in vitro then combined with a porous ceramic within diffusion chambers and implanted into athymic mice. Bone and cartilage formation was found within the chambers primed with cells cultured in the continuous presence of dexamethasone and ascorbate. These tissues were found in close apposition to the ceramic, confirming that the material is biocompatible and bioactive. These findings demonstrate both that appropriately primed human-cell populations can express the fully differentiated osteoblastic phenotype in the diffusion-chamber model, and also that this is a useful system in which to test the interactions of such cell populations with putative biomaterials.


Experience, time investment, and motivators of nursing journal peer reviewers.
To describe nursing journal reviewers' professional backgrounds, reviewing experience, time investment, and perceptions of their role. Exploratory descriptive cross-sectional study. A 69-question survey containing both fixed-option and open-ended questions and accessed via the World Wide Web was completed by 1,675 nursing journal reviewers who had been invited to participate by editors of 52 nursing journals. Participants were from 44 countries, with 74% from the US, and 90% were nurses. The majority were doctorally prepared academics who were involved in research. They reported spending an average of 5 hours on each critique and completed an average of 7-8 reviews per year. The most common reason reported for becoming involved was personal contact with an editor. Lack of time because of competing work commitments was the most commonly cited barrier to reviewing and negative aspect of the role. The most common positive aspect was keeping up to date with the field. Nursing journal peer reviewers express rewards and challenges similar to those reported elsewhere for biomedical journal reviewers. Based on these findings, editors might consider new approaches to recruiting and supporting reviewers, and potential reviewers might gain insight into the role. Support of these distinguished scholars in this important role is critical to sustain the quality of scholarship that informs nursing practice, education, and research. Clinicians, researchers, and educators who rely on the quality of the articles published in nursing journals can learn from this survey about the background and experiences of those who protect that quality by providing expert feedback to authors and editors.


The incidence of p53 mutations increases with progression of head and neck cancer.
To establish a genetic model of the progression of head and neck squamous carcinoma we have defined the incidence and timing of p53 mutations in this type of cancer. We sequenced the conserved regions of the p53 gene in 102 head and neck squamous carcinoma lesions. These included 65 primary invasive carcinomas and 37 noninvasive archival specimens consisting of 13 severe dysplasias and 24 carcinoma in situ lesions. The incidence of p53 mutations in noninvasive lesions was 19% (7/37) and increased to 43% (28/65) in invasive carcinomas. These data suggest that p53 mutations can precede invasion in primary head and neck cancer. Furthermore, the spectrum of codon hotspots is similar to that seen in squamous carcinoma of the lung and 64% of mutations are at G nucleotides, implicating carcinogens from tobacco smoke in the etiology of head and neck squamous carcinoma.


A reorientation strategy for reducing delirium in the critically ill. Results of an interventional study.
A wide variability in the approach towards delirium prevention and treatment in the critically ill results from the dearth of prospective randomised studies. We launched a two-stage prospective observational study to assess delirium epidemiology, risk factors and impact on patient outcome, by enrolling all patients admitted to our Intensive Care Unit (ICU) over a year. The first step - from January to June 2008 was the observational phase, whereas the second one from July to December 2008 was interventional. All the patients admitted to our ICU were recruited but those with pre-existing cognitive disorders, dementia, psychosis and disability after stroke were excluded from the data analysis. Delirium assessment was performed according with Confusion Assessment Method for the ICU twice per day after sedation interruption. During phase 2, patients underwent both a re-orientation strategy and environmental, acoustic and visual stimulation. We admitted a total of respectively 170 (I-ph) and 144 patients (II-ph). The delirium occurrence was significantly lower in (II-ph) 22% vs. 35% in (I-ph) (P=0.020). A Cox's Proportional Hazard model found the applied reorientation strategy as the strongest protective predictors of delirium: (HR 0.504, 95% C.I. 0.313-0.890, P=0.034), whereas age (HR 1.034, 95% CI: 1.013-1.056, P=0.001) and sedation with midazolam plus opiate (HR 2.145, 95% CI: 2.247-4.032, P=0.018) were negative predictors. A timely reorientation strategy seems to be correlated with significantly lower occurrence of delirium.


Identifying the Biosynthetic Gene Cluster for Triacsins with an N-Hydroxytriazene Moiety.
Triacsins are a family of natural products having in common an N-hydroxytriazene moiety not found in any other known secondary metabolites. Though many studies have examined the biological activity of triacsins in lipid metabolism, their biosynthesis has remained unknown. Here we report the identification of the triacsin biosynthetic gene cluster in Streptomyces aureofaciens ATCC 31442. Bioinformatic analysis of the gene cluster led to the discovery of the tacrolimus producer Streptomyces tsukubaensis NRRL 18488 as a new triacsin producer. In addition to targeted gene disruption to identify necessary genes for triacsin production, stable isotope feeding was performed in vivo to advance the understanding of N-hydroxytriazene biosynthesis.


Influence of hypertension with minimal hypertrophy on diastolic function during demand ischemia.
Hearts with advanced pressure-overload hypertrophy from systemic hypertension have been shown to have an increased susceptibility to the development of diastolic dysfunction in response to tissue hypoxia and ischemia. It is not known if this propensity to develop diastolic dysfunction in response to ischemia is dependent on the presence of a substantial increase in left ventricular mass, or alternatively, is characteristic of hearts subjected to mild chronic hypertension early in the development of cardiac hypertrophy. We tested the hypothesis that systemic hypertension associated with mild left ventricular hypertrophy increases the susceptibility to the development of diastolic dysfunction in response to demand ischemia. The effects of demand ischemia (6 minutes) were studied in hearts from New Zealand white rabbits with chronic systemic hypertension produced by the one-kidney, one-wrap method (n = 15) and compared with age-matched, sham-operated control rabbits (n = 11) with similar left ventricular mass (5.4 +/- 0.2 vs. 5.4 +/- 0.3 g, respectively). The hearts were studied using an isolated, isovolumic (balloon in left ventricle) preparation with absent pericardium that was perfused with fresh whole blood. At baseline, coronary perfusion pressure was 100 mm Hg with comparable coronary flow per gram left ventricular weight; the hearts were paced at a physiological rate of 3 Hz, and the left ventricular balloon volume was adjusted to achieve a left ventricular end-diastolic pressure of 15 mm Hg in both groups. Left ventricular balloon volume was similar in both groups and volume was thereafter held constant. At baseline, left ventricular systolic pressure (114 +/- 4 vs. 95 +/- 3 mm Hg, p less than 0.001) and developed pressure (18.9 +/- 1.2 vs. 15.1 +/- 0.9 mm Hg/g, p less than 0.05) were higher in the hearts from the hypertensive group in comparison with the control group. During the first minute of global ischemia produced by reducing coronary perfusion pressure from 100 to 20 mm Hg, there was an immediate fall in left ventricular systolic pressure in both groups without an increase in diastolic pressure. In response to the superimposition of pacing tachycardia (heart rate, 6 Hz) during the remaining 5 minutes of the period of ischemia, left ventricular developed pressure was comparable. However, isovolumic left ventricular end-diastolic pressure (measured during long diastoles obtained with transient cessation of pacing) rose to a significantly higher level in the hearts from hypertensive rabbits than in those from the control rabbits (29 +/- 3 vs. 18 +/- 2 mm Hg, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)


Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial.
Garlic is widely promoted as a cholesterol-lowering agent, but efficacy studies have produced conflicting results. Garlic supplements differ in bioavailability of key phytochemicals. We evaluated the effect of raw garlic and 2 commonly used garlic supplements on cholesterol concentrations in adults with moderate hypercholesterolemia. In this parallel-design trial, 192 adults with low-density lipoprotein cholesterol (LDL-C) concentrations of 130 to 190 mg/dL (3.36-4.91 mmol/L) were randomly assigned to 1 of the following 4 treatment arms: raw garlic, powdered garlic supplement, aged garlic extract supplement, or placebo. Garlic product doses equivalent to an average-sized garlic clove were consumed 6 d/wk for 6 months. The primary study outcome was LDL-C concentration. Fasting plasma lipid concentrations were assessed monthly. Extensive chemical characterization of study materials was conducted throughout the trial. Retention was 87% to 90% in all 4 treatment arms, and chemical stability of study materials was high throughout the trial. There were no statistically significant effects of the 3 forms of garlic on LDL-C concentrations. The 6-month mean (SD) changes in LDL-C concentrations were +0.4 (19.3) mg/dL (+0.01 [0.50] mmol/L), +3.2 (17.2) mg/dL (+0.08 [0.44] mmol/L), +0.2 (17.8) mg/dL (+0.005 [0.46] mmol/L), and -3.9 (16.5) mg/dL (-0.10 [0.43] mmol/L) for raw garlic, powdered supplement, aged extract supplement, and placebo, respectively. There were no statistically significant effects on high-density lipoprotein cholesterol, triglyceride levels, or total cholesterol-high-density lipoprotein cholesterol ratio. None of the forms of garlic used in this study, including raw garlic, when given at an approximate dose of a 4-g clove per day, 6 d/wk for 6 months, had statistically or clinically significant effects on LDL-C or other plasma lipid concentrations in adults with moderate hypercholesterolemia.


A clinical and genetic study of campomelic dysplasia.
Campomelic dysplasia (CMD) is a rare skeletal disorder that is usually lethal. It is characterised by bowing of the lower limbs, severe respiratory distress, and many of the chromosomal (XY) males show sex reversal. Because of a number of reports of familial campomelic dysplasia it is considered to be inherited in an autosomal recessive manner. In this study, details of 36 patients with campomelic dysplasia were collected from genetic centres, radiologists, and pathologists in the United Kingdom. The chromosomal sex ratio was approximately 1:1. There was a preponderance of phenotypic females owing to sex reversal. Three quarters of the chromosomal males were sex reversed or had ambiguous genitalia. Three cases are still alive, two with chromosomal rearrangements involving chromosome 17q. The majority of the others died in the neonatal period. The 36 index cases had 41 sibs of whom only two were affected. Formal segregation analysis gave a segregation ratio of 0.05 (95% CI approximately 0.00 to 0.11). This excludes an autosomal recessive mode of inheritance. The data suggest a sporadic, autosomal dominant mode of inheritance. Patients with a chromosomal rearrangement involving 17q (q23.3-q25.1) show a milder phenotype. The molecular mechanism for the difference is still unknown.


Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells.
The tumor microenvironment plays an important role in cancer progression. Here, we focused on the role of reactive mesenchymal stem cells (MSC) in osteosarcoma (OS), and used human adipose MSC and a panel of OS cell lines (Saos-2, HOS, and 143B) to investigate the mutual effect of normal-cancer cell metabolic programming. Our results showed that MSC are driven by oxidative stress induced by OS cells to undergo Warburg metabolism, with increased lactate production. Therefore, we analyzed the expression of lactate monocarboxylate transporters. By real time PCR and immunofluorescence, in MSC we detected the expression of MCT-4, the transporter for lactate efflux, whereas MCT-1, responsible for lactate uptake, was expressed in OS cells. In agreement, silencing of MCT-1 by siRNA significantly affected the ATP production in OS cancer cells. Thus, cancer cells directly increase their mitochondrial biogenesis using this energy-rich metabolite that is abundantly provided by MSC as an effect of the altered microenvironmental conditions induced by OS cells. We also showed that lactate produced by MSC promotes the migratory ability of OS cells. These data provide novel information to be exploited for cancer therapies targeting the mutual metabolic reprogramming of cancer cells and their stroma.


Ant-mediated ecosystem functions on a warmer planet: effects on soil movement, decomposition and nutrient cycling.
1. Direct and indirect consequences of global warming on ecosystem functions and processes mediated by invertebrates remain understudied but are likely to have major impacts on ecosystems in the future. Among animals, invertebrates are taxonomically diverse, responsive to temperature changes, and play major ecological roles which also respond to temperature changes. 2. We used a mesocosm experiment to evaluate impacts of two warming treatments (+3·5 and +5 °C, set-points) and the presence and absence of the ant Formica subsericea (a major mediator of processes in north temperate ecosystems) on decomposition rate, soil movement, soil respiration and nitrogen availability. 3, Replicate 19-L mesocosms were placed outdoors in lathe houses and continuously warmed for 30 days in 2011 and 85 days in 2012. Warming treatments mimicked expected temperature increases for future climates in eastern North America. 4. In both years, the amount of soil displaced and soil respiration increased in the warming and ant presence treatments (soil movement: 73-119%; soil respiration: 37-48% relative to the control treatments without ants). 5. Decomposition rate and nitrogen availability tended to decrease in the warmest treatments (decomposition rate: -26 to -30%; nitrate availability: -11 to -42%). 6. Path analyses indicated that ants had significant short-term direct and indirect effects on the studied ecosystem processes. These results suggest that ants may be moving more soil and building deeper nests to escape increasing temperatures, but warming may also influence their direct and indirect effects on soil ecosystem processes.


Central obesity and the Mediterranean diet: A systematic review of intervention trials.
Central obesity is associated with chronic low-grade inflammation, and is a risk factor for cardiometabolic syndrome. The Mediterranean diet pattern has a convincing evidence-base for improving cardiometabolic health. This review investigated the impact of Mediterranean diet interventions on central obesity, specifically. A systematic literature search was conducted in the MEDLINE, CINAHL, EMBASE and Cochrane library databases. Search terms included: 'Mediterranean Diet', 'Mediterranean dietary pattern', 'central obesity' and 'visceral fat'. The search was limited to English language and humans ≥18 years. Eighteen articles met the eligibility criteria and reported at least one outcome measure of central obesity with Mediterranean diet intervention. Central obesity measures included waist circumference (16 studies), waist-hip ratio (5 studies) and visceral fat (2 studies). Thirteen (72%) of the studies, totaling 7186 subjects (5168 subjects assigned to a Mediterranean Diet), reported a significant reduction in central obesity with a Mediterranean-type diet. However, seven out of these 13 interventions employed energy restriction, and only three showed a statistically significant favorable effect of the Mediterranean diet relative to a control group. This systematic review highlights the potential for a Mediterranean diet intervention to reduce central obesity and in turn reduce obesity-related chronic disease risk and associated public health burden.


Design and analysis of Bar-seq experiments.
High-throughput quantitative DNA sequencing enables the parallel phenotyping of pools of thousands of mutants. However, the appropriate analytical methods and experimental design that maximize the efficiency of these methods while maintaining statistical power are currently unknown. Here, we have used Bar-seq analysis of the Saccharomyces cerevisiae yeast deletion library to systematically test the effect of experimental design parameters and sequence read depth on experimental results. We present computational methods that efficiently and accurately estimate effect sizes and their statistical significance by adapting existing methods for RNA-seq analysis. Using simulated variation of experimental designs, we found that biological replicates are critical for statistical analysis of Bar-seq data, whereas technical replicates are of less value. By subsampling sequence reads, we found that when using four-fold biological replication, 6 million reads per condition achieved 96% power to detect a two-fold change (or more) at a 5% false discovery rate. Our guidelines for experimental design and computational analysis enables the study of the yeast deletion collection in up to 30 different conditions in a single sequencing lane. These findings are relevant to a variety of pooled genetic screening methods that use high-throughput quantitative DNA sequencing, including Tn-seq.


Toxicity of protease-resistant domains from the delta-endotoxin of Bacillus thuringiensis subsp. israelensis in Culex quinquefasciatus and Aedes aegypti bioassays.
The mosquitocidal glycoprotein endotoxin of Bacillus thuringiensis subsp. israelensis was digested with chymotrypsin to yield protease-resistant domains which were then separated from smaller protease digestion products by high-performance liquid chromatography. Once purified, the domains no longer bound wheat germ agglutinin, a lectin which binds N-acetylglucosamine (GlcNAc) and GlcNAc oligomers. Purified protease-resistant domains were as toxic for Culex quinquefasciatus larvae as intact solubilized toxin. In separate experiments, the toxicity of chymotrypsin-digested endotoxin for Aedes aegypti larvae was reduced fivefold or more. A model is presented in which GlcNAc-containing oligosaccharides are required for toxicity for A. aegypti larvae but not C. quinquefasciatus larvae.


Prevalence of Norovirus in produce sold at retail in the United Kingdom.
To acquire data on contamination with Norovirus in berry fruit and salad vegetables in the United Kingdom, one thousand one hundred and fifty two samples of fresh produce sold at retail in the UK were analysed for Norovirus. Of 568 samples of lettuce, 30 (5.3%) were Norovirus-positive. Most (24/30) lettuce samples which tested positive for Norovirus were grown in the UK and 19 of those 24 samples contained NoV GI. Seven/310 (2.3%) samples of fresh raspberries were Norovirus-positive. Most (6/7) of the positively-testing fresh raspberry samples were imported, but no predominance of a genogroup, or any seasonality, was observed. Ten/274 (3.6%) samples of frozen raspberries were Norovirus-positive. The country of origin of the positively-testing frozen raspberry samples was not identified in most (7/10) instances. The collected data add to the currently limited body of prevalence information on Norovirus in fresh produce, and indicate the need for implementation of effective food safety management of foodborne viruses.


A Breathing Zirconium Metal-Organic Framework with Reversible Loss of Crystallinity by Correlated Nanodomain Formation.
The isoreticular analogue of the metal-organic framework UiO-66(Zr), synthesized with the flexible trans-1,4-cyclohexanedicarboxylic acid as linker, shows a peculiar breathing behavior by reversibly losing long-range crystalline order upon evacuation. The underlying flexibility is attributed to a concerted conformational contraction of up to two thirds of the linkers, which breaks the local lattice symmetry. X-ray scattering data are described well by a nanodomain model in which differently oriented tetragonal-type distortions propagate over about 7-10 unit cells.


Latency, without persistence, of murine cytomegalovirus in the spleen and kidney.
It is not known if murine cytomegalovirus (MCMV) establishes a state of molecular latency independent of low-level persistent infection. The presence of low levels of infectious MCMV distinguishes persistence from molecular latency. Thus, the distinction between persistence and latency has depended on the sensitivity of plaque assays for detecting low levels of infectious virus in tissue of previously infected mice. To determine whether MCMV establishes molecular latency or remains persistent, we developed two assays for detecting low levels of MCMV in tissue. Using prolonged in vitro culture of virus with either mouse embryonic fibroblasts or the murine 3T12 fibroblast cell line, we reproducibly detected a single PFU of MCMV. Inclusion of undiluted sonicated tissue in this assay decreased sensitivity by up to 100-fold. However, sensitivity was improved to 1 PFU of MCMV when sonicated tissue was appropriately diluted. Severe combined immunodeficient (SCID) mice were also used to detect MCMV in sonicated tissue. Infection of SCID mice with a single PFU of MCMV killed two of eight SCID mice, and the 50% lethal dose of MCMV in SCID mice was 2 to 3 PFU. Applying these two methods, we detected infectious virus in 0 of 34 spleens, 1 of 34 kidneys, and 0 of 37 salivary glands from latently infected mice. Spleens and kidneys assessed for persistent virus contained MCMV DNA by PCR and reactivated after 10 to 50 days in explant cultures. Latently infected kidney cells reactivated after adoptive transfer to SCID mice. Quantitation of the MCMV genome by PCR showed that latently infected spleens without detectable infectious MCMV contained about 3,000,000 copies of the MCMV genome. These results demonstrate that MCMV latency in spleen and kidney exists in the absence of low-level persistent infection. Use of assays with defined sensitivity for detection of MCMV in tissue provides a basis for evaluation of cytomegalovirus gene expression in the spleen and kidney during molecular latency.


Antibacterial activity and phytochemical evidence for the plant origin of Turkish propolis from different regions.
Honeybees collect propolis from practically any abundant plant source in the neighborhood of the hive, be it populus, eucalyptus, pine, sugarcane, cashew nut or orange trees. We have described that the origin plants of Turkish propolis are Populus sp., Eucalyptus sp. and Castanea sativa. In our previous study, propolis samples from Middle Anatolia displayed the typical pattern of "poplar" propolis: they contained pinobanksin, caffeic and ferulic acids and their esters. The propolis samples examined in this study were shown not to contain polar phenolics. The main components of Eucalyptus propolis were aromatic acids, mainly cinnamic acid and its esters, that are usually found in Eucalyptus species resins. The second distinct sample originated from West Anatolia. Although it contained low amounts of phenolic substances and aromatic acids, its main components were sugars and glycosides. The study revealed that there was no significant difference between propolis samples in antibacterial activity, however the yeasts were shown to be more sensitive to eucalyptus-propolis. Gram negative bacteria were susceptible to none of the samples tested.


Asthma and rhinitis have different genetic profiles for IL13, IL17A and GSTP1 polymorphisms.
Asthma and rhinitis have a complex etiology, depending on multiple genetic and environmental risk factors. An increasing number of susceptibility genes are currently being identified, but the majority of reported associations have not been consistently replicated across populations of different genetic backgrounds. To evaluate whether polymorphisms of IL4R (rs1805015), IL13 (rs20541), IL17A (rs2275913) and GSTP1 (rs1695) genes are associated with rhinitis and/or asthma in adults of Portuguese ancestry. 192 unrelated healthy individuals and 232 patients, 83 with rhinitis and 149 with asthma, were studied. All polymorphisms were detected by real time polymerase chain reaction (PCR) using TaqMan assays. Comparing to controls, significant association with asthma was observed for GSTP1 rs1695 AA genotype (odds ratio (OR) - 1.96; 95% CI - 1.18 to 3.25; p=0.010). The association sustains for allergic asthma (OR - 2.17; 95% CI - 1.23 to 3.80; p=0.007). IL13 rs20541 GG genotype was associated with less susceptibility to asthma (OR - 0.55, 95% CI - 0.33 to 0.94, p=0.028). Among patients, IL17A rs2275913 AA genotype was less associated with asthma than with rhinitis (OR - 0.20; 95% CI of 0.07 to 0.56; p=0.002). A similar association was found for IL13 rs20541 GG genotype (OR - 0.48; 95% CI of 0.25 to 0.93; p=0.031). There were no significant differences in the distribution of allelic and genotypic frequencies between patients and controls for the IL4R polymorphism' analyzed. These results support the existence of a significant association between GSTP1 rs1695 and IL13 rs20541 SNPs, with susceptibility to asthma, in the population studied. Different genotype profiles of IL17A and IL13 genes seem to influence the clinical pattern of disease expression mainly confined to the upper airways, as rhinitis, or including the lower airways, as asthma.


In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models.
The potential for human adipose-derived mesenchymal stem cells (AMSC) to traffic into various tissue compartments was examined using three murine xenotransplantation models: nonobese diabetic/severe combined immunodeficient (NOD/SCID), nude/NOD/SCID, and NOD/SCID/MPSVII mice. Enhanced green fluorescent protein was introduced into purified AMSC via retroviral vectors to assist in identification of cells after transplantation. Transduced cells were administered to sublethally irradiated immune-deficient mice through i.v., intraperitoneal, or subcutaneous injection. Up to 75 days after transplantation, tissues were harvested and DNA polymerase chain reaction (PCR) was performed for specific vector sequences as well as for human Alu repeat sequences. Duplex quantitative PCR using human beta-globin and murine rapsyn primers assessed the contribution of human cells to each tissue. The use of the novel NOD/SCID/MPSVII mouse as a recipient allowed rapid identification of human cells in the murine tissues, using an enzyme reaction that was independent of surface protein expression or transduction with an exogenous transgene. For up to 75 days after transplantation, donor-derived cells were observed in multiple tissues, consistently across the various administration routes and independent of transduction parameters. Tissue localization studies showed that the primary MSC did not proliferate extensively at the sites of lodgement. We conclude that human AMSC represent a population of stem cells with a ubiquitous pattern of tissue distribution after administration. AMSC are easily obtained and highly amenable to current transduction protocols for retroviral transduction, making them an excellent avenue for cell-based therapies that involve a wide range of end tissue targets.


A nested randomised controlled trial of a newsletter and Post-it® note did not increase postal questionnaire response rates in a falls prevention trial.
Background: Attrition (i.e. when participants do not return the questionnaires) is a problem for many randomised controlled trials. The resultant loss of data leads to a reduction in statistical power and can lead to bias. The aim of this study was to assess whether a pre-notification newsletter and/or a handwritten or printed Post-it® note sticker, as a reminder, increased postal questionnaire response rates for participants of randomised controlled trials. Method: This study was a factorial trial embedded within a trial of a falls-prevention intervention among men and women aged ≥65 years under podiatric care. Participants were randomised into one of six groups: newsletter plus handwritten Post-it®; newsletter plus printed Post-it®; newsletter only; handwritten Post-it® only; printed Post-it® only; or no newsletter or Post-it®. The results were combined with those from previous embedded randomised controlled trials in a meta-analysis. Results: The 12-month response rate was 803/826 (97.2%) (newsletter 95.1%, no newsletter 99.3%, printed Post-it® 97.5%, handwritten Post-it® 97.1%, no Post-it® 97.1%). Pre-notification with a newsletter had a detrimental effect on response rates (adjusted odds ratio (OR), 0.14; 95% CI, 0.04 to 0.48; p<0.01) and time to return the questionnaire (adjusted hazard ratio, 0.86; 95% CI, 0.75 to 0.99; p=0.04). No other statistically significant differences were observed between the intervention groups on response rates, time to response, and the need for a reminder. Conclusions: Post-it® notes have been shown to be ineffective in three embedded trials, whereas the evidence for newsletter reminders is still uncertain.


Community perspectives on developing a sexual health agenda for gay and bisexual men.
Community mobilization around gay rights in the late 1960s and 1970s led to the first efforts to improve the health of gay and bisexual men. In the 1980s the deadly AIDS epidemic was responded to with fierce organizing and community activism, primarily led by gay men. Today, community involvement is crucial to many advocacy and organizing efforts for the health of gay and bisexual men. This article begins with the roots of this history and then describes how they are reflected in a number of key health initiatives for this community including the National Black Gay Men's Advocacy Coalition, the Legacy Project, International Rectal Microbicide Advocates and the Gay Men's Health Agenda. A path forward is described in terms of next steps for advocacy for gay men's health and the health of gay and bisexual men of color emphasizing cultural viability, development of new leaders, and strategic alliances.


Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells.
C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells' receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa.


Empowerment and Indigenous Australian health: a synthesis of findings from Family Wellbeing formative research.
This paper employs a thematic qualitative analysis to synthesise seven discrete formative evaluation reports of an Indigenous Australian family empowerment programme across four study settings in Australia's Northern Territory and Queensland between 1998 and 2005. The aim of the study, which involved a total of 148 adult and 70 school children participants, is to develop a deeper understanding of the contribution of community empowerment education programmes to improving Indigenous health, beyond the evidence derived from the original discrete micro evaluative studies. Within a context beset by trans-generational grief and despair resulting from colonisation and other discriminatory government policies, across the study sites, the participants demonstrated enhanced capacity to exert greater control over factors shaping their health and wellbeing. Evident in the participants' narratives was a heightened sense of Indigenous and spiritual identity, respect for self and others, enhanced parenting and capacity to deal with substance abuse and violence. Changes at the personal level influenced other individuals and systems over time, highlighting the ecological or multilevel dimensions of empowerment. The study reveals the role of psychosocial empowerment attributes as important foundational resources in helping people engage and benefit from health and other behaviour modification programmes, and take advantage of any reforms made within macro policy environments. A key limitation or challenge in the use of psychosocial empowerment programmes relates to the time and resources required to achieve change at population level. A long-term partnership approach to empowerment research that creatively integrates micro community empowerment initiatives with macro policies and programmes is vital if health gains are to be maximised.


Differential arrangements of conserved building blocks among homologs of the Rad50/Mre11 DNA repair protein complex.
Structural maintenance of chromosomes (SMC) proteins have diverse cellular functions including chromosome segregation, condensation and DNA repair. They are grouped based on a conserved set of distinct structural motifs. All SMC proteins are predicted to have a bipartite ATPase domain that is separated by a long region predicted to form a coiled coil. Recent structural data on a variety of SMC proteins shows them to be arranged as long intramolecular coiled coils with a globular ATPase at one end. SMC proteins function in pairs as heterodimers or as homodimers often in complexes with other proteins. We expect the arrangement of the SMC protein domains in complex assemblies to have important implications for their diverse functions. We used scanning force microscopy imaging to determine the architecture of human, Saccharomyces cerevisiae, and Pyrococcus furiosus Rad50/Mre11, Escherichia coli SbcCD, and S.cerevisiae SMC1/SMC3 cohesin SMC complexes. Two distinct architectural arrangements are described, based on the way their components were connected. The eukaryotic complexes were similar to each other and differed from their prokaryotic and archaeal homologs. These similarities and differences are discussed with respect to their diverse mechanistic roles in chromosome metabolism.


Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells.
Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.