Impact of exercise selection on hamstring muscle activation.
To determine which strength training exercises selectively activate the biceps femoris long head (BFLongHead) muscle. We recruited 24 recreationally active men for this two-part observational study. Part 1: We explored the amplitudes and the ratios of lateral (BF) to medial hamstring (MH) normalised electromyography (nEMG) during the concentric and eccentric phases of 10 common strength training exercises. Part 2: We used functional MRI (fMRI) to determine the spatial patterns of hamstring activation during two exercises which (1) most selectively and (2) least selectively activated the BF in part 1. Eccentrically, the largest BF/MH nEMG ratio occurred in the 45° hip-extension exercise; the lowest was in the Nordic hamstring (Nordic) and bent-knee bridge exercises. Concentrically, the highest BF/MH nEMG ratio occurred during the lunge and 45° hip extension; the lowest was during the leg curl and bent-knee bridge. fMRI revealed a greater BF(LongHead) to semitendinosus activation ratio in the 45° hip extension than the Nordic (p<0.001). The T2 increase after hip extension for BFLongHead, semitendinosus and semimembranosus muscles was greater than that for BFShortHead (p<0.001). During the Nordic, the T2 increase was greater for the semitendinosus than for the other hamstring muscles (p≤0.002). We highlight the heterogeneity of hamstring activation patterns in different tasks. Hip-extension exercise selectively activates the long hamstrings, and the Nordic exercise preferentially recruits the semitendinosus. These findings have implications for strategies to prevent hamstring injury as well as potentially for clinicians targeting specific hamstring components for treatment (mechanotherapy).


An artificial solar spectrum substantially alters plant development compared with usual climate room irradiance spectra.
Plant responses to the light spectrum under which plants are grown affect their developmental characteristics in a complicated manner. Lamps widely used to provide growth irradiance emit spectra which are very different from natural daylight spectra. Whereas specific responses of plants to a spectrum differing from natural daylight may sometimes be predictable, the overall plant response is generally difficult to predict due to the complicated interaction of the many different responses. So far studies on plant responses to spectra either use no daylight control or, if a natural daylight control is used, it will fluctuate in intensity and spectrum. An artificial solar (AS) spectrum which closely resembles a sunlight spectrum has been engineered, and growth, morphogenesis, and photosynthetic characteristics of cucumber plants grown for 13 d under this spectrum have been compared with their performance under fluorescent tubes (FTs) and a high pressure sodium lamp (HPS). The total dry weight of the AS-grown plants was 2.3 and 1.6 times greater than that of the FT and HPS plants, respectively, and the height of the AS plants was 4-5 times greater. This striking difference appeared to be related to a more efficient light interception by the AS plants, characterized by longer petioles, a greater leaf unfolding rate, and a lower investment in leaf mass relative to leaf area. Photosynthesis per leaf area was not greater for the AS plants. The extreme differences in plant response to the AS spectrum compared with the widely used protected cultivation light sources tested highlights the importance of a more natural spectrum, such as the AS spectrum, if the aim is to produce plants representative of field conditions.


Phantom surfaces in da Vinci stereopsis.
In binocular viewing of natural three-dimensional scenes, occlusion relationships between objects at different depths create regions of the background that are visible to only one eye. These monocular regions can support depth perception. There are two viewing conditions in which a monocular region can be on the nasal side of a binocular surface--(a) when a background surface is viewed through an aperture and (b) when a region is camouflaged against the background in one eye's view. We created stimuli with a monocular region using complex textures in which camouflage was not possible, and for which there was no physical aperture. For these stimuli, observers perceived a strong phantom contour in near depth at the edge of the monocular region, with the monocular texture perceived behind at the depth of the binocular surface. Depth-matching with a probe showed that the depth of the phantom occluding surface was as precise as for stimuli with regular binocular disparity. Monocular regions of texture on the opposite (temporal) side of the binocular surface were perceived behind, as predicted by occlusion geometry, and there was no phantom surface. We discuss the implications for models of da Vinci stereopsis and stereoscopic edge processing, and consider the involvement of a form of Panum's limiting case. We conclude that the visual system uses a combination of occlusion geometry and complex matching to precisely locate edges in depth that lack a luminance contour.


Identifying genes associated with invasive disease in S. pneumoniae by applying a machine learning approach to whole genome sequence typing data.
Streptococcus pneumoniae, a normal commensal of the upper respiratory tract, is a major public health concern, responsible for substantial global morbidity and mortality due to pneumonia, meningitis and sepsis. Why some pneumococci invade the bloodstream or CSF (so-called invasive pneumococcal disease; IPD) is uncertain. In this study we identify genes associated with IPD. We transform whole genome sequence (WGS) data into a sequence typing scheme, while avoiding the caveat of using an arbitrary genome as a reference by substituting it with a constructed pangenome. We then employ a random forest machine-learning algorithm on the transformed data, and find 43 genes consistently associated with IPD across three geographically distinct WGS data sets of pneumococcal carriage isolates. Of the genes we identified as associated with IPD, we find 23 genes previously shown to be directly relevant to IPD, as well as 18 uncharacterized genes. We suggest that these uncharacterized genes identified by us are also likely to be relevant for IPD.


The changes of hormonal serum levels and ovulation/pregnancy rates after ovarian electrocautery in microlaparoscopy and laparoscopy in patients with PCOS.
To compare the efficacy of ovarian electrocautery performed during microlaparoscopy and laparoscopy, basing on ovulation and pregnancy rates obtained within one year of follow-up. Ovarian drillings, performed with the use of endoscopic methods, were carried out in 135 women with hormonal and ultrasound features of PCOS, aged 30-39 (average age 36 +/- 3.3). Laparoscopic ovarian electrocautery was carried out in 65 cases, whereas microlaparoscopic drilling was conducted in 70 cases. The obtained results were compared in regard to duration of the procedure and ovulation/pregnancy rates within one year of follow-up. Changes in hormonal profiles were also compared in both groups, measured in patients who did not get pregnant before, and 3 months after, the procedures. The difference in durations between the two studied procedures was statistically significant (19 +/- 3 min vs. 24 +/- 4.4 min; p<0.001). However, the ovulation and pregnancy rates did not differ significantly between the two groups (72% vs. 77.7%; p<0.5 and 19.4% vs. 20%; p<0.95, respectively). There were also similar trends in hormonal changes after microlaparoscopic and laparoscopic drilling. The efficacy of ovarian drilling in PCOS, estimated by ovulation and pregnancy rates within 12 months of follow-up is similar for microlaparoscopy and laparoscopy, as well as the trends in hormonal changes. Ovarian electrocautery is significantly longer in microlaparoscopy, but the difference in time is of no practical impact.


Ethnohistory, intertribal relationships, and genetic diversity among Amazonian Indians.
The influence of recent ethnohistorical factors on the microevolution of South American Indians has not been adequately evaluated by population geneticists. This makes difficult a reasonable interpretation of the present genetic structure of these groups. In this article the genetic diversity of 18 tribes of the Amazon and neighboring areas belonging to 3 linguistic groups (Tupi, Carib, and Gê) is analyzed in light of documentary sources about historical events, such as demographic changes, geographic movements, intertribal relationships, and marriage practices, that have taken place since the end of the eighteenth century. The high depopulation rate suffered by the Tupi groups (61.4% on average) is a probable factor conditioning the large intergroup genetic distances in this linguistic stock, for depopulation is a phenomenon associated with random genetic drift caused by a bottleneck effect. On the other hand, the relatively high similarity of the Gê and the Carib shows an association with two main factors: (1) reduced spatial dispersion of the Gê in the recent past, providing adequate conditions for within-stock gene flow, and (2) strong tradition of intergroup contacts among the Carib, frequently followed by genetic admixture and even fusion of groups, as verified for the Wayana and the Aparaí. The patterns of biologic variation of some Tupi tribes (Waiãpi, Emerillon, Parakanã, and Assurini) are better explained by historical and regional contingencies than by linguistic classification.


Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial.
Rates of varicella have decreased substantially in countries implementing routine varicella vaccination. Immunisation is possible with monovalent varicella vaccine or a combined measles-mumps-rubella-varicella vaccine (MMRV). We assessed protection against varicella in naive children administered one dose of varicella vaccine or two doses of MMRV. This study was done in ten European countries with endemic varicella. Healthy children aged 12-22 months were randomised (3:3:1 ratio, by computer-generated randomisation list, with block size seven) to receive 42 days apart (1) two doses of MMRV (MMRV group), or (2) MMR at dose one and monovalent varicella vaccine at dose two (MMR+V group), or (3) two doses of MMR (MMR group; control). Participants and their parents or guardians, individuals involved in assessment of any outcome, and sponsor staff involved in review or analysis of data were masked to treatment assignment. The primary efficacy endpoint was occurrence of confirmed varicella (by detection of varicella zoster virus DNA or epidemiological link) from 42 days after the second vaccine dose to the end of the first phase of the trial. Cases were graded for severity. Efficacy analyses were per protocol. Safety analyses included all participants who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, number NCT00226499. Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. In the efficacy cohort of 5285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8·8), in the MMR+V group was 36 months (8·5) and in the MMR group was 35 months (8·9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94·9% (97·5% CI 92·4-96·6), and against moderate to severe varicella was 99·5% (97·5-99·9). Efficacy of one-dose varicella vaccine against all varicella was 65·4% (57·2-72·1), and against moderate to severe varicella (post hoc) was 90·7% (85·9-93·9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57·4% (95% CI 53·9-60·9) of participants in the MMRV group reported fever of 38°C or more, by contrast with 44·5% (41·0-48·1) with MMR+V, and 39·8% (33·8-46·1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period. These results support the implementation of two-dose varicella vaccination on a short course, to ensure optimum protection from all forms of varicella disease. GlaxoSmithKline Vaccines.


Biochemical studies of membrane fusion at the single-particle level.
To study membrane fusion mediated by synaptic proteins, proteoliposomes have been widely used for in vitro ensemble measurements with limited insights into the fusion mechanism. Single-particle techniques have proven to be powerful in overcoming the limitations of traditional ensemble methods. Here, we summarize current single-particle methods in biophysical and biochemical studies of fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and other synaptic proteins, together with their advantages and limitations.


Benefits of investing in ecosystem restoration.
Measures aimed at conservation or restoration of ecosystems are often seen as net-cost projects by governments and businesses because they are based on incomplete and often faulty cost-benefit analyses. After screening over 200 studies, we examined the costs (94 studies) and benefits (225 studies) of ecosystem restoration projects that had sufficient reliable data in 9 different biomes ranging from coral reefs to tropical forests. Costs included capital investment and maintenance of the restoration project, and benefits were based on the monetary value of the total bundle of ecosystem services provided by the restored ecosystem. Assuming restoration is always imperfect and benefits attain only 75% of the maximum value of the reference systems over 20 years, we calculated the net present value at the social discount rates of 2% and 8%. We also conducted 2 threshold cum sensitivity analyses. Benefit-cost ratios ranged from about 0.05:1 (coral reefs and coastal systems, worst-case scenario) to as much as 35:1 (grasslands, best-case scenario). Our results provide only partial estimates of benefits at one point in time and reflect the lower limit of the welfare benefits of ecosystem restoration because both scarcity of and demand for ecosystem services is increasing and new benefits of natural ecosystems and biological diversity are being discovered. Nonetheless, when accounting for even the incomplete range of known benefits through the use of static estimates that fail to capture rising values, the majority of the restoration projects we analyzed provided net benefits and should be considered not only as profitable but also as high-yielding investments. Beneficios de Invertir en la Restauración de Ecosistemas.


Nucleophilic-alkylation-reoxidation: a functionalization sequence for single-wall carbon nanotubes.
A new reaction sequence for the chemical functionalization of single-wall carbon nanotubes (SWNTs) consisting of the nucleophilic addition of t-BuLi to the sidewalls of the tubes and the subsequent reoxidation of the intermediates t-Bu(n)SWNT(n-) leading to t-Bu(n)SWNT was developed. During the formation of the t-Bu(n)SWNT(n-), a homogeneous dispersion in benzene was formed due to the electrostatic repulsion of the negatively charged intermediates causing debundling. The entire reaction sequence can be repeated, and the degree of functionalization of the products (t-Bu(n))(m)SWNT (m = 1-3) increases with increasing m. Degrees of functionalization expressed as the carbon-to-addend ratio of up to 31 were reached. The reaction was studied in detail by photoelectron spectroscopy, Raman spectroscopy, and scanning tunneling microscopy (STM). The C 1s core level spectra reveal that the nucleophilic attack of the t-BuLi leads to negatively charged SWNTs. Upon oxidation, this negative charge is removed. The valence band spectra of the functionalized samples exhibit a significant reduction in the pi-derived density of states. In STM, the covalently bonded t-butyl groups attached to the sidewalls have been visualized. Raman spectroscopy reveals that addition of the nucleophile to metallic tubes is preferred over the addition to semiconducting tubes.


Deterministic stability and random behavior of a Hepatitis C model.
The deterministic stability of a model of Hepatitis C which includes a term defining the effect of immune system is studied on both local and global scales. Random effect is added to the model to investigate the random behavior of the model. The numerical characteristics such as the expectation, variance and confidence interval are calculated for random effects with two different distributions from the results of numerical simulations. In addition, the compliance of the random behavior of the model and the deterministic stability results is examined.


Induction of transport of organic anions in Malpighian tubules of Rhodnius.
1. The ability of Rhodnius Malpighian tubules to transport organic anions such as p-aminohippuric acid (PAH) and amaranth depends on the physiological state of the insect. Unfed insects progressively lose this ability, but the transport mechanisms rapidly become activated after a blood meal. 2. This induction occurs in adults as well as larval instars and is not prevented by decapitation. 3. No increase in rates of excretion of organic anions follows a meal of Ringer's solution or a single injection of 0-1 mumoles of PAH into the haemolymph. 4. Accelerated PAH excretion is induced in insects fed (a) blood plasma alone or a suspension of red blood cells in saline, (b) solutions of serum albumin or casein, and (c) whole or diluted milk. 5. These results show that the ingestion of a protein-rich meal is sufficient to induce an accelerated transport of organic anions such as PAH and they suggest that this induction is not controlled by a hormone released in response to abdominal distension but depends instead on the continued presence in the haemolymph of some product of digestion of the meal.


Tools to share good chairside teaching practice: a clinical scenario and appreciative questionnaire.
This article provides a scenario for analysis of good chairside teaching practice to serve as a starting point for continued discussion in this complex field. Documented issues of good chairside teaching practice are cross-referenced to a clinical scenario with explanations in the form of a commentary. This provided the context for generating a set of questions that are provided as tools to support good chairside practice. These tools are designed to be used with 'Appreciative Inquiry', which claims that there is much to be gained by discovering where excellence is possible and elaborating upon this. Although this process can be carried out in single units or departments, it is proposed that collaboration between institutions would allow sharing of valuable innovations and greater understanding of educational training, production of good practice guidance and professional development of staff. This article is the third in a series of three and provides a scaffold for a scenario and questions to encourage collaboration in evolving and sharing good chairside teaching practice. The first article investigated the perceptions of stakeholders in chairside teaching at a single dental school and the second evaluated chairside teaching on a UK wide scale. A further accompanying article reviews some of the educational methodology and innovations in teaching and learning that may be applied to dentistry.


Alloantigen receptors on activated T cells in mice. I. Binding of alloantigens and anti-idiotypic antibodies to the same receptors.
B6 alloantigens in supernates from one-way mixed lymphocyte reaction (MLR) cultures of AKR T cells against B6 lymph node cells rebound specifically to (B6)AKR-T-cell blasts after overnight incubation and recovery of these blasts from trypsin treatment. A similar specificity was observed with the binding of SJL alloantigens to (SJL)AKR-T-cell blasts. In both cases, the corresponding alloantigens were rebound several-fold more efficiently than control alloantigens. In a different assay system, T-cell receptors were studied with anti-idiotypic sera. These antisera were raised by repeated injection of purified (B6)AKR-T-cell blasts into (AKR X B6)F1 hybrid mice. These F1a(AKRaB6) sera reacted with the majority of (B6)AKR-T and (B6)(AKR X SJL)F1-T-cell blasts. They also reacted with a lower, though sizable, number of (SJL)AKR-T- and (SJL)(AKR X B6)F1-T-cell blasts. No reaction was observed with (B6)SJL-T, concanavalin A-activated AKR T-cell blasts, normal B6, (AKR X B6)F1, and (AKR X SJL)F1 T cells. Normal AKR T cells were positive only minimally above background. F1a(AKRaB6) sera could be made specific for (B6)AKR-T and (B6)(AKR X SJL)F1-T-cell blasts by absorption of contaminating antibodies with (SJL)AKR-T-cell blasts. Finally, it was shown by competition experiments that the receptors on MLR-activated T-cell blasts that bind alloantigens were the same as those binding anti-idiotypic antibodies. In addition, it was found that at least a fraction of alloantibodies share common idiotypic determinants with receptors on MLR-activated T-cell blasts.


Two new tumor-specific antigenic peptides encoded by gene MAGE-C2 and presented to cytolytic T lymphocytes by HLA-A2.
We have identified 2 antigens recognized by several melanoma-specific cytolytic T lymphocyte clones isolated from a melanoma patient with a clinical history of tumor regression after immunotherapy. Both antigens are presented by HLA-A2 and encoded by gene MAGE-C2, a cancer-germline gene shown previously to be silent in normal somatic tissues and expressed in 40% of melanomas and in other tumor types. One antigen corresponds to peptide ALKDVEERV(336-344), whereas the other corresponds to peptide LLFGLALIEV(191-200). The CTL clones recognizing these 2 peptides also recognized allogeneic tumor cell lines expressing MAGE-C2 and HLA-A2. These 2 new peptides are the first known MAGE-C antigens and represent promising targets for cancer immunotherapy.


Identifying radiation-induced survivorship syndromes affecting bowel health in a cohort of gynecological cancer survivors.
During radiotherapy unwanted radiation to normal tissue surrounding the tumor triggers survivorship diseases; we lack a nosology for radiation-induced survivorship diseases that decrease bowel health and we do not know which symptoms are related to which diseases. Gynecological-cancer survivors were followed-up two to 15 years after having undergone radiotherapy; they reported in a postal questionnaire the frequency of 28 different symptoms related to bowel health. Population-based controls gave the same information. With a modified factor analysis, we determined the optimal number of factors, factor loadings for each symptom, factor-specific factor-loading cutoffs and factor scores. Altogether data from 623 survivors and 344 population-based controls were analyzed. Six factors best explain the correlation structure of the symptoms; for five of these a statistically significant difference (P< 0.001, Mann-Whitney U test) was found between survivors and controls concerning factor score quantiles. Taken together these five factors explain 42 percent of the variance of the symptoms. We interpreted these five factors as radiation-induced syndromes that may reflect distinct survivorship diseases. We obtained the following frequencies, defined as survivors having a factor loading above the 95 percent percentile of the controls, urgency syndrome (190 of 623, 30 percent), leakage syndrome (164 of 623, 26 percent), excessive gas discharge (93 of 623, 15 percent), excessive mucus discharge (102 of 623, 16 percent) and blood discharge (63 of 623, 10 percent). Late effects of radiotherapy include five syndromes affecting bowel health; studying them and identifying the underlying survivorship diseases, instead of the approximately 30 long-term symptoms they produce, will simplify the search for prevention, alleviation and elimination.


Meta-analysis of statin effects in women versus men.
The aim of this study was to evaluate the effect of statins in decreasing cardiovascular events in women and men. Published data reviews have suggested that statins might not be as effective in women as in men in decreasing cardiovascular events. Published data searches and contacts with investigators identified 18 randomized clinical trials of statins with sex-specific outcomes (N = 141,235, 40,275 women, 21,468 cardiovascular events). Odds ratios (ORs) and 95% confidence intervals (CIs) for cardiovascular events were calculated for women and men separately with random effects meta-analyses. The cardiovascular event rate was lower among those randomized to statin intervention than in those randomized to control (low-dose statin in 4 studies, placebo in 11 studies, usual care in 3 studies) and similar in women and men (OR: 0.81, 95% CI: 0.75 to 0.89; p < 0.0001, and OR: 0.77, 95% CI: 0.71 to 0.83, p < 0.0001, respectively). The benefit of statins was statistically significant in both sexes, regardless of the type of control, baseline risk, or type of endpoint and in both primary and secondary prevention. All-cause mortality was also lower with statin therapy both in women and men without significant interaction by sex (p for interaction = 0.4457). Statin therapy is associated with significant decreases in cardiovascular events and in all-cause mortality in women and men. Statin therapy should be used in appropriate patients without regard to sex.


Adherence to Healthy Lifestyle and Cardiovascular Diseases in the Chinese Population.
Adherence to a combination of healthy lifestyle factors has been related to a considerable reduction of cardiovascular risk in white populations; however, little is known whether such associations persist in nonwhite populations like the Asian population. This study aimed to examine the associations of a combination of modifiable, healthy lifestyle factors with the risks of ischemic cardiovascular diseases and estimate the proportion of diseases that could potentially be prevented by adherence to these healthy lifestyle patterns. This study examined the associations of 6 lifestyle factors with ischemic heart disease and ischemic stroke (IS) in the China Kadoorie Biobank of 461,211 participants 30 to 79 years of age who did not have cardiovascular diseases, cancer, or diabetes at baseline. Low-risk lifestyle factors were defined as nonsmoking status or having stopped smoking for reasons other than illness, alcohol consumption of <30 g/day, a median or higher level of physical activity, a diet rich in vegetables and fruits and limited in red meat, a body mass index of 18.5 to 23.9 kg/m2, and a waist-to-hip ratio <0.90 for men and <0.85 for women. During a median of 7.2 years (3.3 million person-years) of follow-up, this study documented 3,331 incident major coronary events (MCE) and 19,348 incident ISs. In multivariable-adjusted analyses, current nonsmoking status, light to moderate alcohol consumption, high physical activity, a diet rich in vegetables and fruits and limited in red meat, and low adiposity were independently associated with reduced risks of MCE and IS. Compared with participants without any low-risk factors, the hazard ratio for participants with ≥4 low-risk factors was 0.42 (95% confidence interval: 0.34 to 0.52) for MCE and 0.61 (95% confidence interval: 0.56 to 0.66) for IS. Approximately 67.9% (95% confidence interval: 46.5% to 81.9%) of the MCE and 39.1% (95% confidence interval: 26.4% to 50.4%) of the IS cases were attributable to poor adherence to healthy lifestyle. Adherence to healthy lifestyle may substantially lower the burden of cardiovascular diseases in Chinese.


Using mass spectrometry to monitor monoclonal immunoglobulins in patients with a monoclonal gammopathy.
A monoclonal gammopathy is defined by the detection a monoclonal immunoglobulin (M-protein). In clinical practice, the M-protein is detected by protein gel electrophoresis (PEL) and immunofixation electrophoresis (IFE). We theorized that molecular mass could be used instead of electrophoretic patterns to identify and quantify the M-protein because each light and heavy chain has a unique amino acid sequence and thus a unique molecular mass whose increased concentration could be distinguished from the normal polyclonal background. In addition, we surmised that top-down MS could be used to isotype the M-protein because each immunoglobulin has a constant region with an amino acid sequence unique to each isotype. Our method first enriches serum for immunoglobulins followed by reduction using DTT to separate light chains from heavy chains and then by microflow LC-ESI-Q-TOF MS. The multiply charged light and heavy chain ions are converted to their molecular masses, and reconstructed peak area calculations for light chains are used for quantification. Using this method, we demonstrate how the light chain portion of an M-protein can be monitored by molecular mass, and we also show that in sequential samples from a patient with multiple myeloma the light chain portion of the M-protein was detected in all samples, even those negative by PEL, IFE, and quantitative FLC. We also present top-down MS isotyping of M-protein light chains using a unique isotype-specific fragmentation pattern allowing for quantification and isotype identification in the same run. Our results show that microLC-ESI-Q-TOF MS provides superior sensitivity and specificity compared to conventional methods and shows promise as a viable method of detecting and isotyping an M-protein.


Medical Ethics and the Biopsychosocial Model for Patient Care: A Case Analysis for Improved Communication, Clinical Time, and Error Avoidance.
The practice of interdisciplinary medicine is one of the most effective and cooperative forms of medical management, which optimizes clinical care and outcomes for a patient. This model of care affords the patient the benefit of receiving the best available therapeutic options from specialists who are experts in their respective disciplines, which would otherwise be limited when compared with the clinical expertise from a single provider managing multiple co-morbidities. However, poor communication between each specialized team managing a patient's care can result in redundancies and superfluous treatment that can have deleterious clinical outcomes that impede the physician-patient relationship and question the bioethical principles of clinical practice. Having a medical provider like an internist who is the primary medical provider for a patient anchors reinforces the physician-patient relationship through familiarity and continuous involvement in the gross clinical course of a patient. Specialty care provides a very focused and limiting scope of practice. However, whether practicing specialty care or being a generalist, utilizing clinical tools, such as the biopsychosocial model and routinely using bioethical principles during clinical encounters, not only help extract pertinent information from the patient's medical history but also furthers the continuity of clinical care by understanding the global context of the patient's medical history. This is a case analysis that exemplifies sub-optimal outcomes in patient care due to undermining the critical role of an internist in patient care and clinical management in addition to challenging several bioethical principles of clinical care. It also highlights the importance of how using the biopsychosocial model of care can avoid clinical errors, improve interdisciplinary and patient communication, and, ultimately, optimize the patient-physician relationship and clinical care.


Alcoholics anonymous careers: patterns of AA involvement five years after treatment entry.
Most formal treatment programs recommend Alcoholics Anonymous (AA) attendance during treatment and as a form of aftercare, but we know very little about treatment seekers' patterns of AA involvement over time and how these relate to abstinence. This paper applies latent class growth curve modeling to longitudinal data from 349 dependent drinkers recruited when they were entering treatment and were re-interviewed at one or more follow-up interviews one, three and five years later, and who reported having attended AA at least once. Four classes of AA "careers" of meeting attendance emerged: The low AA group mainly just attended AA during the 12 months following treatment entry. The medium and high AA groups were characterized by stable attendance at the second and third follow-ups-at about 60 meetings a year for the medium group and over 200 meetings per year for the high group, followed by slight increases for the medium group and slight decreases for the high group by year five. The declining AA group doubled its meeting attendance postbaseline, to almost 200 meetings during the year following treatment entry, but by year five they were only attending about six meetings on average. Decreases in AA meetings did not necessarily signal disengagement from AA; at the five-year follow-up, a third of the low AA group and over half of the declining AA group said they felt like a member of AA. Activities other than meeting attendance, such as having a sponsor, otherwise paralleled the meeting careers, but social networks were similar by year five. Rates of abstinence by year five (for the past 30 days) were 43% for the low AA group, 73% for the medium group, 79% for the high group and 61% for the declining group. Rates of dependence symptoms and social consequences of drinking did not differ between the groups at year five. The prototypical AA careers derived empirically are consistent with anecdotal data about AA meetings: some never connect; some connect but briefly; and others maintain stable (and sometimes quite high) rates of AA attendance. However, contrary to AA lore, many who connect only for a while do well afterwards.


Association of the haem oxygenase-1 gene with inflammatory bowel disease.
The anti-inflammatory genes, haem oxygenase 1 (HO-1, HMOX1) rs2071746 (unrestricted model: p = 9.07 × 10-4; recessive model: p = 4.99 × 10-4; multiplicative model: p = 0.0009; and additive model: p = 1.87 × 10-4) and interleukin-10 (IL-10) rs1800872 (dominant model: p = 0.0277) have been associated with paediatric inflammatory bowel disease. The present family-based case-trio study (n = 52) examined HO-1 gene expression in the presence of proinflammatory lipopolysaccharide and tumour necrosis factor-alpha in four B lymphocyte cell lines established from children with inflammatory bowel disease and demonstrated that mutations in IL-10 and IL-10 receptor B reduced HO-1 messenger RNA expression. This observation supports our hypothesis that HO-1 is regulated by the IL-10/STAT3 pathway and that both genes (IL10 and STAT3) could be involved in the pathogenesis of inflammatory bowel disease. We also compared HO-1 expression in diseased intestinal tissues with adjacent normal tissues from adults with inflammatory bowel disease. Of the 17 Crohn's disease patients, HO-1 expression in diseased tissues was downregulated in 9 patients (53%) and of the 10 ulcerative colitis patients HO-1 was downregulated in 7 patients (70%), compared with adjacent normal tissues. The downregulation of HO-1 gene expression may lower anti-inflammatory effects and worsen tissue injury in affected areas by inflammatory bowel disease.


A model system for in vitro studies of bank vole borne viruses.
The bank vole (Myodes glareolus) is a common small mammal in Europe and a natural host for several important emerging zoonotic viruses, e.g. Puumala hantavirus (PUUV) that causes hemorrhagic fever with renal syndrome (HFRS). Hantaviruses are known to interfere with several signaling pathways in infected human cells, and HFRS is considered an immune-mediated disease. There is no in vitro-model available for infectious experiments in bank vole cells, nor tools for analyses of bank vole immune activation and responses. Consequently, it is not known if there are any differences in the regulation of virus induced responses in humans compared to natural hosts during infection. We here present an in vitro-model for studies of bank vole borne viruses and their interactions with natural host cell innate immune responses. Bank vole embryonic fibroblasts (VEFs) were isolated and shown to be susceptible for PUUV-infection, including a wild-type PUUV strain (only passaged in bank voles). The significance of VEFs as a model system for bank vole associated viruses was further established by infection studies showing that these cells are also susceptible to tick borne encephalitis, cowpox and Ljungan virus. The genes encoding bank vole IFN-β and Mx2 were partially sequenced and protocols for semi-quantitative RT-PCR were developed. Interestingly, PUUV did not induce an increased IFN-β or Mx2 mRNA expression. Corresponding infections with CPXV and LV induced IFN-β but not Mx2, while TBEV induced both IFN-β and Mx2. In conclusion, VEFs together with protocols developed for detection of bank vole innate immune activation provide valuable tools for future studies of how PUUV and other zoonotic viruses affect cells derived from bank voles compared to human cells. Notably, wild-type PUUV which has been difficult to cultivate in vitro readily infected VEFs, suggesting that embryonic fibroblasts from natural hosts might be valuable for isolation of wild-type hantaviruses.


3rd College of paediatrics and child health lecture--the past, the present and the shape of things to come...
The growth trends of Singapore children spanning 5 decades are reviewed, based on 8 anthropometric studies from 1957 till 2002. The heights of pre-school children and school age children appear to have optimised according to their genetic potential, but the weights and body mass indices of children still appear to be increasing from 6 to 18 years for both sexes, probably as a consequence of increasing affluence. This trend is reflected in the increasing obesity prevalence in school children over the past 30 years, and the concomitant increased morbidity associated with the metabolic syndrome, necessitates further research into the causes of obesity. Barker's hypothesis first suggested that changes in the intra-uterine environment can cause fetal adaptations which persist into adulthood, and are responsible for many chronic diseases of adult life. More recently, intense research in the field of epigenetics suggests that the environment can also influence the phenotype through gene expression, through modification of DNA methylation and histones which, in turn, influences gene expression. The challenge for the future is to determine if there are clear epigenetic changes, which are responsible for the increased prevalence of childhood and adolescent obesity, and whether these changes are transmitted through generations. Unravelling these epigenetic mechanisms may be the key to the prevention of obesity and the metabolic syndrome.


Reversible helical chirality of perylene bisimide aggregates: amino acid-directed chiral transfer and chiral inversion.
Through the formation of dynamic covalent bonds, we succeeded, for the first time, in achieving a reversible chiral transfer from amino acids to perylene bisimide aggregates in aqueous solutions. Two opposite helical aggregations are induced with l-phenylalanine and l-tyrosine, respectively. It is possible that the change in configurations of phenyl groups in amino acids leads to the chiral inversion of BAPBI arrangements.


Instability of a pEA29 Marker in Erwinia amylovora Previously Used for Strain Classification.
We examined the use of previously observed restriction fragment length polymorphisms (RFLPs) of a polymerase chain reaction (PCR)-amplified fragment of plasmid pEA29 for differentiating strains of Erwinia amylovora. The PCR fragment from E. amylovora strain CA11 contains a region of 8-bp tandem repeats which is predicted to cause the RFLPs. Examination of a collection of 93 strains revealed the repeat sequence GATTACA(GAATTACA)nGAATTACA in pEA29 with n ranging from 3 to 14. Selected strains were examined after growth in liquid culture to establish the stability of this character. Four strains originally with n = 14, 13, 7, and 3 repeats were grown overnight in liquid culture and streaked onto agar plates to produce individual colonies. Respectively, 4, 10, 1, and 0 out of 17 colonies per strain had an altered copy number when retested. Considering the instability in the number of repeats, it is concluded that the polymorphism in this region of pEA29 is not useful as a marker for following the migration of E. amylovora.


Elevated levels of serum IL-5 are associated with an increased likelihood of major depressive disorder.
Inflammatory mediators in both the peripheral circulation and central nervous system (CNS) are dysregulated in major depressive disorder (MDD). Nevertheless, relatively little is known about the role of the T-helper (Th)-2 effector cytokines interleukin (IL)-5 and IL-13 in MDD. We examined the serum levels of these cytokines and a Th-1 comparison cytokine, interferon (IFN)-γ, in 116 individuals (MDD, n = 58; controls, n = 58). In our basic multivariate model controlling for the effects of potential confounders on the associations between MDD and the examined cytokines, each 1-unit increase in the serum IL-5 level increased the likelihood of belonging to the MDD group by 76% (OR 1.76, 95% CI 1.03-2.99, p = 0.04; model covariates: age, gender, marital status, daily smoking and alcohol use). The likelihood further increased in models additionally controlling for the effects of the use of antidepressants and NSAIDS, and a diagnosis of asthma. No such associations were detected with regard to IL-13 (OR 1.08, 95% CI 0.96-1.22, p = 0.22) or IFN-γ (OR 1.02, 95% CI 0.99-1.05, p = 0.23). Elevated levels of IL-5, which uses the neural plasticity-related RAS GTPase-extracellular signal-regulated kinase (Ras-ERK) pathway to mediate its actions in the central nervous system (CNS), could be one of the factors underlying the depression-related changes in CNS plasticity.


Increasing the Single-Procedure Success Rate of Pulmonary Vein Isolation.
To improve the single-procedural success and long-term outcomes of catheter ablation techniques for AF, there is a need for durable, contiguous and transmural lesions encircling the pulmonary veins (PV). Measurement of contact force (CF) between the catheter tip and the target tissue can optimise ablation procedures. A new approach to obtain single-procedure durable PV isolation (PVI) using the latest CF technology combined with the CARTO VISITAG™ Module with Ablation Index (Biosense Webster) has been shown in small studies to almost eliminate recurrence of paroxysmal AF at 1-year follow up and to make PVI procedures more reproducible. The use of a standardised workflow is expected to increase the reproducibility of results and to increase the efficiency of PVI procedures.


Hospital benchmarking: are U.S. eye hospitals ready?
Benchmarking is increasingly considered a useful management instrument to improve quality in health care, but little is known about its applicability in hospital settings. The aims of this study were to assess the applicability of a benchmarking project in U.S. eye hospitals and compare the results with an international initiative. We evaluated multiple cases by applying an evaluation frame abstracted from the literature to five U.S. eye hospitals that used a set of 10 indicators for efficiency benchmarking. Qualitative analysis entailed 46 semistructured face-to-face interviews with stakeholders, document analyses, and questionnaires. The case studies only partially met the conditions of the evaluation frame. Although learning and quality improvement were stated as overall purposes, the benchmarking initiative was at first focused on efficiency only. No ophthalmic outcomes were included, and clinicians were skeptical about their reporting relevance and disclosure. However, in contrast with earlier findings in international eye hospitals, all U.S. hospitals worked with internal indicators that were integrated in their performance management systems and supported benchmarking. Benchmarking can support performance management in individual hospitals. Having a certain number of comparable institutes provide similar services in a noncompetitive milieu seems to lay fertile ground for benchmarking. International benchmarking is useful only when these conditions are not met nationally. Although the literature focuses on static conditions for effective benchmarking, our case studies show that it is a highly iterative and learning process. The journey of benchmarking seems to be more important than the destination. Improving patient value (health outcomes per unit of cost) requires, however, an integrative perspective where clinicians and administrators closely cooperate on both quality and efficiency issues. If these worlds do not share such a relationship, the added "public" value of benchmarking in health care is questionable.


Injury-induced activation of the MAPK/CREB pathway triggers apoptosis-induced compensatory proliferation in hydra head regeneration.
After bisection, Hydra polyps regenerate their head from the lower half thanks to a head-organizer activity that is rapidly established at the tip. Head regeneration is also highly plastic as both the wild-type and the epithelial Hydra (that lack the interstitial cell lineage) can regenerate their head. In the wild-type context, we previously showed that after mid-gastric bisection, a large subset of the interstitial cells undergo apoptosis, inducing compensatory proliferation of the surrounding progenitors. This asymmetric process is necessary and sufficient to launch head regeneration. The apoptotic cells transiently release Wnt3, which promotes the formation of a proliferative zone by activating the beta-catenin pathway in the adjacent cycling cells. However the injury-induced signaling that triggers apoptosis is unknown. We previously reported an asymmetric immediate activation of the mitogen-activated protein kinase/ribosomal S6 kinase/cAMP response element binding protein (MAPK/RSK/CREB) pathway in head-regenerating tips after mid-gastric bisection. We show here that pharmacological inhibition of the MAPK/ERK pathway or RNAi knockdown of the RSK, CREB, CREB binding protein (CBP) genes prevents apoptosis, compensatory proliferation and blocks head regeneration. As the activation of the MAPK pathway upon injury plays an essential role in regenerating bilaterian species, these results suggest that the MAPK-dependent activation of apoptosis-induced compensatory proliferation represents an evolutionary-conserved mechanism to launch a regenerative process.


Abundance of three bacterial populations in selected streams.
The population sizes of three bacterial species, Acinetobacter calcoaceticus, Burkholderia cepacia, and Pseudomonas putida, were examined in water and sediment from nine streams in different parts of the United States using fluorescent in situ hybridization (FISH). Population sizes were determined from three sites (upstream, midstream, and downstream) in each stream to compare differences in the occurrence and distribution of the species within each stream and among streams. Physical and chemical variables measured reflected differences in environmental conditions among the streams. In the water, B. cepacia numbers were highest in the agricultural, Iowa stream. P. putida numbers were highest in the southern coastal plain streams, Black Creek (GA) and Meyers Branch (SC). Compared to the other two species, the abundance of A. calcoaceticus was similar in all the streams. In sediment, the greatest abundance of all three species was found in the Iowa stream, while the lowest was in Hugh White Creek (NC). Detrended correspondence analysis (DCA) explained 95.8% and 83.9% of the total variation in bacterial numbers in water and sediment of the streams, respectively. In sediments and water, B. cepacia numbers were related to nitrate concentrations. A. calcoaceticus in water clustered with several environmental variables (i.e., SRP, pH, and conductivity) but benthic populations were less well correlated with these variables. This study reveals the potential influence of various environmental conditions on different bacterial populations in stream communities.


Randomised controlled trial of weightlifting exercise in patients with chronic airflow limitation.
BACKGROUND PATIENTS: with chronic airflow obstruction are often limited by muscle fatigue and weakness. As exercise rehabilitation programmes have produced modest improvements at best a study was designed to determine whether specific muscle training techniques are helpful. Thirty four patients with chronic airflow limitation (forced expiratory volume in one second (FEV1) 38% of predicted values) were stratified for FEV1 to vital capacity (VC) ratio less than 40% and arterial oxygen desaturation during exercise and randomised to a control or weightlifting training group. In the experimental group training was prescribed for upper and lower limb muscles as a percentage of the maximum weight that could be lifted once only. It was carried out three times a week for eight weeks. Three subjects dropped out of each group; results in the remaining 14 patients in each group were analysed. Adherence in the training group was 90%. In the trained subjects muscle strength and endurance time during cycling at 80% of maximum power output increased by 73% from 518 (SE69) to 898 (95) s, with control subjects showing no change (506 (86) s before training and 479 (89) s after training). No significant changes in maximum cycle ergometer exercise capacity or distance walked in six minutes were found in either group. Responses to a chronic respiratory questionnaire showed significant improvements in dyspnoea and mastery of daily living activities in the trained group. Weightlifting training may be successfully used in patients with chronic airflow limitation, with benefits in muscle strength, exercise endurance, and subjective responses to some of the demands of daily living.


A reducing milieu renders cofilin insensitive to phosphatidylinositol 4,5-bisphosphate (PIP2) inhibition.
Oxidative stress can lead to T cell hyporesponsiveness. A reducing micromilieu (e.g. provided by dendritic cells) can rescue T cells from such oxidant-induced dysfunction. However, the reducing effects on proteins leading to restored T cell activation remained unknown. One key molecule of T cell activation is the actin-remodeling protein cofilin, which is dephosphorylated on serine 3 upon T cell costimulation and has an essential role in formation of mature immune synapses between T cells and antigen-presenting cells. Cofilin is spatiotemporally regulated; at the plasma membrane, it can be inhibited by phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we show by NMR spectroscopy that a reducing milieu led to structural changes in the cofilin molecule predominantly located on the protein surface. They overlapped with the PIP2- but not actin-binding sites. Accordingly, reduction of cofilin had no effect on F-actin binding and depolymerization and did not influence the cofilin phosphorylation state. However, it did prevent inhibition of cofilin activity through PIP2. Therefore, a reducing milieu may generate an additional pool of active cofilin at the plasma membrane. Consistently, in-flow microscopy revealed increased actin dynamics in the immune synapse of untransformed human T cells under reducing conditions. Altogether, we introduce a novel mechanism of redox regulation: reduction of the actin-remodeling protein cofilin renders it insensitive to PIP2 inhibition, resulting in enhanced actin dynamics.


Catatonic Stupor in Schizophrenic Disorders and Subsequent Medical Complications and Mortality.
Although catatonia can occur secondary to a general medical condition, catatonia itself has been known to lead to various medical compolications. Although case reports on the association of catatonia with subsequent medical complications have been documented, no comprehensive large-scale study has been performed. To investigate specific medical complications after catatonia, we conducted a retrospective cohort study of specific medical complications of schizophrenia patients with catatonia. The 1719 schizophrenia inpatients in our study were categorized into two groups: the catatonia group, i.e., those who exhibited catatonic stupor while they were hospitalized, and the noncatatonia group, i.e., those who never exhibited catatonic stupor. Differences between the two groups in the occurrence of subsequent medical complications were examined using linear and logistic regression analyses, and models were adjusted for potentially confounding factors. The catatonia group had an increased risk for mortality (odds ratio = 4.8, 95% confidence interval = 2.0-10.6, p < .01) and certain specific medical complications, i.e., pneumonia, urinary tract infection, sepsis, disseminated intravascular coagulation, rhabdomyolysis, dehydration, deep venous thrombosis, pulmonary embolism, urinary retention, decubitus, arrhythmia, renal failure, neuroleptic malignant syndrome, hypernatremia, and liver dysfunction (all p values < .01, except for deep venous thrombosis, p = .04 in the multiple linear regression analysis). Catatonic stupor in schizophrenia substantially raises the risk for specific medical complications and mortality. Hyperactivity of the sympathetic nervous system, dehydration, and immobility, which are frequently involved in catatonia, might contribute to these specific medical complications. In catatonia, meticulous care for both mental and medical conditions should be taken to reduce the risk of adverse medical consequences.


Is home delivery safe for all involved? A new arrival breaks grandma's heart. Literally.
Home birth is becoming increasingly popular. Labour in the privacy and comfort of a familiar environment has clear appeal. Home birth is usually as safe for low-risk women with appropriate prenatal care. Yet events during delivery can be unpredictable and may be stressful for unprepared family members. Here we report a case of Tako-tsubo cardiomyopathy, also known as broken-heart syndrome, in a relative attending an impromptu home delivery. Thus, while home delivery is generally safe for the mother we ask: is it safe for everyone involved?


EVALUATION OF THE CURRENT PRACTICE OF DELIVERING INTRAVENOUS OPIOIDS INFUSIONS IN A UK PAEDIATRIC HOSPITAL.
Opiate intravenous infusions are the therapy of choice in severe pain. However, administering infusions to children requires complex dosage calculations, rate adjustments and often multiple manipulations of injectable medicines to obtain the final "ready to use" solution for both continuous infusion and additional boluses; potentially putting children at high risk.1 2 AIM: To investigate the practice and accuracy of healthcare professionals (HCPs) in hospital theatres and wards in preparing morphine infusions for nurse/patient controlled analgesia (N/PCA) use in a UK children's hospital. A mixed methods study in which direct observation of HCPs preparing paediatric morphine infusions for N/PCA in theatres and on wards, focus groups with HCPs and quantitative analysis of morphine concentration in the syringe using UV-Vis Spectrophotometer. The British Pharmacopoeia (BP) reference limits of ±7.5% were used to compare label strength (LS) of morphine infusion with measured concentration. The preparation of 153 syringes was observed which related to 128 paediatric patients [mean age (±sd) 7.5 years±5.6; 65.3% male]. 64% (98/153) were prepared by anaesthetists in theatres, 36% (55/153) by nurses at ward level.Major differences in preparation methods were identified. The final volume prepared was above the required volume (50 mL) in 35.9% (55/153) preparations. Wearing gloves during preparation was not followed in theatre for 83.7% (82/98) of syringes. No decontamination of morphine ampoules was undertaken during preparation of any syringe. Inconsistency in the appropriate syringe size used to withdraw drug from the ampoule was observed in both theatres and wards. Lack of appreciation of the overage in morphine ampoules by HCPs was identified. Of the syringes analysed 61.5% (48/78) had a concentration outside the BP reference limits (92.5-107.5% of LS), most were in excess (83.3%, 40/48). Of these 20.8% (10/48) deviated by more than +20%, with one deviated by 100%. This study identified that variation in preparation techniques followed by HCPs may result in morphine N/PCA dosages that are significantly higher or lower than that prescribed. Also, lack of understanding of ampoule overage, accuracy of the syringe size used and the ability to measure small volumes led to inaccurate concentrations in prepared infusions.


Caregivers' Perspectives on the Sensory Environment and Participation in Daily Activities of Children With Autism Spectrum Disorder.
The purpose of this phenomenological study was to obtain caregivers' perspectives on the impact of the sensory environment on participation in daily activities of their young children with autism spectrum disorders (ASD). Interviews were completed with 34 caregivers of children with ASD ages 3-7 yr. Results strongly suggest that parents and caregivers were pivotal in enabling participation for their children through the implementation of specific strategies and a parental decision-making process. The decision-making process considered amount of effort necessary to support participation and whether participation in a given activity was perceived as essential or nonessential. Strategies enabled participation and reduced the effort required to support the child's participation. Strategies either directly related to the sensory factors of the environment or focused on reducing behavioral responses associated with sensory factors. In this study, we identified important considerations to enhance participation in the home and community environments for children with ASD.


Distance distributions and anisotropy decays of troponin C and its complex with troponin I.
We used frequency domain measurements of fluorescence resonance energy transfer to recover the distribution of distances between Met 25 and Cys 98 in rabbit skeletal troponin C. These residues were labeled with dansylaziridine as energy donor and 5-(iodoacetamido)eosin as acceptor and are located on the N- and C-terminal lobes of the two-domain protein, respectively. We developed a procedure to correct for the fraction of the sample that was incompletely labeled with the acceptor independent of chemical data. At pH 7.5 and in the presence of Mg2+, the mean distance was near 15 A with a half-width of the distribution of 15 A; when Mg2+ was replaced by Ca2+, the mean distance increased to 22 A with a decrease in the half-width by 4 A. Similar but less pronounced differences in the mean distance and half-width between samples containing Mg2+ and Ca2+ were also observed with troponin C complexed to troponin I. The results suggest that the conformation of troponin C is altered by Ca2+ binding to the Ca(2+)-specific sites and displacing bound Mg2+ at the Ca2+/Mg2+ sites. This alteration may play an important role in Ca2+ signaling in muscle. At pH 7.5, the anisotropy decays of the donor-labeled troponin C showed two components, with the long rotational correlation time (12 ns) reflecting the overall motion of the protein. When the pH was lowered from 7.5 to 5.2, the mean distribution distance of apotroponin C increased from 22 to 32 A and the half-width decreased by a factor of 2 from 13 to 7 A. The long correlation time of apotroponin C increased to 19 ns at the acidic pH. These results are discussed in terms of a model in which skeletal troponin C is a dimer at low pH and enable comparison of the solution conformation of the protein at neutral pH with a crystal structure obtained at pH 5.2. While the conformation of the monomeric unit of troponin C dimer at pH 5.2 is extended and consistent with the crystal structure, the conformation at neutral pH is likely more compact than the crystal structure predicts.


No Smoke without Tobacco: A Global Overview of Cannabis and Tobacco Routes of Administration and Their Association with Intention to Quit.
Cannabis and tobacco are common drugs of abuse worldwide and are often used in combination through various routes of administration (ROAs). Here, we aimed to provide an overview of how cannabis and tobacco routes varied across countries and assess the impact of tobacco-based ROAs on motivation to use less cannabis, and less tobacco, in different models. A cross-sectional online survey (Global Drugs Survey 2014) was completed by 33,687 respondents (mean age = 27.9; % female = 25.9) who smoked cannabis at least once in the last 12 months. Most common ROA, frequency of cannabis/tobacco use, and questions about motivation to use less cannabis/tobacco were recorded. Tobacco-based ROA were used by 65.6% of respondents. These were most common in Europe (77.2-90.9%) and Australasia (20.7-51.6%) and uncommon in the Americas (4.4-16.0%). Vaporizer use was most common in Canada (13.2%) and the United States (11.2%). Using a non-tobacco ROA was associated with a 10.7% increase in odds for "desire to use less" tobacco (OR: 1.107, 95% CI: 1.003, 1.221), 80.6% increase in odds for "like help to use less tobacco" (OR: 1.806, 95% CI: 1.556, 2.095), and a 103.9% increase in the odds for "planning to seek help to use less tobacco" (OR: 2.039, 95% CI: 1.638, 2.539), in comparison to using a tobacco-based ROA. Associations between ROA and intentions to use less cannabis were inconsistent. Results support considerable global variation in cannabis and tobacco ROA. Tobacco routes are common, especially "joints with tobacco," especially in Europe, but not in the Americas. Non-tobacco-based routes are associated with increased motivation to change tobacco use. Interventions addressing tobacco and cannabis need to accommodate this finding and encourage non-tobacco routes.


Optimal location and orientation of suture placement in abdominal sacrocolpopexy.
To estimate the strongest location and optimal orientation of suture placement in the anterior longitudinal ligament for abdominal sacrocolpopexy in female cadavers. The anterior longitudinal ligament was exposed below the level of the aortic bifurcation in 23 unembalmed female cadavers. To the right of midline of the vertebral column, sutures were placed in a horizontal orientation into the ligament at the sacral promontory, 1 and 2 cm above (sacral promontory+1 and sacral promontory+2), and 1, 2, and 3 cm below (sacral promontory-1, sacral promontory-2 and sacral promontory-3). At these same locations, but to the left of midline, sutures were placed in a vertical orientation. Pull-out force and ligament thickness at each level of testing were measured. Data were analyzed using Student t test and repeated measures analysis of variance. Sutures (either horizontally or vertically placed) had greater pull-out strengths at or above, compared with those placed below, the level of the sacral promontory. At sacral promontory and sacral promontory+1, there were no differences in the pull-out strengths of the ligament when sutures were placed in either orientation. However, horizontally placed sutures had significantly greater pull-out strengths than vertically placed sutures at sacral promontory+2, sacral promontory-1 and sacral promontory-2. Ligament thickness decreased from 2 cm above (mean+/-standard error of the mean sacral promontory+2, 1.8+/-0.1 mm) to 3 cm below (sacral promontory-3, 1.3+/-0.1 mm) the sacral promontory. Sutures placed in the anterior longitudinal ligament at or above the sacral promontory are more secure than those placed below. Horizontally oriented sutures should be considered for mesh attachment below the sacral promontory because they are significantly stronger when compared with vertically placed sutures.


Advances in progenitor cell therapy using scaffolding constructs for central nervous system injury.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. Current clinical therapy is focused on optimization of the acute/subacute intracerebral milieu, minimizing continued cell death, and subsequent intense rehabilitation to ameliorate the prolonged physical, cognitive, and psychosocial deficits that result from TBI. Adult progenitor (stem) cell therapies have shown promise in pre-clinical studies and remain a focus of intense scientific investigation. One of the fundamental challenges to successful translation of the large body of pre-clinical work is the delivery of progenitor cells to the target location/organ. Classically used vehicles such as intravenous and intra arterial infusion have shown low engraftment rates and risk of distal emboli. Novel delivery methods such as nanofiber scaffold implantation could provide the structural and nutritive support required for progenitor cell proliferation, engraftment, and differentiation. The focus of this review is to explore the current state of the art as it relates to current and novel progenitor cell delivery methods.


Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells.
The neocortex comprises multiple information processing streams mediated by subsets of glutamatergic pyramidal cells (PCs) that receive diverse inputs and project to distinct targets. How GABAergic interneurons regulate the segregation and communication among intermingled PC subsets that contribute to separate brain networks remains unclear. Here we demonstrate that a subset of GABAergic chandelier cells (ChCs) in the prelimbic cortex, which innervate PCs at spike initiation site, selectively control PCs projecting to the basolateral amygdala (BLAPC) compared to those projecting to contralateral cortex (CCPC). These ChCs in turn receive preferential input from local and contralateral CCPCs as opposed to BLAPCs and BLA neurons (the prelimbic cortex-BLA network). Accordingly, optogenetic activation of ChCs rapidly suppresses BLAPCs and BLA activity in freely behaving mice. Thus, the exquisite connectivity of ChCs not only mediates directional inhibition between local PC ensembles but may also shape communication hierarchies between global networks.


Relationships between several quadrat-based statistical measures used to characterize spatial aspects of disease incidence data.
ABSTRACT This article investigates the relationships between various statistical measures that are used to summarize spatial aspects of disease incidence data. The focus is on quadrat data in which each plant in a quadrat is classified as diseased or healthy. We show that spatial autocorrelation plays a central role via the mean intraclass correlation, rho, which is defined as the average correlation of the disease status of all pairs of plants within the quadrat. The value of rho determines the variance of the number of infected plants in the quadrat and, if this variable follows a beta-binomial distribution, the heterogeneity parameter of the beta-binomial distribution is directly related to the mean intraclass correlation. We consider in detail a model in which the spatial autocorrelation depends only on the distance between the plants. For illustration, we consider a specific autocorrelation model that was derived from simulated data. We show that this model leads, approximately, to the binary form of the power law relating the variance of the number of infected plants per quadrat to the mean. Using an approximation technique, we then show how the index of dispersion is related to quadrat size and shape. The index of dispersion increases with quadrat size. The rate of increase is dependent on quadrat shape, but the effect of quadrat shape is small in comparison to the effect of quadrat size. Finally, we note that if the spatial autocorrelation depends on the relative orientation of the plants, as well as the distance between them, there are connections with distance class methods.


A legal primer for the obesity prevention movement.
Public health advocates and scientists working on obesity prevention policy face challenges in balancing legal rights, individual freedom, and societal health goals. In particular, the US Constitution and the 50 state constitutions place limits on the ability of government to act, even in the best interests of the public. To help policymakers avoid crossing constitutional boundaries, we distilled the legal concepts most relevant to formulating policies aimed at preventing obesity: police power; allocation of power among federal, state, and local governments; freedom of speech; property rights; privacy; equal protection; and contract rights. The goal is to allow policymakers to avoid potential constitutional problems in the formation of obesity prevention policy.


Effect of low molecular weight fucoidan and low molecular weight heparin in a rabbit model of arterial thrombosis.
Therapeutic use of unfractionated heparin and low molecular weight heparins (LMWHs) is limited by hemorrhagic adverse effects. We compared the antithrombotic effect of LMW fucoidan (LMWF) and LMWH in an experimental model. Thrombosis was induced in femoral arteries of male New Zealand White rabbits by in situ induction of endothelial apoptosis with staurosporine (10(-5)M for 30 min). Starting the day before apoptosis induction, the animals received subcutaneous LMWF (15 mg/kg), LMWH (enoxaparin 2.5 mg/kg) or saline solution (control group) twice a day for 4 days. The degrees of apoptosis and endothelial denudation were similar in the 3 groups. The thrombotic score was significantly lower in the LMWF group than in the LMWH and control groups (p = 0.01). Tissue factor expression was significantly lower in the LMWF group than in the control and LMWH groups (p = 0.01). The plasma concentration of tissue factor pathway inhibitor was significantly increased after LMWF injection (137 +/- 28 vs. 102 +/- 17; p = 0.01), whereas no change was observed after LMWH treatment. LMWF did not prolong the bleeding time or decrease platelet aggregation. LMWF appeared to be more effective than LMWH for preventing arterial thrombosis in this experimental model. LMWF also had a lower hemorrhagic risk than LMWH.


A comparison of resting state functional magnetic resonance imaging to invasive electrocortical stimulation for sensorimotor mapping in pediatric patients.
Localizing neurologic function within the brain remains a significant challenge in clinical neurosurgery. Invasive mapping with direct electrocortical stimulation currently is the clinical gold standard but is impractical in young or cognitively delayed patients who are unable to reliably perform tasks. Resting state functional magnetic resonance imaging non-invasively identifies resting state networks without the need for task performance, hence, is well suited to pediatric patients. We compared sensorimotor network localization by resting state fMRI to cortical stimulation sensory and motor mapping in 16 pediatric patients aged 3.1 to 18.6 years. All had medically refractory epilepsy that required invasive electrographic monitoring and stimulation mapping. The resting state fMRI data were analyzed using a previously trained machine learning classifier that has previously been evaluated in adults. We report comparable functional localization by resting state fMRI compared to stimulation mapping. These results provide strong evidence for the utility of resting state functional imaging in the localization of sensorimotor cortex across a wide range of pediatric patients.


Infection control practices among hospital health and support workers in Hong Kong.
A report by the Hong Kong government noted that hospital infection control standards were inadequate, requiring audit, development and implementation. In addition, hospital staff needed training in infection control measures. We investigated infection control practices among 162 hospital health workers (109 nurses, 45 doctors and 8 therapists) and 44 support workers in one acute hospital and two rehabilitation hospitals using a non-blinded, observational design. We examined compliance with isolation precautions and infection control guidelines, including proper wearing of a mask, goggles/face shield, or gown; handling patient care equipment, linen, and laundry; routine and terminal cleaning; and terminal cleaning of an isolation room. One major breakdown in compliance was use of sleeveless disposable plastic aprons instead of long-sleeved gowns during procedures likely to generate splashes or sprays of blood and body fluids. In more than half of the observed episodes, participants failed to disinfect medical devices, such as stethoscopes, before re-use. Thorough cleansing of commodes between patients was also lacking. Overall compliance with local and international infection control guidelines was satisfactory, but several aspects required improvement.


Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.
Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03-1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16-2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27-2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.


Identification and characterization of a gain-of-function RAG-1 mutant.
RAG-1 and RAG-2 initiate V(D)J recombination by cleaving DNA at recombination signal sequences through sequential nicking and transesterification reactions to yield blunt signal ends and coding ends terminating in a DNA hairpin structure. Ubiquitous DNA repair factors then mediate the rejoining of broken DNA. V(D)J recombination adheres to the 12/23 rule, which limits rearrangement to signal sequences bearing different lengths of DNA (12 or 23 base pairs) between the conserved heptamer and nonamer sequences to which the RAG proteins bind. Both RAG proteins have been subjected to extensive mutagenesis, revealing residues required for one or both cleavage steps or involved in the DNA end-joining process. Gain-of-function RAG mutants remain unidentified. Here, we report a novel RAG-1 mutation, E649A, that supports elevated cleavage activity in vitro by preferentially enhancing hairpin formation. DNA binding activity and the catalysis of other DNA strand transfer reactions, such as transposition, are not substantially affected by the RAG-1 mutation. However, 12/23-regulated synapsis does not strongly stimulate the cleavage activity of a RAG complex containing E649A RAG-1, unlike its wild-type counterpart. Interestingly, wild-type and E649A RAG-1 support similar levels of cleavage and recombination of plasmid substrates containing a 12/23 pair of signal sequences in cell culture; however, E649A RAG-1 supports about threefold more cleavage and recombination than wild-type RAG-1 on 12/12 plasmid substrates. These data suggest that the E649A RAG-1 mutation may interfere with the RAG proteins' ability to sense 12/23-regulated synapsis.


Surface modification with alginate-derived polymers for stable, protein-repellent, long-circulating gold nanoparticles.
Poly(ethylene) glycol is commonly used to stabilize gold nanoparticles (GNPs). In this study, we evaluated the ability of cysteine-functionalized alginate-derived polymers to both provide colloidal stability to GNPs and avoid recognition and sequestration by the body's defense system. These polymers contain multiple reactive chemical groups (hydroxyl and carboxyl groups) that could allow for ready functionalization with, for example, cell-targeting ligands and therapeutic drugs. We report here that alginate-coupled GNPs demonstrate enhanced stability in comparison with bare citrate-coated GNPs and a similar lack of interaction with proteins in vitro and long in vivo circulation as PEG-coated GNPs.


Tal1, Gata2a, and Gata3 Have Distinct Functions in the Development of V2b and Cerebrospinal Fluid-Contacting KA Spinal Neurons.
Vertebrate locomotor circuitry contains distinct classes of ventral spinal cord neurons which each have particular functional properties. While we know some of the genes expressed by each of these cell types, we do not yet know how several of these neurons are specified. Here, we investigate the functions of Tal1, Gata2a, and Gata3 transcription factors in the development of two of these populations of neurons with important roles in locomotor circuitry: V2b neurons and cerebrospinal fluid-contacting Kolmer-Agduhr (KA) neurons (also called CSF-cNs). Our data provide the first demonstration, in any vertebrate, that Tal1 and Gata3 are required for correct development of KA and V2b neurons, respectively. We also uncover differences in the genetic regulation of V2b cell development in zebrafish compared to mouse. In addition, we demonstrate that Sox1a and Sox1b are expressed by KA and V2b neurons in zebrafish, which differs from mouse, where Sox1 is expressed by V2c neurons. KA neurons can be divided into ventral KA″ neurons and more dorsal KA' neurons. Consistent with previous morpholino experiments, our mutant data suggest that Tal1 and Gata3 are required in KA' but not KA″ cells, whereas Gata2a is required in KA″ but not KA' cells, even though both of these cell types co-express all three of these transcription factors. In gata2a mutants, cells in the KA″ region of the spinal cord lose expression of most KA″ genes and there is an increase in the number of cells expressing V3 genes, suggesting that Gata2a is required to specify KA″ and repress V3 fates in cells that normally develop into KA″ neurons. On the other hand, our data suggest that Gata3 and Tal1 are both required for KA' neurons to differentiate from progenitor cells. In the KA' region of these mutants, cells no longer express KA' markers and there is an increase in the number of mitotically-active cells. Finally, our data demonstrate that all three of these transcription factors are required for later stages of V2b neuron differentiation and that Gata2a and Tal1 have different functions in V2b development in zebrafish than in mouse.


Enhancing community preparedness: an inventory and analysis of disaster citizen science activities.
Disaster citizen science, or the use of scientific principles and methods by "non-professional" scientists or volunteers, may be a promising way to enhance public health emergency preparedness (PHEP) and build community resilience. However, little research has focused on understanding this emerging field and its implications for PHEP. To address research gaps, this paper: (1) assesses the state of disaster citizen science by developing an inventory of disaster citizen science projects; (2) identifies different models of disaster citizen science; and (3) assesses their relevance for PHEP. We searched the English-language peer-reviewed and grey literature for disaster citizen science projects with no time period specified. Following searches, a team of three reviewers applied inclusion/exclusion criteria that defined eligible disasters and citizen science activities. Reviewers extracted the following elements from each project: project name and description; lead and partner entities; geographic setting; start and end dates; type of disaster; disaster phase; citizen science model; and technologies used. A final set of 209 projects, covering the time period 1953-2017, were included in the inventory. Projects were classified across five citizen science models: distributed or volunteer sensing (n = 19; 9%); contributory (n = 98; 47%); distributed intelligence (n = 52; 25%); collaborative research (n = 32; 15%); and collegial research (n = 8; 4%). Overall, projects were conducted across all disaster phases and most frequently for earthquakes, floods, and hurricanes. Although activities occurred globally, 40% of projects were set in the U.S. Academic, government, technology, and advocacy organizations were the most prevalent lead entities. Although a range of technologies were used, 77% of projects (n = 161) required an internet-connected device. These characteristics varied across citizen science models revealing important implications for applications of disaster citizen science, enhancement of disaster response capabilities, and sustainability of activities over time. By increasing engagement in research, disaster citizen science may empower communities to take collective action, improve system response capabilities, and generate relevant data to mitigate adverse health impacts. The project inventory established a baseline for future research to capitalize on opportunities, address limitations, and help disaster citizen science achieve its potential.


A novel collagen scaffold supports human osteogenesis--applications for bone tissue engineering.
Collagen glycosaminoglycan (CG) scaffolds have been clinically approved as an application for skin regeneration. The goal of this study has been to examine whether a CG scaffold is a suitable biomaterial for generating human bone tissue. Specifically, we have asked the following questions: (1) can the scaffold support human osteoblast growth and differentiation and (2) how might recombinant human transforming growth factor-beta (TGF-beta(1)) enhance long-term in vitro bone formation? We show human osteoblast attachment, infiltration and uniform distribution throughout the construct, reaching the centre within 14 days of seeding. We have identified the fully differentiated osteoblast phenotype categorised by the temporal expression of alkaline phosphatase, collagen type 1, osteonectin, bone sialo protein, biglycan and osteocalcin. Mineralised bone formation has been identified at 35 days post-seeding by using von Kossa and Alizarin S Red staining. Both gene expression and mineral staining suggest the benefit of introducing an initial high treatment of TGF-beta(1) (10 ng/ml) followed by a low continuous treatment (0.2 ng/ml) to enhance human osteogenesis on the scaffold. Osteogenesis coincides with a reduction in scaffold size and shape (up to 70% that of original). A notable finding is core degradation at the centre of the tissue-engineered construct after 49 days of culture. This is not observed at earlier time points. Therefore, a maximum of 35 days in culture is appropriate for in vitro studies of these scaffolds. We conclude that the CG scaffold shows excellent potential as a biomaterial for human bone tissue engineering.


Colesevelam in the treatment of hypercholesterolemia and hyperglycemia: a retrospective analysis from an ambulatory care medical network.
To examine outcomes associated with colesevelam treatment among patients with hypercholesterolemia in real-world clinical practice. This analysis was conducted as a retrospective, observational cohort study in an ambulatory-care medical network in Northern California. Patients with orders for colesevelam were identified in the electronic health record between January 2004 and December 2011. The date of the first order during the study period was designated the index date. Patients were evaluated for the following eligibility criteria: a diagnosis of hypercholesterolemia, ≥18 years of age at index date, baseline laboratory values ≤3 months before the index date, ≥12 months of treatment and follow-up, and no prior orders for colesevelam ≤12 months before the index date. Patients who were pregnant during the study period were excluded. Changes in LDL-C and percentage of patients at LDL-C goal were examined. Among patients with diabetes mellitus (DM), changes in glycated hemoglobin (HBA1C) and percentage of patients at HBA1C goal were also examined. Overall, 468 and 181 patients with hypercholesterolemia met the predefined inclusion criteria with treatment and follow-up through 12 and 24 months, respectively. LDL-C decreased significantly from baseline by a mean of 11.4 mg/dL and 15.7 mg/dL (P < 0.0001, for each) at 12 and 24 months, respectively, and the percentages of patients at LDL-C goal increased by 13.9% and 21.0%. Among patients with DM and a baseline HBA1C ≥8%, 113 and 39 had treatment and follow-up through 12 and 24 months, respectively. HBA1C decreased significantly by a mean of 0.72% (P = 0.0001) and 0.75% (P = 0.010) and 11.5% and 12.8% were at HBA1C goal at 12 and 24 months, respectively. This study is limited by its retrospective and observational study design. Colesevelam treatment in a real-world setting was associated with improvements in LDL-C and HBA1C through 24 months of follow-up.


IL17/IL17RA as a Novel Signaling Axis Driving Mesenchymal Stem Cell Therapeutic Function in Experimental Autoimmune Encephalomyelitis.
The therapeutic effect of mesenchymal stem cells (MSCs) in multiple sclerosis (MS) and the experimental autoimmune encephalomyelitis (EAE) model has been well described. This effect is, in part, mediated through the inhibition of IL17-producing cells and the generation of regulatory T cells. While proinflammatory cytokines such as IFNγ, TNFα, and IL1β have been shown to enhance MSCs immunosuppressive function, the role of IL17 remains poorly elucidated. The aim of this study was, therefore, to investigate the role of the IL17/IL17R pathway on MSCs immunoregulatory effects focusing on Th17 cell generation in vitro and on Th17-mediated EAE pathogenesis in vivo. In vitro, we showed that the immunosuppressive effect of MSCs on Th17 cell proliferation and differentiation is partially dependent on IL17RA expression. This was associated with a reduced expression level of MSCs immunosuppressive mediators such as VCAM1, ICAM1, and PD-L1 in IL17RA-/- MSCs as compared to wild-type (WT) MSCs. In the EAE model, we demonstrated that while WT MSCs significantly reduced the clinical scores of the disease, IL17RA-/- MSCs injected mice exhibited a clinical worsening of the disease. The disability of IL17RA-/- MSCs to reduce the progression of the disease paralleled the inability of these cells to reduce the frequency of Th17 cells in the draining lymph node of the mice as compared to WT MSCs. Moreover, we showed that the therapeutic effect of MSCs was correlated with the generation of classical Treg bearing the CD4+CD25+Foxp3+ signature in an IL17RA-dependent manner. Our findings reveal a novel role of IL17RA on MSCs immunosuppressive and therapeutic potential in EAE and suggest that the modulation of IL17RA in MSCs could represent a novel method to enhance their therapeutic effect in MS.


Plasma proteomics shows an elevation of the anti-inflammatory protein APOA-IV in chronic equine laminitis.
Equine laminitis is a devastating disease that causes severe pain in afflicted horses and places a major economic burden on the horse industry. In acute laminitis, the disintegration of the dermal-epidermal junction can cause the third phalanx to detach from the hoof wall, leaving the horse unable to bear weight on the affected limbs. Horses that survive the acute phase transition into a chronic form of laminitis, which is often termed "founder". Some evidence suggests that chronic laminar inflammation might be associated with alterations in the endocrine and immune systems. We investigated this broad hypothesis by using DIGE to assess global differences in the plasma proteome between horses with chronic laminitis and controls. We identified 16 differentially expressed proteins; the majority of these were involved in the interrelated coagulation, clotting, and kininogen cascades. Clinical testing of functional coagulation parameters in foundered horses revealed a slight delay in prothrombin (PT) clotting time, although most other indices were within normal ranges. Upregulation of the intestinal apolipoprotein APOA-IV in horses with chronic laminitis was confirmed by western blot. Our results support the hypothesis that localized laminar inflammation may be linked to systemic alterations in immune regulation, particularly in the gastrointestinal system. Gastrointestinal inflammation has been implicated in the development of acute laminitis but has not previously been associated with chronic laminitis.


Clinical Presentation and Birth Outcomes Associated with Respiratory Syncytial Virus Infection in Pregnancy.
Respiratory syncytial virus (RSV) is the most important cause of viral pneumonia in children worldwide. A maternal vaccine may protect both the mother and infant from RSV illness. The epidemiology and clinical presentation of RSV in pregnant and postpartum women is not well-described. Data were collected from a prospective, randomized trial of influenza immunization in pregnant women in rural southern Nepal. Women were enrolled in their second trimester of pregnancy and followed until six months postpartum. Active weekly home-based surveillance for febrile respiratory illness was performed. Mid-nasal swabs collected with episodes of respiratory illness were tested for RSV by real-time polymerase chain reaction. RSV was detected in 14 (0.4%) illness episodes in 3693 women over 3554 person-years of surveillance from 2011-2014. RSV incidence was 3.9/1000 person-years overall, and 11.8/1000 person-years between September and December. Seven (50%) women sought care for RSV illness; none died. Of the 7 (50%) illness episodes during pregnancy, all had live births with 2 (29%) preterm births and a median birthweight of 3060 grams. This compares to 469 (13%) preterm births and a median birthweight of 2790 grams in women without RSV during pregnancy. Of the 7 mothers with postpartum RSV infection, RSV was detected in 4 (57%) of their infants. RSV was an uncommon cause of febrile respiratory illness in mothers during pregnancy in Nepal. These data will inform prevention and therapeutic strategies against RSV in resource-limited settings.


Journey of a Woman With Terminal Cervical Cancer.
When a cervical cancer diagnosis is made during a terminal stage, a woman is faced with many challenges. Although a terminal illness has many negative effects, such as physical pain, scarring, fear, and sexual dysfunction, women may experience a positive impact on their life, such as improved well-being and a greater appreciation of daily life. The individual experience can lead to personal revelations. Sometimes, the diagnosis can even be seen as a blessing. Understanding a personal experience in a real-life context of the terminal stages of disease is important. This story shares the day-to-day journey of a woman living with a terminal illness of cervical cancer.


Opposite transcriptional activity between the wild type c-myc gene coding for c-Myc1 and c-Myc2 proteins and c-Myc1 and c-Myc2 separately.
E-cadherin expression was previously shown to be activated by RB and c-myc specifically in epithelial cells, through interaction with the AP-2 transcription factor. Here we show that only a wild type c-myc gene, coding for the two c-Myc proteins c-Myc2 and c-Myc1, was able to transactivate the E-cadherin promoter, in contrast to c-Myc2 or c-Myc1 alone which strongly repressed E-cadherin in both epithelial cells and fibroblasts. In addition, overexpression of c-myc2 or c-myc1 inhibited c-myc and RB-mediated activation in a dose-dependent manner, suggesting that the ratio of the two c-Myc proteins is essential for transactivation. We also showed by using several mutants of the E-cadherin promoter, that the AP-2 binding sites were the main target of c-myc2- and c-myc1-mediated repression. AP-2-mediated inhibition was cell-type specific, as was the activation. Nevertheless, when high amounts of c-myc2 and c-myc1 were used, a second c-myc-mediated repression was observed, possibly mediated by the Inr sequence of the E-cadherin promoter. However, this repression was independent of cell type. Our results suggest a new way to regulate c-myc transcriptional activity by interfering with the ratio of the two c-myc proteins, which has already been found to be disrupted in vivo in several tumor types.


Evaluating the Implementation of a Preemptive, Multimodal Analgesia Protocol in a Plastic Surgery Office.
Many patients undergoing plastic surgery experience significant pain postoperatively. The use of preemptive, multimodal analgesia techniques to reduce postoperative pain has been widely described in the literature. This quality improvement project evaluated the implementation of a preemptive, multimodal analgesia protocol in an office-based plastic surgery facility to decrease postoperative pain, decrease postoperative opioid consumption, decrease postanesthesia care time, and increase patient satisfaction. The project included adult patients undergoing surgical procedures at an outpatient plastic and cosmetic surgery office, and the protocol consisted of oral acetaminophen 1,000 mg and gabapentin 1,200 mg. Using a pre-/postintervention design, data were collected from patient medical records and telephone interviews of patients receiving the standard preoperative analgesia regimen (preintervention group: n = 24) and the evidence-based preemptive, multimodal analgesia protocol (postintervention group: n = 23). Results indicated no significant differences between the pre- and postintervention groups for any of the outcomes measured. However, results showed that patients in both groups experienced moderate to severe pain postoperatively. In addition, adverse side effects such as dizziness and drowsiness were higher in the postintervention group than in the preintervention group. Although this quality improvement project did not meet the goals it set out to achieve for patients undergoing plastic surgery, it did illustrate the substantial presence of pain after surgical procedures. Thus, clinicians need to continue to focus on identifying targeted treatment plans that use multimodal, non-opioid-based strategies to manage and prevent postoperative pain.


Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis.
mTORC1 (mammalian target of rapamycin complex 1) is controlled by diverse signals (e.g. hormones, growth factors, nutrients and cellular energy status) and regulates a range of processes including anabolic metabolism, cell growth and cell division. We have studied the impact of inhibiting mTOR on protein synthesis in human cells. Partial inhibition of mTORC1 by rapamycin has only a limited impact on protein synthesis, but inhibiting mTOR kinase activity causes much greater inhibition of protein synthesis. Using a pulsed stable-isotope-labelling technique, we show that the rapamycin and mTOR (mammalian target of rapamycin) kinase inhibitors have differential effects on the synthesis of specific proteins. In particular, the synthesis of proteins encoded by mRNAs that have a 5'-terminal pyrimidine tract is strongly inhibited by mTOR kinase inhibitors. Many of these mRNAs encode ribosomal proteins. mTORC1 also promotes the synthesis of rRNA, although the mechanisms involved remain to be clarified. We found that mTORC1 also regulates the processing of the precursors of rRNA. mTORC1 thus co-ordinates several steps in ribosome biogenesis.


Vegetarian Diet and Cardiometabolic Risk among Asian Indians in the United States.
Research studies have shown that plant-based diets confer cardiovascular and metabolic health benefits. Asian Indians (AIs) in the US (who have often followed plant-based diets) have elevated risk for chronic diseases such as diabetes, metabolic syndrome, and obesity suggesting ethnic vulnerability that imply genetic and/or lifestyle causative links. This study explored the association between this ethnic group and diabetes, obesity, and metabolic syndrome after controlling for demographics, acculturation, family history of diabetes, and lifestyle and clinical risk factors. The sample comprised of 1038 randomly selected adult AIs in seven US sites. Prevalence and metabolic syndrome was estimated, and obesity was calculated using the WHO Asian criteria. Multivariate analysis included multinomial logistic regression. The mean age and length of residency in the US were 47 and 18.5 years, respectively. The majority of respondents were vegetarians (62%) and educated. A vegetarian lifestyle was associated with females, food label users, respondents with poor/fair current health status, less acculturated, and those who reported their diet had not changed after coming to the US. Vegetarian status was a protective factor and lowered the risk for diabetes but not for metabolic syndrome and obesity in the regression model. Results provide a firm basis for educational programs.