Visualisation of three-dimensional microcracks in compact bone.
Microdamage in bone contributes to the loss of bone quality in osteoporosis and is thought to play a major role in both fragility and stress fractures (Schaffler et al. 1995). In this study, in vivo microcracks in human ribs were bulk-stained in basic fuchsin and viewed in longitudinal section and in 3 dimensions using 2 different computer-based methods of reconstruction: (1) serial sectioning of methylmethacrylate embedded sections using a sledge macrotome and identification of microcracks using UV epifluorescence followed by computerised reconstruction of microcracks using software and (2) laser scanning confocal microscopy of thick sections followed by reconstruction of microcracks into a 3-D image. The size and shape of microcracks were found to be similar using both techniques. Both techniques of reconstruction showed microcracks to be approximately elliptical in shape. From the serial sectioning reconstructions (n = 9), microcracks were found to have a mean length of 404 +/- 145 microm (mean +/- S.D.) (in the longitudinal direction) and mean width of 97 +/- 38 microm (in the transverse direction). Using epifluorescence microscopy, 92 microcracks were identified; mean microcrack length was 349 +/- 100 microm in the longitudinal direction. This was consistent with other results (Burr & Martin, 1993) and with the theoretical prediction of an elliptical crack shape with aspect ratio (longitudinal: transverse) of 5:1 deduced from analysis of random 2-D sections (Taylor & Lee, 1998). The results obtained provide new data on the nature of microcracks in bone and the method has the potential to become a useful tool in the calculation of stress intensity values which indicate the probability of an individual microcrack propagating to cause a stress or fragility fracture.


STEM faculty who believe ability is fixed have larger racial achievement gaps and inspire less student motivation in their classes.
An important goal of the scientific community is broadening the achievement and participation of racial minorities in STEM fields. Yet, professors' beliefs about the fixedness of ability may be an unwitting and overlooked barrier for stigmatized students. Results from a longitudinal university-wide sample (150 STEM professors and more than 15,000 students) revealed that the racial achievement gaps in courses taught by more fixed mindset faculty were twice as large as the achievement gaps in courses taught by more growth mindset faculty. Course evaluations revealed that students were demotivated and had more negative experiences in classes taught by fixed (versus growth) mindset faculty. Faculty mindset beliefs predicted student achievement and motivation above and beyond any other faculty characteristic, including their gender, race/ethnicity, age, teaching experience, or tenure status. These findings suggest that faculty mindset beliefs have important implications for the classroom experiences and achievement of underrepresented minority students in STEM.


Anti-osteoporotic activity of the petroleum ether extract of Cissus quadrangularis Linn. in ovariectomized Wistar rats.
The plant Cissus quadrangularis (CQ) is used as an osteoprotective agent in Ayurveda, the Indian system of alternative medicine. The present study was done to validate the anti-osteoporotic role of the petroleum ether extract of CQ on ovariectomy-induced osteoporosis in rats. Female wistar rats were divided into five groups of six rats each; (1) The Normal control (NC) group (n=6) received no surgery and no treatment, (2). The Sham control (SHAM) group (n=6) received sham surgery but no treatment, (3) the Ovariectomized (OVX) group (n=6) received an ovariectomy and normal saline treatment for 90 days, (4) the Ovariectomized+raloxifene (OVX+RAL) group (n=6) received an ovariectomy and treatment with raloxifene, a known anti-osteoporotic agent for 90 days commencing from 22nd post ovariectomy day and (5) the Ovariectomy+Cissus quadrangularis (OVX+CQ) group (n=6) received an ovariectomy, and treatmentwith the petroleum ether extract of CQ 500 mg/kg body weight daily for 90 days commencing from 22nd post ovariectomy day. At the end of the treatment period, rats in all groups were sacrificed and the right femur was used for biomechanical analysis, and the left femur for histomorphometrical analysis. CQ significantly increased the force required to break the femur (p<0.001) and significantly increased the thickness of both cortical (p<0.001) and trabecular bone (p<0.001). This action of CQ was comparable to the action of raloxifene. The petroleum ether extract of CQ stem seems to possess anti-osteoporotic activity in rats.


Effects of GnRH or PGF2α in week 5 postpartum on the incidence of cystic ovarian follicles and persistent corpora lutea and on fertility parameters in dairy cows.
Resumption of ovulatory activity and the timely lysis of the first CL postpartum (pp) are important determinants for the reproductive performance of dairy cows. Cystic ovarian follicles (COFs) and persistent CLs preclude normal ovarian cyclicity and increase the calving interval. The objective of this study was to investigate the effect of GnRH on the incidence of COFs and the effect of PGF2α on the incidence of a prolonged luteal phase (PLP) and on fertility parameters in dairy cows. A total of 476 cows were examined ultrasonographically for the presence of a dominant follicle (12-25 mm, without CL >10 mm; n = 237) or a functional CL (≥20 mm; n = 239) between 28 and 35 days pp and were allocated to one of four groups. Cows with a dominant follicle received 10-μg GnRH (buserelin; group F-T; n = 118) or saline (group F-C; n = 119), and cows with a functional CL received 0.5 mg of a PGF2α analogue (cloprostenol; group CL-T; n = 119) or saline (group CL-C; n = 120) on the day of initial examination, defined as Day 0. Cows were reexamined 7 and 21 days (F-T and F-C) and 3 and 24 days (CL-T and CL-C) later, and COFs were treated immediately after diagnosis in all cows. On the basis of the ovarian findings on Days 21 and 24, cows were treated according to a protocol aimed at timely breeding. The incidence of COFs by Days 7 (F-T vs. F-C; 7.6% vs. 16.8%) and 21 (11.0% vs. 21.8%) decreased (P ≤ 0.03) with GnRH; however, this did not lead to a substantial improvement of calving-to-conception interval (means ± standard error of the mean; 107.91 ± 5.70 vs. 117.94 ± 6.63 days), first-service conception rate (42.3% vs. 41.3%), and number of services per conception (2.06 ± 0.12 vs. 2.31 ± 0.15). Treatment with PGF2α decreased (P < 0.0001) the incidence of PLP by Day 24 (CL-T vs. CL-C; 1.7% vs. 17.5%), decreased calving-to-conception interval(91.28 ± 4.77 vs. 101.75 ± 5.03 days), increased first-service conception rate (63.3% vs. 38.7%), and reduced the number of services per conception (1.65 ± 0.10 vs. 2.08 ± 0.12; each P ≤ 0.01). The results indicate that strategic treatment with GnRH or PGF2α in week 5 pp to induce early ovulation and luteolysis reduces the incidence of COFs and PLP, respectively. Initial treatment with PGF2α also enhanced reproductive performance when used in conjunction with a standardized treatment protocol for all cows in week 8 pp (aimed at timely breeding). In contrast, GnRH did not improve fertility parameters of cystic cows in herds where all cows with COFs were treated as expeditiously as possible.


Manipulating dynamical Rabi-splitting with two-color laser pulses.
We theoretically investigate strong-field ionization of hydrogen atoms by orthogonally polarized two-color (OTC) laser pulses consisting of a fundamental field that is resonant with the 1s - 2p transition and its second harmonic. Numerical simulations are performed by solving the two-dimensional time-dependent Schrödinger equation and recording the photoelectron momentum distribution. In this strong-field resonant ionization, the atom undergoes many Rabi cycles and the electron can be emitted within a completed Rabi-cycle leading to the splitting of the localized momentum distribution. Here, the splitting is attributed to dynamic Rabi-splitting as a result of the dynamic Stark effect. The employed OTC scheme is shown to be efficient for controlling the dynamic Rabi-splitting through the control of quantum-path interferences involved in one-photon and two-photon absorption processes. The control scheme is accomplished by varying the relative ratio intensity and optical phase between the two pulses, and its footprint is mapped in the momentum distribution. This is shown to lead to an asymmetric distribution and suppression of the ionization process. The obtained results suggest the OTC scheme as a tool for coherent control of dynamic Rabi-oscillations via the controlled quantum-path interferences, thus opening new directions towards designing quantum states via the control OTC scheme.


Frozen section analysis of the pancreatic margin during pancreaticoduodenectomy for cancer: Does extending the resection to obtain a secondary R0 provide a survival benefit? Results of a systematic review.
During pancreaticoduodenectomy, frozen section pancreatic margin analysis permits to extend the resection in case of a positive margin, to achieve R0 margin. We aim to assess if patients having an R0 margin following the extension of the pancreatectomy after a positive frozen section (secondary R0) have different survival compared to those with R1 resection or primary R0 resection. A systematic search was performed to identify all studies published up to March 2016 analyzing the survival of patients undergoing pancreaticoduodenectomy according to the results of frozen section pancreatic margin examination. Clinical effectiveness was synthetized through a narrative review with full tabulation of results. Four studies published between 2010 and 2014 were retrieved, including 2580 patients. A primary R0 resection was obtained in a percentage of patients ranging from 36.2% to 85.5%, whereas secondary R0 in 9.4%-57.8% of cases and R1 in 5.1%-9.2%. Median survival ranged from 19 to 29 months in R0 patients, from 11.9 to 18 months in secondary R0, and from 12 to 23 months in R1 patients. None of the study demonstrated a survival benefit of extending the resection to obtain a secondary R0 pancreatic margin. All the studies were concordant, and failed to demonstrate the survival benefit of additional pancreatic resection to obtain a secondary R0. However, inadequate surgery should not be advocated. This review suggests that re-resection of the pancreatic margin may have limited impact on patients' survival.


A population-based study of endometrial cancer and familial risk in younger women. Cancer and Steroid Hormone Study Group.
Endometrial cancer remains an important cause of morbidity and mortality in the United States, and recent genetic evidence supports the hypothesis that hormonal dysregulation is not the only important risk factor for this tumor. This multicenter, population-based case-control study investigated familial aggregation of endometrial cancer and other cancers. Cases were 455 women 20-54 years of age diagnosed with histologically confirmed primary epithelial carcinoma of the endometrium. Controls consisted of 3216 women 20-54 years of age identified by random-digit dialing. Family histories of cancer in female relatives were obtained by interview of cases and controls. Endometrial cancer in a first-degree female relative increased the risk of endometrial cancer by nearly 3-fold [odds ratio (OR), 2.8; 95% confidence interval (CI), 1.9-4.2]. Cases also reported significantly more colorectal cancer in family members than did controls (OR, 1.9; 95% CI, 1.1-3.3). Family history of cancer of the cervix, lung, ovary, and thyroid was not significantly associated with endometrial cancer, and breast cancer was not related unless more than one relative was affected. Family history of endometrial cancer is an independent risk factor for cancer of the endometrium. In addition, the observed association with a family history of colorectal cancer suggests that genes important in familial colorectal cancer may have substantial implications for endometrial cancer. Nearly 5% of incident endometrial cancer among women between the ages of 20 and 54 may be attributable to a family history of endometrial cancer, and 2% may be related to colorectal cancer.


Heterogeneous immunogenetic background in Japanese adults with myasthenia gravis.
The aim of this study was to elucidate the roles of human leukocyte antigen (HLA) class II genes in disease susceptibility in Japanese adult patients with myasthenia gravis (MG). A number of studies have shown that MG is correlated with DR3 in Caucasians. In Japanese, infantile MG is associated with DR9, but the HLA class II alleles associated with adult MG remains unclear. HLA-DRB1 and DQB1 alleles were determined by genotyping in 75 Japanese adult patients with MG and in 115 race-matched healthy adults. No statistically significant difference was observed in the overall prevalences of DRB1 and DQB1 alleles between MG patients and healthy controls, even when the patients and controls were stratified on the basis of their gender. MG patients with DQB1*0604 were younger and those with DQB1*0402 were older at disease onset than those without (P=0.03 and 0.008, respectively). Concomitant autoimmune thyroid disease was associated with DRB1*0803 (P=0.0009, corrected P=0.04). In addition, anti-acetylcholine receptor antibody levels were significantly higher in patients with DQB1*0604 than in those without (P=0.045). These findings indicate that immunogenetic backgrounds in Japanese adult MG patients are heterogeneous and are apparently different from those in Caucasian patients.


Argon laser treatment of trichiasis.
This paper presents the application of argon laser in the treatment of trichiasis. The technique involves the destruction of the follicles of the abnormal cilia. A beam of 50- to 200-micron spot size, 0.1- to 0.2 second time, and 1,000 to 1,200 mW power is used under local anesthesia. This method proved safe, convenient, precise, and effective in 11 cases. The technique is most suitable when a few fine cilia are involved, but repeated treatment may be required for more and thicker eyelashes. The follow-up period in this study varied from a minimum of four months to a maximum of nine months.


Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes.
Delta(9)-Tetrahydrocannabinol (delta(9)-THC), the primary psychoactive constituent of marijuana (Cannabis sativa), is known to bind to two cannabinoid receptors: CB(1) receptors, located primarily in the brain, and CB(2) receptors, located primarily in the periphery. Recent research has suggested that other cannabinoids, including anandamide and WIN 55212-2, may also act at novel non-CB(1), non-CB(2) cannabinoid receptor(s). Anandamide produces a number of in vivo pharmacological effects in CB(1) knockout mice that are not produced by delta(9)-THC and cannot be explained by anandamide's rapid metabolism. In addition, in vitro anandamide and WIN 55212-2 stimulate [35S]GTPgammaS binding in both CB(1) knockout and wildtype mice while delta(9)-THC stimulates this binding only in wildtype mice. Although anandamide and vanilloid agonists share pharmacological effects, anandamide's actions in CB(1) knockout mice do not appear to be mediated by vanilloid VR(1) receptors. While not yet conclusive, these results suggest the possibility of additional cannabinoid receptors in the brain and periphery.


Awareness of and attitudes towards heat waves within the context of climate change among a cohort of residents in Adelaide, Australia.
Heat waves are a public health concern in Australia and unprecedented heat waves have been recorded in Adelaide over recent years. The aim of this study was to examine the perception and attitudes towards heat waves in the context of climate change among a group of residents in Adelaide, an Australian city with a temperate climate. A cross-sectional study was conducted in the summer of 2012 among a sample of 267 residents. The results of the survey found that television (89.9%), radio (71.2%), newspapers (45.3%) were the main sources from which respondents received information about heat waves. The majority of the respondents (73.0%) followed news about heat waves very or somewhat closely. About 26.6% of the respondents were extremely or very concerned about the effects of heat waves on them personally. The main issues that were of personal concern for respondents during a heat wave were their personal comfort (60.7%), their garden (48.7%), and sleeping well (47.6%). Overall, respondents were more concerned about the impacts of heat waves to the society than on themselves. There was a significant association between gender (χ² = 21.2, df = 3, p = 0.000), gross annual household income (p = 0.03) and concern for the societal effects of heat waves. Less than half (43.2%) of the respondents believed that heat waves will extremely or very likely increase in Adelaide according to climate projections. Nearly half (49.3%) believed that the effects of heat waves were already being felt in Adelaide. These findings may inform the reframing and communication strategies for heat waves in Adelaide in the context of climate change.


Neural grafting for Parkinson's disease: challenges and prospects.
Parkinson's disease (PD) is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia nigra. The motor disorder responds well to dopamine-replacement therapies, though these result in significant adverse effects due to non-physiological release of dopamine in the striatum, and off-target effects. Cell-based regenerative treatments offer a potential means for targeted replacement of dopamine, in a physiological manner. Dopaminergic neurons for cell-based therapies can be obtained from several sources. Fetal ventral mesencephalon tissue contains dopaminergic neuron progenitors, and has been transplanted into the striatum of PD patients with good results in a number of cases. However, the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical setting. Induced pluripotent stem cells can be used to generate dopaminergic neurons for transplantation, providing a source of autologous tissue for grafting. This approach means that challenges associated with allografts, such as the potential for immune rejection, can be circumvented. However, the associated cost and difficulty in producing a standardized product from different cell lines means that, at present, this approach is not commercially viable as a cell-based therapy. Dopaminergic neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson's disease, with trials due to commence in the next few years. Though there are ethical considerations to take into account when using embryonic tissue, the possibility of producing a standardized, optimized cell product means that this approach can be both effective, and commercially viable.


Bleeding and venous thromboembolism in the critically ill with emphasis on patients with renal insufficiency.
The purpose of this review is to critique and summarize clinical literature relevant to thromboprophylaxis in critically ill patients with renal insufficiency. The specific objectives are to discuss factors that increase the risks for bleeding and venous thromboembolism in critically ill patients, with a focus on patients with renal insufficiency, and to consider prophylaxis management options and the rationale for their use. Herein, we discuss both bleeding and venous thromboembolism in this population, both of which are of concern as complications. Bleeding is common among critically ill patients and has important clinical consequences. Critically ill patients with renal insufficiency require special consideration in regard to thromboprophylaxis. Such patients have a four-fold higher risk for developing venous thromboembolism compared with ICU patients without renal insufficiency. ICU patients have dynamic risks of thrombosis and bleeding. Invasive procedures may require temporary interruption of anticoagulants. Consequently, approaches to thromboprophylaxis require daily reevaluation. We provide some considerations for practice in the conclusion section.


Differential expression of IgE and IgG4 specific antibody responses in asymptomatic and chronic human filariasis.
A population of 164 adult individuals resident in an area endemic for Brugia malayi lymphatic filariasis has been studied for humoral immune responses to filarial parasites. Antibody levels to Ag extracted from adult worms were determined for each of the IgG subclasses, for IgM and for IgE. The dominant isotype of antifilarial antibody was IgG4, which represented 88% of total IgG in asymptomatic microfilaremics, most of whom possessed 100 to 1000 micrograms/ml of specific antibody of this subclass (geometric mean 762 micrograms/ml). Patients with chronic disease (elephantiasis), who were generally amicrofilaremic, had substantially higher levels of IgG1, IgG2, and IgG3, but a 3.4-fold lower geometric mean level of specific IgG4 (222 micrograms/ml) than asymptomatics with or without microfilaremia. In contrast, specific IgE antibody levels in cases of elephantiasis were on average 4.5 times higher than those found in the asymptomatic carrier state. The majority of microfilaremics were therefore typified by extremely high specific IgG4 concentrations and relatively low IgE reactivities, whereas clinical cases tended to show the reverse relationship. The possible roles of these isotypes and the implications of changing IgG4/IgE balances in disease are discussed.


The PI3K/AKT/mTOR interactive pathway.
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) signalling pathway is hyperactivated or altered in many cancer types and regulates a broad range of cellular processes including survival, proliferation, growth, metabolism, angiogenesis and metastasis. The PI3K/AKT/mTOR pathway is regulated by a wide-range of upstream signalling proteins and it regulates many downstream effectors by collaborating with various compensatory signalling pathways, primarily with RAF/MEK/ERK pathway. Limited clinical success of the available targeted therapeutic agents and challenges mediated by tumour heterogeneity across different cancer types emphasize the importance of alterations in the PI3K/AKT/mTOR pathway in the design of effective personalized treatment strategies. Here we report a comprehensive PI3K/AKT/mTOR network that represents the intricate crosstalk between compensatory pathways, which can be utilized to study the AKT signalling mechanism in detail and improve the personalized combinatorial therapeutic strategies.


Suppression of GABAergic neurons through D2-like receptor secures efficient conditioning in Drosophila aversive olfactory learning.
The GABAergic system serves as a vital negative modulator in cognitive functions, such as learning and memory, while the mechanisms governing this inhibitory system remain to be elucidated. In Drosophila, the GABAergic anterior paired lateral (APL) neurons mediate a negative feedback essential for odor discrimination; however, their activity is suppressed by learning via unknown mechanisms. In aversive olfactory learning, a group of dopaminergic (DA) neurons is activated on electric shock (ES) and modulates the Kenyon cells (KCs) in the mushroom body, the center of olfactory learning. Here we find that the same group of DA neurons also form functional synaptic connections with the APL neurons, thereby emitting a suppressive signal to the latter through Drosophila dopamine 2-like receptor (DD2R). Knockdown of either DD2R or its downstream molecules in the APL neurons results in impaired olfactory learning at the behavioral level. Results obtained from in vivo functional imaging experiments indicate that this DD2R-dependent DA-to-APL suppression occurs during odor-ES conditioning and discharges the GABAergic inhibition on the KCs specific to the conditioned odor. Moreover, the decrease in odor response of the APL neurons persists to the postconditioning phase, and this change is also absent in DD2R knockdown flies. Taken together, our findings show that DA-to-GABA suppression is essential for restraining the GABAergic inhibition during conditioning, as well as for inducing synaptic modification in this learning circuit. Such circuit mechanisms may play conserved roles in associative learning across species.


The Radiology Twitterverse: A Starter's Guide to Utilization and Success.
The rise of social media use in medicine has changed how health care organizations and providers communicate with patients and interact with other members of the medical community. Active social media engagement has been associated with improvements in patient outreach, peer-to-peer interactions, and medical education. In radiology, however, social media is predominantly used among trainees, with significantly lower rates seen in attending physicians who have been in practice for greater than 15 years. Twitter (Twitter.com, San Francisco, California), along with other social media platforms, puts a face to radiology, helping both patients and other health care professionals understand contributions of radiologists to patient care, research, education, and public health. We aim to provide a starter's guide for radiologists unfamiliar with Twitter (1) to highlight benefits of active Twitter involvement and (2) to remove perceived barriers to active Twitter use.


Seismic trapped modes in the oroville and san andreas fault zones.
Three-component borehole seismic profiling of the recently active Oroville, California, normal fault and microearthquake event recording with a near-fault three-component borehole seismometer on the San Andreas fault at Parkfield, California, have shown numerous instances of pronounced dispersive wave trains following the shear wave arrivals. These wave trains are interpreted as fault zone-trapped seismic modes. Parkfield earthquakes exciting trapped modes have been located as deep as 10 kilometers, as shallow as 4 kilometers, and extend 12 kilometers along the fault on either side of the recording station. Selected Oroville and Parkfield wave forms are modeled as the fundamental and first higher trapped SH modes of a narrow low-velocity layer at the fault. Modeling results suggest that the Oroville fault zone is 18 meters wide at depth and has a shear wave velocity of 1 kilometer per second, whereas at Parkfield, the fault gouge is 100 to 150 meters wide and has a shear wave velocity of 1.1 to 1.8 kilometers per second. These low-velocity layers are probably the rupture planes on which earthquakes occur.


Fruit and vegetable intakes in relation to plasma nutrient concentrations in women in Shanghai, China.
To evaluate the validity of fruit and vegetable intakes as it relates to plasma carotenoid and vitamin C concentrations in Chinese women, using three classification schemes. Intakes were calculated using an interviewer-administered FFQ. Fruits and vegetables, botanical groups and high-nutrient groups were evaluated. These three classification schemes were compared with plasma carotenoid and vitamin C concentrations from blood samples collected within 1 week of questionnaire completion. Shanghai, China. Participants (n 2031) comprised women who had participated in a case-control study of diet and breast-related diseases nested within a randomized trial of breast self-examination among textile workers (n 266 064) Fruit intake was significantly (P < 0·05) and positively associated with plasma concentrations of α-tocopherol, β-cryptoxanthin, lycopene, α-carotene, β-carotene, retinyl palmitate and vitamin C. Fruit intake was inversely associated with γ-tocopherol and lutein + zeaxanthin concentrations. Vegetable consumption was significantly and positively associated with γ-tocopherol and β-cryptoxanthin concentrations. Each botanical and high-nutrient group was also significantly associated with particular plasma nutrient concentrations. Fruit and vegetable intakes and most plasma nutrient concentrations were significantly associated with season of interview. These results suggest that the manner in which fruits and vegetables are grouped leads to different plasma nutrient exposure information, which may be an important consideration when testing and generating hypotheses regarding disease risk in relation to diet. Interview season should be considered when evaluating the associations of reported intake and plasma nutrients with disease outcomes.


Holographic memory optical system based on computer-generated Fourier holograms.
Holography is known to be a prospective tool for storing large amounts of digital information, providing long lasting safety and high speed data access. In this paper, we present a new approach to holographic memory system design. Our method is based on an application of discrete Fourier-transform calculations to encode two-dimensional binary data pages as computer-generated amplitude Fourier holograms (CGFHs). These CGFHs, represented as grayscale raster images, can be displayed with the use of a high resolution amplitude spatial light modulator (SLM) in an optical projection system and exposed on holographic medium with multiple reduction. The optical scheme required for the technical realization of this method appears significantly simpler compared with known holographic memory recording devices; moreover, it can be built using either coherent or incoherent light sources. Coding of data pages by precise pseudorandom phase masks during CGFH synthesis allows us to achieve about 3% of the recorded microholograms diffraction efficiency. The experimental results of CGFH projection recorded with a 20× reduction on photosensitive holographic medium and its reconstruction are presented.


Evidence for a dominant gene that suppresses hypercholesterolemia in a family with defective low density lipoprotein receptors.
This paper describes an unusual kindred with familial hypercholesterolemia in which one-third of the relatives with a mutant LDL receptor gene have normal plasma cholesterol concentrations. The proband, a 9-yr-old boy with a plasma cholesterol value greater than 500 mg/dl, is homozygous for a point mutation that changes Ser156 to Leu in the LDL receptor. This substitution in the fourth repeat of the ligand binding domain slows the transport of the protein to the cell surface. The defective receptor cannot bind LDL, which contains apo B-100, but it does bind beta-migrating VLDL, which contains apo E in addition to apo B-100. Although the mother is heterozygous for this mutation, her LDL-cholesterol concentration is consistently in the 28th percentile for the population. Through direct examination of genomic DNA, we identified the mutant gene in heterozygous form in 17 of the mother's relatives, five of whom had normal LDL-cholesterol values. The pedigree was consistent with dominant transmission of a single gene that ameliorates or suppresses the hypercholesterolemic effect of the LDL receptor mutation. Through linkage analysis, we excluded the possibility that this suppressor gene was an allele at the LDL receptor locus. We also excluded the genes for the two ligands for the LDL receptor, apo B-100 and apo E. The existence of this putative suppressor gene may explain the occasional observation of normal LDL-cholesterol concentrations in heterozygotes for LDL receptor mutations.


How to revive breakthrough innovation in the pharmaceutical industry.
Over the past 20 years, pharmaceutical companies have implemented conservative management practices to improve the predictability of therapeutics discovery and success rates of drug candidates. This approach has often yielded compounds that are only marginally better than existing therapies, yet require larger, longer, and more complex trials. To fund them, companies have shifted resources away from drug discovery to late clinical development; this has hurt innovation and amplified the crisis brought by the expiration of patents on many best-selling drugs. Here, we argue that more breakthrough therapeutics will reach patients only if the industry ceases to pursue "safe" incremental innovation, re-engages in high-risk discovery research, and adopts collaborative innovation models that allow sharing of knowledge and costs among collaborators.


Wireless smart meters and public acceptance: the environment, limited choices, and precautionary politics.
Wireless smart meters (WSMs) promise numerous environmental benefits, but they have been installed without full consideration of public acceptance issues. Although societal-implications research and regulatory policy have focused on privacy, security, and accuracy issues, our research indicates that health concerns have played an important role in the public policy debates that have emerged in California. Regulatory bodies do not recognize non-thermal health effects for non-ionizing electromagnetic radiation, but both homeowners and counter-experts have contested the official assurances that WSMs pose no health risks. Similarities and differences with the existing social science literature on mobile phone masts are discussed, as are the broader political implications of framing an alternative policy based on an opt-out choice. The research suggests conditions under which health-oriented precautionary politics can be particularly effective, namely, if there is a mandatory technology, a network of counter-experts, and a broader context of democratic contestation.


Impact of epistasis and pleiotropy on evolutionary adaptation.
Evolutionary adaptation is often likened to climbing a hill or peak. While this process is simple for fitness landscapes where mutations are independent, the interaction between mutations (epistasis) as well as mutations at loci that affect more than one trait (pleiotropy) are crucial in complex and realistic fitness landscapes. We investigate the impact of epistasis and pleiotropy on adaptive evolution by studying the evolution of a population of asexual haploid organisms (haplotypes) in a model of N interacting loci, where each locus interacts with K other loci. We use a quantitative measure of the magnitude of epistatic interactions between substitutions, and find that it is an increasing function of K. When haplotypes adapt at high mutation rates, more epistatic pairs of substitutions are observed on the line of descent than expected. The highest fitness is attained in landscapes with an intermediate amount of ruggedness that balance the higher fitness potential of interacting genes with their concomitant decreased evolvability. Our findings imply that the synergism between loci that interact epistatically is crucial for evolving genetic modules with high fitness, while too much ruggedness stalls the adaptive process.


Let-7f-5p ameliorates inflammation by targeting NLRP3 in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus.
Bone marrow-derived mesenchymal stem cells (MSCs) from systemic lupus erythematosus patients (SLE-BMSCs) exhibited abnormalities in cytokine production and immune modulation. Deregulation of Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in SLE. Herein, we explored whether miRNAs are involved in the regulation of NLRP3 in SLE-BMSCs. ELISA assay was used to detect the levels of inflammatory cytokines. The expression levels of let-7f-5p and gene mRNAs were determined by qRT-PCR assay. The protein levels of NLRP3, Cleaved caspase-1 and ASC were measured by western blot. The interaction between let-7f-5p and NLRP3 was verified using dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In vivo assay was performed to explore whether let-7f-5p upregulation could ameliorate inflammation in MRL/lpr mice. Our data indicated that SLE patients had significantly serum higher levels of IFN-γ, IL-6, IL-18, IL-12, IL-13 and IL-1β. We demonstrated that NLRP3 expression was upregulated in SLE-BMSCs. Let-7f-5p directly targeted NLRP3 and repressed NLRP3 expression. NLRP3 depletion or let-7f-5p upregulation repressed IL-1β production and the expression of NLRP3 inflammasome components. Moreover, upregulated let-7f-5p-mediated anti-inflammation effect was significantly abrogated by NLRP3 expression restoration. Besides, let-7f-5p upregulation ameliorated inflammation through modulating NLRP3 in vivo. In conclusion, our study suggested that high level of let-7f-5p alleviated inflammation in SLE-BMSCs at least partly through targeting NLRP3, highlighting let-7f-5p as a novel promising therapeutic strategy for SLE treatment.


Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture.
Mechanical complications of myocardial infarction (MI) are often fatal. Little is known about endogenous factors that predispose to myocardial rupture after MI. Ectonucleoside triphosphate diphosphohydrolase (CD39) could be a critical mediator of propensity to myocardial rupture after MI due to its role in modulating inflammation and thrombosis. Using a model of permanent coronary artery ligation, rupture was virtually abrogated in cd39-/- mice versus cd39+/+ controls, with elevated fibrin and collagen deposition and marked neutrophil and macrophage influx. Macrophages were found to display increased surface expression of CD301 and CD206, marking a reparative phenotype, driven by increased extracellular ATP and IL-4 in the infarcted myocardium of cd39-/- mice. A myeloid-specific CD39-knockout mouse also demonstrated protection from rupture, with an attenuated rupture phenotype, suggesting that complete ablation of CD39 provides the greatest degree of protection in this model. Absence of CD39, either globally or in a myeloid lineage-restricted fashion, skews the phenotype toward alternatively activated (reparative) macrophage infiltration following MI. These studies reveal a previously unrecognized and unexpected role of endogenous CD39 to skew macrophage phenotype and promote a propensity to myocardial rupture after MI.


Trends in hip and knee joint replacement: socioeconomic inequalities and projections of need.
To examine trends in primary and revision joint (hip and knee) replacement in England between 1991 and 2000. Analysis of hospital episodes statistics between 1 April 1991 and 30 March 2001 for total hip replacement (THR) and total knee replacement (TKR). Descriptive statistics and regression modelling were used to summarise patients' demographic and clinical characteristics and to explore variations in joint surgery rates by age, sex, and deprivation. Between 1991 and 2000, the incidence of primary THR increased by 18%, while the incidence of revision THR more than doubled. The incidence of primary TKR doubled, with revision TKR increasing by 300%. Over the 10 year period, the proportion of THR episodes that involved revision operations rose from 8% to 20%. Substantial variations in operation rates by socioeconomic status were seen, with the most deprived fifth of the population experiencing significantly lower rates. Projections estimate that primary THR numbers could rise by up to 22% by the year 2010, with primary TKR numbers rising by up to 63%. Provision of joint replacement surgery in English NHS hospitals has increased substantially over the past decade. Revision operations in particular have increased markedly. The growth in primary operations has mostly occurred among those aged 60 years and over; rates among young people have changed very little. There is a significant deprivation based gradient in rates. If current trends continue there would be almost 47 000 primary hip and 54 000 primary knee operations annually by 2010.


Organization of heart failure management in European Society of Cardiology member countries: survey of the Heart Failure Association of the European Society of Cardiology in collaboration with the Heart Failure National Societies/Working Groups.
The aim of this document was to obtain a real-life contemporary analysis of the demographics and heart failure (HF) statistics, as well as the organization and major activities of the Heart Failure National Societies (HFNS) in European Society of Cardiology (ESC) member countries. Data from 33 countries were collected from HFNS presidents/representatives during the first Heart Failure Association HFNS Summit (Belgrade, Serbia, 29 October 2011). Data on incidence and/or prevalence of HF were available for 22 countries, and the prevalence of HF ranged between 1% and 3%. In five European and one non-European ESC country, heart transplantation was reported as not available. Natriuretic peptides and echocardiography are routinely applied in the management of acute HF in the median of 80% and 90% of centres, respectively. Eastern European and Mediterranean countries have lower availability of natriuretic peptide testing for acute HF patients, compared with other European countries. Almost all countries have organizations dealing specifically with HF. HFNS societies for HF patients exist in only 12, while in 16 countries HF patient education programmes are active. Most HFNS reported that no national HF registry exists in their country. Fifteen HFNS produced national HF guidelines, while 19 have translated the ESC HF guidelines. Most HFNS (n = 23) participated in the organization of the European HF Awareness Day. This document demonstrated significant heterogeneity in the organization of HF management, and activities of the national HF working groups/associations. High availability of natriuretic peptide and echocardiographic measurements was revealed, with differences between developed countries and countries in transition.


Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux.
The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (Nlrp3) inflammasome plays an important role in inflammation by controlling the maturation and secretion of the cytokines IL-1β and IL-18 in response to multiple stimuli including pore-forming toxins, particulate matter, and ATP. Although the pathways activated by the latter stimuli lead to a decrease in intracellular K(+) concentration, which is required for inflammasome activation, the mechanism by which microbial RNA activates Nlrp3, remains poorly understood. In this study, we found that cytosolic poly(I:C), but not total RNA from healthy macrophages, macrophages undergoing pyroptosis, or mitochondrial RNA, induces caspase-1 activation and IL-1β release through the Nlrp3 inflammasome. Experiments with macrophages deficient in Tlr3, Myd88, or Trif, indicate that poly(I:C) induces Nlrp3 activation independently of TLR signaling. Further analyses revealed that the cytosolic sensors Rig-I and melanoma differentiation-associated gene 5 act redundantly via the common adaptor mitochondrial antiviral signaling (Mavs) to induce Nlrp3 activation in response to poly(I:C), but not ATP or nigericin. Mechanistically, Mavs triggered membrane permeabilization and K(+) efflux independently of the inflammasome which were required for poly(I:C)-induced Nlrp3 activation. We conclude that poly (I:C) activates the inflammasome through an Mavs-dependent surveillance pathway that converges into a common K(+) lowering step in the cytosol that is essential for the induction of Nlrp3 activation.


A randomized controlled study to evaluate the cost-effectiveness in sperm extraction using carbon dioxide and carbon dioxide free system in relation to intrauterine insemination pregnancy.
To evaluate the effectiveness of two different systems i.e. circulating water bath and carbon dioxide (CO(2)) incubator in extracting motile sperm for IUI programme and their effect on pregnancy outcome. The study was performed on sixty-two patients recruited for ovulation induction followed by intrauterine insemination (IUI) in University fertility clinic. The patients were randomly divided into two groups and sperm preparation was performed with either water bath or CO(2) incubator system. The efficiency of the two systems was analyzed in relation to pregnancy outcome. There was no significant difference in the efficacy of water bath and CO(2) system with respect to the quality of sperm extracted and pregnancy outcome. Although pregnancy rate was marginally higher in water bath group, it was not statistically significant. CO(2)-free system can be a cost-effective approach in IUI programme which does not compromise with pregnancy rate.


Targeted delivery of a novel anticancer compound anisomelic acid using chitosan-coated porous silica nanorods for enhancing the apoptotic effect.
Targeted cancer therapies are currently a strong focus in biomedical research. The most common approach is to use nanocarrier-based targeting to specifically deliver conventional anticancer drugs to enhance their therapeutic efficacy, increase bioavailability, and decrease the side-effects on normal cells. A step further towards higher specificity and efficacy would be to employ specific novel drugs along with specific nanocarrier-based targeting. Our recent studies have demonstrated that a plant-derived diterpenoid compound, anisomelic acid (AA), induces apoptosis in cervical cancer cells. In this work, we describe the development of a folic acid (FA)-targeted AA delivery system using chitosan-coated rod-shaped mesoporous silica particles (Chitosan-NR-MSP). The cellular internalization and uptake enhancement of the FA-Chitosan-NR-MSP towards cancerous folate receptor (FR)-positive (SiHa and HeLa) and/or normal FR-negative (HEK 293) cells were assessed, which indicated that the intracellular uptake of FA-conjugated Chitosan-NR-MSP was more target-specific. Furthermore, the induction of apoptosis by AA-loaded chitosan-coated rod-shaped particles on SiHa cells was studied. By employing caspase-3 activation and PARP cleavage as measure of apoptosis, the FA-particle mediated AA treatment was clearly more effective, significantly enhancing apoptosis in comparison to non-targeted Chitosan-NR-MSP or free AA in SiHa cells, suggesting that the FA-Chitosan-NR-MSPs can be potentially utilized as a drug delivery system for cervical cancer treatment.


Posterior capsule opacification: What's in the bag?
Cataract, a clouding of the lens, is the most common cause of blindness in the world. It has a marked impact on the wellbeing and productivity of individuals and has a major economic impact on healthcare providers. The only means of treating cataract is by surgical intervention. A modern cataract operation generates a capsular bag, which comprises a proportion of the anterior capsule and the entire posterior capsule. The bag remains in situ, partitions the aqueous and vitreous humours, and in the majority of cases, houses an intraocular lens (IOL). The production of a capsular bag following surgery permits a free passage of light along the visual axis through the transparent intraocular lens and thin acellular posterior capsule. Lens epithelial cells, however, remain attached to the anterior capsule, and in response to surgical trauma initiate a wound-healing response that ultimately leads to light scatter and a reduction in visual quality known as posterior capsule opacification (PCO). There are two commonly-described forms of PCO: fibrotic and regenerative. Fibrotic PCO follows classically defined fibrotic processes, namely hyperproliferation, matrix contraction, matrix deposition and epithelial cell trans-differentiation to a myofibroblast phenotype. Regenerative PCO is defined by lens fibre cell differentiation events that give rise to Soemmerring's ring and Elschnig's pearls and becomes evident at a later stage than the fibrotic form. Both fibrotic and regenerative forms of PCO contribute to a reduction in visual quality in patients. This review will highlight the wealth of tools available for PCO research, provide insight into our current knowledge of PCO and discuss putative management of PCO from IOL design to pharmacological interventions.


The natural history of pollination and mating in bird-pollinated Babiana (Iridaceae).
Floral variation, pollination biology and mating patterns were investigated in sunbird-pollinated Babiana (Iridaceae) species endemic to the Western Cape of South Africa. The group includes several taxa with specialized bird perches and it has been proposed that these function to promote cross-pollination. Pollinator observations were conducted in 12 populations of five taxa (B. ringens subspp. ringens, australis, B. hirsuta, B. avicularis, B. carminea) and geographic variation in morphological traits investigated in the widespread B. ringens. Experimental pollinations were used to determine the compatibility status, facility for autonomous self-pollination and intensity of pollen limitation in six populations of four taxa. Allozyme markers were employed to investigate mating patterns in four populations of three species. Sunbirds were the primary pollinators of the five Babiana taxa investigated. Correlated geographical variation in perch size, flower size and stigma-anther separation was evident among B. ringens populations. Experimental pollinations demonstrated that B. ringens and B. avicularis were self-compatible with variation in levels of autonomous self-pollination and weak or no pollen limitation of seed set. In contrast, B. hirsuta was self-incompatible and chronically pollen limited. Estimates of outcrossing rate indicated mixed mating with substantial self-fertilization in all species investigated. Despite the possession of specialized bird perches in B. ringens and B. avicularis, these structures do not prevent considerable selfing from occurring, probably as a result of autonomous self-pollination. In eastern populations of B. ringens, smaller flowers and reduced herkogamy appear to be associated with a shift to predominant selfing. Relaxed selection on perch function due to increased selfing may explain the increased incidence of apical flowers in some populations.


Electrochemistry and electrogenerated chemiluminescence of all-trans conjugated polymer poly[distyrylbenzene-b-(ethylene oxide)]s.
The electrochemistry and electrogenerated chemiluminescence (ECL) of two linear, stereoregular, and structurally defined PPV derivatives, poly[distyrylbenzene-b-(ethylene oxide)]s, with respective 12 and 16 of ethylene oxide repeat units in the backbone, abbreviated as DE-1 and DE-2, have been studied on glassy carbon and Pt electrodes in CH2Cl2 and CH3CN containing 0.10 M tetra-n-butylammonium perchlorate (TBAP). In CH2Cl2, a one-electron transfer, reversible oxidation at approximately 0.75 V vs Ag/Ag+ (10 mM AgNO3 in CH3CN) was observed for both polymers. Porous polymer films were electrochemically formed on the electrode with multiple cyclic potential scanning. Cast films of DE-1 and DE-2 on the electrode prepared from 1.0 mM of the corresponding CH2Cl2 solutions were used for studies in CH3CN containing 0.10 M TBAP due to their limited solubility in the solvent. A film-type of oxidation was found at approximately 0.80 V vs Ag/Ag+ in CH3CN when a scan rate of less than 1 V/s was used. The soluble oxidation product can be captured and reduced and then reoxidized in solution-phase at the electrode at a relatively high scan rate of, e.g., 2 V/s. ECL responses with a maximum emission at approximately 1.10 V vs Ag/Ag+ were obtained with the cast films in CH3CN (0.10 M TBAP) in the presence of 43 mM tri-n-propylamine (TPrA) after both TPrA and film were oxidized. The ECL is believed to be resulted from the interaction between the oxidized polymer species and the strong reducing TPrA free radical (TPrA*) generated after the deprotonation of TPrA*+ cation species.


Geochemical survey of Levante Bay, Vulcano Island (Italy), a natural laboratory for the study of ocean acidification.
Shallow submarine gas vents in Levante Bay, Vulcano Island (Italy), emit around 3.6t CO2 per day providing a natural laboratory for the study of biogeochemical processes related to seabed CO2 leaks and ocean acidification. The main physico-chemical parameters (T, pH and Eh) were measured at more than 70 stations with 40 seawater samples were collected for chemical analyses. The main gas vent area had high concentrations of dissolved hydrothermal gases, low pH and negative redox values all of which returned to normal seawater values at distances of about 400m from the main vents. Much of the bay around the vents is corrosive to calcium carbonate; the north shore has a gradient in seawater carbonate chemistry that is well suited to studies of the effects of long-term increases in CO2 levels. This shoreline lacks toxic compounds (such as H2S) and has a gradient in carbonate saturation states.


Flaxseed influences urinary lignan excretion in a dose-dependent manner in postmenopausal women.
Dietary estrogens, such as lignans, are similar in structure to endogenous sex steroid hormones and may act in vivo to alter hormone metabolism and subsequent cancer risk. The objective of this study was to examine the effect of dietary intake of a lignan-rich plant food (flaxseed) on urinary lignan excretion in postmenopausal women. This randomized, cross-over trial consisted of three 7-week feeding periods during which 31 healthy postmenopausal women, ages 52-82 years, consumed their habitual diets plus 0, 5, or 10 grams of ground flaxseed per day. Urine samples collected for 2 consecutive days during the last week of each feeding period were analyzed for lignan content (enterodiol, enterolactone, and matairesinol) by isotope dilution gas chromatography/mass spectrometry. Compared with the 0-gram flaxseed diet, consumption of 5 or 10 grams of flaxseed significantly increased excretion of enterodiol by 1,009 and 2,867 nmol/day, respectively; significantly increased excretion of enterolactone by 21,242 and 52,826 nmol/day, respectively; and significantly increased excretion of total lignans (enterodiol + enterolactone + matairesinol) by 24,333 and 60,640 nmol/day, respectively. Excretion of matairesinol was not significantly altered by flaxseed consumption. Consumption of flax, a significant source of dietary estrogens, in addition to their habitual diets increased excretion of enterodiol and enterolactone, but not matairesinol, in a dose-dependent manner in this group of postmenopausal women. Urinary excretion of lignan metabolites is a dose-dependent biomarker of flaxseed intake within the context of a habitual diet.


Gender-based Assessment of Survival in Trauma-hemorrhagic Shock: A Retrospective Analysis of Indian Population.
Trauma-hemorrhagic shock (THS) is a leading cause of death. Female rats and women experience better outcomes in terms of survival after major trauma as compared to males. There are limited data in Indian population. Authors studied the gender-based outcome of patients with Class IV hemorrhagic shock due to blunt trauma and the distribution of factors among males and females which are known to affect outcome. It was a retrospective study with data of trauma victims between January 2008 and July 2013. Road traffic crash (RTC), fall, or assault of all ages with Class IV hemorrhagic shock on arrival was included in the study, and data were collected on demographic, clinical, and laboratory parameters. Drowning, burns, penetrating injuries, and septic, neurogenic, and cardiogenic shock were excluded from the study. Seven hundred and eighty-one patients were analyzed under three groups: (i) overall group including all patients (n = 781), (ii) male group (n = 609), and (iii) female group (n = 172). After adjusting all variables, mortality was significantly lower in females as compared to males following THS (P < 0.05). Age, blood pressure, pulse, male gender, and fall and RTC as mode of injury (MOI) were independent predictors of mortality (P < 0.05) in overall group. Among males, age, pulse, and RTC as a MOI were significant (P < 0.05), while in females, only systolic blood pressure (SBP) was independent predictor of mortality. Females had better survival as compared to males following THS. SBP was an independent predictor of mortality in females with THS.


Statement of Retraction. Nuts as a Replacement for Carbohydrates in the Diabetic Diet. Diabetes Care 2011;34:1706-1711. DOI: 10.2337/dc11-0338.
The authors wish to retract this article because of an unintended error in statistical applications. A subsequent reanalysis of the data has shown that a number of the findings of the study described in this publication are no longer definitively different. The corresponding author voluntarily reported these discrepancies to the editors of Diabetes Care. The decision to retract the article is supported by all the authors based on their reevaluation of the data. The decision to retract the article is also supported by the editors of the journal and the American Diabetes Association, the publisher of Diabetes Care. At a later date, the authors intend to submit a revised article to Diabetes Care for full peer review with the appropriate statistical analysis applied.


Valvular heart disease: diagnosis and management.
Valvular heart disease (VHD) encompasses a number of common cardiovascular conditions that account for 10% to 20% of all cardiac surgical procedures in the United States. A better understanding of the natural history coupled with the major advances in diagnostic imaging, interventional cardiology, and surgical approaches have resulted in accurate diagnosis and appropriate selection of patients for therapeutic interventions. A thorough understanding of the various valvular disorders is important to aid in the management of patients with VHD. Appropriate work-up for patients with VHD includes a thorough history for evaluation of causes and symptoms, accurate assessment of the severity of the valvular abnormality by examination, appropriate diagnostic testing, and accurate quantification of the severity of valve dysfunction and therapeutic interventions, if necessary. It is also important to understand the role of the therapeutic interventions vs the natural history of the disease in the assessment of outcomes. Prophylaxis for infective endocarditis is no longer recommended unless the patient has a history of endocarditis or a prosthetic valve.


Diurnal patterns of gas-exchange and metabolic pools in tundra plants during three phases of the arctic growing season.
Arctic tundra plant communities are subject to a short growing season that is the primary period in which carbon is sequestered for growth and survival. This period is often characterized by 24-h photoperiods for several months a year. To compensate for the short growing season tundra plants may extend their carbon uptake capacity on a diurnal basis, but whether this is true remains unknown. Here, we examined in situ diurnal patterns of physiological activity and foliar metabolites during the early, mid, and late growing season in seven arctic species under light-saturated conditions. We found clear diurnal patterns in photosynthesis and respiration, with midday peaks and midnight lulls indicative of circadian regulation. Diurnal patterns in foliar metabolite concentrations were less distinct between the species and across seasons, suggesting that metabolic pools are likely governed by proximate external factors. This understanding of diurnal physiology will also enhance the parameterization of process-based models, which will aid in better predicting future carbon dynamics for the tundra. This becomes even more critical considering the rapid changes that are occurring circumpolarly that are altering plant community structure, function, and ultimately regional and global carbon budgets.


Poly(sarcosine)-Based Nano-Objects with Multi-Protease Resistance by Aqueous Photoinitiated Polymerization-Induced Self-Assembly (Photo-PISA).
Poly(sarcosine) (PSar) is a non-ionic hydrophilic polypeptoid with numerous biologically relevant properties, making it an appealing candidate for the development of amphiphilic block copolymer nanostructures. In this work, the fabrication of poly(sarcosine)-based diblock copolymer nano-objects with various morphologies via aqueous reversible addition-fragmentation chain-transfer (RAFT)-mediated photoinitiated polymerization-induced self-assembly (photo-PISA) is reported. Poly(sarcosine) was first synthesized via ring-opening polymerization (ROP) of sarcosine N-carboxyanhydride, using high-vacuum techniques. A small molecule chain transfer agent (CTA) was then coupled to the active ω-amino chain end of the telechelic polymer for the synthesis of a poly(sarcosine)-based macro-CTA. Controlled chain-extensions of a commercially available water-miscible methacrylate monomer (2-hydroxypropyl methacrylate) were achieved via photo-PISA under mild reaction conditions, using PSar macro-CTA. Upon varying the degree of polymerization and concentration of the core-forming monomer, morphologies evolving from spherical micelles to worm-like micelles and vesicles were accessed, as determined by dynamic light scattering and transmission electron microscopy, resulting in the construction of a detailed phase diagram. The resistance of both colloidally stable empty vesicles and enzyme-loaded nanoreactors against degradation by a series of proteases was finally assessed. Overall, our findings underline the potential of poly(sarcosine) as an alternative corona-forming polymer to poly(ethylene glycol)-based analogues of PISA assemblies for use in various pharmaceutical and biomedical applications.


Autism: the role of cholesterol in treatment.
Cholesterol is essential for neuroactive steroid production, growth of myelin membranes, and normal embryonic and fetal development. It also modulates the oxytocin receptor, ligand activity and G-protein coupling of the serotonin-1A receptor. A deficit of cholesterol may perturb these biological mechanisms and thereby contribute to autism spectrum disorders (ASDs), as observed in Smith-Lemli-Opitz syndrome (SLOS) and some subjects with ASDs in the Autism Genetic Resource Exchange (AGRE). A clinical diagnosis of SLOS can be confirmed by laboratory testing with an elevated plasma 7DHC level relative to the cholesterol level and is treatable by dietary cholesterol supplementation. Individuals with SLOS who have such cholesterol treatment display fewer autistic behaviours, infections, and symptoms of irritability and hyperactivity, with improvements in physical growth, sleep and social interactions. Other behaviours shown to improve with cholesterol supplementation include aggressive behaviours, self-injury, temper outbursts and trichotillomania. Cholesterol ought to be considered as a helpful treatment approach while awaiting an improved understanding of cholesterol metabolism and ASD. There is an increasing recognition that this single-gene disorder of abnormal cholesterol synthesis may be a model for understanding genetic causes of autism and the role of cholesterol in ASD.


Therapeutic efficacy of favipiravir against Bourbon virus in mice.
Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV.


Lactate, glucose and energy metabolism in the ischemic brain (Review).
For many decades, lactate was considered to be an end product of anaerobic glycolysis in mammalian tissues with no other function in metabolism. As determination of lactate level became a routine in hospital blood work, fluctuations in its levels were associated with situations other than oxygen lack. It was just a matter of time before elevated lactate blood levels emerged as a 'red flag' for potential malaise and frequently was blamed as the of it. Lactate and its accompanying acidosis are still considered today to be major contributors to selective neuronal damage in cerebral ischemia despite the emergence of alternative, more compelling postulates as to the causes of this damage. The attitude, especially among clinicians, has been difficult to change despite recent findings that strongly indicate lactate to be a possible beneficial intermediate in brain energy metabolism. This review revisits briefly the annals that brought about the lingering negative attitude toward lactate and expands on the more recent findings and debates that have illuminated this monocarboxylate in a different, more positive light.


The next big LEAP2 understanding ghrelin function.
Ghrelin is a key signal driving energy seeking and storage in order to reverse energy deficit. In line with this view, the metabolic status of an organism predicts sensitivity to ghrelin, with fasting increasing and obesity decreasing ghrelin sensitivity. However, the mechanism responsible for controlling this sensitivity is unknown. In this issue of the JCI, Mani and colleagues show that plasma levels of plasma liver-enriched antimicrobial peptide-2 (LEAP2), a recently identified hormone that antagonizes the ghrelin receptor, are inversely correlated with those of plasma acyl-ghrelin under conditions of both energy deficit and energy surplus in mice and humans. Their results show that a fall in plasma LEAP2 during energy deficit facilitates the actions of acyl-ghrelin, whereas increased LEAP2 in obesity suppresses the actions of acyl-ghrelin. This important discovery helps reshape our understanding of ghrelin function and may provide a new approach to aiding weight maintenance after diet-induced weight loss.


HomSI: a homozygous stretch identifier from next-generation sequencing data.
In consanguineous families, as a result of inheriting the same genomic segments through both parents, the individuals have stretches of their genomes that are homozygous. This situation leads to the prevalence of recessive diseases among the members of these families. Homozygosity mapping is based on this observation, and in consanguineous families, several recessive disease genes have been discovered with the help of this technique. The researchers typically use single nucleotide polymorphism arrays to determine the homozygous regions and then search for the disease gene by sequencing the genes within this candidate disease loci. Recently, the advent of next-generation sequencing enables the concurrent identification of homozygous regions and the detection of mutations relevant for diagnosis, using data from a single sequencing experiment. In this respect, we have developed a novel tool that identifies homozygous regions using deep sequence data. Using *.vcf (variant call format) files as an input file, our program identifies the majority of homozygous regions found by microarray single nucleotide polymorphism genotype data. HomSI software is freely available at www.igbam.bilgem.tubitak.gov.tr/softwares/HomSI, with an online manual.


PRODUCTION OF A PRELIMINARY QUALITY CONTROL PIPELINE FOR SINGLE NUCLEI RNA-SEQ AND ITS APPLICATION IN THE ANALYSIS OF CELL TYPE DIVERSITY OF POST-MORTEM HUMAN BRAIN NEOCORTEX.
Next generation sequencing of the RNA content of single cells or single nuclei (sc/nRNA-seq) has become a powerful approach to understand the cellular complexity and diversity of multicellular organisms and environmental ecosystems. However, the fact that the procedure begins with a relatively small amount of starting material, thereby pushing the limits of the laboratory procedures required, dictates that careful approaches for sample quality control (QC) are essential to reduce the impact of technical noise and sample bias in downstream analysis applications. Here we present a preliminary framework for sample level quality control that is based on the collection of a series of quantitative laboratory and data metrics that are used as features for the construction of QC classification models using random forest machine learning approaches. We've applied this initial framework to a dataset comprised of 2272 single nuclei RNA-seq results and determined that ~79% of samples were of high quality. Removal of the poor quality samples from downstream analysis was found to improve the cell type clustering results. In addition, this approach identified quantitative features related to the proportion of unique or duplicate reads and the proportion of reads remaining after quality trimming as useful features for pass/fail classification. The construction and use of classification models for the identification of poor quality samples provides for an objective and scalable approach to sc/nRNA-seq quality control.


On the plausibility of socioeconomic mortality estimates derived from linked data: a demographic approach.
Reliable estimates of mortality according to socioeconomic status play a crucial role in informing the policy debate about social inequality, social cohesion, and exclusion as well as about the reform of pension systems. Linked mortality data have become a gold standard for monitoring socioeconomic differentials in survival. Several approaches have been proposed to assess the quality of the linkage, in order to avoid the misclassification of deaths according to socioeconomic status. However, the plausibility of mortality estimates has never been scrutinized from a demographic perspective, and the potential problems with the quality of the data on the at-risk populations have been overlooked. Using indirect demographic estimation (i.e., the synthetic extinct generation method), we analyze the plausibility of old-age mortality estimates according to educational attainment in four European data contexts with different quality issues: deterministic and probabilistic linkage of deaths, as well as differences in the methodology of the collection of educational data. We evaluate whether the at-risk population according to educational attainment is misclassified and/or misestimated, correct these biases, and estimate the education-specific linkage rates of deaths. The results confirm a good linkage of death records within different educational strata, even when probabilistic matching is used. The main biases in mortality estimates concern the classification and estimation of the person-years of exposure according to educational attainment. Changes in the census questions about educational attainment led to inconsistent information over time, which misclassified the at-risk population. Sample censuses also misestimated the at-risk populations according to educational attainment. The synthetic extinct generation method can be recommended for quality assessments of linked data because it is capable not only of quantifying linkage precision, but also of tracking problems in the population data. Rather than focusing only on the quality of the linkage, more attention should be directed towards the quality of the self-reported socioeconomic status at censuses, as well as towards the accurate estimation of the at-risk populations.


CD138 expression is a molecular signature but not a developmental requirement for RORγt+ NKT17 cells.
Invariant NKT (iNKT) cells are potent immunomodulatory cells that acquire effector function during their development in the thymus. IL-17-producing iNKT cells are commonly referred to as NKT17 cells, and they are unique among iNKT cells to express the heparan sulfate proteoglycan CD138 and the transcription factor RORγt. Whether and how CD138 and RORγt contribute to NKT17 cell differentiation, and whether there is an interplay between RORγt and CD138 expression to control iNKT lineage fate, remain mostly unknown. Here, we showed that CD138 expression was only associated with and not required for the differentiation and IL-17 production of NKT17 cells. Consequently, CD138-deficient mice still generated robust numbers of IL-17-producing RORγt+ NKT17 cells. Moreover, forced expression of RORγt significantly promoted the generation of thymic NKT17 cells, but did not induce CD138 expression on non-NKT17 cells. These results indicated that NKT17 cell generation and IL-17 production were driven by RORγt, employing mechanisms that were independent of CD138. Therefore, our study effectively dissociated CD138 expression from the RORγt-driven molecular pathway of NKT17 cell differentiation.


Modulation of cytokine and cytokine receptor/antagonist by treatment with doxycycline and tetracycline in patients with dengue fever.
Dengue virus infection can lead to dengue fever (DF) or dengue hemorrhagic fever (DHF). Disease severity has been linked to an increase in various cytokine levels. In this study, we evaluated the effectiveness of doxycycline and tetracycline to modulate serum levels of IL-6, IL-1B, and TNF and cytokine receptor/receptor antagonist TNF-R1 and IL-1RA in patients with DF or DHF. Hospitalized patients were randomized to receive standard supportive care or supportive care combined with doxycycline or tetracycline therapy. Serum cytokine and cytokine receptor/antagonist levels were determined at the onset of therapy and after 3 and 7 days. Cytokine and cytokine receptor/antagonist levels were substantially elevated at day 0. IL-6, IL-1β, and TNF remained at or above day 0 levels throughout the study period in untreated patients. Treatment with tetracycline or doxycycline resulted in a significant decline in cytokine levels. Similarly, IL-1RA and TNF-R1 serum concentrations were elevated at baseline and showed a moderate increase among untreated patients. Both drugs resulted in a significant rise in IL-1Ra levels by day 3 in patients. In contrast, treatment did not affect a similar result for TNF-R1. When compared to the control group, however, a significant rise post-treatment was seen upon intragroup analysis. Further analysis demonstrated that doxycycline was significantly more effective at modulating cytokine and cytokine receptor/antagonist levels than tetracycline.


A comparative study of voiding and sexual function after total mesorectal excision with autonomic nerve preservation for rectal cancer: laparoscopic versus robotic surgery.
To evaluate the protection of the urogenital function after robot-assisted total mesorectal excision (R-TME) for rectal cancer compared to those of laparoscopic TME (L-TME). 69 patients who underwent L-TME (n = 39) or R-TME (n = 30) were prospectively enrolled. Their urogenital function was evaluated by uroflowmetry, a standard questionnaire of the international prostate symptom score (IPSS) and the international index of erectile function (IIEF) before surgery and 1, 3, 6, and 12 months after surgery. The pre- and postoperative IPSS and IIEF scores were compared to detect functional deterioration by paired t test for each group. How postoperative IPSS and IIEF scores and uroflowmetry data deviated from the preoperative values (Δ) were statistically compared between the two groups. The IPSS score significantly increased 1 month after surgery; the recovery from decreased urinary function took 6 months for patients in the L-TME group (8.2 ± 6.3; P = 0.908) but 3 months in the R-TME group (8.36 ± 5.5; P = 0.075). The ΔIPSS scores were significantly different between the two groups at 3 months (P = 0.036). In male patients (L-TME 20, R-TME 18), the total IIEF score in R-TME and L-TME significantly decreased 1 month after surgery, L-TME gradually recovered over 12 months (46.00 ± 16.9; P = 0.269), but R-TME recovered within 6 months (44.61 ± 13.76; P = 0.067). The ΔIIEF score value was not significantly different at any time between the two groups, but in an itemized analysis of the change in erectile function and sexual desire, there were significant differences at 3 months between the two groups. R-TME for rectal cancer is associated with earlier recovery of normal voiding and sexual function compared to patients who underwent L-TME, although this result needs to be verified by larger prospective comparative studies.


Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol(®) 888ATO as Lipid Excipient.
Tablets containing metoprolol succinate and Compritol(®) 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol(®) 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol(®) 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol(®) 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm(2) exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm(2) with 6.90% of total porosity revealing influence of compression force. Compritol(®) 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate.


The Limited Utility of Multiunit Data in Differentiating Neuronal Population Activity.
To date, single neuron recordings remain the gold standard for monitoring the activity of neuronal populations. Since obtaining single neuron recordings is not always possible, high frequency or 'multiunit activity' (MUA) is often used as a surrogate. Although MUA recordings allow one to monitor the activity of a large number of neurons, they do not allow identification of specific neuronal subtypes, the knowledge of which is often critical for understanding electrophysiological processes. Here, we explored whether prior knowledge of the single unit waveform of specific neuron types is sufficient to permit the use of MUA to monitor and distinguish differential activity of individual neuron types. We used an experimental and modeling approach to determine if components of the MUA can monitor medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) in the mouse dorsal striatum. We demonstrate that when well-isolated spikes are recorded, the MUA at frequencies greater than 100Hz is correlated with single unit spiking, highly dependent on the waveform of each neuron type, and accurately reflects the timing and spectral signature of each neuron. However, in the absence of well-isolated spikes (the norm in most MUA recordings), the MUA did not typically contain sufficient information to permit accurate prediction of the respective population activity of MSNs and FSIs. Thus, even under ideal conditions for the MUA to reliably predict the moment-to-moment activity of specific local neuronal ensembles, knowledge of the spike waveform of the underlying neuronal populations is necessary, but not sufficient.


Rational modulation of the innate immune system for neuroprotection in ischemic stroke.
The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood-brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-β, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-β. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction.


AcrAB-TolC Inhibition by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Antibiotic Activity in Vitro and in Vivo.
Overexpression of bacterial efflux pumps is a driver of increasing antibiotic resistance in Gram-negative pathogens. The AcrAB-TolC efflux pump has been implicated in resistance to a number of important antibiotic classes including fluoroquinolones, macrolides, and β-lactams. Antisense technology, such as peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), can be utilized to inhibit expression of efflux pumps and restore susceptibility to antibiotics. Targeting of the AcrAB-TolC components with PPMOs revealed a sequence for acrA, which was the most effective at reducing antibiotic efflux. This acrA-PPMO enhances the antimicrobial effects of the levofloxacin and azithromycin in a panel of clinical Enterobacteriaceae strains. Additionally, acrA-PPMO enhanced azithromycin in vivo in a K. pneumoniae septicemia model. PPMOs targeting the homologous resistance-nodulation-division (RND)-efflux system in P. aeruginosa, MexAB-OprM, also enhanced potency to several classes of antibiotics in a panel of strains and in a cell culture infection model. These data suggest that PPMOs can be used as an adjuvant in antibiotic therapy to increase the efficacy or extend the spectrum of useful antibiotics against a variety of Gram-negative infections.


Developmental change in amygdala reactivity during adolescence: effects of family history of depression and stressful life events.
Although heightened amygdala reactivity is observed in patients with major depression, two critical gaps in our knowledge remain. First, it is unclear whether heightened amygdala reactivity is a premorbid vulnerability or a consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The authors sought to address these gaps by evaluating developmental change in threat-related amygdala reactivity in adolescents at high or low risk for depression based on family history, before onset of disorder. At baseline and again 2 years later, adolescents (initially 11-15 years of age) participated in a functional MRI paradigm that elicited threat-related amygdala reactivity. After quality control, data were available for 232 adolescents at wave 1 and 197 adolescents at wave 2; longitudinal data meeting quality control at both waves were available for 157 of these participants. Change in amygdala reactivity was assessed as a function of family history of depression and severity of stressful life events. Threat-related amygdala reactivity increased with age in participants with a positive family history regardless of the severity of life stress reported, and it increased in adolescents with a negative family history who reported relatively severe life stress. These changes in amygdala reactivity with age occurred in the absence of clinical disorder or increases in depressive symptoms. These results suggest that heightened amygdala reactivity emerges during adolescence, prior to the development of depression, as a function of familial risk or, in the absence of familial risk, stressful life events.


Predicting longitudinal growth curves of height and weight using ecological factors for children with and without early growth deficiency.
Growth curve models were used to examine the effect of genetic and ecological factors on changes in height and weight of 225 children from low income, urban families who were assessed up to eight times in the first 6 y of life. Children with early growth deficiency [failure to thrive (FTT)] (n = 127) and a community sample of children without growth deficiency (n = 98) were examined to evaluate how genetic, child and family characteristics influenced growth. Children of taller and heavier parents, who were recruited at younger ages and did not have a history of growth deficiency, had accelerated growth from recruitment through age 6 y. In addition, increases in height were associated with better health, less difficult temperament, nurturant mothers and female gender; increases in weight were associated with better health. Children with a history of growth deficiency demonstrated slower rates of growth than children in the community group without a history of growth deficiency. In the community group, changes in children's height and weight were related to maternal perceptions of health and temperament and maternal nurturance during feeding, whereas in the FTT group, maternal perceptions and behavior were not in synchrony with children's growth. These findings suggest that, in addition to genetic factors, growth is dependent on a nurturant and sensitive caregiving system. Interventions to promote growth should consider child and family characteristics, including maternal perceptions of children's health and temperament and maternal mealtime behavior.


Bladder tumors in rats fed cyclohexylamine or high doses of a mixture of cyclamate and saccharin.
Papillary transitional cell tumors were found in the urinary bladders in 8 rats out of 80 that received 2600 milligrams per kilogram of body weight per day of a mixture of sodium cyclamate and sodium saccharin (10:1) for up to 105 weeks. From week 79 on, several of these rats received cyclohexylamine hydrochloride (125 milligrams per kilogram per day, the molecular equivalent of the conversion of about 10 percent of the cyclamate dosage to cyclohexylamine) in addition to the sodium cyclamate and sodium saccharin. In another study in which 50 rats were fed daily 15 milligrams of cyclohexylamine sulfate per kilogram of body weight for 2 years, eight males and nine females survived. One of the eight males had a tumor of the urinary bladder. In neither study were bladder tumors found in the control rats or in rats treated with lower doses of the compounds.


Thermodynamic penalty arising from burial of a ligand polar group within a hydrophobic pocket of a protein receptor.
Here, we examine the thermodynamic penalty arising from burial of a polar group in a hydrophobic pocket that forms part of the binding-site of the major urinary protein (MUP-I). X-ray crystal structures of the complexes of octanol, nonanol and 1,8 octan-diol indicate that these ligands bind with similar orientations in the binding pocket. Each complex is characterised by a bridging water molecule between the hydroxyl group of Tyr120 and the hydroxyl group of each ligand. The additional hydroxyl group of 1,8 octan-diol is thereby forced to reside in a hydrophobic pocket, and isothermal titration calorimetry experiments indicate that this is accompanied by a standard free energy penalty of +21 kJ/mol with respect to octanol and +18 kJ/mol with respect to nonanol. Consideration of the solvation thermodynamics of each ligand enables the "intrinsic" (solute-solute) interaction energy to be determined, which indicates a favourable enthalpic component and an entropic component that is small or zero. These data indicate that the thermodynamic penalty to binding derived from the unfavourable desolvation of 1,8 octan-diol is partially offset by a favourable intrinsic contribution. Quantum chemical calculations suggest that this latter contribution derives from favourable solute-solute dispersion interactions.


Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo.
Human interferon-inducible protein 10 (IP-10), a member of the alpha chemokine family, inhibits bone marrow colony formation, has antitumor activity in vivo, is chemoattractant for human monocytes and T cells, and promotes T cell adhesion to endothelial cells. Here we report that IP-10 is a potent inhibitor of angiogenesis in vivo. IP-10 profoundly inhibited basic fibroblast growth factor-induced neovascularization of Matrigel (prepared by H. K. Kleinman) injected subcutaneously into athymic mice. In addition, IP-10, in a dose-dependent fashion, suppressed endothelial cell differentiation into tubular capillary structures in vitro. IP-10 had no effect on endothelial cell growth, attachment, and migration as assayed in vitro. These results document an important biological property of IP-10 and raise the possibility that IP-10 may participate in the regulation of angiogenesis during inflammation and tumorigenesis.


Home telemonitoring of vital signs and cardiorespiratory signals in heart failure patients: system architecture and feasibility of the HHH model.
The Home or Hospital in Heart Failure Study (HHH) is a European Community funded trial (QLGA-CT-2001-02424) which compares usual care of heart failure (HF) with three home-based interventions in a multicenter, multicountry (Italy, Poland and UK), randomized controlled clinical trial. Home telemonitoring (HT) of clinical parameters represents a potential alternative (or addition) to traditional home care models. Nocturnal respiratory disorders (periodic breathing, sleep apnea) are very common in HF, and are associated with increased morbidity and mortality. We developed an integrated HT system for monitoring of both vital signs and respiration. All measurements were patient-managed. This paper describes the architecture of this system, and assesses its feasibility. 461 clinically stable patients were randomized first to usual vs home-monitored care; the latter were further randomized to 3 strategies. Over a 12-month follow-up 2 of these 3 groups (195 patients, age: 60+/-11 years, NYHA class II-III: 97%, LVEF 28+/-7%) underwent self-administered home monitoring of vital signs (weekly--12 parameters using an interactive voice response system) and respiration (monthly--24-hour recording). Data were transmitted over conventional telephone lines; 81% of actually practicable vital signs measurements were completed by the patients (range: 75% (PL)-93% (UK)), as well as 92% of practicable respiratory recordings (range: 85% (PL)-99% (UK)). 87% of nighttime recordings were eligible for the study (good quality signals for > or = 2.5 h). This study, the largest so far, demonstrates that self-managed home telemonitoring of both vital signs and respiration is feasible in HF patients, with surprisingly high compliance. We found an excellent rate of acceptable nocturnal respiratory recordings, which are those with the greatest clinical relevance.


Gap junctional conductance is a simple and sensitive function of intracellular pH.
The pH of the cytoplasm (pHt) measured with pH-sensitive microelectrodes in cleavage-stage blastomeres of amphibian (Ambystoma) and teleost (Fundulus) embryos is about 7.7. In electrotonically coupled cell pairs, junctional conductance is rapidly and reversibly reduced by acidification of the cytoplasm. The relation between junctional conductance and pHi is the same for increasing and decreasing pH and is independent of the rate of change over a wide range. The relation is well fitted by a Hill curve with K = 50 nM (pK = 7.3) and n = 4 to 5. The closure of gap junction channels at low pHi appears to be a cooperative process involving several charged sites. The absence of hysteresis and identity of effects for fast and slow pHi changes implies that protons act directly on the channel macromolecules and not through an intermediate in the cytoplasm.


ACC Glu/GABA ratio is decreased in euthymic bipolar disorder I patients: possible in vivo neurometabolite explanation for mood stabilization.
Bipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (1H-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T 1H-MRS in the dACC (2 × 2 × 4.5 cm3) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood states.ClincalTrials.gov registration: NCT01237158.


[Cognitive performance and mortality in people over 50 in Mexico].
Determine the correlation between the low cognitive performance recorded in 2001 in the National Study on Health and Aging in Mexico (ENASEM) and the mortality reported in 2003 during the second phase of that same study. The subjects selected were people aged 50 or over who had completed the sections in the 2001 survey pertaining to cognitive exercises, health status, and functionality and assistance with daily activities. Cognitive performance was assessed in 2001 using an abridged version of the Cross-Cultural Cognitive Examination (scale: 0 to 80 points). In 2003, there was a follow-up to the interviewees, in which their survival or death was recorded. The groups of interviewees scoring less than 40 had a cumulative survival rate of 96.1%, with a mean of 26.49 months of survival (CI 95% 26.41-26.57), while those scoring 40 points or over had a cumulative survival rate of 98.7%, with a mean of 28.76 months (CI 95% 28.68-28.85) (Log Rank chi(2) = 59,230 P < 0,001). A score of less than 40 in the cognitive assessment was associated with a relative risk of death of 1.863 (CI: 95% 1.30-2.65) in the multivariate analysis. Also associated with higher mortality was older age, self-reported diabetes, cancer, having smoked at some time, receiving assistance in at least one instrumental activity of daily living, and scoring higher on the depression scale. A score of less than 40 in the abridged version of the Cross-Cultural Cognitive Examination was independently correlated with an increase in mortality within the next two years.


General subpopulation framework and taming the conflict inside populations.
Structured evolutionary algorithms have been investigated for some time. However, they have been under explored especially in the field of multi-objective optimization. Despite good results, the use of complex dynamics and structures keep the understanding and adoption rate of structured evolutionary algorithms low. Here, we propose a general subpopulation framework that has the capability of integrating optimization algorithms without restrictions as well as aiding the design of structured algorithms. The proposed framework is capable of generalizing most of the structured evolutionary algorithms, such as cellular algorithms, island models, spatial predator-prey, and restricted mating based algorithms. Moreover, we propose two algorithms based on the general subpopulation framework, demonstrating that with the simple addition of a number of single-objective differential evolution algorithms for each objective, the results improve greatly, even when the combined algorithms behave poorly when evaluated alone at the tests. Most importantly, the comparison between the subpopulation algorithms and their related panmictic algorithms suggests that the competition between different strategies inside one population can have deleterious consequences for an algorithm and reveals a strong benefit of using the subpopulation framework.