GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab.
Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.


Menarche and father absence in a national probability sample.
The relation between women's timing of menarche and father absence was examined in a national probability sample of Great Britain (NATSAL 2000; N>5000). Current body mass index (as a proxy for childhood weight) was examined as a potential mediator of this relationship, along with the potential moderating role that siblings (e.g. number of older brothers) had on this relationship. As in a number of previous studies, an absent father (but not an absent mother) during childhood predicted an earlier age of puberty (i.e. an early menarche). There was no evidence that weight mediated this relationship or that siblings moderated it. Both a lower body mass index and more siblings (e.g. more younger sisters and brothers) were independent predictors of a later timing of puberty. The results confirm that certain psychosocial factors (i.e. father absence; presence of siblings) may affect the timing of sexual maturation in adolescent girls.


Species delimitation in northern European water scavenger beetles of the genus Hydrobius (Coleoptera, Hydrophilidae).
The chiefly Holarctic Hydrobius species complex (Coleoptera, Hydrophilidae) currently consists of Hydrobius arcticus Kuwert, 1890, and three morphological variants of Hydrobius fuscipes (Linnaeus, 1758): var. fuscipes, var. rottenbergii and var. subrotundus in northern Europe. Here molecular and morphological data are used to test the species boundaries in this species complex. Three gene segments (COI, H3 and ITS2) were sequenced and analyzed with Bayesian methods to infer phylogenetic relationships. The Generalized Mixed Yule Coalescent (GMYC) model and two versions of the Bayesian species delimitation method BPP, with or without an a priori defined guide tree (v2.2 & v3.0), were used to evaluate species limits. External and male genital characters of primarily Fennoscandian specimens were measured and statistically analyzed to test for significant differences in quantitative morphological characters. The four morphotypes formed separate genetic clusters on gene trees and were delimited as separate species by GMYC and by both versions of BPP, despite specimens of Hydrobius fuscipes var. fuscipes and Hydrobius fuscipes var. subrotundus being sympatric. Hydrobius arcticus and Hydrobius fuscipes var. rottenbergii could only be separated genetically with ITS2, and were delimited statistically with GMYC on ITS2 and with BPP on the combined data. In addition, six or seven potentially cryptic species of the Hydrobius fuscipes complex from regions outside northern Europe were delimited genetically. Although some overlap was found, the mean values of six male genital characters were significantly different between the morphotypes (p < 0.001). Morphological characters previously presumed to be diagnostic were less reliable to separate Hydrobius fuscipes var. fuscipes from Hydrobius fuscipes var. subrotundus, but characters in the literature for Hydrobius arcticus and Hydrobius fuscipes var. rottenbergii were diagnostic. Overall, morphological and molecular evidence strongly suggest that Hydrobius arcticus and the three morphological variants of Hydrobius fuscipes are separate species and Hydrobius rottenbergii Gerhardt, 1872, stat. n. and Hydrobius subrotundus Stephens, 1829, stat. n. are elevated to valid species. An identification key to northern European species of Hydrobius is provided.


Perovskite Solar Cells: Influence of Hole Transporting Materials on Power Conversion Efficiency.
The recent advances in perovskite solar cells (PSCs) created a tsunami effect in the photovoltaic community. PSCs are newfangled high-performance photovoltaic devices with low cost that are solution processable for large-scale energy production. The power conversion efficiency (PCE) of such devices experienced an unprecedented increase from 3.8 % to a certified value exceeding 20 %, demonstrating exceptional properties of perovskites as solar cell materials. A key advancement in perovskite solar cells, compared with dye-sensitized solar cells, occurred with the replacement of liquid electrolytes with solid-state hole-transporting materials (HTMs) such as 2,2',7,7'-tetrakis-(N,N-di-4-methoxyphenylamino)-9,9'-spirobifluorene (Spiro-OMeTAD), which contributed to enhanced PCE values and improved the cell stability. Following improvements in the perovskite crystallinity to produce a smooth, uniform morphology, the selective and efficient extraction of positive and negative charges in the device dictated the PCE of PSCs. In this Review, we focus mainly on the HTMs responsible for hole transport and extraction in PSCs, which is one of the essential components for efficient devices. Here, we describe the current state-of-the-art in molecular engineering of hole-transporting materials that are used in PSCs and highlight the requisites for market-viability of this technology. Finally, we include an outlook on molecular engineering of new functional HTMs for high efficiency PSCs.


Correlated firing of cat retinal ganglion cells. I. Spontaneously active inputs to X- and Y-cells.
1. The shared inputs to cat retinal ganglion cells have been investigated by studying correlations in the maintained firing of neighboring ganglion cells. The firing of one cell was recorded from its axon in the optic tract, while that of a neighboring cell was simultaneously recorded with a second electrode in the retina. The recorded cells were of the X- or Y-type and viewed a uniform screen having a luminance of 10 cd/m2. 2. Ganglion cells with overlapping receptive-field centers showed two basic forms of correlated firing: if they had the same center sign (both on-center or both off-center), then they tended to fire at the same time, as shown by a peak in their cross-correlogram; but if they had opposite center signs (an on- and and off-center cell), they tended not to fire at the same time, as shown by a well, or dip, in their cross-correlogram. 3. Both of these tendencies were strongest for cells that were close together and did not appear for cells with nonoverlapping receptive-field centers. The strongest correlations were between neighboring Y-cells, cells with large fields, and the weakest were between X-cells, cells with small fields. In general, the strength of the correlations depended primarily on the area of the overlap between fields. 4. These correlations in maintained firing appear to be principally or entirely caused by shared inputs to the ganglion cells from more distal retinal neurons. The signals from these distal neurons appear to have strong, brief (4-8 ms), well-defined effects on ganglion cells, which are observed even in the absence of a visual stimulus. The inputs responsible for the correlated firing are thus referred to as spontaneously active inputs or simply as active inputs. 5. An analysis of the features in the various types of cross-correlograms supports the following statements about these spontaneously active inputs. a) There are two types of active inputs: inputs excitatory to on-center cells and simultaneously inhibitory to off-center center cells and inputs excitatory to off-center cells and simultaneously inhibitory to on-center cells. b) The active inputs of each type provide excitation to both X- and Y-cells of one center sign and inhibition to both X- and Y-cells of the other center sign. There is no evidence for a special class of more selective inputs providing input only to X-cells or only to Y-cells. c) Active inputs account for the majority (about 80%) of the spikes in the maintained activity of Y-cells but only a small fraction (about 15%) of the spikes in the maintained activity of X-cells. 6. A likely source of the active input signals appears to be spiking amacrine cells with a low rate of spontaneous activity.


The separation of trypanosomes from blood by anion exchange chromatography: From Sheila Lanham's discovery 50 years ago to a gold standard for sleeping sickness diagnosis.
Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease that is fatal if untreated, caused by Trypanosoma brucei gambiense and T. brucei rhodesiense. In its 2012 roadmap, WHO targeted HAT for elimination as a public health problem in 2020 and for zero transmission in 2030. Diagnosis of HAT is a multistep procedure comprising of clinical suspicion, confirmation, and stage determination. Suspects are identified on clinical signs and/or on screening for specific antibodies. Parasitological confirmation of suspects remains mandatory to avoid unnecessary toxic drug administration. The positive predictive value of the antibody detection tests is low. Simple parasite detection techniques, microscopic examination of lymph node aspirate, or stained thick blood films lack sensitivity, whereas in T. brucei gambiense patients, the number of blood trypanosomes may be very low. Parasite concentration techniques are therefore indispensable. Half a century ago, Sheila Lanham discovered a technique to separate trypanosomes from the blood of infected rodents, based on anion exchange chromatography with diethyl amino ethyl (DEAE) cellulose, a weak anion exchanger. Between pH 6-9, trypanosome surface is less negatively charged than that of blood cells. When blood is poured on top of a DEAE cellulose column, blood cells are retained, whereas parasites pass the column together with the elution buffer. The result is a pure suspension of trypanosomes that retain their morphology and infectivity. Because cell surface charges vary among trypanosome and mammal species, the optimal buffer pH and ionic strength conditions for different combinations of host and trypanosome species were established. Lanham's technique revolutionized the diagnosis of HAT. It is indispensable in the production of the Card Agglutination Test for Trypanosomiasis (CATT), the most used field test for screening in T. brucei gambiense HAT foci and essential to confirm the diagnosis in suspected people. Lumsden and colleagues developed the mini anion exchange centrifugation technique (mAECT). After adaptation for field conditions, its superior diagnostic and analytical sensitivity compared to another concentration technique was demonstrated. It was recommended as the most sensitive test for demonstrating trypanosomes in human blood. At the beginning of the 21st century, the mAECT was redesigned, allowing examination of a larger volume of blood, up to 0.35 ml with whole blood and up to 10 ml with buffy coat. The plastic collector tube in the new kit is also used for detection of trypanosomes in the cerebrospinal fluid. Unfortunately, mAECT also has some disadvantages, including its price, the need to centrifuge the collector tube, and the fact that it is manufactured on a noncommercial basis at only two research institutes. In conclusion, 50 years after Sheila Lanham's discovery, CATT and mAECT have become essential elements in the elimination of HAT.


Prescribing of psychotropic medications to the elderly population of a Canadian province: a retrospective study using administrative databases.
Background. Psychotropic medications, in particular second-generation antipsychotics (SGAs) and benzodiazepines, have been associated with harm in elderly populations. Health agencies around the world have issued warnings about the risks of prescribing such medications to frail individuals affected by dementia and current guidelines recommend their use only in cases where the benefits clearly outweigh the risks. This study documents the use of psychotropic medications in the entire elderly population of a Canadian province in the context of current clinical guidelines for the treatment of behavioural disturbances. Methods. Prevalent and incident utilization of antipsychotics, benzodiazepines and related medications (zopiclone and zaleplon) were determined in the population of Manitobans over age 65 in the time period 1997/98 to 2008/09 fiscal years. Comparisons between patients living in the community and those living in personal care (nursing) homes (PCH) were conducted. Influence of sociodemographic characteristics on prescribing was assessed by generalized estimating equations. Non-optimal use was defined as the prescribing of high dose of antipsychotic medications and the use of combination therapy of a benzodiazepine (or zopiclone/zaleplon) with an antipsychotic. A decrease in intensity of use over time and lower proportions of patients treated with antipsychotics at high dose or in combination with benzodiazepines (or zopiclone/zaleplon) was considered a trend toward better prescribing. Multiple regression analysis determined predictors of non-optimal use in the elderly population. Results. A 20-fold greater prevalent utilization of SGAs was observed in PCH-dwelling elderly persons compared to those living in the community. In 2008/09, 27% of PCH-dwelling individuals received a prescription for an SGA. Patient characteristics, such as younger age, male gender, diagnoses of dementia (or use of an acetylcholinesterase inhibitor) or psychosis in the year prior the prescription, were predictors of non-optimal prescribing (e.g., high dose antipsychotics). During the period 2002/3 and 2007/8, amongst new users of SGAs, 10.2% received high doses. Those receiving high dose antipsychotics did not show high levels of polypharmacy. Conclusions. Despite encouraging trends, the use of psychotropic medications remains high in elderly individuals, especially in residents of nursing homes. Clinicians caring for such patients need to carefully assess risks and benefits.


Lotus seed skin proanthocyanidin extract exhibits potent antioxidant property via activation of the Nrf2-ARE pathway.
Lotus seed is well known as traditional food and medicine, but its skin is usually discarded. Recent studies have shown that lotus seed skin contains a high concentration of proanthocyanidins that have multi-functions, such as antioxidation, anti-inflammation, and anti-cancer effects. In the present study, we aimed to isolate and purify the proanthocyanidins from lotus seed skin by acetone extraction and rotary evaporation, identify their chemical structures by HPLC-MS-MS and NMR, and further investigate the antioxidant properties of the extract purified by macroporous resin (PMR) from lotus seed skin both in vitro and in vivo. The results showed that PMR mainly contained oligomeric proanthocyanidins, especially dimeric procyanidin B1 (PB1), procyanidin B2 and procyanidin B4. Although it had limited ability to directly scavenge radicals in vitro, PMR could significantly enhance the expressions of antioxidant proteins via activation of nuclear factor-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway in HepG2 cells. Molecular data revealed that PB1, a major component in PMR, stabilized Nrf2 by inhibiting the ubiquitination of Nrf2, which led to subsequent activation of the Nrf2-ARE pathway, including the enhancements of Nrf2 nuclear translocation, Nrf2-ARE binding and ARE transcriptional activity. Moreover, the in vivo results in high fat diet-induced mice further verified the powerful antioxidant property of PMR. These results revealed that lotus seed skin is a promising resource for functional food development.


Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A-HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC-prone microenvironment. Here, we have identified and validated an A-HSC-specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue-related, A-HSC-specific gene expression is associated with recurrence and poor survival. Analyses of A-HSC-specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A-HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A-HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation. A-HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse.


Progesterone therapy for the treatment of non-cancer cachexia: a systematic review.
Cachexia describes a complex pathological syndrome of muscle wasting, anorexia and weight loss. Progesterone therapies have been shown to improve appetite and promote weight gain in patients with cachexia; however, research has focused heavily on patients with cancer, and its effectiveness in other diseases remains unclear. This systematic review aimed to present the evidence available for progesterone therapy as a treatment for non-cancer cachexia. Surrogate outcome measures used were weight change, lean body mass (LBM), muscle strength, appetite, health-related quality of life (HRQOL) and serum albumin. Both randomised and non-randomised trials were included. A literature search of clinical trials using the medical subject heading (MeSH) terms 'cachexia' OR 'anorexia' OR 'weight' OR 'frail (truncated)' OR 'appetite' OR 'wasting syndrome' PLUS 'megestrol acetate' OR 'medroxyprogesterone acetate' was performed. Eighteen studies were included in this review; 12 randomised control trials and 6 non-randomised trials. This collated results from 916 patients with HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD) and geriatric cachexia. Meta-analysis comparing progesterone therapy with placebo concluded mean change in weight was not significant (mean difference (MD) 1.56, 95% CI -0.36 to 3.52, p=0.12). There was little evidence to show significant impact on LBM, and no trials looked at muscle strength. There was a paucity of evidence looking at appetite and HRQOL; however, results were generally positive. Current evidence does not support the use of progesterone therapies for non-cancer cachexia. There may however be a limited role for its use as an appetite stimulant in a palliative context on a case-by-case basis.


Diffusion tensor imaging and cognitive function in older adults with no dementia.
To determine the patterns of diffusivity associated with cognitive domain functions in older adults without dementia. We studied older adults without dementia (n = 220) who underwent neuropsychometric testing and a diffusion tensor imaging (DTI) examination at 3 T in a cross-sectional study. Memory, language, attention/executive function, and visual-spatial processing domains were assessed within 4 months of the MRI examination. A fluid-attenuated inversion recovery-based DTI sequence that enabled uncontaminated cortical diffusion measurements was performed. Associations between cortical mean diffusivity (MD) and cognitive function were tested using voxel-based regression analysis. Association between tract diffusivity and cognitive function was tested with regions of interest drawn on color-coded fractional anisotropy (FA) maps. Memory function was associated with the medial temporal lobe cortical MD on voxel-based analysis (p < 0.001, corrected for multiple comparisons), and inferior longitudinal fasciculus and posterior and anterior cingulum FA on tract-based analysis (p < 0.001). Language function was associated with the left temporal lobe cortical MD (p < 0.001, corrected for multiple comparisons), inferior longitudinal fasciculus, fornix, and posterior cingulum FA (p < 0.05). Attention and executive function was associated with the posterior and anterior cingulum FA, and visual-spatial function was associated with posterior cingulum FA (p < 0.01). Specific cognitive domain functions are associated with distinct patterns of cortical and white matter diffusivity in elderly with no dementia. Posterior cingulum tract FA was associated with all 4 cognitive domain functions, in agreement with the hypothesis that the posterior cingulate cortex is the main connectivity hub for cognitive brain networks. Microstructural changes identified on DTI may be associated with neurodegenerative pathologies underlying cognitive changes in older adults without dementia.


Laparoscopic management of dermoid cysts in patients of reproductive age.
Ovarian dermoid cysts are one of the most common germ cell tumors in women. The aim of the study was to analyze the use of laparoscopy in dermoid cysts treatment in women of reproductive age. The studied material consisted of 95 patients, aged 17-49, operated on because of dermoid cyst suspicion at the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, in the years 1996-2005. All the patients had pre-operative CA-125 antigen evaluation and transvaginal sonography with Doppler assessment of the ovarian pathology. All the women with tumors less than 8 cm in diameter were qualified for laparoscopic management. The majority of patients were below 40 years of age (86 women; 90.5%). Out of 95 studied cases, 93 (97.9%) had the cyst removed during laparoscopy, mostly elective. Dermoid cyst enucleation was the most commonly applied procedure, while oophorectomy was the least frequent. The whole gonad was removed in 33 patients (34.7%), generally because of the total loss of functional ovarian tissue surrounding the cyst (28 women; 29.5%). All the extracted material was submitted for a histopathological examination--the diagnosis of mature ovarian cystic teratoma was confirmed in 100% of cases. The correspondence of pre-operative sonographic imaging and intraoperative macroscopic assessment was evaluated. In 85 (89.5%) operated patients an ovarian tumor was earlier described as a dermoid cyst. Laparoscopic treatment of ovarian dermoid cysts is a safe method, offering many advantages in comparison to classical surgery. However, proper early qualification, based on medical history, gynecological and sonographic examination is of great importance.


Systems Thinking as a Framework for Analyzing Commercial Determinants of Health.
Policy Points: Worldwide, more than 70% of all deaths are attributable to noncommunicable diseases (NCDs), nearly half of which are premature and apply to individuals of working age. Although such deaths are largely preventable, effective solutions continue to elude the public health community. One reason is the considerable influence of the "commercial determinants of health": NCDs are the product of a system that includes powerful corporate actors, who are often involved in public health policymaking. This article shows how a complex systems perspective may be used to analyze the commercial determinants of NCDs, and it explains how this can help with (1) conceptualizing the problem of NCDs and (2) developing effective policy interventions. The high burden of noncommunicable diseases (NCDs) is politically salient and eminently preventable. However, effective solutions largely continue to elude the public health community. Two pressing issues heighten this challenge: the first is the public health community's narrow approach to addressing NCDs, and the second is the involvement of corporate actors in policymaking. While NCDs are often conceptualized in terms of individual-level risk factors, we argue that they should be reframed as products of a complex system. This article explores the value of a systems approach to understanding NCDs as an emergent property of a complex system, with a focus on commercial actors. Drawing on Donella Meadows's systems thinking framework, this article examines how a systems perspective may be used to analyze the commercial determinants of NCDs and, specifically, how unhealthy commodity industries influence public health policy. Unhealthy commodity industries actively design and shape the NCD policy system, intervene at different levels of the system to gain agency over policy and politics, and legitimize their presence in public health policy decisions. It should be possible to apply the principles of systems thinking to other complex public health issues, not just NCDs. Such an approach should be tested and refined for other complex public health challenges.


Complex organization of human primary motor cortex: a high-resolution fMRI study.
A traditional view of the human motor cortex is that it contains an overlapping sequence of body part representations from the tongue in a ventral location to the foot in a dorsal location. In this study, high-resolution functional MRI (1.5x1.5x2 mm) was used to examine the somatotopic map in the lateral motor cortex of humans, to determine whether it followed the traditional somatotopic order or whether it contained any violations of that somatotopic order. The arm and hand representation had a complex organization in which the arm was relatively emphasized in two areas: one dorsal and the other ventral to a region that emphasized the fingers. This violation of a traditional somatotopic order suggests that the motor cortex is not merely a map of the body but is topographically shaped by other influences, perhaps including correlations in the use of body parts in the motor repertoire.


Introducing a Standardized Acupuncture Protocol for Peripheral Neuropathy: A Case Series.
Background: Peripheral neuropathy (PN) is defined as damage to the peripheral nervous system caused by a primary lesion or dysfunction. Multiple recent trials have suggested that acupuncture is beneficial for treating neuropathic pain. One challenge in acupuncture research is the lack of standardization of point selection, number of needles used, needle-retention time, needling depth, amount of needle manipulation, and use of moxibustion and electroacupuncture (EA). Objectives: This article presents a standardized acupuncture protocol for the treatment of PN that incorporates structural acupuncture principles based on proximity to peripheral nerves and on traditional approaches to the treatment of neuropathic pain. Materials and Methods: Ten consecutive patients diagnosed with large- or small-fiber neuropathy of various etiologies were treated with a standardized protocol, based on anatomical correlations of peripheral nerves and acupuncture points. Manual acupuncture was applied to left LR 4, LU 5; bilateral LI 11, KI 27, ST 36, GB 34, SP 6, SP 9, LI 4, TE 5, and BaFeng (except for the space between the first and second digits of the toes; LR 3 was used for that space). EA was applied to bilateral KI 3-1 and bilateral ST 41-LR 3. Patients underwent at least six acupuncture sessions, although the total number of sessions varied. Outcomes were measured using a visual analogue scale (VAS) and clinical signs and symptoms. Results: All 10 patients indicated improvement on the VAS and in clinical presentation. Conclusions: This standardized protocol appears to be effective for the treatment of neuropathy of various causes, including large- and small-fiber involvement. Further studies with larger sample sizes and randomized comparisons against sham acupuncture and other acupuncture regimens will be helpful to determine if this protocol could be established as a guideline for approaching peripheral neuropathy.


Changes in neurofilament transport coincide temporally with alterations in the caliber of axons in regenerating motor fibers.
The delivery of neurofilaments via axonal transport has been proposed as an important mechanism for regulating axonal caliber. If this hypothesis is correct, alterations in axonal caliber should appear coincident with changes in the delivery of neurofilaments to the axon. The purpose of this study was to determine whether alterations in the caliber of axons in the proximal stumps of transected motor fibers precede, coincide with, or occur substantially later than changes in the delivery of neurofilaments via axonal transport. Between 3 d and 12 wk after crushing the sciatic nerves of 7-wk-old rats, lumbar motor neurons were labeled by the intraspinal injection of [35S]methionine. In neurons labeled between 3 d and 6 wk after axotomy, the relative amount of neurofilament protein in the slow component, as reflected by the ratio of the radioactivities of the 145-kD neurofilament protein to tubulin, was reduced to 30-40% of the control value. Moreover, as determined by immunoreactivity on blots, the amounts of neurofilament protein and tubulin in these nerve fibers were reduced fourfold and twofold, respectively. Thus, changes in the ratio of labeled neurofilament protein to tubulin correlated with comparable changes in the quantities of these proteins in nerve fibers. This decrease in the quantity of neurofilament proteins delivered to axons coincided temporally with reductions in axonal caliber. After regeneration occurred, the delivery of neurofilament proteins returned to pre-axotomy levels (i.e., 8 wk after axotomy), and caliber was restored with resumption of normal age-related radial growth of these axons. Thus, changes in axonal caliber coincided temporally with alterations in the delivery of neurofilament proteins. These results suggest that the majority of neurofilaments in these motor fibers continuously move in the anterograde direction as part of the slow component of axonal transport and that the transport of neurofilaments plays an important role in regulating the caliber of these axons.


Campylobacter genotyping to determine the source of human infection.
Campylobacter species cause a high proportion of bacterial gastroenteritis cases and are a significant burden on health care systems and economies worldwide; however, the relative contributions of the various possible sources of infection in humans are unclear. National-scale genotyping of Campylobacter species was used to quantify the relative importance of various possible sources of human infection. Multilocus sequence types were determined for 5674 isolates obtained from cases of human campylobacteriosis in Scotland from July 2005 through September 2006 and from 999 Campylobacter species isolates from 3417 contemporaneous samples from potential human infection sources. These data were supplemented with 2420 sequence types from other studies, representing isolates from a variety of sources. The clinical isolates were attributed to possible sources on the basis of their sequence types with use of 2 population genetic models, STRUCTURE and an asymmetric island model. The STRUCTURE and the asymmetric island models attributed most clinical isolates to chicken meat (58% and 78% of Campylobacter jejuni and 40% and 56% of Campylobacter coli isolates, respectively), identifying it as the principal source of Campylobacter infection in humans. Both models attributed the majority of the remaining isolates to ruminant sources, with relatively few isolates attributed to wild bird, environment, swine, and turkey sources. National-scale genotyping was a practical and efficient methodology for the quantification of the contributions of different sources to human Campylobacter infection. Combined with the knowledge that retail chicken is routinely contaminated with Campylobacter, these results are consistent with the view that the largest reductions in human campylobacteriosis in industrialized countries will come from interventions that focus on the poultry industry.


3D Printing Neuron Equivalent Circuits: An Undergraduate Laboratory Exercise.
The electrical equivalent circuit for a neuron is composed of common electrical components in a configuration that replicates the passive electrical properties and behaviors of the neural membrane. It is a powerful tool used to derive such fundamental neurophysiological equations as the Hodgkin-Huxley equations, and it is also the basis for well-known exercises that help students to model the passive (Ohmic) properties of the neuronal membrane. Unfortunately, as these exercises require basic knowledge of electronics, they are generally not physically conducted in biomedical courses, but remain merely conceptual exercises in a book or simulations on a computer. In such manifestations, they lack the "hands-on" appeal for students and teachers afforded by laboratory experimentations. Here, we propose a new approach to these experiments in which a desktop 3D printer and conductive paint are used to build the circuit and the popular programmable microcontroller, the Arduino UNO, is used as a graphical oscilloscope when connected to a standard computer. This set-up has the advantage of being very easy to build and less clumsy than a circuit in a prototyping board or connected with alligator clips, with the added benefit of being conveniently portable for classroom demonstrations. Most importantly, this method allows the monitoring of real-time changes in the current flowing through the circuit by means of a graphical display (by way of the Arduino) at a fraction of the cost of commercially available oscilloscopes.


Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies.
Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. To evaluate the association between dietary fiber intake and risk of colorectal cancer. From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725,628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. Incident colorectal cancer. During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07). In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer.


Differential interactions of bacterial lipopolysaccharides with lipid membranes: implications for TRPA1-mediated chemosensation.
Bacterial lipopolysaccharides (LPS) activate the TRPA1 cation channels in sensory neurons, leading to acute pain and inflammation in mice and to aversive behaviors in fruit flies. However, the precise mechanisms underlying this effect remain elusive. Here we assessed the hypothesis that TRPA1 is activated by mechanical perturbations induced upon LPS insertion in the plasma membrane. We asked whether the effects of different LPS on TRPA1 relate to their ability to induce mechanical alterations in artificial and cellular membranes. We found that LPS from E. coli, but not from S. minnesota, activates TRPA1. We then assessed the effects of these LPS on lipid membranes using dyes whose fluorescence properties change upon alteration of the local lipid environment. E. coli LPS was more effective than S. minnesota LPS in shifting Laurdan's emission spectrum towards lower wavelengths, increasing the fluorescence anisotropy of diphenylhexatriene and reducing the fluorescence intensity of merocyanine 540. These data indicate that E. coli LPS induces stronger changes in the local lipid environment than S. minnesota LPS, paralleling its distinct ability to activate TRPA1. Our findings indicate that LPS activate TRPA1 by producing mechanical perturbations in the plasma membrane and suggest that TRPA1-mediated chemosensation may result from primary mechanosensory mechanisms.


Inhibition of the colony-stimulating-factor-1 receptor affects the resistance of lung cancer cells to cisplatin.
In the present work we show that multiple lung cancer cell lines contain cisplatin resistant cell subpopulations expressing the Colony-Stimulating-Factor-Receptor-1 (CSF-1R) and surviving chemotherapy-induced stress. By exploiting siRNA-mediated knock down in vitro and the use of an investigational CSF-1R TKI (JNJ-40346527) in vitro and in vivo, we show that expression and function of the receptor are required for the clonogenicity and chemoresistance of the cell lines. Thus, inhibition of the kinase activity of the receptor reduced the levels of EMT-associated genes, stem cell markers and chemoresistance genes. Additionally, the number of high aldehyde dehydrogenase (ALDH) expressing cells was reduced, consequent to the lack of cisplatin-induced increase of ALDH isoforms. This affected the collective chemoresistance of the treated cultures. Treatment of tumor bearing mice with JNJ-40346527, at pharmacologically relevant doses, produced strong chemo-sensitizing effects in vivo. These anticancer effects correlated with a reduced number of CSF-1Rpos cells, in tumors excised from the treated mice. Depletion of the CD45pos cells within the treated tumors did not, apparently, play a major role in mediating the therapeutic response to the TKI. Thus, lung cancer cells express a functional CSF-1 and CSF-1R duo which mediates pro-tumorigenic effects in vivo and in vitro and can be targeted in a therapeutically relevant way. These observations complement the already known role for the CSF-1R at mediating the pro-tumorigenic properties of tumor-infiltrating immune components.


Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations.
Glucagon cell adenomatosis (GCA) was recently recognized as a multifocal hyperplastic and neoplastic disease of the glucagon cells unrelated to multiple endocrine neoplasia type 1 and von-Hippel-Lindau disease. The study focused on the molecular analysis of the glucagon receptor (GCGR) gene in GCA and a description of the clinicopathological features of GCA with and without GCGR mutations. Pancreatic tissues from patients showing multiple glucagon cell tumors were morphologically characterized and macro- or microdissected. All exons of the GCGR gene were analyzed for mutations by Sanger and next-generation sequencing. Genotyping for all detected GCGR variants was performed in 2560 healthy individuals. Six patients with GCA, and the parents of one patient were included in the study. The main outcome measures were the correlations between the patients' GCGR mutation status and the respective clinicopathological data. GCGR germline mutations were found in three of six patients. Patient 1 harbored a homozygous stop mutation. This patient's parents showed an identical but heterozygous GCGR mutation. Patient 2 had two different heterozygous point mutations leading each to premature stop codons. Patient 3 exhibited two homozygous missense mutations. No GCGR mutations were identified in the three other patients and in a large cohort of healthy subjects. The patients harboring GCGR mutations exhibited a greater number of tumors and larger tumors than patients with wild-type GCGR. One of the patients with wild-type GCGR showed lymph node micrometastases. GCA with GCGR germline mutations seems to follow an autosomal-recessive trait. By interrupting the GCGR signaling pathways GCGR mutations probably cause GCA via glucagon cell hyperplasia. GCA also occurs in patients without GCGR mutations, but seems to be associated with fewer and smaller tumors.


Role of the renin-angiotensin-aldosterone system in the pathogenesis of atherosclerosis.
Renin-angiotensin-aldosterone (RAAS) is a hormone system which acts on multiple physiologic pathways primarily by regulating blood pressure and fluid balance, but also by local autocrine and paracrine actions. In pathophysiologic conditions RAAS also contributes to the development of atherosclerosis and its various manifestations, both directly and indirectly through the actions on other systems. RAAS mainly acts as a promoter of atherosclerosis by its action on vessels, and by promoting the development of hypertension, insulin resistance and diabetes, obesity, vascular and systemic inflammation. As RAAS plays a key role in the pathogenesis of cardiovascular diseases, RAAS genes have been extensively studied as candidate genes for atherosclerosis and coronary artery disease. Several polymorphisms of its genes have been found to be in relationship with atherosclerosis and cardiovascular diseases. In this review we will discuss these issues and present the most recent advances about this topic.


Functional annotation of a divergent genome using sequence and structure-based similarity.
Microsporidia are a large taxon of intracellular pathogens characterized by extraordinarily streamlined genomes with unusually high sequence divergence and many species-specific adaptations. These unique factors pose challenges for traditional genome annotation methods based on sequence similarity. As a result, many of the microsporidian genomes sequenced to date contain numerous genes of unknown function. Recent innovations in rapid and accurate structure prediction and comparison, together with the growing amount of data in structural databases, provide new opportunities to assist in the functional annotation of newly sequenced genomes. In this study, we established a workflow that combines sequence and structure-based functional gene annotation approaches employing a ChimeraX plugin named ANNOTEX (Annotation Extension for ChimeraX), allowing for visual inspection and manual curation. We employed this workflow on a high-quality telomere-to-telomere sequenced tetraploid genome of Vairimorpha necatrix. First, the 3080 predicted protein-coding DNA sequences, of which 89% were confirmed with RNA sequencing data, were used as input. Next, ColabFold was used to create protein structure predictions, followed by a Foldseek search for structural matching to the PDB and AlphaFold databases. The subsequent manual curation, using sequence and structure-based hits, increased the accuracy and quality of the functional genome annotation compared to results using only traditional annotation tools. Our workflow resulted in a comprehensive description of the V. necatrix genome, along with a structural summary of the most prevalent protein groups, such as the ricin B lectin family. In addition, and to test our tool, we identified the functions of several previously uncharacterized Encephalitozoon cuniculi genes. We provide a new functional annotation tool for divergent organisms and employ it on a newly sequenced, high-quality microsporidian genome to shed light on this uncharacterized intracellular pathogen of Lepidoptera. The addition of a structure-based annotation approach can serve as a valuable template for studying other microsporidian or similarly divergent species.


Subpopulations of Staphylococcus aureus clonal complex 121 are associated with distinct clinical entities.
We investigated the population structure of Staphylococcus aureus clonal complex CC121 by mutation discovery at 115 genetic housekeeping loci from each of 154 isolates, sampled on five continents between 1953 and 2009. In addition, we pyro-sequenced the genomes from ten representative isolates. The genome-wide SNPs that were ascertained revealed the evolutionary history of CC121, indicating at least six major clades (A to F) within the clonal complex and dating its most recent common ancestor to the pre-antibiotic era. The toxin gene complement of CC121 isolates was correlated with their SNP-based phylogeny. Moreover, we found a highly significant association of clinical phenotypes with phylogenetic affiliations, which is unusual for S. aureus. All isolates evidently sampled from superficial infections (including staphylococcal scalded skin syndrome, bullous impetigo, exfoliative dermatitis, conjunctivitis) clustered in clade F, which included the European epidemic fusidic-acid resistant impetigo clone (EEFIC). In comparison, isolates from deep-seated infections (abscess, furuncle, pyomyositis, necrotizing pneumonia) were disseminated in several clades, but not in clade F. Our results demonstrate that phylogenetic lineages with distinct clinical properties exist within an S. aureus clonal complex, and that SNPs serve as powerful discriminatory markers, able to identify these lineages. All CC121 genomes harboured a 41-kilobase prophage that was dissimilar to S. aureus phages sequenced previously. Community-associated MRSA and MSSA from Cambodia were extremely closely related, suggesting this MRSA arose in the region.


Atomic images by electron-wave holography.
Direct views of electron clouds in atoms h-ave been observed visually and photographed by means of a two-stage holographic miscroscope based on Gabor's principle of image reconstruction. Holograms are produced with 40-kilo-volt electron radiation and decoded with an optical laser. The obviation of an objective lens makes feasible a numerical aperture of 0.37 and a resolving power exceeding 0.1 angstrom.


A Comparative Evaluation of Different Diagnostic Modalities in the Diagnosis of Typhoid Fever Using a Composite Reference Standard: A Tertiary Hospital Based Study in Central India.
Enteric fever, caused by Salmonella spp. is a major cause of morbidity and mortality worldwide and endemic in many developing countries including India and other South-East Asian countries. Blood culture is regarded as the gold standard for diagnosis. Currently, the standard serological method is tube agglutination with moderate sensitivity and specificity. Dot blot assay detecting IgM and IgG antibodies to a specific 50kD Outer Membrane Protein (OMP) antigen of Salmonella spp. is a simple, reliable, affordable and rapid test which can help in the early diagnosis of typhoid fever. To systematically evaluate the different diagnostic modalities against a composite reference standard for the better diagnosis of typhoid fever in clinically suspected cases of typhoid fever. This cross-sectional, prospective analytical study was carried out at a tertiary care hospital attached to Medical College in central India from November 2011 to June 2013. A total of 163 blood samples, collected aseptically from patients clinically diagnosed of enteric fever, were tested using various component tests like blood culture, Tube Widal and Dot Enzyme Immuno Assay (Dot EIA) for IgG and/or IgM. Composite Reference Standard (CRS) was created for defining the confirmed cases of typhoid fever using the component tests, wherein culture positive and in absence of culture positivity any two component test positive patients were taken as confirmed cases. All the component tests were evaluated against the CRS for sensitivity, specificity, PPV and NPV and their significance in relation to the duration of illness using statistical tests of significance. Blood culture was positive in 16 (9.81%) whereas, Tube Widal, IgM, IgG and IgM+IgG in combination were positive in 88(54%), 58(35.58%), 30 (18.40%) and 75 (46.01%) respectively. Using a two test criteria of CRS framed, a total of 104 patients were considered as confirmed cases. Though specificity of blood culture was 100%, the sensitivity was low with significant detection rate in 1st week of illness. Tube Widal showed a sensitivity of 65.38% and specificity of 89.83% with significant detection rate in 2nd week. Dot blot assay for IgM, IgG and Combined IgM and IgG showed a sensitivity of 71.15%, 65.28% and 51.72% respectively whereas, the specificity was 10.16%, 47.45% and 74.57% respectively with significant detection rate in 2nd and 3rd week of illness. It can be concluded that though blood culture is still the gold standard, Dot blot assay found to have high sensitivity and good specificity might be a practical alternative test for the rapid diagnosis of typhoid fever if interpreted with care particularly using a composite reference standard. Further, it is reliable, simple to perform and rapid; results being available in 1 hour when compared to 48 hours for blood culture and 18 hours for Tube Widal test.


Measurement of parity violation in electron-quark scattering.
Symmetry permeates nature and is fundamental to all laws of physics. One example is parity (mirror) symmetry, which implies that flipping left and right does not change the laws of physics. Laws for electromagnetism, gravity and the subatomic strong force respect parity symmetry, but the subatomic weak force does not. Historically, parity violation in electron scattering has been important in establishing (and now testing) the standard model of particle physics. One particular set of quantities accessible through measurements of parity-violating electron scattering are the effective weak couplings C2q, sensitive to the quarks' chirality preference when participating in the weak force, which have been measured directly only once in the past 40 years. Here we report a measurement of the parity-violating asymmetry in electron-quark scattering, which yields a determination of 2C2u - C2d (where u and d denote up and down quarks, respectively) with a precision increased by a factor of five relative to the earlier result. These results provide evidence with greater than 95 per cent confidence that the C2q couplings are non-zero, as predicted by the electroweak theory. They lead to constraints on new parity-violating interactions beyond the standard model, particularly those due to quark chirality. Whereas contemporary particle physics research is focused on high-energy colliders such as the Large Hadron Collider, our results provide specific chirality information on electroweak theory that is difficult to obtain at high energies. Our measurement is relatively free of ambiguity in its interpretation, and opens the door to even more precise measurements in the future.


Listening Comprehension and Listening Effort in the Primary School Classroom.
In the primary school classroom, children are exposed to multiple factors that combine to create adverse conditions for listening to and understanding what the teacher is saying. Despite the ubiquity of these conditions, there is little knowledge concerning the way in which various factors combine to influence listening comprehension and the effortfulness of listening. The aim of the present study was to investigate the combined effects of background noise, voice quality, and visual cues on children's listening comprehension and effort. To achieve this aim, we performed a set of four well-controlled, yet ecologically valid, experiments with 245 eight-year-old participants. Classroom listening conditions were simulated using a digitally animated talker with a dysphonic (hoarse) voice and background babble noise composed of several children talking. Results show that even low levels of babble noise interfere with listening comprehension, and there was some evidence that this effect was reduced by seeing the talker's face. Dysphonia did not significantly reduce listening comprehension scores, but it was considered unpleasant and made listening seem difficult, probably by reducing motivation to listen. We found some evidence that listening comprehension performance under adverse conditions is positively associated with individual differences in executive function. Overall, these results suggest that multiple factors combine to influence listening comprehension and effort for child listeners in the primary school classroom. The constellation of these room, talker, modality, and listener factors should be taken into account in the planning and design of educational and learning activities.


Recent progress in synthesis and application of mussel-inspired adhesives.
The rapid and robust adhesion of marine mussels to diverse solid surfaces in wet environments is mediated by the secreted mussel adhesive proteins which are abundant in a catecholic amino acid, l-3,4-dihydroxyphenylalanine (Dopa). Over the last two decades, enormous efforts have been devoted to the development of synthetic mussel-inspired adhesives with water-resistant adhesion and cohesion properties by modifying polymer systems with Dopa and its analogues. In the present review, an overview of the unique features of various mussel foot proteins is provided in combination with an up-to-date understanding of catechol chemistry, which contributes to the strong interfacial binding via balancing a variety of covalent and noncovalent interactions including oxidative cross-linking, electrostatic interaction, metal-catechol coordination, hydrogen bonding, hydrophobic interactions and π-π/cation-π interactions. The recent developments of novel Dopa-containing adhesives with on-demand mechanical properties and other functionalities are then summarized under four broad categories: viscous coacervated adhesives, soft adhesive hydrogels, smart adhesives, and stiff adhesive polyesters, where their emerging applications in engineering, biological and biomedical fields are discussed. Limitations of the developed adhesives are identified and future research perspectives in this field are proposed.


Extreme spatial heterogeneity in carbonate accretion potential on a Caribbean fringing reef linked to local human disturbance gradients.
The capacity of coral reefs to maintain their structurally complex frameworks and to retain the potential for vertical accretion is vitally important to the persistence of their ecological functioning and the ecosystem services they sustain. However, datasets to support detailed along-coast assessments of framework production rates and accretion potential do not presently exist. Here, we estimate, based on gross bioaccretion and bioerosion measures, the carbonate budgets and resultant estimated accretion rates (EAR) of the shallow reef zone of leeward Bonaire - between 5 and 12 m depth - at unique fine spatial resolution along this coast (115 sites). Whilst the fringing reef of Bonaire is often reported to be in a better ecological condition than most sites throughout the wider Caribbean region, our data show that the carbonate budgets of the reefs and derived EAR varied considerably across this ~58 km long fringing reef complex. Some areas, in particular the marine reserves, were indeed still dominated by structurally complex coral communities with high net carbonate production (>10 kg CaCO3 m-2 year-1 ), high live coral cover and complex structural topography. The majority of the studied sites, however, were defined by relatively low budget states (<2 kg CaCO3 m-2 year-1 ) or were in a state of net erosion. These data highlight the marked spatial heterogeneity that can occur in budget states, and thus in reef accretion potential, even between quite closely spaced areas of individual reef complexes. This heterogeneity is linked strongly to the degree of localized land-based impacts along the coast, and resultant differences in the abundance of reef framework building coral species. The major impact of this variability is that those sections of reef defined by low-accretion rates will have limited capacity to maintain their structural integrity and to keep pace with current projections of climate change induced sea-level rise (SLR), thus posing a threat to reef functioning and biodiversity, potentially leading to trophic cascades. Since many Caribbean reefs are more severely degraded than those found around Bonaire, it is to be expected that the findings presented here are rather the rule than the exception, but the study also highlights the need for similar high spatial resolution (along-coast) assessments of budget states and accretion rates to meaningfully explore increasing coastal risk at the country level. The findings also more generally underline the significance of reducing local anthropogenic disturbance and restoring framework building coral assemblages. Appropriately focussed local preservation efforts may aid in averting future large-scale above reef water depth increases on Caribbean coral reefs and will limit the social and economic implications associated with the loss of reef goods and services.


Gender differences in Brazilian street youth's family circumstances and experiences on the street.
It has been proposed that homeless street girls are more likely to be from dysfunctional families and exhibit psychological distress than homeless street boys, reflecting cultural factors that result in differential norms for male and female behavior. The current analysis examined whether male and female street youth in a mid-sized Brazilian city differed in their family circumstances and day-to-day functioning on the street. The opportunity sample consisted of 33 male (mean age 14.3, range 10-17 years) and 33 female (mean age 14.6, range 11-18 years) street youth who participated in a sentence completion task and structured interview examining family experiences and ability to meet daily needs on the street. Consistent with the cultural hypothesis, girls described more negative family backgrounds than boys (e.g., they were more likely to have left home because of conflict or abuse, and reported more negative relationships with their parents). However, girls' functioning on the street was similar to, and in some cases more positive than, that of boys (e.g., fewer girls reported police violence and begging to earn money). The few gender differences that emerged in this study offer little support for the cultural hypothesis. The findings make sense if local factors, such as services available for male and female youth and public response to street youth, are considered. It appears that street youth differ in their experiences depending on local circumstances, highlighting the need for caution in generalizing about the situation of street youth in different countries.


A within-implant comparison to evaluate the concept of platform switching: a randomised controlled trial.
To evaluate whether platform switching could preserve marginal bone around implants up to 6 months after loading. 15 patients were selected for a randomised controlled trial. Each patient received one customised wide body implant, with the external hex connection located eccentrically, allowing an extra 1 mm switch on one side. The hex was positioned at random at the mesial or distal side and the implant was loaded after 6 months of non-submerged healing. Patients were examined at 3, 6 and 12 months after surgery, during which a radiograph was taken to evaluate bone levels. At 12 months, the mucosal thickness was measured using a perio-probe. All implants survived and the mean overall bone loss, calculated from both the switched and non-switched side, was 0.39 mm (SD 0.33, range 0.00-1.45), 0.85 mm (SD 0.59, range 0.10-2.50) and 0.80 mm (SD 0.46, 0.26-1.89) after 3, 6 and 12 months, respectively. The bone loss continued up to 6 months but stabilised thereafter (P = 0.615). Significantly more bone loss was observed at the non-switched side compared to the switched side at 3 months (0.51 mm versus 0.28 mm, P = 0.019), 6 months (1.05 mm versus 0.64 mm, P = 0.002) and 12 months (0.94 mm versus 0.66 mm, P = 0.002). The mean mucosal thickness was 4.22 mm (SD 1.45; range 1.50-7.00), and was not significantly different between the switched and non-switched sides (P = 0.882). However, using a post-hoc analysis with the mean thickness as a threshold, the mean bone loss was only significantly different between switched and non-switched sides when the mucosa was thicker than 4.22 mm (P = 0.036). The outcome of this randomised trial is in accordance with earlier studies suggesting that that platform switching decreases bone loss by 30%. Although the sample size was limited, it seems that the creation of a biologic width affects peri-implant bone loss to a significant extent and that platform switching is only effective when the mucosal thickness allows the establishment of a biologic width.


Spatial coherence of synchrotron radiation.
The spatial coherence properties of a monochromatic component of synchrotron radiation from an insertion device in the Fraunhofer limit are analyzed in the general case when the coherence distance is comparable with the beam width, expressing them by simple products and convolutions of Fourier transforms and autocorrelations on the single-electron field amplitude and the electron-beam position and angular distributions. In particular, the Gaussian approximation is discussed, in which case the far-field amplitude satisfies the Schell condition (its statistical properties can be described by a coherence factor depending only on the difference of the reciprocal space coordinates), and this discussion leads to simple estimates of the coherence widths. The coherence widths deviate from the Van Cittert-Zernike values when one or more of the phase space widths of the electron beam are close to (or smaller than) the diffraction limit.


Statistical modelling for clinical mastitis in the dairy cow: problems and solutions.
Modelling case occurrence and risk factors for clinical mastitis, as a key multifactorial disease in the dairy cow, requires statistical models. The type of model used depends on the choice of perception or the study level: herd, lactation, animal, udder and quarter. The validity of the tests that are performed through these models is especially ensured when hypotheses of independence between statistical units are respected, and when the model adjustments do not involve overdispersion faced with the observed data. In the article, the main sources of overdispersion are identified according to the different levels of perception of mastitis risk. Then, the proposed solutions to control for overdispersion at each study level are discussed and the difficulty to compare the study results is highlighted through a variety of methodological choices of the authors. Two main categories of models are used for modelling clinical mastitis, i.e. generalist exploratory models and explanatory designed models. The contribution of the explanatory models to improve modelling accuracy and relevance is documented through the two main published methodological approaches, the first one being based on a states model, and the second on a survival model. The integration and optimisation of such explanatory modelling methods should be possible in the future in order to develop a more global explanatory model including herd risk factors, which could pertinently predict udder infections (both clinical and subclinical) at the cow, lactation, or even udder and quarter levels.


Detection of seizure activity in EEG by an artificial neural network: a preliminary study.
Neural networks, inspired by the organizational principles of the human brain, have recently been used in various fields of application such as pattern recognition, identification, classification, speech, vision, signal processing, and control systems. In this study, a two-layered neural network has been trained for the recognition of temporal patterns of the electroencephalogram (EEG). This network is called a Learning Vector Quantization (LVQ) neural network since it learns the characteristics of the signal presented to it as a vector. The first layer is a competitive layer which learns to classify the input vectors. The second, linear, layer transforms the output of the competitive layer to target classes defined by the user. We have tested and evaluated the LVQ network. The network successfully detects epileptiform discharges (EDs) when trained using EEG records scored by a neurologist. Epochs of EEG containing EDs from one subject have been used for training the network, and EEGs of other subjects have been used for testing the network. The results demonstrate that the LVQ detector can generalize the learning to previously "unseen" records of subjects. This study shows that the LVQ network offers a practical solution for ED detection which is easily adjusted to an individual neurologist's style and is as sensitive and specific as an expert visual analysis.


Physical impairment in HIV infections and AIDS: responses to resistance and aerobic training.
The aim of this paper was to examine impairments in muscle strength and aerobic power associated with HIV and AIDS, to define optimal regimes of resistance and aerobic training, and to explore possible influences of HAART treatment upon responses. Data from HealthStar/Ovid (1985 to 2013) were supplemented by references in identified articles and material in the author's personal files, yielding 133 citations. Detailed analysis was restricted to controlled trials (16 studies of resistance training, 17 of aerobic training). HIV infection and AIDS are often marked by substantial muscle wasting of multi-factorial origin. Impairment of aerobic function is more variable, with possible effects from physical inactivity, HAART therapy and muscular weakness. Most patients respond well to moderate resistance and aerobic training, showing substantial gains of strength, smaller improvements of aerobic power, and no adverse changes in CD4+ count or viral load. Moreover, these responses do not seem adversely affected by HAART therapy. Patients with HIV and AIDS should participate in moderate combined resistance and aerobic training programs. Such training elicits substantial gains in strength and cardiac function, and improves mood state and quality of life without adverse effects upon disease progression. Moreover, responses are not adversely affected by HAART therapy. The main challenge in the western world is to maintain compliance, since adherence to rehabilitation programs is often poor. There is also a need to develop exercise programs appropriate to regions where the disease is most prevalent, and to monitor possible interactions between rehabilitation and newly emerging forms of treatment.


A non-invasive method for measuring preimplantation embryo physiology.
The physiology of the early embryo may be indicative of embryo vitality and therefore methods for non-invasively monitoring physiological parameters from embryos could improve preimplantation diagnoses. The self-referencing electrophysiological technique is capable of non-invasive measurement of the physiology of individual cells by monitoring the movement of ions and molecules between the cell and the surrounding media. Here we use this technique to monitor gradients of calcium, potassium, oxygen and hydrogen peroxide around individual mouse preimplantation embryos. The calcium-sensitive electrode in self-referencing mode identified a region of elevated calcium concentration (approximately 0.25 pmol) surrounding each embryo. The calcium gradient surrounding embryos was relatively steep, such that the region of elevated calcium extended into the medium only 4 microns from the embryo. By contrast, using an oxygen-sensitive electrode an extensive gradient of reduced dissolved oxygen concentration was measured surrounding the embryo and extended tens of micrometres into the medium. A gradient of neither potassium nor hydrogen peroxide was observed around unperturbed embryos. We also demonstrate that monitoring the physiology of embryos using the self-referencing technique does not compromise their subsequent development. Blastocyts studied with the self-referencing technique implanted and developed to term at the same frequency as did unexamined, control embryos. Therefore, the self-referencing electrode provides a valuable non-invasive technique for studying the physiology and pathophysiology of individual embryos without hindering their subsequent development.


Tumor spectrum in ARF-deficient mice.
The p19ARF product of the INK4a/ARF locus is induced in response to potentially oncogenic hyperproliferative signals and activates p53 by interfering with its negative regulator, Mdm2. Mice lacking ARF are highly prone to tumor development, and in this study, 80% of these animals spontaneously developed tumors and died within their first year of life. Mice that were heterozygous for ARF also developed tumors after a longer latency, whereas their wild-type littermates did not. In heterozygotes, tumor formation was accompanied by loss of the residual ARF allele and/or lack of ARF mRNA expression, implying that ARF can act as a canonical "two-hit" tumor suppressor gene. Tumors occurred earlier in life in ARF-null animals that were neonatally irradiated or given dimethylbenzanthrene, and several animals treated with carcinogen simultaneously developed multiple forms of malignancy arising from distinct cell lineages. Although p53-null mice primarily develop lymphomas and fibrosarcomas, the frequency of these two tumor types was inverted in ARF-null animals, with undifferentiated sarcomas predominating in a 3:2 ratio; 28% of ARF-null animals developed carcinomas and tumors of the nervous system, which have been rarely observed in untreated p53-null mice. The longer latency of tumor formation in ARF-null versus p53-null mice, therefore, appears to enable a broader spectrum of tumors to emerge.


Simultaneous phenotyping of leaf growth and chlorophyll fluorescence via GROWSCREEN FLUORO allows detection of stress tolerance in Arabidopsis thaliana and other rosette plants.
Stress caused by environmental factors evokes dynamic changes in plant phenotypes. In this study, we deciphered simultaneously the reaction of plant growth and chlorophyll fluorescence related parameters using a novel approach which combines existing imaging technologies (GROWSCREEN FLUORO). Three different abiotic stress situations were investigated demonstrating the benefit of this approach to distinguish between effects related to (1) growth, (2) chlorophyll-fluorescence, or (3) both of these aspects of the phenotype. In a drought stress experiment with more than 500 plants, poly(ADP-ribose) polymerase (PARP) deficient lines of Arabidopsis thaliana (L.) Heynh showed increased relative growth rates (RGR) compared with C24 wild-type plants. In chilling stress, growth of PARP and C24 lines decreased rapidly, followed by a decrease in Fv/Fm. Here, PARP-plants showed a more pronounced decrease of Fv/Fm than C24, which can be interpreted as a more efficient strategy for survival in mild chilling stress. Finally, the reaction of Nicotiana tabacum L. to altered spectral composition of the intercepted light was monitored as an example of a moderate stress situation that affects chlorophyll-fluorescence related, but not growth-related parameters. The examples investigated in this study show the capacity for improved plant phenotyping based on an automated and simultaneous evaluation of growth and photosynthesis at high throughput.


p16/CDKN2A FISH in Differentiation of Diffuse Malignant Peritoneal Mesothelioma From Mesothelial Hyperplasia and Epithelial Ovarian Cancer.
It can be difficult to differentiate diffuse malignant peritoneal mesothelioma (DMPM) from reactive mesothelial hyperplasia (RMH) or peritoneal dissemination of gynecologic malignancies, such as epithelial ovarian cancer (EOC), which cause a large amount of ascites. Detection of the homozygous deletion of p16/CDKN2A (p16) by fluorescence in situ hybridization (FISH) is an effective adjunct in the diagnosis of malignant pleural mesothelioma. The aim of this study was to investigate the ability of the p16 FISH assay to differentiate DMPM from RMH and EOC. p16 FISH was performed in 28 DMPMs (successful in 19), 30 RMHs, and 40 EOC cases. The cutoff values of p16 FISH were more than 10% for homozygous deletion and more than 40% for heterozygous deletion. According to the above criteria, nine (47.4%) of 19 successful DMPM cases were homozygous deletion positive, and three (15.8%) of 19 were heterozygous deletion positive, whereas all RMH cases were negative for the p16 deletion. In all four major histologic subtypes of EOC, neither p16 homozygous nor heterozygous deletions were detected. To differentiate DMPM from RMH or EOC, the sensitivity of the p16 homozygous deletion was 32% (9/28), and the specificity was 100%. Our study suggests that p16 FISH analysis is useful in differentiating DMPM from RMH and EOC when homozygous deletion is detected.


Relationship Between Dental Fluorosis and Intelligence Quotient of School Going Children In and Around Lucknow District: A Cross-Sectional Study.
Fluoridation of drinking water, despite being regarded as one of the top ten public health achievements of the twentieth century, has remained a much debated concept. Various studies on animals and aborted human fetuses have confirmed that excessive fluoride intake during infancy and early childhood, causes a number of irreversible structural and functional changes in the CNS leading to memory, learning and intellectual deficits. To compare the IQ levels of school children of two different locations, having different fluoride levels in water, and to establish a relationship between fluoride levels, prevalence of fluorosis and its effect on IQ levels. A cross-sectional study was conducted among 429 children aged 6 - 12 years, selected by stratified random sampling from two different areas with different levels of fluoride in drinking water in and around Lucknow district. Dental fluorosis was measured using Dean's Fluorosis Index. Intelligence Quotient was measured using Raven's Coloured Progressive Matrices (1998 edition). Majority of the fluorosis free children (76.3%) had an IQ grade 2 (definitely above the average). Majority of the children suffering from very mild and mild dental fluorosis were found to have IQ grade 3 (Intellectually average). Children with moderate cases of dental fluorosis were found to have IQ grade 4 (Definitely below average). Only 5 children with severe fluorosis were included in the study and they all were found to have an IQ grade 5. Hence, a trend of increase in the IQ grade (decrease in intellectual capacity) was observed indicating a strong correlation between fluorosis grade and IQ grade. Findings of this study suggest that the overall IQ of the children exposed to high fluoride levels in drinking water and hence suffering from dental fluorosis were significantly lower than those of the low fluoride area.


Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans.
Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance.


Clostridium difficile cure with fecal microbiota transplantation in a child with Pompe disease: a case report.
Recurrent Clostridium difficile infection is a growing problem among children due to both the increasing survival of medically fragile children with complicated chronic medical conditions resulting in prolonged antibiotic exposure and hospitalization and the emergence of strains of Clostridium difficile that are hypervirulent and associated with high rates of relapse. This case describes a medically complex 21-month-old Hispanic girl with Pompe disease and B cell immunodeficiency with recurrent Clostridium difficile infection refractory to antimicrobial management. She presented with nine recurrent episodes of Clostridium difficile infection including fever, foul smelling diarrhea, and respiratory distress with failed sustained responses to compliant treatment using metronidazole and pulsed vancomycin therapy. Maternal donor fecal microbiota transplantation was performed with complete symptom resolution and produced a sustained cure, now 5 years in duration. This patient presented with symptomatic Clostridium difficile at an early age causing significant morbidity and reduced quality of life. After nearly one year of failed medical management, fecal microbiota transplantation provided a cure. Further evidence-based research is necessary to test the safety and efficacy of this low technology, low cost, and morbidity-sparing therapy in children.


The impact of power generation emissions on ambient PM2.5 pollution and human health in China and India.
Emissions from power plants in China and India contain a myriad of fine particulate matter (PM2.5, PM ≤ 2.5 μm in diameter) precursors, posing significant health risks among large, densely settled populations. Studies isolating the contributions of various source classes and geographic regions are limited in China and India, but such information could be helpful for policy makers attempting to identify efficient mitigation strategies. We quantified the impact of power generation emissions on annual mean PM2.5 concentrations using the state-of-the-art atmospheric chemistry model WRF-Chem (Weather Research Forecasting model coupled with Chemistry) in China and India. Evaluations using nationwide surface measurements show the model performs reasonably well. We calculated province-specific annual changes in mortality and life expectancy due to power generation emissions generated PM2.5 using the Integrated Exposure Response (IER) model, recently updated IER parameters from Global Burden of Disease (GBD) 2015, population data, and the World Health Organization (WHO) life tables for China and India. We estimate that 15 million (95% Confidence Interval (CI): 10 to 21 million) years of life lost can be avoided in China each year and 11 million (95% CI: 7 to 15 million) in India by eliminating power generation emissions. Priorities in upgrading existing power generating technologies should be given to Shandong, Henan, and Sichuan provinces in China, and Uttar Pradesh state in India due to their dominant contributions to the current health risks.


Silica Measurement with High Flow Rate Respirable Size Selective Samplers: A Field Study.
High and low flow rate respirable size selective samplers including the CIP10-R (10 l min(-1)), FSP10 (11.2 l min(-1)), GK2.69 (4.4 l min(-1)), 10-mm nylon (1.7 l min(-1)), and Higgins-Dewell type (2.2 l min(-1)) were compared via side-by-side sampling in workplaces for respirable crystalline silica measurement. Sampling was conducted at eight different occupational sites in the USA and five different stonemasonry sites in Ireland. A total of 536 (268 pairs) personal samples and 55 area samples were collected. Gravimetric analysis was used to determine respirable dust mass and X-ray diffraction analysis was used to determine quartz mass. Ratios of respirable dust mass concentration, quartz mass concentration, respirable dust mass, and quartz mass from high and low flow rate samplers were compared. In general, samplers did not show significant differences greater than 30% in respirable dust mass concentration and quartz mass concentration when outliers (ratio <0.3 or >3.0) were removed from the analysis. The frequency of samples above the limit of detection and limit of quantification of quartz was significantly higher for the CIP10-R and FSP10 samplers compared to low flow rate samplers, while the GK2.69 cyclone did not show significant difference from low flow rate samplers. High flow rate samplers collected significantly more respirable dust and quartz than low flow rate samplers as expected indicating that utilizing high flow rate samplers might improve precision in quartz measurement. Although the samplers did not show significant differences in respirable dust and quartz concentrations, other practical attributes might make them more or less suitable for personal sampling.


Importance of post-exercise hypotension in plasma volume restoration.
The aim of this study was to test the hypothesis that post-exercise hypotension was the mechanism for the plasma volume and albumin gain during recovery. Seven healthy young men completed two experiments (> or =1 week apart) to exercise continuously at 65% of peak aerobic capacity for 60 min followed by the recovery without (experiment 1) or with phenylephrine infusion (experiment 2) to counteract post-exercise hypotension. Heart rate, arterial pressure (Finapres), plasma volume (PV, Evans blue dye dilution), haematocrit, haemoglobin, plasma total solutes (refractometer), albumin, total proteins (colorimetric method), [Na+] and [K+] were not different prior to the experiments. Exercise decreased PV -13.7% (-521 mL) and -14.2% (-566 mL) at the end of 60 min in experiments 1 and 2, respectively, associated with increases in the concentrations of plasma albumin, total protein and solutes. These changes were similar between the two experiments. Following 30 min recovery in experiment 1 the decreased PV was not significantly different from the baseline. Although the volume restoration was complete at the end of 90 min recovery, the change in the albumin concentration was still above zero, indicating a gain of 11 g albumin (P < 0.05). When phenylephrine was infused during recovery, there was no gain in intravascular albumin associated with a sustained decrease in PV (-7% or -280 mL, P < 0.05) observed at the end of experiment 2. These data suggest that post-exercise hypotension may be the mechanism for a gain of intravascular albumin via the lymph return, which enhances plasma water retention and PV restoration during recovery from exercise induced hypovolaemia, even without rehydration.


The disappearing income gradient in New York City birth outcomes: thirteen years of convergence from 1988 to 2001.
Income has long been identified as a potent determinant of infant mortality, yet little is known about the stability of its influence over time in defined populations. The objective of this study was to characterize trends in the income gradient in infant mortality in New York City from 1988 to 2001. An ecological analysis was conducted of infant, neonatal, and postneonatal mortality rates in 30 health districts from 14 years (1988-2001) of birth cohorts of the 5 boroughs of New York City divided by quartile of income based on the 1990 census (N = 1,692721 births). Infant mortality (deaths occurring at <365 days of age), neonatal mortality (deaths occurring at <28 days of age), and postneonatal mortality (deaths occurring from 28 to 364 days of age) expressed as rates per 1000 live births were measured. From 1988 to 2001, infant mortality in the highest income quartile in New York City fell 50.5% from 10.5 to 5.2, whereas in the lowest income quartile, it fell 62.6% from 17.4 to 6.5 per 1000 live births. The equivalent declines in neonatal mortality were 46.6% from 7.3 to 3.9 in the highest income quartile and 61.4% from 11.4 to 4.4 per 1000 live births in the lowest income quartile. For postneonatal mortality, rates fell 58.1% from 3.1 to 1.3 in the highest income quartile and 65% from 6 to 2.1 per 1000 live births in the lowest income quartile. Adjusted for covariates, relative to the highest income quartile, infant, neonatal, and postneonatal morality rates in the lowest income quartile declined 0.36 (95% confidence interval [CI]: -0.52 to -0.19), 0.20 (95% CI: -0.34 to -0.07), and 0.15 (95% CI: -0.23 to -0.07) per 1000 live births more per year. From 1988 to 2001, New York City witnessed a significant convergence in the income gradients of infant, neonatal, and postneonatal mortality rates. Understanding the origins of this trend should constitute an important public policy priority.


Enhanced subgenual cingulate response to altruistic decisions in remitted major depressive disorder.
Major depressive disorder (MDD) is associated with functional abnormalities in fronto-meso-limbic networks contributing to decision-making, affective and reward processing impairments. Such functional disturbances may underlie a tendency for enhanced altruism driven by empathy-based guilt observed in some patients. However, despite the relevance of altruistic decisions to understanding vulnerability, as well as everyday psychosocial functioning, in MDD, their functional neuroanatomy is unknown. Using a charitable donations experiment with fMRI, we compared 14 medication-free participants with fully remitted MDD and 15 demographically-matched control participants without MDD. Compared with the control group, the remitted MDD group exhibited enhanced BOLD response in a septal/subgenual cingulate cortex (sgACC) region for charitable donation relative to receiving simple rewards and higher striatum activation for both charitable donation and simple reward relative to a low level baseline. The groups did not differ in demographics, frequency of donations or response times, demonstrating only a difference in neural architecture. We showed that altruistic decisions probe residual sgACC hypersensitivity in MDD even after symptoms are fully remitted. The sgACC has previously been shown to be associated with guilt which promotes altruistic decisions. In contrast, the striatum showed common activation to both simple and altruistic rewards and could be involved in the so-called "warm glow" of donation. Enhanced neural response in the depression group, in areas previously linked to altruistic decisions, supports the hypothesis of a possible association between hyper-altruism and depression vulnerability, as shown by recent epidemiological studies.


Decreased T lymphocyte migration in patients with malignancy mediated by a suppressor cell population.
The migration and concentration of lymphocytes at sites of antigenic challenge are an integral part of the expression of delayed cutaneous hypersensitivity, as well as of tumor and graft rejection. In this study, we have analyzed the migration of T lymphocytes from patients with malignancy. We used casein and concanavalin A (Con A)-stimulated mononuclear cell supernatants to stimulate T cell locomotion. Peripheral blood T lymphocytes from 30 patients with established malignancy, 10 patients with indolent malignancy or benign tumor, and 42 normal adult controls were tested. Data are expressed as a migration index (MI), which represents the difference in micrometers between the distance migrated in response to a stimulus and the distance migrated in response to media alone. We observed a marked depression in casein-stimulated T lymphocyte migration in patients with established malignancy (mean MI +/- 1 SD = 17.0 +/- 9 microns) as compared with normal adult controls (mean MI +/- 1 SD = 35.3 +/- 10 microns). Similar results were observed with migration in response to Con A supernatants. T cells from patients with established malignancy had a mean MI of 5.8 +/- 4 microns to Con A supernatants as compared with 24.5 +/- 5 for controls. This depressed migration was apparent both in the distance that cells migrated and in the number of cells that migrated into the membrane. Of 10 patients with indolent malignancy or benign tumor, T cell migration in 8 was not significantly decreased as compared with controls. When we mixed equal concentrations of normal control T lymphocytes with T lymphocytes from patients with cancer and added the mixture directly to the upper compartment of the chemotaxis chamber, the response of the normal T cells to casein was inhibited by an average of 48%. We observed inhibition of this migration of normal cells when we added as little as 10% of patient cells to normal cells. When we mixed normal control T lymphocytes from different donors and added them directly to the upper compartment of the chemotaxis chamber, T lymphocyte migration in response to casein was not significantly altered. If T cells from patients with cancer were cultured overnight, the suppressive effect on lymphocyte locomotion was lost. Our results indicate that there is a population of T lymphocytes in patients with cancer that suppress normal T lymphocyte migration. This suppressor activity may partially explain the subversion of immunosurveillance in established neoplastic states, as well as the defective inflammatory reaction to intradermal injection of antigen observed in many patients with malignancy.


Perspectives on childhood resilience among the Aboriginal community: an interview study.
To describe Aboriginal community members' perspectives on the outcomes and origins of resilience among Aboriginal children. Face-to-face interviews were conducted with 36 Aboriginal adults (15 health service professionals, 8 youth workers and 13 community members) at two urban and one regional Aboriginal Community Controlled Health Service in New South Wales. Interviews were transcribed and analysed thematically. We identified six themes: withstanding risk (displaying normative development, possessing inner fortitude); adapting to adversity (necessary endurance, masking inner vulnerabilities); positive social influences (secure family environments, role modelling healthy behaviours and relationships); instilling cultural identity (investing in Aboriginal knowledge, building a strong cultural self-concept); community safeguards (offering strategic sustainable services, holistic support, shared responsibility, providing enriching opportunities); and personal empowerment (awareness of positive pathways, developing self-respect, fostering positive decision making). Community members believed that resilient Aboriginal children possessed knowledge and self-belief that encouraged positive decision making despite challenging circumstances. A strong sense of cultural identity and safe, stable and supportive family environments were thought to promote resilient behaviours. Implications for public health: Many Aboriginal children continue to face significant adversity. More sustainable, Aboriginal-led programs are needed to augment positive family dynamics, identify at-risk children and provide safeguards during periods of familial adversity.


Mesoporous Silica Nanoparticles with Dispersibility in Organic Solvents and Their Versatile Surface Modification.
Recently, colloidal mesoporous silica nanoparticles (MSNs) have attracted keen interest in scientific and technological fields. A significant issue regarding the effective use of colloidal MSNs is their dispersibility in various solvents, which is essential for their applications through surface modification. However, the dispersion media for colloidal MSNs have been extremely limited. Here, we report a new method for obtaining stable colloidal MSNs dispersed in various organic solvents through a gradual solvent exchange of colloidal MSNs from acidic water to an organic solvent by dialysis. This allows the colloidal MSNs to be dispersed as primary nanoparticles in organic solvents such as 1-butanol, 1-dodecanol, and tetrahydrofuran (THF), which are capable of hydrogen bonding with surface silanol groups. In addition, MSNs dispersed in THF can be modified with chlorosilanes while maintaining colloidal stability. Various organosilyl groups, such as trimethylsilyl and dimethylsilyl groups, can be densely grafted on the surfaces of MSNs. After trimethylsilylation, MSNs become dispersible even in a nonpolar and hydrophobic solvent like octane through the solvent exchange due to the preferential evaporation of THF. This method will offer a versatile approach to functionalizing colloidal MSNs toward a wide range of applications.


Intracellular Availability of pDNA and mRNA after Transfection: A Comparative Study among Polyplexes, Lipoplexes, and Lipopolyplexes.
Intracellular availability of nucleic acids from synthetic vectors is critical and directly influences the transfection efficiency (TE). Herein, we evaluated the TE of polymer- and lipid-based nanoplexes (polyplexes, lipoplexes and lipopolyplexes) of EGFP-encoding mRNA and pDNA. To determine the translation and transcription efficiency of each nucleic acid nanoplex, in vitro expression was measured in HEK293T7 cells that permit gene expression in the cytoplasmic region. Globally, mRNA transfection profile was well corroborative with cytoplasmic transfection of pT7-pDNA as well as with nuclear transfection of pCMV-DNA. Irrespective of the nucleic acid, high TE was observed with histidinylated l-polyethylenimine (His-lPEI) polyplexes and dioleyl succinyl paromomycin/O,O-dioleyl-N-histamine phosphoramidate (DOPS/MM27) lipoplexes. Moreover, His-lPEI polyplexes yielded higher in vitro expression of EGFP for pDNA than for mRNA. Furthermore, a significant enhancement in the TE in the presence of an excess of His-lPEI was observed indicating that this polymer promotes cytosolic delivery. Compared to other nanoplexes, His-lPEI polyplex showed high intracellular availability of DNA and mRNA along with low cytotoxicity, owing to its rapid (complete or partial) unpacking in the cytosol and/or endosomes. This study gives an insight that, whether with mRNA or pDNA, enhancing nanoplex unpacking in the endosomes and cytosol would improve the delivery of nucleic acid in the cytosol and particularly in the case of pDNA where a sufficient available amount of pDNA in the cytoplasm would definitely improve its transport toward the nucleus.


Sexual initiation, contraceptive use, and pregnancy among young adolescents.
To present new data on sexual initiation, contraceptive use, and pregnancy among US adolescents aged 10 to 19, and to compare the youngest adolescents' behaviors with those of older adolescents. Using nationally representative data from several rounds of the National Survey of Family Growth, we performed event history (ie, survival) analyses to examine timing of sexual initiation and contraceptive use. We calculated adolescent pregnancy rates by single year of age using data from the National Center for Health Statistics, the Guttmacher Institute, and the US Census Bureau. Sexual activity is and has long been rare among those 12 and younger; most is nonconsensual. By contrast, most older teens (aged 17-19) are sexually active. Approximately 30% of those aged 15 to 16 have had sex. Pregnancy rates among the youngest teens are exceedingly low, for example, ∼1 per 10 000 girls aged 12. Contraceptive uptake among girls as young as 15 is similar to that of their older counterparts, whereas girls who start having sex at 14 or younger are less likely to have used a method at first sex and take longer to begin using contraception. Sexual activity and pregnancy are rare among the youngest adolescents, whose behavior represents a different public health concern than the broader issue of pregnancies to older teens. Health professionals can improve outcomes for teenagers by recognizing the higher likelihood of nonconsensual sex among younger teens and by teaching and making contraceptive methods available to teen patients before they become sexually active.