Studies of congenitally immunologically mutant New Zealand mice. IX. Age-related microenvironmental effects on autoantibody production in NZB and NZB.Xid mice studied by transplantation.
The mechanism of polyclonal expansion of B cells and subsequent autoantibody production in New Zealand mice remains a critical question. We have been studying the requirements for autoantibody production both in NZB mice as well as NZB mice congenic with the Xid gene of CBA/N mice. In this study, we have attempted to alter the immunologic phenotype of NZB.Xid mice by transfer of cells from young and old NZB mice. There was little difficulty in restoring normal levels of serum IgM, IgG3, splenic Lyb-5 cells, and response to DNP-Ficoll in young NZB.Xid mice that were injected with young NZB bone marrow cells. Although such animals had an almost immediate change in their immune profile to values characteristic of NZB mice, they required, much like unmanipulated NZB mice, a latency period of an additional 6 mo before autoantibodies were detected. In contrast, adult NZB.Xid mice, who likewise developed an immune profile similar to NZB after transfer of bone marrow cells from young NZB mice, began to express autoantibodies immediately without any latency period. NZB.Xid mice who were recipients of adult NZB bone marrow cells did not show sustained autoantibody production, reflecting the limited state of B cell precursors in adult NZB mice. Thus, the age of both donor cells and the age of recipient mice are critical factors for determining the latency period and the age at which autoantibodies will appear. Similarly we attempted to alter the production of autoantibodies in NZB mice that were irradiated and injected with bone marrow cells from NZB.Xid animals. NZB mice had a major amelioration of disease when they received cell transfers from young NZB.Xid mice. This amelioration, which included the acquisition of the immune profile of NZB.Xid animals, was not seen in adult NZB mice that were recipient of young NZB cells. We suggest that although Lyb-5 cells may be the effective mechanism for autoantibody production, there are other interacting influences that may selectively turn on or turn off autoantibodies and that are required and are responsible for the latency period.


Genetic analysis of simian virus 40 from brains and kidneys of macaque monkeys.
Simian virus 40 (SV40) was isolated from the brains of three rhesus monkeys and the kidneys of two other rhesus monkeys with simian immunodeficiency virus-induced immunodeficiency. A striking feature of these five cases was the tissue specificity of the SV40 replication. SV40 was also isolated from the kidney of a Taiwanese rock macaque with immunodeficiency probably caused by type D retrovirus infection. Multiple full-length clones were derived from all six fresh SV40 isolates, and two separate regions of their genomes were sequenced: the origin (ori)-enhancer region and the coding region for the carboxy terminus of T antigen (T-ag). None of the 23 clones analyzed had two 72-bp enhancer elements as are present in the commonly used laboratory strain 776 of SV40; 22 of these 23 clones were identical in their ori-enhancer sequences, and these had only a single 72-bp enhancer element. We found no evidence for differences in ori-enhancer sequences associated with tissue-specific SV40 replication. The T-ag coding sequence that was analyzed was identical in all clones from kidney. However, significant variation was observed in the carboxy-terminal region of T-ag in SV40 isolated from brain tissues. This sequence variation was located in a region previously reported to be responsible for SV40 host range in cultured cell lines. Thus, SV40 appears to be an opportunistic pathogen in the setting of simian immunodeficiency virus-induced immunodeficiency, similarly to JC virus in human immunodeficiency virus-infected humans, the enhancer sequence organization generally attributed to SV40 is not representative of natural SV40 isolates, and sequence variation near the carboxy terminus of T-ag may play a role in tissue-specific replication of SV40.


Neuroblast migration along the anteroposterior axis of C. elegans is controlled by opposing gradients of Wnts and a secreted Frizzled-related protein.
The migration of neuroblasts along the anteroposterior body axis of C. elegans is controlled by multiple Wnts that act partially redundantly to guide cells to their precisely defined final destinations. How positional information is specified by this system is, however, still largely unknown. Here, we used a novel fluorescent in situ hybridization methods to generate a quantitative spatiotemporal expression map of the C. elegans Wnt genes. We found that the five Wnt genes are expressed in a series of partially overlapping domains along the anteroposterior axis, with a predominant expression in the posterior half of the body. Furthermore, we show that a secreted Frizzled-related protein is expressed at the anterior end of the body axis, where it inhibits Wnt signaling to control neuroblast migration. Our findings reveal that a system of regionalized Wnt gene expression and anterior Wnt inhibition guides the highly stereotypic migration of neuroblasts in C. elegans. Opposing expression of Wnts and Wnt inhibitors has been observed in basal metazoans and in the vertebrate neurectoderm. Our results in C. elegans support the notion that a system of posterior Wnt signaling and anterior Wnt inhibition is an evolutionarily conserved principle of primary body axis specification.


The Correlation between Corneal Topographic Indices and Corneal High Order Aberrations in Keratoconus.
This study was performed to investigate aberrometric changes of Keratoconus (KC) and its correlation with corneal topographic indices. In a cross sectional study, the researchers included 170 eyes of 138 candidates that were seeking corneal refractive surgery in Sohag refractive center, Sohag, Egypt and had been diagnosed as clinical KC. Patients were divided to mild, moderate, and severe KC. All eyes included in this study were subjected to corneal tomographic evaluation. Corneal aberrometry data was collected from the Sirius topography (Sirius, Costruzione Strumenti Oftalmici, Italy) over a 5-mm diameter. The collected data included Zernike coefficients for corneal aberrations, including total Root Mean Square (RMS), RMS Spherical Aberration (SA), RMS Coma, and RMS astigmatism. The study population was divided to mild, moderate, and severe KC. Mild KC cases included 58 eyes of 46 patients, moderate KC were 64 eyes of 52 patients, and severe KC were 48 eyes of 40 patients. Root mean square total was statistically significant in all groups with a higher p value in moderate KC (P = 0.001) and also was statistically significant when compared in the three groups altogether (P = 0.0001). Coma aberration was statistically significant in mild and moderate KC and when compared between the three groups (P = 0.0001). Root mean square Trefoil aberration was statistically significant only in moderate KC yet was statistically significant when compared in all groups (P = 0.0001). Root mean square astigmatism was statistically significant in mild KC only and when compared in the three groups altogether (P = 0.0001). Spherical aberration was also statistically significant in moderate and severe KC with a P value of < 0.0001 and 0.001, respectively. There was a positive correlation between posterior elevation and RMS values in mild and moderate KC while there was negative or very weak positive correlation in severe KC. There were negative correlations between the thinnest location and RMS values in nearly all variables in the three groups except weak positive correlation with RMS astigmatism in mild KC and with RMS total and coma aberration in severe KC .In conclusion corneal higher order aberrations measured by the Sirius topography system had low to moderate correlation with corneal topographic indices provided by the same device in different grades of KC.


Process evaluation outcomes from a global child obesity prevention intervention.
While it is acknowledged that child obesity interventions should cover multiple ecological levels (downstream, midstream and upstream) to maximize their effectiveness, there is a lack of evaluation data to guide the development and implementation of such efforts. To commence addressing this knowledge gap, the present study provides process evaluation data relating to the experiences of groups implementing the EPODE approach to child obesity prevention in various locations around the world. The aim of this exploratory study was to investigate the barriers and facilitators to program implementation in program sites around the world to assist in developing strategies to enhance program outcomes. An online survey that included open-ended questions was distributed to the 25 EPODE programs in operation at the time of the survey (May 2012). The survey items asked respondents to comment on those aspects of program implementation that they found challenging and to suggest areas for future improvement. Eighteen programs representing 14 countries responded to the request to participate in the survey, yielding a 72% response rate. The responses were analyzed via the constant comparative method using NVivo qualitative data analysis software. The main concerns of the various EPODE programs were their ability to secure ongoing funding and their access to evidence-based intervention methods and policy advice relating to relationships with third parties. These issues were in turn impacted by other factors, including (i) access to user-friendly information relating to the range of intervention strategies available and appropriate evaluation measures; (ii) assistance with building and maintaining stakeholder relationships; and (iii) assurance of the quality, independence, and transparency of policies and practices. The findings are facilitating the ongoing refinement of the EPODE approach. In particular, standardized and tailored information packages are being made available to advise program members of (i) the various evaluation methods and tools at their disposal and (ii) methods of acquiring private partner support. Overall, the study results relating to the types of issues encountered by program members are likely to be useful in guiding the future design and implementation of multi-level initiatives seeking to address other complex and intractable health-related problems.


Nasal continuous positive airway pressure and outcomes in preterm infants: A retrospective analysis.
The aim of the present retrospective study was to describe the use of nasal continuous positive airway pressure (NCPAP) and the prevalence of bronchopulmonary dysplasia (BPD). Data from 1526 neonates with gestational age less than 32 weeks, admitted to Children's and Women's Health Centre of British Columbia (Vancouver, British Columbia) between period 1 (1996 to 2000) and period 2 (2000 to 2004) were analyzed. The use of respiratory therapies and outcomes were retrospectively compared before and after the introduction of a NCPAP approach to respiratory support. A significant increase in the use of NCPAP was noted between periods 1 and 2 (60% versus 71%), as well as a significant reduction in the use of surfactant (50% versus 41%), postnatal steroids (30% versus 10%) and the need for mechanical ventilation (77% versus 64%). In period 2, there was a significant reduction in the prevalence of BPD at 28 days (33% versus 26%), higher prevalence of severe retinopathy of prematurity (3% versus 6%) and less periventricular leukomalacia (4% versus 2%). A significant increase in the use of NCPAP therapy in the neonatal unit has been associated with a decrease in the use of more invasive therapies. The incidence of BPD has decreased if defined as need for supplemental oxygen at 28 days of age, but not when the 36 weeks' postconceptional age criterion was used. NCPAP therapy may decrease the use of more invasive therapies and may improve respiratory outcomes. The impact of this intervention on nonrespiratory outcomes warrants further investigation.


A catalytic molecule machine-driven biosensing method for amplified electrochemical detection of exosomes.
Nowadays, exosomes that carry abundant information have attracted increasing attention as potent biomarkers of liquid biopsy and ideal candidates for early diagnosis and treatment of cancers. In this work, we propose a "principle-of-proof" biosensing method for amplified electrochemical detection of exosomes by using HepG2-derived exosomes as models. Specifically, target exosomes are enriched on anti-CD63-functionalized immunobeads and then recognized by a DNA chain containing CD63 aptamer region, which subsequently initiates a catalytic molecule machine that relies on cascade toehold-mediated strand displacement reaction. Benefiting from high efficiency of the molecule machine, the method shows a linear range from 1 × 105 to 5 × 107 particles/mL and a detection limit of 1.72 × 104 particles/mL toward target exosomes, better than most existing detection methods. Moreover, the method demonstrates a high specificity even in serum samples and suggests a potential use in clinic, which may provide sufficient information for disease diagnosis, especially early detection and prognosis monitoring of tumors.


Study on skylight polarization patterns over the ocean for polarized light navigation application.
Polarized skylight navigation has excellent navigation performance with no error accumulation over time and low susceptibility to interference. The skylight polarization distribution contains rich directional information, such as the solar meridian, the neutral point, and the polarization angle, which plays a key role in the polarization navigation. But up to now the polarizations of both sunlit and moonlit skies have been investigated mainly over the land. In this work, the polarization distribution patterns of the skylight over the East China Sea and the Yellow Sea were studied. The polarization patterns were captured continuously during daytime and nighttime by using a full-sky imaging polarimetry system and then compared with the simulation results using the libRadtran radiative transfer software package. The result shows that the skylight polarization distribution over the sea has almost the same pattern as that on the land. The accuracy of the angle of polarization and the degree of polarization dropped significantly under the cloudy sky. It was found that when the ship sailed on the sea, the direction of the real meridian was close to the solar azimuth during the daytime and close to the lunar azimuth during the nighttime. It was also found that the nautical twilight polarization distribution was affected by both the solar polarization and the lunar polarization, but the solar polarization was dominant. The experiments show that the skylight polarization distribution pattern over the sea can still be applied in the field of polarization navigation. Thus, it is feasible for ships and unmanned aerial vehicles to use the polarized skylight to navigate and orient on the sea.


Utilization of interventional radiology in the postoperative management of patients after surgery for locally advanced and recurrent rectal cancer.
The surgical management of locally advanced primary rectal cancer and locally recurrent rectal cancer requires complex operations frequently resulting in complicated postoperative courses. We sought to evaluate the utilization of interventional radiologic (IR) procedures in the management of postoperative complications. Under Institutional Review Board approval, a prospective database of colorectal cancer patients undergoing resection from July 1999 to January 2010 was analyzed. Data collected included demographics, operative procedure, complications, length of stay, and IR utilization. Fisher's exact tests and logistic regression explored associations with necessitating an IR procedure during the postoperative period. Continuous variables were analyzed using Wilcoxon rank sum tests. One hundred and one patients underwent surgery and 66 received intraoperative electron radiotherapy (IOERT). Primary procedures included pelvic exenteration (n = 35), abdominoperineal resection (n = 25), low anterior resection (n = 23), paraaortic node dissection (n = 7), resection of isolated pelvic/retroperitoneal tumor (n = 7), and colectomy (n = 4). Sixty-two patients required multivisceral resection including partial/total cystectomy (n = 30), small bowel resection (n = 25), oophorectomy (n = 15), vaginectomy (n = 12), hysterectomy (n = 12), hepatectomy (n = 3), and nephrectomy (n = 3). Seventeen partial sacral resections and 47 pelvic sidewall resections were also required. One hundred and thirty-eight complications were identified in 72 patients, 30 of which required a procedural intervention. Twenty-seven IR procedures were performed including drainage of fluid collections (n = 14), nephrostomy tube placement (n = 8), arterial embolization (n = 2), inferior vena cava filter placement (n = 2), and pleural drainage (n = 1). Only three reoperations were required, none related to failure of IR procedures. There were no deaths. Estimated blood loss > 2000 mL (P = 0.002), IOERT (P = 0.03), and incomplete resection (P = 0.02) were found to be associated with postoperative IR utilization. Surgery for locally advanced primary rectal cancer and locally recurrent rectal cancer is associated with significant morbidity but low mortality. IR procedures play a significant role in the postoperative management of these patients and may decrease the need for reoperation.


Treatment of burns casualties after fire at Bradford City football ground.
On 11 May 1985 the main stand of Bradford City Football Club caught fire. Within four minutes the stand was alight from end to end. Fifty three people were burnt to death and about 250 injured; 83 required admission to hospital, and 55 of these were treated by primary excision of their burns and skin grafting. In such disasters the help of staff from other hospitals and areas is essential. Patients should be assessed to see whether they have burns that will ultimately be fatal; if they have they should not be sent to regional burns units, where they would take up beds that could be used for patients with treatable burns. All districts should ensure that their plans for accidents in which burns injuries predominate are adequate.


Association of flavonoid-rich foods and statins in the management of hypercholesterolemia: a dangerous or helpful combination?
Statins and dietary modifications are the cornerstone of hypercholesterolemia management. Although it is well known that possible adverse effect of statins can occur due to drug-drug interactions, food-drug interactions are a commonly overlooked aspect. In particular, flavonoids could interfere with statins' bioavailability through different mechanisms, such as competition with cytochrome P450 (CYP) enzymes, esterases, uridine diphosphate glucuronosyltransferases and transporters (P-glycoprotein, multi-drug resistance-associated proteins, organic anion transporting polypeptides, breast cancer-resistance protein and monocarboxylate transporters). Transporters are characterized by low substrate specificity and flavonoid- rich foods could interfere with the bioavailability of all statins at this level. On the other hand, in addition to being substrates of drug metabolism/ transport systems, flavonoids are also able to modulate gene expression of enzymes and transporters. Therefore, long-term transcriptional induction may increase the clearance of statins, despite flavonoids act as competitive inhibitors after bolus consumption. In humans, major interactions were observed between grapefruit juice and statins that are substrates of P-glycoprotein/CYP3A, but other fruit juices also affect the bioavailability of statins that are not metabolised by CYP. Even if flavonoids could play a role in the prevention of hypercholesterolemia, the question whether there's a helpful or dangerous association between flavonoid-rich foods and statins, due to the interactions between flavonoid-rich foods and statins and the potential associated adverse effects of statins, remain unanswered. Therefore, the anamnesis of patients must include detailed information about their eating habits and the present review suggests monitoring and reporting any possible case of interaction between a prescribed statin and food.


Synchronous Environmental and Cultural Change in the Emergence of Agricultural Economies 10,000 Years Ago in the Levant.
The commonly held belief that the emergence and establishment of farming communities in the Levant was a smooth socio-economic continuum during the Pre-Pottery Neolithic (ca. 12,000-9,000 cal BP) with only rare minor disruptions is challenged by recently obtained evidence from this region. Using a database of archaeological radiocarbon dates and diagnostic material culture records from a series of key sites in the northern Levant we show that the hitherto apparent long-term continuity interpreted as the origins and consolidation of agricultural systems was not linear and uninterrupted. A major cultural discontinuity is observed in the archaeological record around 10,000 cal BP in synchrony with a Holocene Rapid Climate Change (RCC), a short period of climatic instability recorded in the Northern Hemisphere. This study demonstrates the interconnectedness of the first agricultural economies and the ecosystems they inhabited, and emphasizes the complex nature of human responses to environmental change during the Neolithic period in the Levant. Moreover, it provides a new environmental-cultural scenario that needs to be incorporated in the models reconstructing both the establishment of agricultural economy in southwestern Asia and the impact of environmental changes on human populations.


Hippocampal volumes among older Indian adults: Comparison with Alzheimer's disease and mild cognitive impairment.
Hippocampal volume data from India have recently been reported in younger adults. Data in older adults are unknown. The present paper describes hippocampal volume from India among older adults and compares the same with patients having Alzheimer's disease (AD) and mild cognitive impairment (MCI). A total of 32 cognitively normal subjects, 20 patients with AD, and 13 patients with MCI were enrolled. Patients were evaluated for the diagnosis of AD/MCI using the National Institute of Neurological and Communicative Disorders and Stroke and the Related Disorders Association criteria and the Clinical Dementia Rating (CDR) Scale (score = 0.5), respectively. Hippocampal volume was measured using magnetic resonance imaging (MRI) machine by manual segmentation (Megnatom Symphony 1.5T scanner) three-dimensional (3D) sequences. Age and duration of illness in the MCI group were 70.6 ± 8.6 years and 1.9 ± 0.9 years, respectively. In the AD group, age and duration of illness were 72 ± 8.1 years and 3.1 ± 2.2 years, respectively. In cognitively normal subjects, the age range was 45-88 years (66.9 ± 10.32) years. Mean mini-mental status examination (MMSE) score of healthy subjects was 28.28 ± 1.33. In the MCI group, MMSE was 27.05 ± 1.79. In the AD group, MMSE was 13.32 ± 5.6. In the healthy group, the hippocampal volume was 2.73 ± 0.53 cm(3) on the left side and 2.77 ± 0.6 cm(3) on the right side. Likewise, in MCI, the volume on the left side was 2.35 ± 0.42 cm(3) and the volume on the right side was 2.36 ± 0.38 cm(3). Similarly, in the AD group, the volume on the right side was 1.64 ± 0.55 cm(3) and on the left side it was 1.59 ± 0.55 cm(3). Post hoc analysis using Tukey's honestly significant difference (HSD) showed, using analysis of variance (ANOVA) that there was a statistically significant difference between healthy and AD (P ≤ 0.01), and between healthy and MCI (P ≤ 0.01) subjects. There was a correlation between MMSE score and hippocampal volume in the AD group. The volume of the hippocampus in older Indian adults was 2.77 ± 0. 6 cm(3) on the right side and 2.73 ± 0.52 cm(3) on the left side. There was a significant hippocampal volume loss in MCI/AD compared to cognitively normal subjects.


Oral status among seniors in nine nursing homes in Styria, Austria.
To investigate the oral state in participants cared for in residences for senior citizens in Styria, Austria. Four hundred and nine participants in Styria from nine homes for senior citizens were examined employing parameters in accordance with those of Folstein's Mini Mental Status (MMS), DMFT, basic periodontal examination, the modified oral hygiene index, pain experienced during the preceding year, the subjective and objective need for treatment, and also requirements involving surgical and prosthetic treatment. Furthermore, the habitual methods of maintaining oral hygiene were examined establishing by whom this was carried out - whether by the patient, the nurse, or by patient and nurse together. Four hundred and nine participants were examined, 48.3% were found to have retained on average 4.9 of their own teeth while 69% were fitted with dentures; however, 81% of the participants required prosthetic treatment. 28.9% of the participants had experienced acute dental pain during the preceding year and surgical treatment was found to be necessary in 47.7% of those with original teeth. Eighty-four per cent of the participants showed acute inflammation of the periodontium while the state of oral hygiene, measured on a scale of 0-4, reached an average of 2.43. Oral hygiene was carried out by the nurses in only 7.46% of the cases which showed an average MMS measurement of 18. The results compared with those reported in other recent surveys and our data show an urgent need in Austria to improve the standards in dental care for the hospitalised elderly. Regular dental checks, carried out in the actual home by a dental surgeon should be introduced, whilst the nursing staff should be made fully aware of the problems caused by insufficient oral care and receive regular support from specialised oral hygiene assistants. The results of this survey also suggest that nursing staff should be equipped with simple instruments in order to judge to the extent to which the patient is capable of carrying out oral care independently and then according to the results to supplement this with additional care.


A measure of the information content of EIT data.
We ask: how many bits of information (in the Shannon sense) do we get from a set of EIT measurements? Here, the term information in measurements (IM) is defined as: the decrease in uncertainty about the contents of a medium, due to a set of measurements. This decrease in uncertainty is quantified by the change from the inter-class model, q, defined by the prior information, to the intra-class model, p, given by the measured data (corrupted by noise). IM is measured by the expected relative entropy (Kullback-Leibler divergence) between distributions q and p, and corresponds to the channel capacity in an analogous communications system. Based on a Gaussian model of the measurement noise, (Sigma(n)), and a prior model of the image element covariances (Sigma(x)), we calculate IM = 1/2 summation operator log(2)([SNR](i) + 1), where [SNR](i) is the signal-to-noise ratio for each independent measurement calculated from the prior and noise models. For an example, we consider saline tank measurements from a 16 electrode EIT system, with a 2 cm radius non-conductive target, and calculate IM =179 bits. Temporal sequences of frames are considered, and formulae for IM as a function of temporal image element correlations are derived. We suggest that this measure may allow novel insights into questions such as distinguishability limits, optimal measurement schemes and data fusion.


Oncology Rehabilitation Provision and Practice Patterns across Canada.
Rehabilitation is increasingly recognized as an important therapeutic intervention for people with cancer. The main objective of this study was to explore the current practice pattern and provision of oncology rehabilitation in Canada. A descriptive cross-sectional online survey was administered to Canadian facilities offering cancer treatment and/or listed as offering rehabilitation services during or after cancer treatment (cancer centres, rehabilitation hospitals, community centres, and private clinics). Of the 116 sites contacted, 62 completed the questionnaire, 20 of which reported having an oncology rehabilitation programme. The majority of respondents indicated that they are not meeting their clients' rehabilitation needs. Rehabilitation programmes were provided by multidisciplinary health care teams, the majority of which included a physiotherapist. Funding and availability of resources were identified as the main barriers to the development of oncology rehabilitation programmes. Formal oncology rehabilitation programmes appear to be scarce, despite growing evidence that rehabilitation offers benefits across the cancer survivorship continuum.


A national survey on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan.
To conduct a national survey of systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Based on current information on the use of MMF, we aimed to evaluate its efficacy and safety for childhood-onset (c-) SLE. We evaluated 115 patients by questionnaire on MMF use for c-SLE in medical facilities specializing in pediatric rheumatic and renal diseases. Average age at SLE onset was 10.6 (range, 2-15) years; average age at the time of starting MMF was 12.3 (range, 2-15) years. Average dose per body surface area was 1,059.3 mg/m(2)/day. Corticosteroid dosing was 20.9 mg/day before treatment but 7.7 mg/day after treatment. Laboratory values before and after MMF treatment were as follows: C3 increased from 67.0 to 84.9 mg/dl (p < 0.001), C4 increased from 10.2 to 15.1 mg/dl (p < 0.001), and anti-DNA antibody decreased from 154.2 to 18.4 IU/ml (p < 0.001). 24 adverse events in 21 cases were reported, but MMF was not discontinued in any. The amount of MMF for c-SLE in Japan is similar to the standard dose in other countries. Reduction of corticosteroid dose and improvement of laboratory values represent efficacy of MMF. The side effects recorded here indicated tolerability of the drug.


Multiscale stereo analysis based on local-color-phase congruency in the color monogenic signal framework.
A multiscale method based on local-color-phase congruency in the color monogenic signal framework is proposed to match feature points and estimate disparity maps for stereo images. As the monogenic signal is the extension of the analytic signal to gray-level images using the Dirac operator and the Laplace equation, the scale-space color monogenic signal is the extension of the monogenic signal to color images based on Clifford algebras. The local color phase, which is estimated by computing the geometric product between the color monogenic signal and a unit reference vector in red-green-blue color space, contains the color and geometric structure information and is robust against noise and brightness change. Experimental results on synthetic and natural stereo images show the performance of the proposed approach.


Characterization of Patients with Psoriasis in Challenging-to-Treat Body Areas in the Corrona Psoriasis Registry.
Real-world studies evaluating patients with challenging-to-treat localizations of psoriasis (scalp, nail, and palmoplantar) are limited. To characterize patients with versus without psoriasis in challenging-to-treat areas seen in routine US clinical practice. This retrospective observational study included all adult patients with psoriasis enrolled in the Corrona Psoriasis Registry between April 2015 and May 2018 who initiated a biologic therapy at registry enrollment. Patients were stratified by the presence of scalp, nail, or palmoplantar psoriasis (nonmutually exclusive groups). Patient demographics, clinical char-acteristics, disease activity, and patient-reported outcome measures (pain, fatigue, itch, EuroQol visual analog scale [EQ VAS], Dermatology Life Quality Index [DLQI], and Work Productivity and Activity Impairment questionnaire [WPAI]) were assessed at registry enrollment and compared between patients with versus without each challenging-to-treat area using nonparametric Kruskal-Wallis tests for continuous variables and χ2 or Fisher exact tests for categorical variables. Generalized linear regression models were used to estimate differences in disease activity and patient-reported outcomes between patients with versus without each challenging-to-treat area. Among 2,042 patients with psoriasis (mean age [±SD], 49.6 ± 14.7 years; 51.5% male), 38.4% had psoriatic arthritis (PsA), 38.1% had scalp psoriasis, 16.0% had nail psoriasis, 10.9% had palmoplantar psoriasis, and 26.2% had a combination of ≥2 challenging-to-treat areas and PsA; only 34.2% had body plaque psoriasis without PsA or challenging-to-treat areas. Patients in all challenging-to-treat groups reported higher (mean [95% CI]) itch (scalp, 58.01 [57.62-58.40] vs. 54.35 [53.99-54.72]; nail, 56.42 [56.02-56.81] vs. 55.59 [55.20-55.97]; palmoplantar, 60.22 [59.86-60.59] vs. 55.15 [54.79-55.54]) and lower EQ VAS (scalp, 68.12 [67.78-68.48] vs. 69.46 [69.12-69.81]; nail, 66.21 [65.89-66.55] vs. 69.48 [69.14-69.83]; palmoplantar, 66.21 [66.07-66.75] vs. 69.29 [68.94-69.94]) scores than those without the respective challenging-to-treat localization. Patients with nail or palmoplantar psoriasis reported higher pain, fatigue, and DLQI scores than those without. Higher proportions of patients with scalp or palmoplantar psoriasis reported work impairment compared with those without. Two-thirds of patients with psoriasis who initiated biologic therapy had PsA and/or ≥1 challenging-to-treat area. Patients with challenging-to-treat areas had worse patient-reported outcome scores than those without, indicating a significant burden of challenging-to-treat areas on patients' quality of life.


Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.
Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. Spark Therapeutics.


Conserved virulence of C to B capsule switched Neisseria meningitidis clinical isolates belonging to ET-37/ST-11 clonal complex.
Capsule switching in Neisseria meningitidis is thought to occur by horizontal DNA exchange between meningococcal strains. Antigenic variants may be generated by allelic replacement of the siaD gene; the variants may then be selected by specific immunity against the capsular antigen. There were several vaccination campaigns against serogroup C in France in 2002, following an increase in the prevalence of invasive isolates of serogroup C of the phenotype C:2a:P1.5 and C:2a:P1.5,2 belonging to the ET-37/ST-11 clonal complex. We evaluated the emergence of capsule variants by the detection of B:2a:P1.5 and B:2a:P1.5,2 meningococcal isolates of the ET-37/ST-11 clonal complex. These isolates were significantly more frequent after the year 2002. Pulsed field gel electrophoresis profiles of the serogroup B (ET-37/ST-11) isolates differed from that of serogroup C (ET-37/ST-11) isolates by the bands that harbor the siaD genes responsible for the serogroup specificity. However, serogroup B and C, ET37/ST-11 isolates both express similar virulence as assessed from colonization and invasiveness in a mouse model. Our results indicate that capsule switching events within the same clonal complex can arise frequently with no alteration in virulence. This justifies an enhanced system of surveillance by molecular typing of such isolates, particularly after serogroup-specific vaccination.


Brain and spinal stimulation therapies for phantom limb pain: a systematic review.
Although many treatments exist for phantom limb pain (PLP), the evidence supporting them is limited and there are no guidelines for PLP management. Brain and spinal cord neurostimulation therapies are targeted at patients with chronic PLP but have yet to be systematically reviewed. To determine which types of brain and spinal stimulation therapy appear to be the best for treating chronic PLP. Systematic reviews of effectiveness and epidemiology studies, and a survey of NHS practice. All patients with PLP. Invasive interventions - deep brain stimulation (DBS), motor cortex stimulation (MCS), spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation. Non-invasive interventions - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Phantom limb pain and quality of life. Twelve databases (including MEDLINE and EMBASE) and clinical trial registries were searched in May 2017, with no date limits applied. Two reviewers screened titles and abstracts and full texts. Data extraction and quality assessments were undertaken by one reviewer and checked by another. A questionnaire was distributed to clinicians via established e-mail lists of two relevant clinical societies. All results were presented narratively with accompanying tables. Seven randomised controlled trials (RCTs), 30 non-comparative group studies, 18 case reports and 21 epidemiology studies were included. Results from a good-quality RCT suggested short-term benefits of rTMS in reducing PLP, but not in reducing anxiety or depression. Small randomised trials of tDCS suggested the possibility of modest, short-term reductions in PLP. No RCTs of invasive therapies were identified. Results from small, non-comparative group studies suggested that, although many patients benefited from short-term pain reduction, far fewer maintained their benefits. Most studies had important methodological or reporting limitations and few studies reported quality-of-life data. The evidence on prognostic factors for the development of chronic PLP from the longitudinal studies also had important limitations. The results from these studies suggested that pre-amputation pain and early PLP intensity are good predictors of chronic PLP. Results from the cross-sectional studies suggested that the proportion of patients with severe chronic PLP is between around 30% and 40% of the chronic PLP population, and that around one-quarter of chronic PLP patients find their PLP to be either moderately or severely limiting or bothersome. There were 37 responses to the questionnaire distributed to clinicians. SCS and DRG stimulation are frequently used in the NHS but the prevalence of use of DBS and MCS was low. Most responders considered SCS and DRG stimulation to be at least sometimes effective. Neurosurgeons had mixed views on DBS, but most considered MCS to rarely be effective. Most clinicians thought that a randomised trial design could be successfully used to study neurostimulation therapies. There was a lack of robust research studies. Currently available studies of the efficacy, effectiveness and safety of neurostimulation treatments do not provide robust, reliable results. Therefore, it is uncertain which treatments are best for chronic PLP. Randomised crossover trials, randomised N-of-1 trials and prospective registry trials are viable study designs for future research. The study is registered as PROSPERO CRD42017065387. The National Institute for Health Research Health Technology Assessment programme.


Techno-economics of integrating bioethanol production from spent sulfite liquor for reduction of greenhouse gas emissions from sulfite pulping mills.
Flow sheet options for integrating ethanol production from spent sulfite liquor (SSL) into the acid-based sulfite pulping process at the Sappi Saiccor mill (Umkomaas, South Africa) were investigated, including options for generation of thermal and electrical energy from onsite bio-wastes, such as bark. Processes were simulated with Aspen Plus® for mass- and energy-balances, followed by an estimation of the economic viability and environmental impacts. Various concentration levels of the total dissolved solids in magnesium oxide-based SSL, which currently fuels a recovery boiler, prior to fermentation was considered, together with return of the fermentation residues (distillation bottoms) to the recovery boiler after ethanol separation. The generation of renewable thermal and electrical energy from onsite bio-wastes were also included in the energy balance of the combined pulping-ethanol process, in order to partially replace coal consumption. The bio-energy supplementations included the combustion of bark for heat and electricity generation and the bio-digestion of the calcium oxide SSL to produce methane as additional energy source. Ethanol production from SSL at the highest substrate concentration was the most economically feasible when coal was used for process energy. However this solution did not provide any savings in greenhouse gas (GHG) emissions for the concentration-fermentation-distillation process. Maximizing the use of renewable energy sources to partially replace coal consumption yielded a satisfactory economic performance, with a minimum ethanol selling price of 0.83 US$/l , and a drastic reduction in the overall greenhouse gas emissions for the entire facility. High substrate concentrations and conventional distillation should be used when considering integrating ethanol production at sulfite pulping mills. Bio-wastes generated onsite should be utilized at their maximum potential for energy generation in order to maximize the GHG emissions reduction.


Embryonic development of the self-fertilizing mangrove killifish Kryptolebias marmoratus.
The mangrove killifish, Kryptolebias marmoratus, is a self-fertilizing vertebrate offering vast potential as a model species in many biological disciplines. Previous studies have defined developmental stages but lacked visual representations of the various embryonic structures. We offer detailed photographic images of K. marmoratus development with revised descriptions. An improved dechorionation method was developed to provide high resolution photographs, in addition to a microinjection technique enabling cell marking in the yolk syncytial layer. Embryos were also treated with PTU (1-phenyl 2-thiourea), an inhibitor of melanogenesis, to provide optical transparency revealing internal structures in late stages of development. Chemical exposures (PTU and retinoic acid) demonstrated that K. marmoratus embryos were sensitive to chemicals, illustrating further their usefulness in developmental biology studies. Our data suggest that K. marmoratus embryos are easily used and manipulated, supporting the use of this hermaphroditic vertebrate as a strong comparative model system in embryology, evolution, genetics, environmental and medical biology.


Conformational evolution of ubiquitin ions in electrospray mass spectrometry: molecular dynamics simulations at gradually increasing temperatures.
Evidence from cross section data indicates that ubiquitin +13 ions lose their secondary and tertiary structure in mass spectrometric experiments. These transitions from the folded state into the near linear final structure occur at the experimental temperatures on time scales that are far too long for conventional molecular dynamics simulations. In this study, an approach to mass spectrometric unfolding processes is developed and a detailed application to an ubiquitin +13 ion system is presented. The approach involves a sequence of molecular dynamics simulations at gradually increasing temperatures leading to identification of major intermediate states, and the unfolding pathway. The unfolding rate at any temperature can then be calculated by a Rice-Ramsperger-Kassel (RRK) approach. For ubiquitin +13, three interesting intermediate states were found and the final near linear geometry was computed. The several relevant energy barriers calculated for the process are in the range of 7 to 15 kcal mol(-1). The unfolding time scale at 300 K was computed to be 2 ms. Cross section calculations using a hard sphere scattering model were carried out for the final structure and found to be in good accord with the results of electrospray experiments supporting the theoretical model used. The approach employed here should be applicable to any other solvent-free protein system.


Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy.
Diabetic nephropathy (DN) is the most common complication of diabetes and is prone to kidney failure. Dihydromyricetin (DHM) has been reported to have a variety of pharmacological activities. This study aims to explore the effect of DHM on DN and the underlying molecular mechanism. An in vivo DN rat model was established. The degree of renal interstitial fibrosis (RIF) was detected by hematoxylin-eosin (HE) staining, Masson's trichrome staining, and immunohistochemistry (IHC). In vitro, NRK-52E cells were divided into four groups: normal glucose (NG), high glucose (HG), HG+DHM, and HG+rapamycin (autophagy inhibitor). The levels of autophagy- and fibrosis-related proteins were analyzed by western blotting. The expression of miR-155-5p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and their relationship were assessed by quantitative reverse transcription (qRT)-PCR and dual luciferase reporter gene assay. Our results showed that RIF was increased in DN rat model and in HG-induced NRK-52E cells. DHM treatment attenuated the increased RIF and also increased autophagy. MiR-155-5p expression was increased, while PTEN expression was decreased in DN rat and cell model, and DHM reversed both effects. Dual luciferase assay showed that PTEN was the target gene of miR-155-5p. DHM inhibited HG-induced fibrosis and promoted autophagy by inhibiting miR-155-5p expression in NRK-52E cells. In addition, DHM promoted autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, DHM promotes autophagy and attenuates RIF by regulating the miR-155-5p/PTEN signaling and PI3K/AKT/mTOR signaling pathway in DN.


Yoga and body image: Findings from a large population-based study of young adults.
This study explored the potential for yoga to promote body satisfaction in a general population of young adults. The sample included 1664 participants (M age: 31.1, SD=1.6years) in Project EAT, a 15-year longitudinal study. Data from the third and fourth waves (EAT-III and EAT-IV), collected five years apart, were utilized. Practicing yoga (≥30min/week) was reported by 16.2% of young adults. After adjusting for EAT-III body satisfaction and body mass index, yoga practitioners had higher concurrent body satisfaction at EAT-IV than those not practicing yoga (difference: 1.5 units [95% CI: 0.1-2.8], p=.03). Among participants within the lowest quartile of prior (EAT-III) body satisfaction, there was preliminary evidence that body satisfaction at EAT-IV was higher among yoga practitioners than in other young adults. Findings suggest that yoga may be associated with improved body satisfaction, particularly among young adults with low prior body satisfaction.


Effects of early psychosocial deprivation on the development of memory and executive function.
This study investigated the effects of early institutional care on memory and executive functioning. Subjects were participants in the Bucharest Early Intervention Project (BEIP) and included institutionalized children, children with a history of institutionalization who were assigned to a foster care intervention, and community children in Bucharest, Romania. Memory and executive functioning were assessed at the age of 8 years using the Cambridge Neuropsychological Test and Automated Battery (CANTAB). As expected, children with a history of early institutional care performed worse on measures of both visual memory and executive functioning compared to their peers without a history of institutional care. In comparing children randomly assigned to the foster care intervention with their peers who had continued care in the institution, initial comparisons did not show significant differences on any of the memory or executive functioning outcomes. However, for one of the measures of executive functioning, after controlling for birth weight, head circumference, and duration of time spent in early institutional care, the foster care intervention was a significant predictor of scores. These results support and extend previous findings of deficits in memory and executive functioning among school-age children with a history of early deprivation due to institutional care. This study has implications for the millions of children who continue to experience the psychosocial deprivation associated with early institutional care.


Controlling enzyme function through immobilisation on graphene, graphene derivatives and other two dimensional nanomaterials.
Robust enzyme immobilisation methods that preserve enzyme activity while enabling enzymes to be recovered and reused multiple times have important applications in biocatalysis. However, immobilisation can change the functionality of enzymes, both in terms of their level of activity and their selectivity. These changes in activity are unpredictable and at present cannot be controlled, but if fully understood at a fundamental level could offer the opportunity to create highly targetted enzyme systems for specific applications. In this review, we will highlight the use of two dimensional nanomaterials (2D NMs), particularly graphene and its derivatives, as immobilisation materials to modify and control the selectivity and activity of various enzymes. The fundamental information obtained from immobilising enzymes on 2D NMs allows for the implementation of improved immobilisation strategies and assists in the design of next generation nano- and macro-materials for enzyme immobilisation. We hope that this review will highlight the potential for tailoring enzyme activity and selectivity through immobilisation.


Blackawton bees.
Real science has the potential to not only amaze, but also transform the way one thinks of the world and oneself. This is because the process of science is little different from the deeply resonant, natural processes of play. Play enables humans (and other mammals) to discover (and create) relationships and patterns. When one adds rules to play, a game is created. the process of playing with rules that enables one to reveal previously unseen patterns of relationships that extend our collective understanding of nature and human nature. When thought of in this way, science education becomes a more enlightened and intuitive process of asking questions and devising games to address those questions. But, because the outcome of all game-playing is unpredictable, supporting this 'messyness', which is the engine of science, is critical to good science education (and indeed creative education generally). Indeed, we have learned that doing 'real' science in public spaces can stimulate tremendous interest in children and adults in understanding the processes by which we make sense of the world. The present study (on the vision of bumble-bees) goes even further, since it was not only performed outside my laboratory (in a Norman church in the southwest of England), but the 'games' were themselves devised in collaboration with 25 8- to 10-year-old children. They asked the questions, hypothesized the answers, designed the games (in other words, the experiments) to test these hypotheses and analysed the data. They also drew the figures (in coloured pencil) and wrote the paper. Their headteacher (Dave Strudwick) and I devised the educational programme (we call 'i,scientist'), and I trained the bees and transcribed the childrens' words into text (which was done with smaller groups of children at the school's local village pub). So what follows is a novel study (scientifically and conceptually) in 'kids speak' without references to past literature, which is a challenge. Although the historical context of any study is of course important, including references in this instance would be disingenuous for two reasons. First, given the way scientific data are naturally reported, the relevant information is simply inaccessible to the literate ability of 8- to 10-year-old children, and second, the true motivation for any scientific study (at least one of integrity) is one's own curiousity, which for the children was not inspired by the scientific literature, but their own observations of the world. This lack of historical, scientific context does not diminish the resulting data, scientific methodology or merit of the discovery for the scientific and 'non-scientific' audience. On the contrary, it reveals science in its truest (most naive) form, and in this way makes explicit the commonality between science, art and indeed all creative activities. 'We discovered that bumble-bees can use a combination of colour and spatial relationships in deciding which colour of flower to forage from. We also discovered that science is cool and fun because you get to do stuff that no one has ever done before. (Children from Blackawton)'.


Improving Nutrition Information in the Eastern Mediterranean Region: Implementation of Front-Of-Pack Nutrition Labelling.
The provision of simplified nutrition information, in a prominent place on the front of food packages, is recommended as an important element of comprehensive strategies to tackle the burden of death and disease caused by unhealthy diets. There is growing evidence that front-of-pack nutrition labels are preferred by consumers, are more likely to be looked at or noticed than nutrition labelling on the back or side of packages and can help consumers to better identify healthier and less healthy products. This review summarizes current implementation of front-of-pack nutrition labelling policies in the countries of the WHO Eastern Mediterranean Region. Implementation of front-of-pack nutrition labelling in the Eastern Mediterranean Region remains limited, but three types of scheme were identified as having been implemented or at an advanced stage of development by governments in six countries. Through a review of reviews of existing research and evidence from country implementation, the authors suggest some pointers for implementation for other countries in the Region deciding to implement front-of-pack nutrition labelling policies.


Fast reactions in carbon monoxide binding to heme proteins.
Using fast flash photolysis, we have measured the binding of CO to carboxymethylated cytochrome c and to heme c octapeptide as a function of temperature (5 degrees-350 degreesK) over an extended time range (100 ns(-1) ks). Experiments used a microsecond dye laser (lambda = 540 nm), and a mode-locked frequency-doubled Nd-glass laser (lambda = 530 nm). At low temperatures (5 degrees-120 degreesK) the rebinding exhibits two components. The slower component (I) is nonexponential in time and has an optical spectrum corresponding to rebiding from an S = 2, CO-free deoxy state. The fast component (I*) is exponential in time with a lifetime shorter than 10 mus and an optical spectrum different from the slow component. In myoglobin and the separated alpha and beta chains of hemoglobin, only process I is visible. The optical absorption spectrum of I* and its time dependence suggest that it may correspond to recombination from an excited state in which the iron has not yet moved out of the heme plane. The temperature dependences of both processes have been measured. Both occur via quantum mechanical tunneling at the lowest temperatures and via over-the-barrier motion at higher temperatures.


Prolactin receptor gene expression in the fetal rat.
The expression of mRNA encoding the long and short forms of the prolactin receptor (PRLR) in the fetal rat was examined using the method of reverse transcription-PCR. A 742 bp PCR product encoding the extracellular and transmembrane domains of the PRLR was detected in maternal and fetal liver and in fetal adrenal, kidney, small intestine, pancreas, brain, pituitary, thymus, lung and skin but not in fetal heart. Highest levels of the 742 bp PRLR transcript were detected in fetal adrenal (45.2% of levels in maternal liver), kidney (27.2%), small intestine (21.7%), pancreas (18.3%) and liver (10.8%), and tissue levels of the 742 bp product correlated positively (r = 0.92, P < 0.01) with the specific binding of the fetal lactogenic hormone rat placental lactogen II (rPL-II). These findings suggest that the PRLR may serve as a physiological binding protein for rPL-II in the rat fetus. There were striking differences in the relative expression of mRNA encoding the long and short forms of the PRLR. The long form of the receptor was expressed in maternal liver and placenta and in all fetal tissues studied except fetal heart. The short form of the receptor was also detected in maternal liver and placenta and fetal adrenal, kidney, small intestine, liver and thymus; in contrast, there was limited expression of the short-form of the receptor in fetal pancreas, pituitary and brain and no short form transcripts were detected in fetal lung, skin or heart.(ABSTRACT TRUNCATED AT 250 WORDS)


A Pecan-Rich Diet Improves Cardiometabolic Risk Factors in Overweight and Obese Adults: A Randomized Controlled Trial.
Evidence from observational and intervention studies has shown a high intake of tree nuts is associated with a reduced risk of cardiovascular disease (CVD), mortality from type 2 diabetes (T2DM), and all-cause mortality. However, there is limited data regarding their effects on indicators of cardiometabolic risk other than hypercholesterolemia, and little is known about the demonstrable health benefits of pecans (Carya illinoensis (Wangenh.) K.Koch). We conducted a randomized, controlled feeding trial to compare the effects of a pecan-rich diet with an isocaloric control diet similar in total fat and fiber content, but absent nuts, on biomarkers related to CVD and T2DM risk in healthy middle-aged and older adults who are overweight or obese with central adiposity. After 4 weeks on a pecan-rich diet, changes in serum insulin, insulin resistance (HOMA-IR) and beta cell function (HOMA-β) were significantly greater than after the control diet (p < 0.05). Pecan consumption also lowered the risk of cardiometabolic disease as indicated by a composite score reflecting changes in clinically relevant markers. Thus, compared to the control diet, the pecan intervention had a concurrent and clinically significant effect on several relevant markers of cardiometabolic risk.


Single molecule real-time (SMRT) sequencing comes of age: applications and utilities for medical diagnostics.
Short read massive parallel sequencing has emerged as a standard diagnostic tool in the medical setting. However, short read technologies have inherent limitations such as GC bias, difficulties mapping to repetitive elements, trouble discriminating paralogous sequences, and difficulties in phasing alleles. Long read single molecule sequencers resolve these obstacles. Moreover, they offer higher consensus accuracies and can detect epigenetic modifications from native DNA. The first commercially available long read single molecule platform was the RS system based on PacBio's single molecule real-time (SMRT) sequencing technology, which has since evolved into their RSII and Sequel systems. Here we capsulize how SMRT sequencing is revolutionizing constitutional, reproductive, cancer, microbial and viral genetic testing.


International variation in neighborhood walkability, transit, and recreation environments using geographic information systems: the IPEN adult study.
The World Health Organization recommends strategies to improve urban design, public transportation, and recreation facilities to facilitate physical activity for non-communicable disease prevention for an increasingly urbanized global population. Most evidence supporting environmental associations with physical activity comes from single countries or regions with limited variation in urban form. This paper documents variation in comparable built environment features across countries from diverse regions. The International Physical Activity and the Environment Network (IPEN) study of adults aimed to measure the full range of variation in the built environment using geographic information systems (GIS) across 12 countries on 5 continents. Investigators in Australia, Belgium, Brazil, Colombia, the Czech Republic, Denmark, China, Mexico, New Zealand, Spain, the United Kingdom, and the United States followed a common research protocol to develop internationally comparable measures. Using detailed instructions, GIS-based measures included features such as walkability (i.e., residential density, street connectivity, mix of land uses), and access to public transit, parks, and private recreation facilities around each participant's residential address using 1-km and 500-m street network buffers. Eleven of 12 countries and 15 cities had objective GIS data on built environment features. We observed a 38-fold difference in median residential densities, a 5-fold difference in median intersection densities and an 18-fold difference in median park densities. Hong Kong had the highest and North Shore, New Zealand had the lowest median walkability index values, representing a difference of 9 standard deviations in GIS-measured walkability. Results show that comparable measures can be created across a range of cultural settings revealing profound global differences in urban form relevant to physical activity. These measures allow cities to be ranked more precisely than previously possible. The highly variable measures of urban form will be used to explain individuals' physical activity, sedentary behaviors, body mass index, and other health outcomes on an international basis. Present measures provide the ability to estimate dose-response relationships from projected changes to the built environment that would otherwise be impossible.


Expression profile of the putative catalytic subunit of the telomerase gene.
Telomerase, a ribonucleoprotein complex, adds hexameric repeats called telomeres to the growing ends of chromosomal DNA. The enzyme telomerase activity is present in a vast majority of tumors but is repressed in most normal tissues. Recently, two groups have reported the molecular cloning of the putative catalytic subunit (hEST2/hTRT) of the telomerase gene. We investigated the expression of this gene in diverse tumor-derived cell lines and tumors as well as in various normal tissues. The expression of hEST2/hTRT was detectable in tumor-derived cell lines, primary breast tumors, pancreatic tumors, and kidney tumors. Furthermore, the expression of hEST2/hTRT was down-regulated in response to a differentiation inducer. However, several normal tissues also expressed varying levels of hEST2/hTRT. Early passage cultures of endothelial fibroblasts and some epithelial cells also expressed the telomerase gene, albeit at low levels. In contrast, the expression of TLP1/TP1, the human homologue of Tetrahymena p80 telomerase subunit, was similar in all of these samples. Our results indicate that the differences in expression of hEST2/hTRT in tumor versus normal cells are relative and are not absolute.


Effects of health care interventions on quality of life among frail elderly: a systematized review.
Many health care interventions have been developed that aim to improve or maintain the quality of life for frail elderly. A clear overview of these health care interventions for frail elderly and their effects on quality of life is missing. To provide a systematic overview of the effect of health care interventions on quality of life of frail elderly. A systematic search was conducted in Embase, Medline (OvidSP), Cochrane Central, Cinahl, PsycInfo and Web of Science, up to and including November 2017. Studies describing health care interventions for frail elderly were included if the effect of the intervention on quality of life was described. The effects of the interventions on quality of life were described in an overview of the included studies. In total 4,853 potentially relevant articles were screened for relevance, of which 19 intervention studies met the inclusion criteria. The studies were very heterogeneous in the design: measurement of frailty, health care intervention and outcome measurement differ. Health care interventions described were: multidisciplinary treatment, exercise programs, testosterone gel, nurse home visits and acupuncture. Seven of the nineteen intervention studies, describing different health care interventions, reported a statistically significant effect on subdomains of quality of life, two studies reported a statistically significant effect of the intervention on the overall quality of life score. Ten studies reported no statistically significant difference between the intervention and control groups. Reported effects of health care interventions on frail elderly persons' quality of life are inconsistent, with most of the studies reporting no differences between the intervention and control groups. As the number of frail elderly persons in the population will continue to grow, it will be important to continue the search for effective health care interventions. Alignment of studies in design and outcome measurements is needed.


Discovery of early-stage biomarkers for diabetic kidney disease using ms-based metabolomics (FinnDiane study).
Diabetic kidney disease (DKD) is a devastating complication that affects an estimated third of patients with type 1 diabetes mellitus (DM). There is no cure once the disease is diagnosed, but early treatment at a sub-clinical stage can prevent or at least halt the progression. DKD is clinically diagnosed as abnormally high urinary albumin excretion rate (AER). We hypothesize that subtle changes in the urine metabolome precede the clinically significant rise in AER. To test this, 52 type 1 diabetic patients were recruited by the FinnDiane study that had normal AER (normoalbuminuric). After an average of 5.5 years of follow-up half of the subjects (26) progressed from normal AER to microalbuminuria or DKD (macroalbuminuria), the other half remained normoalbuminuric. The objective of this study is to discover urinary biomarkers that differentiate the progressive form of albuminuria from non-progressive form of albuminuria in humans. Metabolite profiles of baseline 24 h urine samples were obtained by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) to detect potential early indicators of pathological changes. Multivariate logistic regression modeling of the metabolomics data resulted in a profile of metabolites that separated those patients that progressed from normoalbuminuric AER to microalbuminuric AER from those patients that maintained normoalbuminuric AER with an accuracy of 75% and a precision of 73%. As this data and samples are from an actual patient population and as such, gathered within a less controlled environment it is striking to see that within this profile a number of metabolites (identified as early indicators) have been associated with DKD already in literature, but also that new candidate biomarkers were found. The discriminating metabolites included acyl-carnitines, acyl-glycines and metabolites related to tryptophan metabolism. We found candidate biomarkers that were univariately significant different. This study demonstrates the potential of multivariate data analysis and metabolomics in the field of diabetic complications, and suggests several metabolic pathways relevant for further biological studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0291-6) contains supplementary material, which is available to authorized users.


Solution-processable low-molecular weight extended arylacetylenes: versatile p-type semiconductors for field-effect transistors and bulk heterojunction solar cells.
We report the synthesis and characterization of a series of five extended arylacetylenes, 9,10-bis-{[m,p-bis(hexyloxy)phenyl]ethynyl}-anthracene (A-P6t, 1), 9,10-bis-[(p-{[m,p-bis(hexyloxy) phenyl]ethynyl}phenyl)ethynyl]-anthracene (PA-P6t, 2), 4,7-bis-{[m,p-bis(hexyloxy)phenyl]ethynyl}-2,1,3-benzothiadiazole (BTZ-P6t, 5), 4,7-bis(5-{[m,p-bis(hexyloxy)phenyl]ethynyl}thien-2-yl)-2,1,3-benzothiadiazole (TBTZ-P6t, 6), and 7,7'-({[m,p-bis(hexyloxy)phenyl]ethynyl}-2,1,3-benzothiadiazol-4,4'-ethynyl)-2,5-thiophene (BTZT-P6t, 7), and two arylvinylenes, 9,10-bis-{(E)-[m,p-bis(hexyloxy)phenyl]vinyl}-anthracene (A-P6d, 3), 9,10-bis-[(E)-(p-{(E)-[m,p-bis(hexyloxy)phenyl]vinyl}phenyl)vinyl]-anthracene (PA-P6d, 4). Trends in optical absorption spectra and electrochemical redox processes are first described. Next, the thin-film microstructures and morphologies of films deposited from solution under various conditions are investigated, and organic field-effect transistors (OFETs) and bulk heterojunction photovoltaic (OPV) cells fabricated. We find that substituting acetylenic for olefinic linkers on the molecular cores significantly enhances device performance. OFET measurements reveal that all seven of the semiconductors are FET-active and, depending on the backbone architecture, the arylacetylenes exhibit good p-type mobilities (mu up to approximately 0.1 cm(2) V(-1) s(-1)) when optimum film microstructural order is achieved. OPV cells using [6,6]-phenyl C(61)-butyric acid methyl ester (PCBM) as the electron acceptor exhibit power conversion efficiencies (PCEs) up to 1.3% under a simulated AM 1.5 solar irradiation of 100 mW/cm(2). These results demonstrate that arylacetylenes are promising hole-transport materials for p-channel OFETs and promising donors for organic solar cells applications. A direct correlation between OFET arylacetylene hole mobility and OPV performance is identified and analyzed.


Real limits in the virtual world: self-limiting behavior of Internet gamblers.
The recent expansion of Internet gambling has stimulated debate, policy, and research on this relatively new phenomenon and its potential consequences. The current study focuses on bettors experiencing problems by sampling Internet gamblers who imposed limits on the amount they were allowed to deposit to a betting site. We analyzed the betting transactions over 18 months of all gamblers who subscribed to an online betting site in February, 2005 (N = 47,134), 567 of whom utilized the site's self-limit feature. Self-limiting gamblers played a wider variety of games and placed more bets than others prior to imposing limits. After imposing limits, self-limiters reduced their activity, but did not reduce the amount they wagered per bet. Time spent gambling, not just money spent, appears to be an important indicator of gambling problems. Self-limit programs appear to be promising options for Internet gamblers at-risk for gambling problems.


Meal Replacement Beverage Twice a Day in Overweight and Obese Adults (MDRC2012-001).
This open label, single arm, prospective, interventional, weight loss trial evaluated a meal replacement beverage (Right Size(®) Smoothie) used to replace breakfast and lunch each day for 12 weeks (7 clinic visits) as part of a calorie-restricted diet in overweight and obese adults. A total of 155 individuals were screened, 55 enrolled and 28 completed this 12 week study. Subjects were obese (mean weight: 206 pounds and BMI: 32.7 kg/m(2)) and the mean age was 40 years including 42 (76.4%) female and 13 (23.6%) male volunteers. The modified Intent to Treat and Completer groups lost an average of 10.6 and 13.8 pounds and reduced their average BMI by 1.7 and 2.2 kg/m(2) respectively during this 12 week trial. The Per Protocol group lost 15.2 pounds and 2.4 kg/m(2) and the Optimal Weight Loss group lost 18.5 pounds and 2.9 kg/m(2). Using the Satiety Labeled Intensity Magnitude scale (SLIM) questionnaire, subjects reported feeling relatively hungry before they consumed the beverage, then feeling relatively full 15 minutes following the beverage with the sensation of some fullness lasting more than 2 hours and then feeling relatively hungry again at 3 hours after consuming the beverage. Study subjects reported significant improvements in physical functioning, general health, vitality and mental health as well as increased cognitive restraint of eating, reduced disinhibition and reduced hunger during the trial. The study beverages were well tolerated and no Serious Adverse Events (SAE) reported. This study suggests the study beverage aids in weight loss by helping to curb hunger during a reduced calorie diet program.


Mass spectrometry-based proteomics for system-level characterization of biological responses to engineered nanomaterials.
The widespread use of engineered nanomaterials or nanotechnology makes the characterization of biological responses to nanomaterials an important area of research. The application of omics approaches, such as mass spectrometry-based proteomics, has revealed new insights into the cellular responses of exposure to nanomaterials, including how nanomaterials interact and alter cellular pathways. In addition, exposure to engineered nanomaterials often leads to the generation of reactive oxygen species and cellular oxidative stress, which implicates a redox-dependent regulation of cellular responses under such conditions. In this review, we discuss quantitative proteomics-based approaches, with an emphasis on redox proteomics, as a tool for system-level characterization of the biological responses induced by engineered nanomaterials. Graphical abstract .


Enabling pathways to health equity: developing a framework for implementing social capital in practice.
Mounting evidence linking aspects of social capital to health and wellbeing outcomes, in particular to reducing health inequities, has led to intense interest in social capital theory within public health in recent decades. As a result, governments internationally are designing interventions to improve health and wellbeing by addressing levels of social capital in communities. The application of theory to practice is uneven, however, reflecting differing views on the pathways between social capital and health, and divergent theories about social capital itself. Unreliable implementation may restrict the potential to contribute to health equity by this means, yet to date there has been limited investigation of how the theory is interpreted at the level of policy and then translated into practice. The paper outlines a collaborative research project designed to address this knowledge deficit in order to inform more effective implementation. Undertaken in partnership with government departments, the study explored the application of social capital theory in programs designed to promote health and wellbeing in Adelaide, South Australia. It comprised three case studies of community-based practice, employing qualitative interviews and focus groups with community participants, practitioners, program managers and policy makers, to examine the ways in which the concept was interpreted and operationalized and identify the factors influencing success. These key lessons informed the development of practical resources comprising a guide for practitioners and briefing for policy makers. Overall the study showed that effective community projects can contribute to population health and wellbeing and reducing health inequities. Of specific relevance to this paper, however, is the finding that community projects rely for their effectiveness on a broader commitment expressed through policies and frameworks at the highest level of government decision making. In particular this relationship requires long term vision, endorsement for cross-sectoral work, well-developed relationships and theoretical and practical knowledge. Attention to the practical application of social capital theory shows that community projects require structural support in their efforts to improve health and wellbeing and reduce health inequities. Sound community development techniques are essential but do not operate independently from frameworks and policies at the highest levels of government. Recognition of the interdependence of policy and practice will enable government to achieve these goals more effectively.


Academic Stress and Self-Regulation among University Students in Malaysia: Mediator Role of Mindfulness.
Academic stress is the most common emotional or mental state that students experience during their studies. Stress is a result of a wide range of issues, including test and exam burden, a demanding course, a different educational system, and thinking about future plans upon graduation. A sizeable body of literature in stress management research has found that self-regulation and being mindful will help students to cope up with the stress and dodge long-term negative consequences, such as substance abuse. The present study aims to investigate the influence of academic stress, self-regulation, and mindfulness among undergraduate students in Klang Valley, Malaysia, and to identify mindfulness as the mediator between academic stress and self-regulation. For this study, a total of 384 undergraduate students in Klang Valley, Malaysia were recruited. Using Correlational analysis, results revealed that there was a significant relationship between academic stress, self-regulation, and mindfulness. However, using SPSS mediational analysis, mindfulness did not prove the mediator role in the study.


Structural and functional diversity among bacterial interspersed mosaic elements (BIMEs).
Palindromic units (PU or REP) were defined as 40-nucleotide DNA sequences which are highly repeated in the genome of several members of the Enterobacteriaceae. They were shown to be a constituent of the bacterial interspersed mosaic element (BIME), in which they are associated with other repetitive sequences. We report here that Escherichia coli PU sequences contain three motifs (Y, Z1 and Z2), leading to the definition of two BIME families. The BIME-1 family, highly conserved over 145 nucleotides, contains two PUs (motifs Y and Z1). The BIME-2 family contains a variable number of PUs (motifs Y and Z2). We present evidence, using band shift experiments, that each PU motif binds DNA gyrase with a different affinity. This suggests that the two families are functionally distinct.


Effects of a live educational music therapy intervention on acute psychiatric inpatients' perceived social support and trust in the therapist: a four-group randomized effectiveness study.
Social support is associated with enhanced illness management and recovery in persons with mental illness, making it an important topic addressed through acute inpatient psychoeducational programs. In addition, trust in the therapist may mediate clinical outcomes in this patient population. To date, few studies have examined the effect of music-based psychoeducational programs on these variables. The purpose of this study was to isolate and examine the component parts of a live educational music therapy intervention, and its effect on acute psychiatric inpatients' perceived social support from significant others, family, and friends and trust in the therapist. This study also explored whether trust in therapist varied across conditions, but did not examine it as a mediator for social support. Participants (N = 96) were cluster-randomized in a single-session posttest-only design to one of four conditions: live educational music therapy, recorded educational music therapy, education without music, or recreational music therapy without education. Conditions were designed to isolate the following intervention components: live vs. recorded music, educational vs. non-educational content, and music vs. nonmusic modality. Dependent measures were assessed post intervention via established self-report instruments evaluating perceived social support and trust in the therapist. There were no significant between-group differences for social support or trust in therapist total scores. However, subscale score analyses revealed two significant between-group differences: (a) participants in the Live Educational Music Therapy condition reported significantly higher perceived therapist competence compared with the Recorded Educational Music Therapy condition; (b) participants in the Live Educational Music Therapy condition reported significantly higher perceived support from friends compared with the Recreational Music Therapy condition. Live educational music therapy may be a way to heighten psychiatric inpatients' perceived social support concerning friends and perceptions of the therapist's competence. The current results demonstrated differences between live and recorded music therapy in psychiatric music therapy and provide empirical support for competent musicianship. Implications for clinical practice, limitations, and suggestions for future research are included.


Association of change in depression and anxiety symptoms with functional outcomes in pulmonary rehabilitation patients.
Pulmonary rehabilitation (PR) has emerged over the last decade as an essential component of an integrated approach to managing patients with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). We sought to examine how depression and anxiety symptom changes relate to disease-specific quality of life outcomes following PR. We performed a cohort study of 81 patients with COPD who completed PR at a Veterans Administration Medical Center. Pulmonary rehabilitation consisted of supervised exercise training and education twice weekly for 8 weeks. Beck Depression and Anxiety Inventories (BDI and BAI) assessed symptom burden at baseline and completion of PR. We measured change in disease-specific quality of life using the dyspnea, mastery, emotion and fatigue domains of the Chronic Respiratory Questionnaire Self-Reported (CRQ-SR) from baseline to completion of PR. Participants were 69.8±9.1 years old and all male. Forced expiratory volume in 1 s (FEV1) was 1.23±0.39 L. The CRQ-SR scores improved significantly: dyspnea (P<.0001), mastery (P=.015) and fatigue (P=.017). The BDI scores improved significantly (13.1±10.5 to 10.8±9.9, P=.003; BAI: 13.1±10.1 to 12.1±11.7). Multivariate regression models controlling for age, FEV1, depression treatment and anxiety treatment showed that improvement in depressive symptoms were associated with improvement in fatigue (P=.003), emotion (P=.003) and mastery (P=.01). Anxiety symptom change was not significantly associated with change in disease-specific quality of life domains. Addressing anxiety symptoms in PR patients may be indicated because disease-specific quality of life improvement appears to be associated with mood.


Stroke prevention trial in sickle cell anemia.
Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.


Interventions for tobacco use cessation in people in treatment for or recovery from substance use disorders.
Smoking rates in people with alcohol and other drug dependencies are two to four times those of the general population. Concurrent treatment of tobacco dependence has been limited due to concern that these interventions are not successful in this population or that recovery from other addictions could be compromised if tobacco cessation was combined with other drug dependency treatment. To evaluate whether interventions for tobacco cessation are associated with tobacco abstinence for people in concurrent treatment for or in recovery from alcohol and other drug dependence. We searched the Cochrane Tobacco Addiction Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and clinicaltrials.gov databases, with the most recent search completed in August 2016. A grey literature search of conference abstracts from the Society on Nicotine Research and Treatment and the ProQuest database of digital dissertations yielded one additional study, which was excluded. We included randomised controlled trials assessing tobacco cessation interventions among people in concurrent treatment for alcohol or other drug dependence or in outpatient recovery programmes. Two review authors independently assessed study risk of bias and extracted data. We resolved disagreements by consensus. The primary outcome was abstinence from tobacco use at the longest period of follow-up, and the secondary outcome was abstinence from alcohol or other drugs, or both. We reported the strictest definition of abstinence. We summarised effects as risk ratios and 95% confidence intervals (CI). Two clustered studies did not provide intraclass correlation coefficients, and were excluded from the sensitivity analysis. We used the I2 statistic to assess heterogeneity. Thirty-five randomised controlled trials, one ongoing, involving 5796 participants met the criteria for inclusion in this review. Included studies assessed the efficacy of tobacco cessation interventions, including counselling, and pharmacotherapy consisting of nicotine replacement therapy (NRT) or non-NRT, or the two combined, in both inpatient and outpatient settings for participants in treatment and in recovery. Most studies did not report information to assess the risk of allocation, selection, and attrition bias, and were classified as unclear.Analyses considered the nature of the intervention, whether participants were in treatment or recovery and the type of dependency. Of the 34 studies included in the meta-analysis, 11 assessed counselling, 11 assessed pharmacotherapy, and 12 assessed counselling in combination with pharmacotherapy, compared to usual care or no intervention. Tobacco cessation interventions were significantly associated with tobacco abstinence for two types of interventions. Pharmacotherapy appeared to increase tobacco abstinence (RR 1.60, 95% CI 1.22 to 2.12, 11 studies, 1808 participants, low quality evidence), as did combined counselling and pharmacotherapy (RR 1.74, 95% CI 1.39 to 2.18, 12 studies, 2229 participants, low quality evidence) at the period of longest follow-up, which ranged from six weeks to 18 months. There was moderate evidence of heterogeneity (I2 = 56% with pharmacotherapy and 43% with counselling plus pharmacotherapy). Counselling interventions did not significantly increase tobacco abstinence (RR 1.33, 95% CI 0.90 to 1.95).Interventions were significantly associated with tobacco abstinence for both people in treatment (RR 1.99, 95% CI 1.59 to 2.50) and people in recovery (RR 1.33, 95% CI 1.06 to 1.67), and for people with alcohol dependence (RR 1.47, 95% CI 1.20 to 1.81) and people with other drug dependencies (RR 1.85, 95% CI 1.43 to 2.40).Offering tobacco cessation therapy to people in treatment or recovery for other drug dependence was not associated with a difference in abstinence rates from alcohol and other drugs (RR 0.97, 95% CI 0.91 to 1.03, 11 studies, 2231 participants, moderate evidence of heterogeneity (I2 = 66%)).Data on adverse effect of the interventions were limited. The studies included in this review suggest that providing tobacco cessation interventions targeted to smokers in treatment and recovery for alcohol and other drug dependencies increases tobacco abstinence. There was no evidence that providing interventions for tobacco cessation affected abstinence from alcohol and other drugs. The association between tobacco cessation interventions and tobacco abstinence was consistent for both pharmacotherapy and combined counselling and pharmacotherapy, for participants both in treatment and in recovery, and for people with alcohol dependency or other drug dependency. The evidence for the interventions was low quality due primarily to incomplete reporting of the risks of bias and clinical heterogeneity in the nature of treatment. Certain results were sensitive to the length of follow-up or the type of pharmacotherapy, suggesting that further research is warranted regarding whether tobacco cessation interventions are associated with tobacco abstinence for people in recovery, and the outcomes associated with NRT versus non-NRT or combined pharmacotherapy. Overall, the results suggest that tobacco cessation interventions incorporating pharmacotherapy should be incorporated into clinical practice to reduce tobacco addiction among people in treatment for or recovery from alcohol and other drug dependence.


Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site.
A 12-yr-old hypothyroid girl was diagnosed at birth as athyreotic because her thyroid gland could not be visualized by isotope scanning. Goiter development due to incomplete thyrotropin suppression, a thyroidal radioiodide uptake of < 1%, and a low saliva to plasma ratio of 2.5 suggested iodide (I-) transport defect. mRNA isolated from her thyroid gland and injected into Xenopus oocytes failed to increase I- transport. Sequencing of the entire Na+/I- symporter (NIS) cDNA revealed a C to G transversion of nucleotide (nt) 1146 in exon 6, resulting in a Gln 267 (CAG) to Glu (GAG) substitution. This missense mutation produces an NIS with undetectable I- transport activity when expressed in COS-7 cells. Although only this missense mutation was identified in thyroid and lymphocyte cDNA, genotyping revealed that the proposita and her unaffected brother and father were heterozygous for this mutation. However, amplification of cDNA with a primer specific for the wild-type nt 1146 yielded a sequence lacking 67 nt. Genomic DNA showed a C to G transversion of nt 1940, producing a stop codon as well as a new downstream cryptic 3' splice acceptor site in exon 13, responsible for the 67 nt deletion, frameshift, and premature stop predicting an NIS lacking 129 carboxy-terminal amino acids. This mutation was inherited from the mother and present in the unaffected sister. Thus, although the proposita is a compound heterozygote, because of the very low expression (< 2.5%) of one mutant allele, she is functionally hemizygous for an NIS without detectable bioactivity.


Risk of valvular heart disease after treatment for Hodgkin lymphoma.
Hodgkin lymphoma (HL) survivors are at increased risk of developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response. A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided. Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02). Radiation dose to the heart valves can increase the risk of clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up.


3D Bioprinting and Differentiation of Primary Skeletal Muscle Progenitor Cells.
Volumetric loss of skeletal muscle can occur through sports injuries, surgical ablation, trauma, motor or industrial accident, and war-related injury. Likewise, massive and ultimately catastrophic muscle cell loss occurs over time with progressive degenerative muscle diseases, such as the muscular dystrophies. Repair of volumetric loss of skeletal muscle requires replacement of large volumes of tissue to restore function. Repair of larger lesions cannot be achieved by injection of stem cells or muscle progenitor cells into the lesion in absence of a supportive scaffold that (1) provides trophic support for the cells and the recipient tissue environment, (2) appropriate differentiational cues, and (3) structural geometry for defining critical organ/tissue components/niches necessary or a functional outcome. 3D bioprinting technologies offer the possibility of printing orientated 3D structures that support skeletal muscle regeneration with provision for appropriately compartmentalized components ranging across regenerative to functional niches. This chapter includes protocols that provide for the generation of robust skeletal muscle cell precursors and methods for their inclusion into methacrylated gelatin (GelMa) constructs using 3D bioprinting.


Emerging trends in the discovery of natural product antibacterials.
This article highlights current trends and advances in exploiting natural sources for the deployment of novel and potent anti-infective countermeasures. The key challenge is to therapeutically target bacterial pathogens that exhibit a variety of puzzling and evolutionarily complex resistance mechanisms. Special emphasis is given to the strengths, weaknesses, and opportunities in the natural product antibacterial drug discovery arena, and to emerging applications driven by advances in bioinformatics, chemical biology, and synthetic biology in concert with exploiting bacterial phenotypes. These efforts have identified a critical mass of natural product antibacterial lead compounds and discovery technologies with high probability of successful implementation against emerging bacterial pathogens.