Exposure to advertising and perception, interest, and use of e-cigarettes among adolescents: findings from the US National Youth Tobacco Survey.
US adolescents are exposed to high levels of advertisements for electronic cigarettes (e-cigarettes). This study aimed to examine the associations between exposure to e-cigarette advertisements and perception, interest, and use of e-cigarettes among US middle school and high school students. Data from the 2014 cross-sectional National Youth Tobacco Survey were used. Logistic regressions were conducted to model four outcomes, including perception of reduced harmfulness compared to regular cigarettes, perception of reduced addictiveness, intention to use, and current use of e-cigarettes. Main predictors were exposure to e-cigarette advertisements via four sources, including Internet, newspaper/magazines, retail stores, and TV. When all the four sources of e-cigarette advertisements exposure were evaluated jointly, exposure via the Internet was associated with elevated likelihood of reporting all four outcomes related to e-cigarettes, while exposure via retail stores was associated with higher likelihood of current e-cigarette use and perception of reduced harmfulness of e-cigarettes compared to regular cigarettes ( p < .05). However, exposure via newspaper/magazines and TV was associated with lower likelihood of perceiving e-cigarettes to be less harmful or addictive ( p < .05). Exposure to e-cigarette advertisements via the Internet and retail stores may play a significant role in adolescents' use and perception of e-cigarettes. The results call for more research on the influence of different sources of advertising exposure on e-cigarette use to help public health programmes curtail the fast growing use of e-cigarette products among youth.


Polar motion prediction using the combination of SSA and Copula-based analysis.
The real-time estimation of polar motion (PM) is needed for the navigation of Earth satellite and interplanetary spacecraft. However, it is impossible to have real-time information due to the complexity of the measurement model and data processing. Various prediction methods have been developed. However, the accuracy of PM prediction is still not satisfactory even for a few days in the future. Therefore, new techniques or a combination of the existing methods need to be investigated for improving the accuracy of the predicted PM. There is a well-introduced method called Copula, and we want to combine it with singular spectrum analysis (SSA) method for PM prediction. In this study, first, we model the predominant trend of PM time series using SSA. Then, the difference between PM time series and its SSA estimation is modeled using Copula-based analysis. Multiple sets of PM predictions which range between 1 and 365 days have been performed based on an IERS 08 C04 time series to assess the capability of our hybrid model. Our results illustrate that the proposed method can efficiently predict PM. The improvement in PM prediction accuracy up to 365 days in the future is found to be around 40% on average and up to 65 and 46% in terms of success rate for the PM x and PM y , respectively.


Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer.
Breast involution following pregnancy has been implicated in the high rates of metastasis observed in postpartum breast cancers; however, it is not clear how this remodeling process promotes metastasis. Here, we demonstrate that human postpartum breast cancers have increased peritumor lymphatic vessel density that correlates with increased frequency of lymph node metastases. Moreover, lymphatic vessel density was increased in normal postpartum breast tissue compared with tissue from nulliparous women. In rodents, mammary lymphangiogenesis was upregulated during weaning-induced mammary gland involution. Furthermore, breast cancer cells exposed to the involuting mammary microenvironment acquired prolymphangiogenic properties that contributed to peritumor lymphatic expansion, tumor size, invasion, and distant metastases. Finally, in rodent models of postpartum breast cancer, cyclooxygenase-2 (COX-2) inhibition during the involution window decreased normal mammary gland lymphangiogenesis, mammary tumor-associated lymphangiogenesis, tumor cell invasion into lymphatics, and metastasis. Our data indicate that physiologic COX-2-dependent lymphangiogenesis occurs in the postpartum mammary gland and suggest that tumors within this mammary microenvironment acquire enhanced prolymphangiogenic activity. Further, our results suggest that the prolymphangiogenic microenvironment of the postpartum mammary gland has potential as a target to inhibit metastasis and suggest that further study of the therapeutic efficacy of COX-2 inhibitors in postpartum breast cancer is warranted.


Pouch and Roux-en-Y reconstruction after gastrectomy.
We evaluated a reconstruction procedure of the upper gastrointestinal tract after total gastrectomy with the exclusive use of the EEA, GIA, and TA surgical stapling devices (United States Surgical Corp, Norwalk, Conn). Twenty patients with gastric carcinoma entered the study. A total gastrectomy and lymphadenectomy was performed in each patient and the upper gastrointestinal tract was reconstructed by the Roux-en-Y technique with the creation of a Hunt-Lawrence-Rodino pouch. For all operational steps, surgical staplers were used exclusively, as follows: (1) duodenal closure, GIA or TA; (2) Roux-en-Y anastomosis, EEA 25; (3) pouch construction, GIA (three to four times); (4) esophagojejunostomy, EEA 25; and (5) pouch closure, TA 55 or 90. There was a one-hour difference in operating time between patients operated on exclusively by the staple technique and TNM-matched patients operated on manually. Four patients suffered from general complications. Two patients had clinically relevant suture deficiencies. We concluded that current reconstruction methods after gastrectomy that fulfill the reservoir function (pouch) and reflux prevention (Roux-en-Y reconstruction) can be achieved by the combination and systematic use of straight and circular staplers. The advantages are intraoperative time saving and a relaxation of limitations imposed on an abdominal intervention by age and localization of the tumor.


Long-term follow up of a physical therapy programme for patients with fibromyalgia syndrome.
The purpose of this study was to evaluate, in a long-term perspective, the impact of a physical therapy-based educational programme on patients with fibromyalgia syndrome (FMS). The programme includes information about the syndrome, information about pain and muscle physiology, training in warm water, stretching, body awareness therapy and relaxation in groups of 15 patients twice weekly, 2 hours during 10 weeks. A total of 240 patients with FMS participated in the study before and immediately after the programme and at a follow up with a mean of 35 months after the programme. Health status as measured with the Fibromyalgia Impact Questionnaire was answered by the patients at all three measurement points. Questionnaires concerning self-care, self-motivation and sense of coherence (SOC) were distributed at the follow up. The results showed a significant improvement on several symptoms when comparing before and after the programme, and at the time of follow up the patients' rated well-being was still improved. The results also showed that the patients' pretreatment perception of symptoms, well-being and SOC are predictors to the perception of general health at the follow up of a physical therapy programme. The conclusion is that a physical therapy programme for patients with FMS may have a positive impact on patients' general well-being but not on other symptoms.


Factors related to the willingness of Palestinian dentists to treat patients with blood-borne diseases.
This study aimed to explore, using groups of simulated patients, the willingness of Palestinian dentists to treat patients with blood-borne diseases. Simulated patients conducted a telephone survey of a random sample of dentists registered with the Palestinian Dental Association. A random system was used to assign dentists to one of two groups, in which simulated patients randomly identified themselves with either human immunodeficiency virus (HIV) or hepatitis B virus (HBV) and asked for a dental appointment. Three-hundred and four dentists (76%) responded to our telephone survey. Sixty-six per cent accepted requests for appointments and 34% declined the appointment requests. Sixty-eight per cent of the dentists declined appointment requests from patients with HIV and 32% declined appointments from patients with HBV. Dentist's gender, 'blood-borne disease type', 'place of private practice', 'country of graduation' and 'years since graduation' were all significant predictors in the final logistic model. More than one-third of our respondents declined appointment requests from patients with blood-borne disease, two-thirds of which were for patients who identified themselves as having HIV. Education and training programmes are needed to improve attitudes of dentists - especially female dentists, older dentists and dentists practising in northern governorates - towards patients with blood-borne diseases.


Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia.
Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia.


Sleepiness in professional truck drivers measured with an objective alertness test during routine traffic controls.
Accurate data about sleepiness in professional drivers at the wheel are rare because it is difficult to perform objective and reliable sleepiness tests in the field. In this pilot study, we investigate the practicability, robustness and viability of the pupillographic sleepiness test (PST, F2D by Amtech GmbH, Germany) during routine police controls. PST analyses and quantifies the so-called sleepiness waves, spontaneous pupillary movements in the dark. PST was recorded in 137 truck drivers, who were redirected by the police out of the freeway traffic to a service station for a spot check of their trip recorder, load and papers. Participation in the sleepiness test was voluntarily. The drivers' subjective sleepiness was determined with two questionnaires, the Stanford Sleepiness Scale (SSS) and the Epworth Sleepiness Scale (ESS). The PST provides the pupillary unrest index (PUI), which describes the magnitude of the spontaneous oscillation of the pupil. The PUI values within 1 standard deviation are classified as normal, between 1 and 2 SD as borderline and above 2 SD as sleepy. The net examination time for the PST was 11 min, allowing it to be performed within the time required for the police to perform their control of load, truck and papers. In 126 truck drivers, the data sets were complete and of sufficient quality and could be evaluated (92%). Values of PUI more than 2 SDs were detected in 5.6% of drivers, whereas 72.2% were classified as normal and alert and 22.2% as borderline. The correlation of the PST score with the SSS score (p = 0.064) borders on significance, whereas no correlation could be found in comparison with ESS. Sleepiness in drivers, assessed by the PST, can be tested during routine police controls. The results of this study show comparable values to those previously published, confirming the robustness and technical practicability of the method. Nevertheless, there is strong need for further evaluation of PST and its relation to driving performance. For justifiable values similar to the development of the drunk-driving law, there are detailed investigations needed.


Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations.
A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public.


Nonmelanoma skin cancers and infection with the human immunodeficiency virus.
Forty-eight human immunodeficiency virus-infected patients with nonmelanoma skin cancers seen during a four-year period were evaluated in a retrospective, case-control study. Patients were followed up after therapy and recurrence rates were determined. One hundred and sixteen nonmelanoma skin cancers were identified, 101 of which were basal cell carcinomas (87%), mostly superficial multicentric (67%) of the trunk (62%). There were 15 low-grade squamous cell carcinomas, most commonly of the head and neck. Half of the patients had multiple cancers. Compared with age-matched controls, the patients with skin cancer more commonly had blue/hazel eyes (89% vs 66%; odds ratio [OR] 4.1; confidence interval [CI], 1.25 to 13.44; P = .033), blond hair (42% vs 13%; OR = 4.53; CI, 1.40 to 13.74, P = .003), a family history of skin cancer (45% vs 5%; OR = 11.88; CI, 2.85 to 49.57; P = .00), and a history of regular sunbathing (92% vs 48%; OR = 11.24; CI, 3.17 to 39.83; P = .00). The number of cancers or the presence of squamous cell carcinoma did not correlate with the degree of immunosuppression. The recurrence rate for basal cell carcinomas following standard treatment methods (mostly curettage and electrodesiccation and excision) was 5.4% for those tumors followed up for longer than 12 months. Three of the 15 squamous cell carcinomas recurred, all following curettage and electrodesiccation. Nonmelanoma skin cancers are a not uncommon cutaneous finding in human immunodeficiency virus-infected patients. The major risk factors for developing skin cancer in association with human immunodeficiency virus disease seem to be the same as in the normal population--fair skin, a positive family history, and sun exposure. Standard treatment methods seem to be associated with acceptable cure rates, except for squamous cell carcinomas, which had a high (20%) recurrence rate following curettage and electrodesiccation.


Current status of Zika vaccine development: Zika vaccines advance into clinical evaluation.
Zika virus (ZIKV), a mosquito-borne flavivirus, was first identified in the 1940s in Uganda in Africa and emerged in the Americas in Brazil in May 2015. In the 30 months since ZIKV emerged as a major public health problem, spectacular progress has been made with vaccine development cumulating with the publication of three reports of phase 1 clinical trials in the 4th quarter of 2017. Clinical trials involving candidate DNA and purified inactivated virus vaccines showed all were safe and well-tolerated in the small number of volunteers and all induced neutralizing antibodies, although these varied by vaccine candidate and dosing regimen. These results suggest that a Zika vaccine can be developed and that phase 2 clinical trials are warranted. However, it is difficult to compare the results from the different phase 1 studies or with neutralizing antibodies induced by licensed flavivirus vaccines (Japanese encephalitis, tick-borne encephalitis, and yellow fever) as neutralizing antibody assays vary and, unfortunately, there are no standards for Zika virus neutralizing antibodies. In addition to clinical studies, substantial progress continues to be made in nonclinical development, particularly in terms of the ability of candidate vaccines to protect reproductive tissues, and the potential use of monoclonal antibodies for passive prophylaxis.


Foetal pain?
The majority of commentary on foetal pain has looked at the maturation of neural pathways to decide a lower age limit for foetal pain. This approach is sensible because there must be a minimal necessary neural development that makes pain possible. Very broadly, it is generally agreed that the minimal necessary neural pathways for pain are in place by 24 weeks gestation. Arguments remain, however, as to the possibility of foetal pain before or after 24 weeks. Some argue that the foetus can feel pain earlier than 24 weeks because pain can be supported by subcortical structures. Others argue that the foetus cannot feel pain at any stage because it is maintained in a state of sedation in the womb and lacks further neural and conceptual development necessary for pain. Much of this argument rests on the definition of terms such as 'wakefulness' and 'pain'. If a behavioural and neural reaction to a noxious stimulus is considered sufficient for pain, then pain is possible from 24 weeks and probably much earlier. If a conceptual subjectivity is considered necessary for pain, however, then pain is not possible at any gestational age. Regardless of how pain is defined, it is clear that pain for conceptual beings is qualitatively different than pain for non-conceptual beings. It is therefore a mistake to draw an equivalence between foetal pain and pain in the older infant or adult.


Divergent biological effects of adenosine and dibutyryl adenosine 3',5'-monophosphate on the isolated fat cell.
Adenosine 3',5'-monophosphate stimulated production of carbon dioxide and lipid from glucose, whereas its dibutyryl derivative inhibited this conversion. Addition of the dibutyryl derivative to the isolated fat cell further stimulated lipolysis induced by adrenocorticotropic hormone, whereas addition of adenosine 3',5'-monophosphate inhibited this lipolysis. Hence, measured by these two parameters, the biologic properties of adenosine 3',5'-monophosphate and its dibutyryl derivative are distinctly different.


Birefringence and polarization mode-dispersion in spun single-mode fibers.
A theoretical and experimental analysis of the polarization properties of twisted single-mode fibers is presented. It is shown that whereas a conventionally twisted fiber possesses considerable optical rotation, a fiber which has a permanent twist imparted by spinning the preform during fiber drawing exhibits almost no polarization anisotropy. It is thus possible to virtually eliminate the commonly observed fiber linear birefringence. As a consequence, fibers made in this way are ideally suited for use in the Faraday-effect current transducer. It is further shown that a permanent twist of a few turns/meter effectively eliminates polarization mode-dispersion. The technique therefore appears attractive for enhancing the bandwidth of very long unrepeatered telecommunication links.


Revealing genome-scale transcriptional regulatory landscape of OmpR highlights its expanded regulatory roles under osmotic stress in Escherichia coli K-12 MG1655.
A transcription factor (TF), OmpR, plays a critical role in transcriptional regulation of the osmotic stress response in bacteria. Here, we reveal a genome-scale OmpR regulon in Escherichia coli K-12 MG1655. Integrative data analysis reveals that a total of 37 genes in 24 transcription units (TUs) belong to OmpR regulon. Among them, 26 genes show more than two-fold changes in expression level in an OmpR knock-out strain. Specifically, we find that: 1) OmpR regulates mostly membrane-located gene products involved in diverse fundamental biological processes, such as narU (encoding nitrate/nitrite transporter), ompX (encoding outer membrane protein X), and nuoN (encoding NADH:ubiquinone oxidoreductase); 2) by investigating co-regulation of entire sets of genes regulated by other stress-response TFs, stresses are surprisingly independently regulated among each other; and, 3) a detailed investigation of the physiological roles of the newly discovered OmpR regulon genes reveals that activation of narU represents a novel strategy to significantly improve osmotic stress tolerance of E. coli. Thus, the genome-scale approach to elucidating regulons comprehensively identifies regulated genes and leads to fundamental discoveries related to stress responses.


An analysis of risk factors for developing Hepatocellular carcinoma in a group of Hepatitis C patients with stage 3 fibrosis following interferon therapy.
The risk of Hepatocellular carcinoma (HCC) is high in HCV-infected patients who have biochemically and histologically active chronic hepatitis. To observe the long prognosis of Chronic Hepatitis C (CHC) patients with stage 3 fibrosis (F3), 55 CHC patients after initial Interferon (IFN) therapy were followed up for up to 12 years (average 9.8 +/- 2.3 years). According to the annual average alanine aminotransferase (ALT) levels, patients were grouped into, low (ALT <or= 30 IU/l); moderate (ALT >30 <80 IU/l) and high (ALT >or= 80 IU/l) ALT groups. Eleven patients were re-treated with IFN. During the follow-up period of 12 years, HCC developed in 26 patients with an average annual incidence of 3.9%. Biochemical responders to initial IFN therapy (n = 8) and those re-treated with IFN (n = 10), except 1, did not develop HCC. Cox regression analysis to evaluate risk factors for HCC occurrence, found development of Liver Cirrhosis within 3 years of initial IFN therapy(P = 0.05) and the 3 year annual average ALT post initial IFN therapy (P = 0.033) to be significant. The 12 year annual average ALT was also found to be significantly related to HCC occurrence (P = 0.016), on univariate analysis. Patients belonging to the continuously low ALT group (ALT <or= 30 IU/l for >or=3 years), did not develop HCC or receive IFN re-treatment. In CHC patients with F3, after initial IFN therapy, keeping ALT continuously low, below 30 IU/l for 3 years or more seems important. Continuing treatment with anti-inflammatory drugs along with subsequent IFN re-treatment may prevent or delay HCC even in elderly patients.


Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells.
Constitutive activation of STAT3 has been shown in several human cancers and transformed cell lines including hepatocellular carcinoma (HCC). In the present report, we investigated whether diosgenin, a steroidal saponin isolated from fenugreek can modulate the STAT3 signaling pathway. We found that diosgenin inhibited both constitutive and inducible activation of STAT3 with no effect on STAT5. The activation of c-Src, JAK1 and JAK2 implicated in STAT3 activation, were also suppressed by this saponin. Pervanadate reversed the diosgenin-induced downregulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that diosgenin can induce the expression of Src homology 2 phosphatase 2 (SH-PTP2) that correlated with downregulation of constitutive STAT3 activation. Diosgenin also downregulated the expression of various STAT3-regulated gene products, inhibited proliferation and potentiated the apoptotic effects of paclitaxel and doxorubicin. Overall, these results suggest that diosgenin is a novel blocker of the STAT3 activation pathway, with a potential role in the treatment of HCC and other cancers.


Living apart-together: Microhabitat differentiation of cryptic nematode species in a saltmarsh habitat.
Coexistence of highly similar species is at odds with ecological theory of competition; coexistence, then, requires stabilizing mechanisms such as differences in ecological niche. In the bacterivore nematode Litoditis marina species complex, which occurs associated with macro-algae, four cryptic lineages (Pm I-IV) co-occur in the field along the south-western coast and estuaries of The Netherlands. Here we investigate the temporal and/or spatial niche differentiation in their natural environment using a qPCR-based detection and relative quantification method. We collected different algal species (i.e. two Fucus species and Ulva sp.) and separated algal structures (i.e. receptacula, thalli, non-fertile tips and bladders) at different sampling months and times (i.e. twice per sampling month), to examine differences in microhabitat use between coexisting L. marina species. Results demonstrate that the cryptic species composition varied among different algal species and algal structures, which was also subject to temporal shifts. Pm I dominated on Fucus spp., Pm II showed dominance on Ulva sp., while Pm III overall had the lowest frequencies. Microhabitat partitioning was most pronounced between the two cryptic species which had similar microbiomes (Pm I and Pm II), and less so between the two species which had significantly different microbiomes (Pm I and Pm III), suggesting that species which share the same microhabitats may avoid competition through resource partitioning. The interplay of microhabitat differentiation and temporal dynamics among the cryptic species of L. marina implies that there is a complex interaction between biotic components and abiotic factors which contributes to their coexistence in the field.


An in silico perception for newly isolated flavonoids from peach fruit as privileged avenue for a countermeasure outbreak of COVID-19.
3'-Hydroxy-4'-methoxy-chroman-7-O-β-d-glucopyranoside 4 was first isolated from a natural source, together with three known compounds, the ferulic acid heptyl ester 1, naringenin 2, and 4,2',4'-trihydroxy-6'-methoxychalcone-4'-O-β-d-glucopyranoside 3, which were isolated from peach [Prunus persica (L.) Batsch] fruits. These compounds were subjected to different virtual screening strategies in order to examine their activity to combat the COVID-19 outbreak. The study design composed of some major aspects: (a) docking with main protease (Mpro), (b) docking with spike protein, (c) 3D shape similarity study (Rapid Overlay Chemical Similarity-ROCS) to the clinically used drugs in COVID-19 patients, and finally, (d) the rule of five and the estimated pre-ADMT properties of the separated flavonoids. Docking study with Mpro of SARS-CoV-2 (PDB ID:6LU7, and 6Y2F) showed that compound 3, its aglycone part, and compound 4 have a strong binding mode to a protease receptor with key amino acids, especially Gln:166AA, and having a similar docking pose to co-crystalized ligands. Docking with the spike protein of SARS-CoV-2 illustrated that compounds 3 and 4 have a good binding affinity to PDB ID:6VSB through the formation of HBs with Asp:467A and Asn:422A. According to ROCS analysis, compounds 1, 3, and 4 displayed high similarities to drugs that prevent SARS-Co2 entry to the lung cells or block the inflammatory storm causing lung injury. Compounds 3 and 4 are good candidates for drug development especially because they showed predicted activity against SARS-CoV-2 through different mechanisms either by preventing genome replication or by blocking inflammatory storm that trigger lung injury. These compounds were isolated from peach fruit, and the study supports data and continues with the recommendation of peach fruits in controlling and managing COVID-19 cases.


Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia.
Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children's Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged <18 years completed treatment, only 57% of patients aged ≥18 years completed treatment. This scenario suggests that issues associated with age and treating physician may be a factor. Due to its improved survival rates compared with historical controls, the CALGB 10403 regimen is now a standard of care. The hope is that the rate of protocol completion will increase as more familiarity is gained with this regimen. These trials were registered at www.clinicaltrials.gov as #NCT00558519 (CALGB 10403) and #NCT00075725 (COG AALL0232).


Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging.
Sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of conventional MR imaging in predicting glioma grade are not high. Relative cerebral blood volume (rCBV) measurements derived from perfusion MR imaging and metabolite ratios from proton MR spectroscopy are useful in predicting glioma grade. We evaluated the sensitivity, specificity, PPV, and NPV of perfusion MR imaging and MR spectroscopy compared with conventional MR imaging in grading primary gliomas. One hundred sixty patients with a primary cerebral glioma underwent conventional MR imaging, dynamic contrast-enhanced T2*-weighted perfusion MR imaging, and proton MR spectroscopy. Gliomas were graded as low or high based on conventional MR imaging findings. The rCBV measurements were obtained from regions of maximum perfusion. Metabolite ratios (choline [Cho]/creatine [Cr], Cho/N-acetylaspartate [NAA], and NAA/Cr) were measured at a TE of 144 ms. Tumor grade determined with the three methods was then compared with that from histopathologic grading. Logistic regression and receiver operating characteristic analyses were performed to determine optimum thresholds for tumor grading. Sensitivity, specificity, PPV, and NPV for identifying high-grade gliomas were also calculated. Sensitivity, specificity, PPV, and NPV for determining a high-grade glioma with conventional MR imaging were 72.5%, 65.0%, 86.1%, and 44.1%, respectively. Statistical analysis demonstrated a threshold value of 1.75 for rCBV to provide sensitivity, specificity, PPV, and NPV of 95.0%, 57.5%, 87.0%, and 79.3%, respectively. Threshold values of 1.08 and 1.56 for Cho/Cr and 0.75 and 1.60 for Cho/NAA provided the minimum C2 and C1 errors, respectively, for determining a high-grade glioma. The combination of rCBV, Cho/Cr, and Cho/NAA resulted in sensitivity, specificity, PPV, and NPV of 93.3%, 60.0%, 87.5%, and 75.0%, respectively. Significant differences were noted in the rCBV and Cho/Cr, Cho/NAA, and NAA/Cr ratios between low- and high-grade gliomas (P <.0001,.0121,.001, and.0038, respectively). The rCBV measurements and metabolite ratios both individually and in combination can increase the sensitivity and PPV when compared with conventional MR imaging alone in determining glioma grade. The rCBV measurements had the most superior diagnostic performance (either with or without metabolite ratios) in predicting glioma grade. Threshold values can be used in a clinical setting to evaluate tumors preoperatively for histologic grade and provide a means for guiding treatment and predicting postoperative patient outcome.


The costs of schizophrenia and predictors of hospitalisation from the statutory health insurance perspective.
The aim of the study was to determine the costs of treating schizophrenia from the perspective of the statutory health insurance, as well as the identification of predictors of hospitalisation of formerly stable schizophrenia patients. Claims data for the years 2004-2006 were analysed. Patients who did not have to be treated in a hospital as a result of an ICD diagnosis F20 both in the year 2005 as well as also in 2006 were defined as stable patients. In contrast, those patients who had to be treated in a hospital in 2006 because of a diagnosis of schizophrenia were defined as unstable. In addition to the overall healthcare costs, the costs specific to schizophrenia were also analysed. Also, based on binary logistic regression analysis, predictors for hospital treatment were determined. 8497 stable and 1449 unstable patients were identified. The schizophrenia specific costs for stable patients were € 1605 and the overall costs were € 4029 in 2006, respectively. Unstable patients had indication-specific costs amounting to € 12864 and overall health care costs of € 16824. For unstable patients, the costs of hospital treatment were identified as being a substantial cost area. Predictors for a higher probability of hospital treatment were: female patients, at least one rehabilitation measure, at least one stay in hospital in 2004, and being co-morbid with substance abuse. In contrast, older patients, who were treated with concomitant medications, and if they received a continuous drug therapy in all quarters of a year had a lower probability of hospitalisation. In addition, an increased number of visits to a doctor reduced the probability of hospitalisation. The variable 'depot medication' were close to significance and the variable 'inability to work lasting more than six weeks' had, in contrast, no significant influence. The schizophrenia specific and overall health care costs of unstable patients were clearly higher than was the case with stable patients and mainly determined by inpatient hospital treatment. A range of potential predicting factors which can be extracted from routine claims data have a positive or negative influence on the probability of treatment in hospital.


Disentangling the impacts of heat wave magnitude, duration and timing on the structure and diversity of sessile marine assemblages.
Extreme climatic events, including heat waves (HWs) and severe storms, influence the structure of marine and terrestrial ecosystems. Despite growing consensus that anthropogenic climate change will increase the frequency, duration and magnitude of extreme events, current understanding of their impact on communities and ecosystems is limited. Here, we used sessile invertebrates on settlement panels as model assemblages to examine the influence of HW magnitude, duration and timing on marine biodiversity patterns. Settlement panels were deployed in a marina in southwest UK for ≥5 weeks, to allow sufficient time for colonisation and development of sessile fauna, before being subjected to simulated HWs in a mesocosm facility. Replicate panel assemblages were held at ambient sea temperature (∼17 °C), or +3 °C or +5 °C for a period of 1 or 2 weeks, before being returned to the marina for a recovery phase of 2-3 weeks. The 10-week experiment was repeated 3 times, staggered throughout summer, to examine the influence of HW timing on community impacts. Contrary to our expectations, the warming events had no clear, consistent impacts on the abundance of species or the structure of sessile assemblages. With the exception of 1 high-magnitude long-duration HW event, warming did not alter not assemblage structure, favour non-native species, nor lead to changes in richness, abundance or biomass of sessile faunal assemblages. The observed lack of effect may have been caused by a combination of (1) the use of relatively low magnitude, realistic heat wave treatments compared to previous studies (2), the greater resilience of mature adult sessile fauna compared to recruits and juveniles, and (3) the high thermal tolerance of the model organisms (i.e., temperate fouling species, principally bryozoans and ascidians). Our study demonstrates the importance of using realistic treatments when manipulating climate change variables, and also suggests that biogeographical context may influence community-level responses to short-term warming events, which are predicted to increase in severity in the future.


A strategy to determine operating parameters in tissue engineering hollow fiber bioreactors.
The development of tissue engineering hollow fiber bioreactors (HFB) requires the optimal design of the geometry and operation parameters of the system. This article provides a strategy for specifying operating conditions for the system based on mathematical models of oxygen delivery to the cell population. Analytical and numerical solutions of these models are developed based on Michaelis-Menten kinetics. Depending on the minimum oxygen concentration required to culture a functional cell population, together with the oxygen uptake kinetics, the strategy dictates the model needed to describe mass transport so that the operating conditions can be defined. If c(min) ≫ K(m) we capture oxygen uptake using zero-order kinetics and proceed analytically. This enables operating equations to be developed that allow the user to choose the medium flow rate, lumen length, and ECS depth to provide a prescribed value of c(min) . When c(min) />>K(m), we use numerical techniques to solve full Michaelis-Menten kinetics and present operating data for the bioreactor. The strategy presented utilizes both analytical and numerical approaches and can be applied to any cell type with known oxygen transport properties and uptake kinetics.


Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression.
Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large-scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline). Multi-class and binary classification using Machine Learning (ML) and regularization algorithms using iterative and univariate feature selection methods, including InfoGain, mRMR, ANOVA, and Chi Square, were used to uncover genomic markers associated with AD response. Relevant genes were selected based on Jaccard distance and carried forward for gene-network analysis. Linear association methods uncovered only one gene associated with drug treatment response. The implementation of ML algorithms, together with feature reduction methods, revealed a set of 204 genes associated with SSRI and 241 genes associated with NRI response. Although only 10% of genes overlapped across the two drugs, network analysis shows that both drugs modulated the CREB pathway, through different molecular mechanisms. Through careful implementation and optimisations, the algorithms detected a weak signal used to predict whether an animal was treated with nortriptyline (77%) or escitalopram (67%) on an independent testing set. The results from this study indicate that the molecular signature of AD treatment may include a much broader range of genomic markers than previously hypothesized, suggesting that response to medication may be as complex as the pathology. The search for biomarkers of antidepressant treatment response could therefore consider a higher number of genetic markers and their interactions. Through predominately different molecular targets and mechanisms of action, the two drugs modulate the same Creb1 pathway which plays a key role in neurotrophic responses and in inflammatory processes. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.


Doxycycline modulates VEGF-A expression: Failure of doxycycline-inducible lentivirus shRNA vector to knockdown VEGF-A expression in transgenic mice.
Vascular endothelial growth factor-A (VEGF-A) is the master regulator of angiogenesis, vascular permeability and growth. However, its role in mature blood vessels is still not well understood. To better understand the role of VEGF-A in the adult vasculature, we generated a VEGF-A knockdown mouse model carrying a doxycycline (dox)-regulatable short hairpin RNA (shRNA) transgene, which silences VEGF-A. The aim was to find the critical level of VEGF-A reduction for vascular well-being in vivo. In vitro, the dox-inducible lentiviral shRNA vector decreased VEGF-A expression efficiently and dose-dependently in mouse endothelial cells and cardiomyocytes. In the generated transgenic mice plasma VEGF-A levels decreased shortly after the dox treatment but returned back to normal after two weeks. VEGF-A expression decreased shortly after the dox treatment only in some tissues. Surprisingly, increasing the dox exposure time and dose led to elevated VEGF-A expression in some tissues of both wildtype and knockdown mice, suggesting that dox itself has an effect on VEGF-A expression. When the effect of dox on VEGF-A levels was further tested in naïve/non-transduced cells, the dox administration led to a decreased VEGF-A expression in endothelial cells but to an increased expression in cardiomyocytes. In conclusion, the VEGF-A knockdown was achieved in a dox-regulatable fashion with a VEGF-A shRNA vector in vitro, but not in the knockdown mouse model in vivo. Dox itself was found to regulate VEGF-A expression explaining the unexpected results in mice. The effect of dox on VEGF-A levels might at least partly explain its previously reported beneficial effects on myocardial and brain ischemia. Also, this effect on VEGF-A should be taken into account in all studies using dox-regulated vectors.


White light Bessel-like beams generated by miniature all-fiber device.
Micron-sized white light propagation invariant beams generated by a simple and compact fiber device are presented. The all-fiber device is fabricated by splicing a short piece of large-core multimode fiber onto a small-core single mode white light delivery fiber. Because this fiber device offers an inherent spatial coherence, nondiffracting white light beams can be created with a temporally incoherent broadband light source (a halogen bulb) and, most importantly, the surrounding fringes don't fade as the bandwidth of the light source increases because the underlying physics of this fiber device is different from that of the axicon. White light Bessel-like beams have been generated from multimode fibers with core diameters of 50 μm, 105 μm, and 200 μm. The distance of nondiffracting propagation of the white light Bessel beam increases with increasing core size of the multimode fiber. Propagation characteristics of red, green, and blue individual beams are also presented.


Energy expenditure and substrate metabolism measured by 24 h whole-body calorimetry in patients receiving cyclic and continuous total parenteral nutrition.
1. Twenty-four hour energy expenditure and its components, i.e. 'basal metabolic rate', activity energy expenditure and diet-induced thermogenesis were measured, using continuous whole-body indirect calorimetry, in patients receiving total parenteral nutrition while in remission from Crohn's disease (weight 51.9 +/- 9.9 kg, body mass index 19.2 +/- 2.0 kg/m2). 2. Total parenteral nutrition was infused continuously over 24 h in four subjects and cyclically, between 22.00 and 10.00 hours, in eight subjects. Twenty-four hour energy expenditure (6.83 +/- 1.10 MJ/24 h) was lower than total energy intake (10.09 +/- 1.63 MJ/24 h), resulting in a positive energy balance (3.26 +/- 1.42 MJ) in all subjects. Repeated measurements of resting energy expenditure in the continuously fed subjects (5.82 +/- 1.11 MJ/24 h) did not change significantly at different times of day (coefficient of variation 2.2-6.6%). In contrast, in cyclically fed subjects, resting energy expenditure was 24.2 +/- 9.0% higher towards the end of the 12 h feeding period than the 'basal metabolic rate', which was measured just before the start of the feeding period. 3. Diet-induced thermogenesis, calculated as the increment in resting energy expenditure above 'basal metabolic rate' over the 24 h period (adjusted for the reduction in energy expenditure during sleep), was found to be 0.60 +/- 0.29 MJ or 6.1 +/- 3.1% of the energy intake. 4. The energy cost of activity (activity energy expenditure) in the continuously fed patients, calculated as the difference between 24 h energy expenditure and the integrated 24 h measurements of resting energy expenditure, was 0.88 +/- 0.53 MJ, i.e. 12.9 +/- 5.9% of the 24 h energy expenditure. 5. The non-protein non-glycerol respiratory quotient exceeded 1.0 for varying periods of time (0.5-17 h) in 11 subjects, indicating net lipogenesis from carbohydrate. 6. The results demonstrate favourable rates of deposition, during intravenous feeding, of both energy and nitrogen over a 24 h period in patients recovering from an episode of Crohn's disease. The efficacy of these commonly used total parenteral nutrition regimens in these patients is related to three features that are absent in normal healthy individuals, namely a low basal metabolic rate, a low activity-related energy expenditure and prolonged periods of lipogenesis from carbohydrate.


Cholesterol screening: comparative evaluation of on-site and laboratory-based measurements.
We measured cholesterol in capillary blood samples from 9683 volunteers over a four-day on-site community screening program, using the "Reflotron" desk-top analyzer (Boehringer-Mannheim Diagnostics, Indianapolis, IN). We also measured cholesterol in venous blood samples from 3% of those screened (a) with the Reflotron at the screening sites, (b) in a qualified hospital clinical laboratory, and (c) in a Centers for Disease Control standardized lipoprotein research laboratory. The sensitivity (and specificity) of the Reflotron measurements, with use of the lipoprotein laboratory measurements as the point of reference, was 0.95 (0.73) in capillary blood samples and 0.88 (0.93) in venous blood samples, compared with 0.99 (0.87) in the hospital clinical laboratory. The Reflotron measurements correlated less well with the lipoprotein laboratory values in both venous blood (r = 0.91) and capillary blood (r = 0.89) samples than did the clinical laboratory values (r greater than 0.99). Furthermore, the capillary blood measurements averaged 7% higher than venous measurements when both kinds of samples were analyzed in the Reflotron.


Endonuclease Activity Inhibition of the NS1 Protein of Parvovirus B19 as a Novel Target for Antiviral Drug Development.
Human parvovirus B19 (B19V), a member of the genus Erythroparvovirus of the family Parvoviridae, is a small nonenveloped virus that has a single-stranded DNA (ssDNA) genome of 5.6 kb with two inverted terminal repeats (ITRs). B19V infection often results in severe hematological disorders and fetal death in humans. B19V replication follows a model of rolling hairpin-dependent DNA replication, in which the large nonstructural protein NS1 introduces a site-specific single-strand nick in the viral DNA replication origins, which locate at the ITRs. NS1 executes endonuclease activity through the N-terminal origin-binding domain. Nicking of the viral replication origin is a pivotal step in rolling hairpin-dependent viral DNA replication. Here, we developed a fluorophore-based in vitro nicking assay of the replication origin using the origin-binding domain of NS1 and compared it with the radioactive in vitro nicking assay. We used both assays to screen a set of small-molecule compounds (n = 96) that have potential antinuclease activity. We found that the fluorophore-based in vitro nicking assay demonstrates sensitivity and specificity values as high as those of the radioactive assay. Among the 96 compounds, we identified 8 which have an inhibition of >80% at 10 µM in both the fluorophore-based and radioactive in vitro nicking assays. We further tested 3 compounds that have a flavonoid-like structure and an in vitro 50% inhibitory concentration that fell in the range of 1 to 3 µM. Importantly, they also exhibited inhibition of B19V DNA replication in UT7/Epo-S1 cells and ex vivo-expanded human erythroid progenitor cells.


Data mining on DNA sequences of hepatitis B virus.
Extraction of meaningful information from large experimental data sets is a key element in bioinformatics research. One of the challenges is to identify genomic markers in Hepatitis B Virus (HBV) that are associated with HCC (liver cancer) development by comparing the complete genomic sequences of HBV among patients with HCC and those without HCC. In this study, a data mining framework, which includes molecular evolution analysis, clustering, feature selection, classifier learning, and classification, is introduced. Our research group has collected HBV DNA sequences, either genotype B or C, from over 200 patients specifically for this project. In the molecular evolution analysis and clustering, three subgroups have been identified in genotype C and a clustering method has been developed to separate the subgroups. In the feature selection process, potential markers are selected based on Information Gain for further classifier learning. Then, meaningful rules are learned by our algorithm called the Rule Learning, which is based on Evolutionary Algorithm. Also, a new classification method by Nonlinear Integral has been developed. Good performance of this method comes from the use of the fuzzy measure and the relevant nonlinear integral. The nonadditivity of the fuzzy measure reflects the importance of the feature attributes as well as their interactions. These two classifiers give explicit information on the importance of the individual mutated sites and their interactions toward the classification (potential causes of liver cancer in our case). A thorough comparison study of these two methods with existing methods is detailed. For genotype B, genotype C subgroups C1, C2, and C3, important mutation markers (sites) have been found, respectively. These two classification methods have been applied to classify never-seen-before examples for validation. The results show that the classification methods have more than 70 percent accuracy and 80 percent sensitivity for most data sets, which are considered high as an initial scanning method for liver cancer diagnosis.


GP-provided couple-based expanded preconception carrier screening in the Dutch general population: who accepts the test-offer and why?
Next generation sequencing has enabled fast and relatively inexpensive expanded carrier screening (ECS) that can inform couples' reproductive decisions before conception and during pregnancy. We previously showed that a couple-based approach to ECS for autosomal recessive (AR) conditions was acceptable and feasible for both health care professionals and the non-pregnant target population in the Netherlands. This paper describes the acceptance of this free test-offer of preconception ECS for 50 severe conditions, the characteristics of test-offer acceptors and decliners, their views on couple-based ECS and reasons for accepting or declining the test-offer. We used a survey that included self-rated health, intention to accept the test-offer, barriers to test-participation and arguments for and against test-participation. Fifteen percent of the expected target population-couples potentially planning a pregnancy-attended pre-test counselling and 90% of these couples proceeded with testing. Test-offer acceptors and decliners differed in their reproductive characteristics (e.g. how soon they wanted to conceive), educational level and stated barriers to test-participation. Sparing a child a life with a severe genetic condition was the most important reason to accept ECS. The most important reason for declining was that the test-result would not affect participants' reproductive decisions. Our results demonstrate that previously uninformed couples of reproductive age, albeit a selective part, were interested in and chose to have couple-based ECS. Alleviating practical barriers, which prevented some interested couples from participating, is recommended before nationwide implementation.


The influence of proton pump inhibitors and other commonly used medication on the gut microbiota.
Proton pump inhibitors (PPIs), used to treat gastro-esophageal reflux and prevent gastric ulcers, are among the most widely used drugs in the world. The use of PPIs is associated with an increased risk of enteric infections. Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI-use on the gut microbiota. We discovered profound differences in the gut microbiota of PPI users: 20% of their bacterial taxa were statistically significantly altered compared with those of non-users. Moreover, we found that it is not only PPIs, but also antibiotics, antidepressants, statins and other commonly used medication were associated with distinct gut microbiota signatures. As a consequence, commonly used medications could affect how the gut microbiota resist enteric infections, promote or ameliorate gut inflammation, or change the host's metabolism. More studies are clearly needed to understand the role of commonly used medication in altering the gut microbiota as well as the subsequent health consequences.


Removing financial barriers to organ and bone marrow donation: the effect of leave and tax legislation in the U.S.
Many U.S. states have passed legislation providing leave to organ and bone marrow donors and/or tax benefits for live and deceased organ and bone marrow donations and to employers of donors. We exploit cross-state variation in the timing of such legislation to analyze its impact on organ donations by living and deceased persons, on measures of the quality of the transplants, and on the number of bone marrow donations. We find that these provisions do not have a significant impact on the quantity of organs donated. The leave laws, however, do have a positive impact on bone marrow donations, and the effect increases with the size of the population of beneficiaries and with the generosity of the legislative provisions. Our results suggest that this legislation works for moderately invasive procedures such as bone marrow donation, but these incentives may be too low for organ donation, which is riskier and more burdensome.


TGF-β1, EGF and FGF4 synergistically induce differentiation of the seminoma cell line TCam-2 into a cell type resembling mixed non-seminoma.
Malignant germ-cell tumours arise from a neoplastic precursor, the carcinoma in situ, and develop into seminomas and/or non-seminomas (embryonal carcinomas, teratomas, yolk-sac tumours and choriocarcinomas). Based on histological and clinical findings, it has been postulated that seminomas can eventually transform into non-seminomas. Here, we used the cell line TCam-2 as model for seminomas and interrogated their differentiation potential. We demonstrate that TCam-2 cells are able to differentiate into mixed non-seminomatous lineages after supplementing the media with TGF-β1, EGF and FGF4. On a molecular level, the differentiation is initiated by repression of BMP/SMAD signalling. As a consequence, BLIMP1, a molecule known to inhibit the differentiation of murine primordial germ cells, is down-regulated and differentiation-inhibiting histone modifications are lost. The appearance of multinucleated giant cells and the expression of marker genes indicate that cells differentiate predominantly into extra-embryonic choriocarcinoma-like cells. This is most likely due to the presence of components of the Hippo pathway, TEAD4 and YAP1. These molecules have been described to trigger extra-embryonic fate determination in the murine system. This study supports the model that seminomas indeed have an intrinsic ability to transform into a non-seminoma. In addition, the data suggest that the transformation does not require an additional mutation, but can be triggered by changes in the tumour microenvironment.


Brewster's angle attenuator for terahertz pulses.
A variable attenuator for terahertz (THz) pulses is developed on the basis of the change in reflectivity of lithium niobate wafers with incident angle in a Brewster configuration. We can vary the THz field transmission from 22% to 54%, a change of a factor of 2.5, while preserving the shape of the THz pulse spectrum. Changes in the THz spectrum are shown to be much smaller when the Brewster attenuator is used than when either the near-infrared pump power or the bias voltage on a THz photoconductive antenna is varied. The Brewster attenuator should prove especially useful for varying THz field strength in nonlinear optical studies that use broadband THz pulses.


Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress.
Oxidative stress with hydrogen peroxide (H(2)O(2)) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H(2)O(2) on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H(2)O(2) (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94%) aged (24-26 mo) rat hearts, 0.1 mM H(2)O(2) caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (life span, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 microM) but not by its inactive form (KN-92, 1 microM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H(2)O(2) in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90%; middle-aged rabbit hearts had less fibrosis (5-35%), whereas young adult rat and rabbit hearts had <4% fibrosis. In aged rat hearts, EADs and TA arose most frequently (70%) from the left ventricular base where fibrosis was intermediate ( approximately 30%). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level.


Work and Family Stress and Well-Being: An Examination of Person-Environment Fit in the Work and Family Domains.
Research indicates that work and family are significant sources of stress. However, this research has underemphasized the cognitive appraisal process by which work and family generate stress. This study used person-environment fit theory to examine how the comparison of work and family experiences to the person's values relates to stress and well-being. Using data from 1758 employees, we assessed fit regarding autonomy, relationships, security, and segmentation for both work and family, and examined the relationship of fit with work and family satisfaction, anxiety, depression, irritation, and somatic symptoms. In general, well-being improved as experiences increased toward values and improved to a lesser extent as experiences exceeded values. Well-being was also higher when experiences and values were both high than when both were low. These relationships were generally strongest for within-domain fit and well-being (i.e., work fit and work satisfaction, family fit and family satisfaction), and several relationships were moderated by work and family centrality. Copyright 1999 Academic Press.


Unidirectional emission of a quantum dot coupled to a nanoantenna.
Nanoscale quantum emitters are key elements in quantum optics and sensing. However, efficient optical excitation and detection of such emitters involves large solid angles because their interaction with freely propagating light is omnidirectional. Here, we present unidirectional emission of a single emitter by coupling to a nanofabricated Yagi-Uda antenna. A quantum dot is placed in the near field of the antenna so that it drives the resonant feed element of the antenna. The resulting quantum-dot luminescence is strongly polarized and highly directed into a narrow forward angular cone. The directionality of the quantum dot can be controlled by tuning the antenna dimensions. Our results show the potential of optical antennas to communicate energy to, from, and between nano-emitters.


Rehabilitation of older adults with hearing impairment: a critical review.
Hearing impairment, which affects both peripheral and central structures of the auditory system, is highly prevalent among older adults and has serious consequences both for the people with hearing impairment and for those around them. This article provides an updated overview of the rehabilitation of this population. This article critically reviews the rehabilitation interventions available to older adults with hearing impairment: hearing aids, hearing assistance technology, and communication programs. Current evidence suggests positive outcomes of similar magnitude for the three rehabilitation interventions, however their availability/uptake and adherence are suboptimal. To improve the current situation, two changes to practice are warranted. First, availability of the range of rehabilitation interventions should be improved. Second, in accordance with the self-management of other chronic health conditions, older adults with hearing impairment should be invited to be actively involved in their rehabilitation.


Highest reported visual acuity after electronic retinal implantation.
To report the highest attained visual acuity with an electronic retinal implant for the treatment of advanced retinal degeneration following a novel intensive period of visual training. A case study as part of the prospective, international, multi-centre, interventional clinical trial (ClinicalTrials.gov NCT02720640 and NCT01024803) of patients with the Retina Implant Alpha AMS (Retina Implant AG, Reutlingen, Germany) for advanced retinal degeneration. A patient with subretinal device implanted into worse-seeing eye with no useful perception of light vision secondary to USH2A retinal degeneration underwent intensive period of visual training. The device remains functional with no safety concerns at 3 years postsurgical implantation, and following visual training, the patient achieved the highest visual acuity so far with an electronic retinal device, with real, digitally unenhanced, reading vision of 0.04 decimal (equivalent to 1.39 LogMAR and 20/500 or 6/150 Snellen). In addition, perception as well as partial identification of obstacles and evaluation of distances was possible in both daylight and night-time settings. Retinal implants are currently the only available therapy option for advanced retinal degeneration. Visual rehabilitation postimplantation has potential to maximize visual percepts. The novel concept of intensive visual training presented herein shows what is achievable with electronic retinal implants and has implications for other therapeutic options, such as optogenetics, that aim to stimulate remaining inner retinal cells in advanced retinal degeneration.


Smartphone use and primary headache: A cross-sectional hospital-based study.
To determine the association of smartphone use with occurrence of new-onset headache and/or increased severity of headaches in patients with primary headache. In a cross-sectional study between June 2017 and December 2018, patients with primary headache were divided into 2 groups: smartphone users (SUs) and non-smartphone users (NSUs). A questionnaire was administered for headache characteristics and treatment taken. The primary objective was to determine the association of smartphone use with new-onset headache or increase severity. The secondary objective was to determine any differences in the requirement of acute medication and prophylaxis. Four hundred patients were included in the study, of which 194 were NSUs and 206 were SUs. The NSUs were older with lower education and socioeconomic status. The headache characteristics were similar in both the groups, except for higher occurrence of aura (NSUs: 15 [7.7%] vs SUs: 36 [17.5%]; p = 0.003) in the SU group. There was, however, higher proportion of patients taking analgesics (NSUs: 157 [80.9%] vs SUs: 197 [95.6%]; p < 0.001), with less relief in headache with medication in the SU group. This was driven by increased pill count (low SUs: 5.0 [3.0; 10.0] vs high SUs: 10.0 [5.0; 15.0]; p = 0.007) and poor response to medication in the high SU group. The use of smartphone was associated with increase in requirement of acute medication and less relief with acute medication. Longitudinal studies may be required to confirm these findings.


Advances in transoral fundoplication for oesophageal reflux.
The purpose of this review was to evaluate transoral fundoplication devices for gastro-oesophageal reflux disease that have been commercially available within the last 5 years. Literature databases including Medline and Pubmed were searched from January 2005 to November 2010. Both blinded and unblinded randomized studies were evaluated. We reviewed the literature for evaluations of primary transoral endoluminal fundoplication devices which included EndoCinch, NDO Plicator, Esophyx, and Stretta. Reviews of all studies with greater than 20 patients were evaluated to assess the efficacy and safety of transoral fundoplication devices. These endoluminal devices were primary matched against sham procedures. The EndoCinch and Stretta procedures were the only devices compared to laparoscopic fundoplication, the current standard for surgical management of gastro-oesophageal reflux disease. The field of endoluminal treatment of gastro-oesophageal reflux disease has gained popularity over the last several years. Endoluminal treatment of gastro-oesophageal reflux disease has been shown to be safe and effective in recent studies. We still believe more randomized prospective studies need to be carried out to determine if endoluminal therapies will be a durable option for patients with gastro-oesophageal reflux disease. Continuing research will further the advancement of endoluminal gastro-oesophageal reflux disease procedures in the future.


Erectile function status is highly associated with prostate-specific antigen bounce in localized prostate cancer patients treated with permanent prostate brachytherapy.
To examine the relationship between erectile function status and prostate-specific antigen bounce after prostate brachytherapy for localized prostate cancer. We identified 154 patients who were followed up for at least 24 months after brachytherapy. Erectile function status was assessed prospectively before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15 questionnaire. Prostate-specific antigen bounce was defined as an increase of at least 0.4 ng/mL from a previous prostate-specific antigen level with a subsequent decline equal to, or less than, the initial nadir without treatment. A logistic regression analysis was used to identify a significant set of independent predictors of prostate-specific antigen bounce after brachytherapy. Prostate-specific antigen bounce was observed in 38 (24.7%) men. The prostate-specific antigen bounce group had a higher erectile function domain score, higher orgasmic function domain score, and higher total International Index of Erectile Function-15 score before (at baseline) and after brachytherapy (3, 6, 12, 18, 24 and 36 months after brachytherapy) than their counterparts (P < 0.05). Of the 77 patients who completed the International Index of Erectile Function-15 questionnaire 18 months after brachytherapy (the median time of prostate-specific antigen bounce), sexual desire and intercourse satisfaction domain scores, and total International Index of Erectile Function scores 18 months after brachytherapy correlated with the occurrence of prostate-specific antigen bounce. A multivariate analysis identified the intercourse satisfaction domain score 18 months after brachytherapy as an independent indicator for the occurrence of prostate-specific antigen bounce (P = 0.008). International Index of Erectile Function-15 score seems to be correlated with the prostate-specific antigen bounce in prostate cancer patients undergoing brachytherapy, and an occurrence of prostate-specific antigen bounce seems to be more likely in those who are more sexually active.


Considerations for a Primary Care Physician Assistant in Treating Kidney Transplant Recipients.
The escalating amount of kidney transplant recipients (KTRs) represents a significant dilemma for primary care providers. As the number of physician assistants (PAs) has been steadily increasing in primary care in the United States, the utilization of these healthcare professionals presents a solution for the care of post-kidney transplant recipients. A physician assistant (PA) is a state licensed healthcare professional who practices medicine under physician supervision and can alleviate some of the increasing demands for primary patient care. Here we provide an outline of the crucial components and considerations for PAs caring for kidney transplant recipients. These include renal function and routine screenings, drug monitoring (both immunosuppressive and therapeutic), pre-existing and co-existing conditions, immunizations, nutrition, physical activity, infection, cancer, and the patient's emotional well-being. PAs should routinely monitor renal function and blood chemistry of KTRs. Drug monitoring of KTRs is a crucial responsibility of the PA because of the possible side-effects and potential drug-drug interactions. Therefore, PAs should obtain a careful and detailed patient history from KTRs. PAs should be aware of pre- and co-existing conditions of KTRs as this impacts treatment decisions. Regarding immunization, PAs should avoid administering vaccines containing live or attenuated viruses to KTRs. Because obesity following kidney transplantation is associated with decreased allograft survival, PAs should encourage KTRs to maintain a balanced diet with limited sugar. In addition, KTRs should be urged to gradually increase their levels of physical activity over subsequent years following surgery. PAs should be aware that immunosuppressive medications diminish immune defenses and make KTRs more susceptible to bacterial, viral, and fungal infections. Moreover, KTRs should be screened routinely for cancer due to the higher risk of development from immunosuppressive therapy. PAs must remain cognizant of the emotional well-being of the KTR, as many transplant patients struggle with fear, frustration, and acceptance.


Separation of drug effects on timing and behavioral inhibition by increased stimulus control.
Impulsive behavior may represent, in part, a failure of behavioral inhibition (the ability to delay or inhibit a response). In this study, use of a multiple signaled-unsignaled differential-reinforcement-of-low-rates (DRL) 15-s schedule allowed examination of drug effects in conditions in which level of stimulus control differed. Results showed that whereas diazepam increased premature responding during signaled and unsignaled DRL components, amphetamine and delta9-tetrahydrocannabinol increased premature responding primarily during unsignaled components when timing was necessary for efficient performance on the task. In contrast, pimozide and desipramine increased long-delay responses across both components, resulting in longer mean interresponse times. Collectively, these results suggest that the use of different levels of stimulus control may aid in separation of drug effects on timing and other behavioral processes, including behavioral inhibition.


Assembly and transfer of tripartite integrative and conjugative genetic elements.
Integrative and conjugative elements (ICEs) are ubiquitous mobile genetic elements present as "genomic islands" within bacterial chromosomes. Symbiosis islands are ICEs that convert nonsymbiotic mesorhizobia into symbionts of legumes. Here we report the discovery of symbiosis ICEs that exist as three separate chromosomal regions when integrated in their hosts, but through recombination assemble as a single circular ICE for conjugative transfer. Whole-genome comparisons revealed exconjugants derived from nonsymbiotic mesorhizobia received three separate chromosomal regions from the donor Mesorhizobium ciceri WSM1271. The three regions were each bordered by two nonhomologous integrase attachment (att) sites, which together comprised three homologous pairs of attL and attR sites. Sequential recombination between each attL and attR pair produced corresponding attP and attB sites and joined the three fragments to produce a single circular ICE, ICEMcSym1271 A plasmid carrying the three attP sites was used to recreate the process of tripartite ICE integration and to confirm the role of integrase genes intS, intM, and intG in this process. Nine additional tripartite ICEs were identified in diverse mesorhizobia and transfer was demonstrated for three of them. The transfer of tripartite ICEs to nonsymbiotic mesorhizobia explains the evolution of competitive but suboptimal N2-fixing strains found in Western Australian soils. The unheralded existence of tripartite ICEs raises the possibility that multipartite elements reside in other organisms, but have been overlooked because of their unusual biology. These discoveries reveal mechanisms by which integrases dramatically manipulate bacterial genomes to allow cotransfer of disparate chromosomal regions.


The diagnosis and management of dyscalculia.
Dyscalculia is defined as difficulty acquiring basic arithmetic skills that is not explained by low intelligence or inadequate schooling. About 5% of children in primary schools are affected. Dyscalculia does not improve without treatment. In this article, we selectively review publications on dyscalculia from multiple disciplines (medicine, psychology, neuroscience, education/special education). Many children and adolescents with dyscalculia have associated cognitive dysfunction (e.g., impairment of working memory and visuospatial skills), and 20% to 60% of those affected have comorbid disorders such as dyslexia or attention deficit disorder. The few interventional studies that have been published to date document the efficacy of pedagogic-therapeutic interventions directed toward specific problem areas. The treatment is tailored to the individual patient's cognitive functional profile and severity of manifestations. Psychotherapy and/or medication are sometimes necessary as well. The early identification and treatment of dyscalculia are very important in view of its frequent association with mental disorders. Sufferers need a thorough, neuropsychologically oriented diagnostic evaluation that takes account of the complexity of dyscalculia and its multiple phenotypes and can thus provide a basis for the planning of effective treatment.


Decreased anterior cingulate volume in combat-related PTSD.
Neuroanatomical data point to functional relationships between the anterior cingulate cortex (ACC) and subcortical centers regulating fear, in particular, the amygdala. Functional brain imaging has disclosed divergent patterns of ACC activation in persons with posttraumatic stress disorder (PTSD). In addition, two preliminary structural imaging studies have found evidence of smaller ACC volume in PTSD. We explored associations between PTSD and ACC volume in a relatively large sample of adult combat veterans in which PTSD, lifetime alcohol abuse/dependence, and Vietnam versus Gulf War service were crossed. Subjects were US military combat veterans of the Vietnam and Gulf Wars recruited from two metropolitan areas served by allied Department of Veterans Affairs PTSD treatment/research centers. Anterior cingulate cortex volume was analyzed as a function of grouping factors with and without adjustment for body size. Posttraumatic stress disorder was associated with smaller anterior cingulate cortex volume. This effect persisted in subjects without histories of alcoholism, did not interact with cohort effects, and was not modified by adjustment for body size. Anterior cingulate cortex volume is substantially smaller in association with combat-related PTSD, a finding broadly consistent with cingulate hypofunctionality in that disorder.


Deindustrialising economies, plant closures and affected communities: Identifying potential pathways to health inequities.
Deindustrialisation and transitions from traditional manufacturing to new technologies and service industries in many high-income countries including Australia has resulted in rising employment insecurity, unemployment and increased income and health inequities. In this paper, we explore potential impacts of an automotive plant closure on health in a disadvantaged area of South Australia. Our aim was to examine how prevailing factors affecting social and health inequity might be further affected following the plant closure and to identify levers for potential policy responses. In workshop discussions with 28 policy and 14 community stakeholders through an iterative process participants discussed how existing factors contributing to community social and health inequity might be worsened (or remediated) by the looming economic shock from the plant closure. We identified eight key themes highlighted in the workshops. In particular local economic investment, availability of job opportunities, and appropriate training were identified as key factors influencing individual financial security, which was in turn linked to social and health impacts. The pathways mapped between the plant closure and social and health equity impacts highlighted differential potential impacts on individuals and the community, and identified policy levers to reduce adverse health outcomes resulting from economic shocks such as the closure of a major employer. SO WHAT?: The study highlighted a broad range of intersecting factors affecting the health of the local community that policy responses to the plant closure needed to address to promote health and health equity. This included novel factors identified by community members, reinforcing the importance of including community perspectives when constructing policy responses.


Prenatal exposure of diclofenac sodium alters the behavioral development of young Wistar rats.
Diclofenac sodium (DS), a potent inhibitor of cyclooxygenase, reduces the release of arachidonic acid and formation of prostaglandins. Being a nonsteroid drug that shows antiinflammatory action, the possible side effects of fetal DS administration gain importance in public and medical applications. Herein, the effects of DS administration (1 mg/kg) during gestational days 5-20 were investigated on the performance of Wistar rat pups in a variety of behavioral tasks. Four-week-old pups were subjected to sensory motor tests, a plus maze, an open field, the Morris water maze, and a radial arm maze. Fetal DS disrupted some sensory motor performances, such as visual placing and climbing in both females and males. In the open field, DS females had a higher level of anxiety and male DS pups habituated to the environment slowly compared to controls. The DS pups showed slower rates of learning, whereas no substantial between-group differences were found in the performance of spatial memory compared to both controls. Furthermore, working memory was negatively affected by fetal DS. In conclusion, it was indicated that DS administration during pregnancy had slight behavioral impacts with a delay in learning and a defect in the short-term memory in juvenile rats.


Trypanosoma brucei: trypanosome strain typing using PCR analysis of mobile genetic elements (MGE-PCR).
We describe the development of a single-primer amplification system, which uses the trypanosomal mobile genetic element RIME as a molecular marker for the differentiation of Trypanosoma brucei stocks. Using a well-characterised set of T. brucei stocks from southeast Uganda, Kenya and Zambia, we have evaluated the application of this technique, termed MGE-PCR (mobile genetic element PCR) for the typing of trypanosome strains. The technique revealed considerable variation between stocks and was sufficiently specific to amplify trypanosomal DNA in the presence of host DNA. The results showed a clear distinction between human-infective and non-human-infective stocks. Comparative studies on these stocks using markers for the human serum resistance associated (SRA) gene, which identifies human-infective stocks, demonstrated complete agreement between MGE-PCR derived groups and human-infectivity status. Furthermore, MGE-PCR detects high levels of variability within the T. b. brucei and T. b. rhodesiense groups and is therefore a powerful discriminatory tool for tracking individual T. brucei genotypes and strains.


Bridging consent: from toll bridges to lift bridges?
The ability to share human biological samples, associated data and results across disease-specific and population-based human research biobanks is becoming increasingly important for research into disease development and translation. Although informed consent often does not anticipate such cross-domain sharing, it is important to examine its plausibility. The purpose of this study was to explore the feasibility of bridging consent between disease-specific and population-based research. Comparative analyses of 1) current ethical and legal frameworks governing consent and 2) informed consent models found in disease-specific and population-based research were conducted. Ethical and legal frameworks governing consent dissuade cross-domain data sharing. Paradoxically, analysis of consent models for disease-specific and population-based research reveals such a high degree of similarity that bridging consent could be possible if additional information regarding bridging was incorporated into consent forms. We submit that bridging of consent could be supported if current trends endorsing a new interpretation of consent are adopted. To illustrate this we sketch potential bridging consent scenarios. A bridging consent, respectful of the spirit of initial consent, is feasible and would require only small changes to the content of consents currently being used. Under a bridging consent approach, the initial data and samples collection can serve an identified research project as well as contribute to the creation of a resource for a range of other projects.


Ultrastructural changes of adult Schistosoma mansoni worms recovered from C57BL/6 mice passively immunized with normal and vaccinated rabbit sera in vivo.
The purpose of the study is to explore the role of humoral immunity against Schistosoma mansoni infection in C57BL/6 mice using highly resistant rabbits that had been exposed to three separate immunizations with ultraviolet (UV)-irradiated cercariae (8,000 attenuated cercariae/rabbit in each immunization), and their sera were tested for their ability to transfer protection against S. mansoni challenge. The present study showed the reduction in challenge worm burden had reached 32.76-43.64% when compared with recipients of normal serum or no serum. The surface topography of the worms collected from immunized mice with either normal rabbit sera (NRS) or vaccinated rabbit sera (VRS) revealed severe tegumental alterations, especially in the VRS group. Worms collected from groups that were immunized by NRS or VRS postinfection (200 normal cercariae/mouse) by day 42. Worms from group immunized with NRS showed damage in the tegument, characterized by severe swelling or erosion of tegumental folds, accompanied by changes in tubercles, swelling, shortening, and loss of spines in male worms. The alteration in female tegument was characterized by swelling of tegumental folds, atrophy of ventral sucker, damage of sensory papillae along all the body, severe peeling in some regions, and appearance of few small blebs. VRS induced more severe tegumental damage than NRS in both male and female worms. Severe shrunken vesicles were protruded from the surface between the two suckers. The tegument of the male showed a collapse of tubercles followed by the appearance of vesicles on their surfaces, fusion, erosion, and superficial focal peeling of tegumental folds. In the female worms, severe damage to the oral sucker, the surface between the two suckers, extensive peeling, severe swelling of the tegument, and damage of sensory papillae. In conclusion, the present study support the hypothesis that high levels of antibodies were developed in rabbit sera after multiple exposures to attenuated cercariae of S. mansoni. Furthermore, immunization might have transferred protection against the infection, indicated by severe morphological alterations, a sign of elimination of the worms. Further investigation is being carried out to reveal the molecular mechanisms underlying the transfer of protection.


ISWI complexes in Saccharomyces cerevisiae.
The imitation switch (ISWI) class of chromatin remodeling ATPase is ubiquitous in eukaryotes. It is becoming clear that these enzymes exist as part of larger complexes and the nature of the associated proteins dictate the function associated with a complex both in biochemical assays and in the cell. Much progress has been made in understanding these relationships in the budding yeast Saccharomyces cerevisiae, containing two ATPases, Isw1p and Isw2p. This has been aided by the ease of genetic manipulation, by a number of systematic screens designed to specifically detect ISWI function and by the plethora of data generated from a number of global screens for function. At present, many functions for yeast Isw1p and Isw2p are related to effects on RNA levels and are associated with the controlled repression of gene expression that crudely fall into three types: displacement of the basal transcription machinery to repress or silence transcription of genes (Isw2 complex and Isw1/Ioc3 complex); control of the activation of expression leading to coordination of transcription elongation; and efficient termination of transcription (Isw1/Ioc4/Ioc2 complex). The latter two functions are regulated by specific phosphorylation of residues within the carboxy terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII). Other functions may relate to the ability of ISWI complex to displace transcription factors or enzymes from the template. Other ISWI-containing complexes that have yet to be characterized indicate that much remains to be learnt about yeast ISWI itself and importantly, how the various forms cooperate with different classes of chromatin remodeling ATPase, complexes containing histone acetylases, deacetylases, methylases and both DNA and RNA polymerases.


Impact of different pack sizes of paracetamol in the United Kingdom and Ireland on intentional overdoses: a comparative study.
In order to reduce fatal self-poisoning legislation was introduced in the UK in 1998 to restrict pack sizes of paracetamol sold in pharmacies (maximum 32 tablets) and non-pharmacy outlets (maximum 16 tablets), and in Ireland in 2001, but with smaller maximum pack sizes (24 and 12 tablets). Our aim was to determine whether this resulted in smaller overdoses of paracetamol in Ireland compared with the UK. We used data on general hospital presentations for non-fatal self-harm for 2002-2007 from the Multicentre Study of Self-harm in England (six hospitals), and from the National Registry of Deliberate Self-harm in Ireland. We compared sizes of overdoses of paracetamol in the two settings. There were clear peaks in numbers of non-fatal overdoses, associated with maximum pack sizes of paracetamol in pharmacy and non-pharmacy outlets in both England and Ireland. Significantly more pack equivalents (based on maximum non-pharmacy pack sizes) were used in overdoses in Ireland (mean 2.63, 95% CI 2.57-2.69) compared with England (2.07, 95% CI 2.03-2.10). The overall size of overdoses did not differ significantly between England (median 22, interquartile range (IQR) 15-32) and Ireland (median 24, IQR 12-36). The difference in paracetamol pack size legislation between England and Ireland does not appear to have resulted in a major difference in sizes of overdoses. This is because more pack equivalents are taken in overdoses in Ireland, possibly reflecting differing enforcement of sales advice. Differences in access to clinical services may also be relevant.


Structure of In31, a blaIMP-containing Pseudomonas aeruginosa integron phyletically related to In5, which carries an unusual array of gene cassettes.
The location and environment of the acquired blaIMP gene, which encodes the IMP-1 metallo-beta-lactamase, were investigated in a Japanese Pseudomonas aeruginosa clinical isolate (isolate 101/1477) that produced the enzyme. In this isolate, blaIMP was carried on a 36-kb plasmid, and similar to the identical alleles found in Serratia marcescens and Klebsiella pneumoniae clinical isolates, it was located on a mobile gene cassette inserted into an integron. The entire structure of this integron, named In31, was determined. In31 is a class 1 element belonging to the same group of defective transposon derivatives that originated from Tn402-like ancestors such as In0, In2, and In5. The general structure of In31 appeared to be most closely related to that of In5 from pSCH884, suggesting a recent common phylogeny for these two elements. In In31, the blaIMP cassette is the first of an array of five gene cassettes that also includes an aacA4 cassette and three original cassettes that have never been described in other integrons. The novel cassettes carry, respectively, (i) a new chloramphenicol acetyltransferase-encoding allele of the catB family, (ii) a qac allele encoding a new member of the small multidrug resistance family of proteins, and (iii) an open reading frame encoding a protein of unknown function. All the resistance genes carried on cassettes inserted in In31 were found to be functional in decreasing the in vitro susceptibilities of host strains to the corresponding antimicrobial agents.


Learning more from microarrays: insights from modules and networks.
Global gene expression patterns can provide comprehensive molecular portraits of biologic diversity and complex disease states, but understanding the physiologic meaning and genetic basis of the myriad gene expression changes have been a challenge. Several new analytic strategies have now been developed to improve the interpretation of microarray data. Because genes work together in groups to carry out specific functions, defining the unit of analysis by coherent changes in biologically meaningful sets of genes, termed modules, improves our understanding of the biological processes underlying the gene expression changes. The gene module approach has been used in exploratory discovery of defective oxidative phosphorylation in diabetes mellitus and also has allowed definitive hypothesis testing on a genomic scale for the relationship between wound healing and cancer and for the oncogenic mechanism of cyclin D. To understand the genetic basis of global gene expression patterns, computational modeling of regulatory networks can highlight key regulators of the gene expression changes, and many of these predictions can now be experimentally validated using global chromatin-immunoprecipitation analysis.


1H, 13C, and 15N backbone chemical shift assignments of the C-terminal dimerization domain of SARS-CoV-2 nucleocapsid protein.
The current outbreak of the highly infectious COVID-19 respiratory disease is caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). To fight the pandemic, the search for promising viral drug targets has become a cross-border common goal of the international biomedical research community. Within the international Covid19-NMR consortium, scientists support drug development against SARS-CoV-2 by providing publicly available NMR data on viral proteins and RNAs. The coronavirus nucleocapsid protein (N protein) is an RNA-binding protein involved in viral transcription and replication. Its primary function is the packaging of the viral RNA genome. The highly conserved architecture of the coronavirus N protein consists of an N-terminal RNA-binding domain (NTD), followed by an intrinsically disordered Serine/Arginine (SR)-rich linker and a C-terminal dimerization domain (CTD). Besides its involvement in oligomerization, the CTD of the N protein (N-CTD) is also able to bind to nucleic acids by itself, independent of the NTD. Here, we report the near-complete NMR backbone chemical shift assignments of the SARS-CoV-2 N-CTD to provide the basis for downstream applications, in particular site-resolved drug binding studies.


Anaplasia in pilocytic astrocytoma predicts aggressive behavior.
The clinical significance of anaplastic features, a rare event in pilocytic astrocytoma (PA), is not fully established. We reviewed 34 PA with anaplastic features (Male = 21, Female = 13; median age 35 y, 5 to 75) among approximately 2200 PA cases (1.7%). Tumors were included which demonstrated brisk mitotic activity [at least 4 mitoses/10 high power fields (400 x )], in addition to hypercellularity and moderate-to-severe cytologic atypia, with or without necrosis. The tumors either had a PA precursor, coexistent (n = 14) (41%) or documented by previous biopsy (n = 10) (29%), or exhibited typical pilocytic features in an otherwise anaplastic astrocytoma (n = 10) (29%). Clinical features of neurofibromatosis type-1 were present in 24% and a history of radiation for PA precursor in 12%. Histologically, the anaplastic component was classified as pilocytic like (41%), small cell (32%), epithelioid (15%), or fibrillary (12%). Median MIB1 labeling index was 24.7% in the anaplastic component and 2.6% in the precursor, although overlapping values were present. Strong p53 staining (3+) was limited to areas with anaplasia (19%), with overlapping values for 1 and 2+ in areas without anaplasia. Median overall and progression-free survivals after diagnosis for the entire study group were 24 and 14 months, respectively. Overall and progression-free survivals were shorter in the setting of prior radiation for a PA precursor (P = 0.007, 0.028), increasing mitotic activity (P = 0.03, 0.02), and presence of necrosis (P = 0.02, 0.02), after adjusting for age and site. The biologic behavior of PAs with high-mitotic rates and those with necrosis paralleled that of St Anne-Mayo grades 2 and 3 diffuse astrocytomas, respectively. In summary, PA with anaplastic features exhibits a spectrum of morphologies and is associated with decreased survival when compared with typical PA.