Acaricidal activity of a 2-methoxy-clovan-9-ol rich fraction from Eugenia copacabanensis (Myrtaceae) extract on Rhipicephalus microplus (Acari: Ixodidae).
Rhipicephalus microplus (Ixodidae, canestrini, 1888) is an invasive ectoparasite of cattle which causes high economic losses in emerging countries such as Brazil. Phytochemical compounds have been tested as an alternative to synthetic acaricides due to potentially lower mammalian toxicity. This study evaluated the acaricidal activity against R. microplus of the 2-methoxy-clovan-9-ol rich fraction obtained from Eugenia copacabanensis Kiaersk.leaves, a little known Myrtaceae species from the Brazilian Atlantic Forest. This fraction was obtained by maceration with methanol, partition with n-hexane and purification by normal-phase column chromatography. GC-MS, 1H and 13C NMR and IR analysis contributed to the identification of a major compound as the sesquiterpene 2-methoxy-clovan-9-ol, reported for the first time for the Myrtaceae family. The fraction was tested against R. microplus unfed larvae and engorged females and a 93% larval mortality was observed at the concentration of 50 mg mL-1. Lower concentrations of the solution tested demonstrated a significant difference in egg mass weight, hatching and control percentage. Experiments with 50.0 mg mL-1 showed significative results, with lower concentration and maximum efficacy for both assays. The IC50 values for unfed larvae and engorged females were 21.76 and 11.13 mg mL-1, respectively. These results were similar to those obtained in other studies with isolated botanical compounds and essential oils. The lower IC50 for engorged females than for unfed R. microplus larvae had also been described for other plant materials, including plants from the same Myrtaceae family. The present result suggested different mechanisms of action of the compound on the reproductive biology of engorged females, improving its effect against egg viability. These results are important for tick control, suggesting that 2-methoxy-clovan-9-ol could be a potential natural acaricidal product against both R. microplus unfed larvae and engorged females.


Defective galactosylation in galactosemia: is low cell UDPgalactose an explanation?
There is circumstantial evidence that defective galactosylation of complex glycoconjugates exists in tissues from galactosemic patients. Whether this is an etiologic factor in the long-term complications of the disorder is not known. Also not evident is the basis for the impaired galactosylation. The hypothesis that abnormally low cellular uridine diphosphate galactose (UDPgal) content is responsible has not been established. There is a tendency for galactosemic red cell UDPgal to be in the low normal range with a high uridine diphosphate glucose to UDP-gal ratio. This may reflect an inability of red cell UDPgal-4'-epimerase to maintain a normal ratio and consequently higher levels of UDPgal. In the more complex white blood cells and cultured fibroblasts, the UDPgal content and the uridine diphosphate glucose to UDPgal ratio of galactosemics are normal. Therefore, defective galactosylation observed in galactosemic fibroblasts must result from a defect in the transfer of galactose from UDPgal to these moieties.


Drawing light from the pandemic: Rethinking strategies for health policy and beyond.
The COVID-19 pandemic is a catastrophe. It was also preventable. The potential impacts of a novel pathogen were foreseen and for decades scientists and commentators around the world warned of the threat. Most governments and global institutions failed to heed the warnings or to pay enough attention to risks emerging at the interface of human, animal, and environmental health. We were not ready for COVID-19, and people, economies, and governments around the world have suffered as a result. We must learn from these experiences now and implement transformational changes so that we can prevent future crises, and if and when emergencies do emerge, we can respond in more timely, robust and equitable ways, and minimize immediate and longer-term impacts. In 2020-21 the Pan-European Commission on Health and Sustainable Development assessed the challenges posed by COVID-19 in the WHO European region and the lessons from the response. The Commissioners have addressed health in its entirety, analyzing the interactions between health and sustainable development and considering how other policy priorities can contribute to achieving both. The Commission's final report makes a series of policy recommendations that are evidence-informed and above all actionable. Adopting them would achieve seven key objectives and help build truly sustainable health systems and fairer societies.


The 6-minute stepper test and the sit-to-stand test predict complications after major pulmonary resection via minimally invasive surgery: a prospective inception cohort study.
How well do the 6-minute stepper test (6MST) and sit-to-stand test (STST) predict complications after minimally invasive lung cancer resection? Do the 6MST and STST provide supplementary information on the risk of postoperative complications in addition to the prognostic variables that are currently used, such as age and the American Society of Anesthesiology (ASA) score? Prospective inception cohort study with follow-up for 90 days. Consecutive sample of adults undergoing major lung resection with video-assisted thoracic surgery (VATS) or robot-assisted thoracic surgery (RATS). Patients had a preoperative functional evaluation with the 6MST and STST. The number of steps, heart rate change, saturation and dyspnoea during the 6MST and the number of lifts during the STST were recorded. Complications graded ≥ 2 on the Clavien-Dindo classification were recorded for 90 days after surgery. Between November 2018 and November 2019, 118 patients with a mean age of 65 years (SD 9) were included and analysed. Their surgeries were via VATS in 88 (75%) and via RATS in 30 (25%). For predicting a postoperative complication graded ≥ 2 on the Clavien-Dindo classification, the area under the Receiver Operating Characteristic curve was: 0.82 (95% CI 0.75 to 0.90) for the number of steps during the 6MST, with an optimum cut-off of 140 steps; and 0.85 (95% CI 0.77 to 0.93) for the number of lifts during the STST, with an optimum cut-off of 20 lifts. The 6MST and STST predicted morbidity and mortality after lung cancer resection via minimally invasive surgery. The preoperative use of these exercise tests in clinical practice may be useful for risk stratification. NCT03824977.


Success in the Achieving CARdiovascular Excellence in Colorado (A CARE) Home Blood Pressure Monitoring Program: A Report from the Shared Networks of Colorado Ambulatory Practices and Partners (SNOCAP).
Blood pressure (BP) control among primary care patients with hypertension is suboptimal. Home BP monitoring (HBPM) has been shown to be effective but is underused. This study was a quasi-experimental evaluation of the impact of the A CARE HBPM program on hypertension control. Nonpregnant adults with hypertension or cardiovascular disease risk factors were given validated home BP monitors and reported monthly average home BP readings by Internet or phone. Patients and providers received feedback. Change in average home and office BP and the percentage of patients achieving target BP were assessed based on patient HBPM reports and a chart audit of office BPs. A total of 3578 patients were enrolled at 26 urban and rural primary care practices. Of these, 36% of participants submitted ≥2 HBPM reports. These active participants submitted a mean of 13.5 average HBPM reports, with a mean of 19.3 BP readings per report. The mean difference in home BP between initial and final HBPM reports for active participants was -6.5/-4.4 mmHg (P < .001) and -6.7/-4.7 mmHg (P < .001) for those with diabetes. The percentage of active participants at or below target BP increased from 34.5% to 53.3% (P < .001) and increased 24.6% to 40.0% (P < .001) for those with diabetes. The mean difference in office BP over 1 year between participants and nonparticipants was -5.4/-2.7 mmHg (P < .001 for systolic BP, P = .01 for diastolic BP) for all participants and -8.5/-1.5 mmHg (P = .014 for systolic BP, P = .405 for diastolic BP) for those with diabetes. An HBPM program with patient and provider feedback can be successfully implemented in a range of primary care practices and can play a significant role in BP control and decreased cardiovascular disease risk in patients with hypertension.


2-Allylaminothiazole and 2-allylaminodihydrothiazole derivatives: synthesis, characterization, and evaluation of bioactivity.
Some reactions of selected chlorooxoesters and haloesters with a 1-allylthiourea under various conditions have been performed. The reactions have been performed in methanol in alkaline and neutral environment. Condensation of 1-allylthiourea with chlorooxoesters has been further led via acetal as intermediate compound. As a result, the compounds containing thiazole and a 4,5-dihydrothiazole ring with a good yield have been obtained. The structures of the compounds were verified by 1H NMR, 13C NMR as well as X-ray diffraction analysis. Due to the potential biological activity of the synthesized compounds, the parameters of their bioavailability have been determined, and the probability of pharmacological action has been defined. All of the obtained compounds fulfilled the rule of five, which indicate their good absorption after oral intake. The probability of pharmacological action and potential targets calculated for the obtained compounds show that they can be potential drugs.


Analytical methodologies for the detection of SARS-CoV-2 in wastewater: Protocols and future perspectives.
In March 2020 the World Health Organization announced a pandemic outbreak. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen for the coronavirus disease-19 (COVID-19) pandemic. The authorities worldwide use clinical science to identify infected people, but this approach is not able to track all symptomatic and asymptomatic cases due to limited sampling capacity of the testing laboratories. This drawback is eliminated by the Wastewater-Based Epidemiology (WBE) approach. In this review, we summarized the peer-reviewed published literature (available as of September 28, 2020), in the field of WBE. The commonly used steps (sampling, storage, concentration, isolation, detection) of the analytical protocols were identified. The potential limitations of each stage of the protocols and good practices were discussed. Finally, new methods for the efficient detection of SARS-CoV-2 were proposed.


Factors influencing the stewardship activities of Antimicrobial Management Teams: a national cross-sectional survey.
The link between inappropriate antibiotic prescribing and the global threat of antimicrobial resistance is well documented. International strategies recommend antimicrobial stewardship (AMS) programmes, with improvement interventions to safeguard antibiotics. This study sought to systematically evaluate the impact of multi-professional Antimicrobial Management Team (AMT) staff resource availability on stewardship activities. We conducted an on-line, cross-sectional survey of AMTs in each regional Health Board and the national specialist hospital in Scotland (N = 15). Responses were analysed descriptively, exploring observed relationships between variables to identify patterns. Results highlighted apparent variation in the levels of AMT resource availability across Scotland, not directly influenced by Health Board size, with some larger Health Boards having proportionately poorer AMT resource allocation. However, the range and frequency of activities to support AMS was not directly linked to either Health Board size or staff resource allocation, indicating a more complex inter-relationship between factors. There is apparent inequity in staff resource available for AMTs across Scotland, with significantly lower resource allocation in comparison with recommendations from other international studies. However, considering these survey findings with our earlier qualitative research indicates that leadership style and team member enthusiasm may be as, if not more, influential than resource availability on the scope of AMT activities. These findings have international relevance for hospital service managers considering the recruitment, training and ongoing support of AMTs, in order to maximize impact from a limited resource.


Teratoma and teratocarcinoma in experimental animals.
Different models of spontaneous and experimentally induced teratomas and teratocarcinomas were presented. The role of various control mechanisms operating in the tumor-bearing host is outlined.


"Setting people up for success and then failure" - health care and service providers' experiences of using prize-based contingency management.
Over the last 50 years, there has been a growing interest in and use of contingency management (CM) for people who use substances. Yet, despite showing some level of efficacy (albeit only short-term) and being praised by researchers as beneficial and cost-saving, it continues to be underutilized by health care and service providers. Why that is remains unclear. Recognizing a gap, we conducted a targeted analysis of a larger set of qualitative interviews conducted on the experience of health care and service providers with incentives (including prize-based CM) (n = 25). Four themes were identified during the analysis: 1) The specificities of prize-based CM, 2) The role of providers in administering prize-based CM, 3) The positive and negative impact on the relationship, and 4) The ethical concerns arising from prize-based CM. Overall, our findings are consistent with existing literature and suggest that providers are wary of using prize-based CM because they tend to value effort over success, support over reward, honesty over deceit, and certainty over probability and variability. Our analysis offers additional insights into the experiences of providers who use prize-based CM and possibly some indications as to why they may not wish to work with this type of incentive. The question raised here is not whether there is enough evidence on the effectiveness of prize-based CM, but rather if this type of incentive is appropriate and ethical when caring for people who use substances.


Covid-19 still rife in Iran.
An analysis of covid-19 infections among Iranian people casts further doubt on the idea that herd immunity can be achieved without vaccination, reports Catherine Shaffer.


Pharmacology versus social process: competing or complementary views on the nature of addiction?
Pharmacological/physiological models and social process/cognitive models of addiction are compared. These are discussed both in terms of the types of data produced and the philosophies of knowledge that underlie the two approaches. It is suggested that the notion of addiction confounds these two sets of issues, especially with respect to the notions of volition and compulsion. The problem is highlighted by data that reveal verbal reports to be variable and context dependent. It is concluded that a better understanding of the nature of addiction requires a clearer distinction between the pharmacological/physiological approach and the social process/cognitive approach. Both approaches contribute usefully to knowledge and have predictive value. Confusion arises, however, where workers fail to see not merely the benefits, but also the limitations, of these two approaches to the addiction problem.


Early-stage splenic diffuse large B-cell lymphoma is highly associated with hepatitis C virus infection.
Splenic marginal zone lymphoma (SMZL) and splenic diffuse large B-cell lymphoma (DLBCL) are the most common types of lymphomas involving the spleen. Geographic variation in hepatitis C virus (HCV) seroprevalence is characteristic of splenic lymphomas. In Italy, HCV seroprevalence was higher in patients with SMZL and splenic DLBCL than in patients with all types of lymphoma. In Japan, HCV seroprevalence was higher in patients with splenic DLBCL than in patients with all types of lymphoma; however, HCV seroprevalence in patients with SMZL was similar to that in patients with all types of lymphoma. In this study, clinicopathological data of 74 splenic lymphoma cases between 1988 and 2011 collected from the Department of Pathology at National Taiwan University Hospital were analyzed. Serology for HCV infection was available for 41 cases. Splenic DLBCL and SMZL accounted for 36% (n = 27) and 42% (n = 31) of splenic lymphomas, respectively. Microscopically, most cases of DLBCL (26/27) presented with circumscribed tumor and most cases of SMZL (28/31) presented with white pulp expansion. HCV seroprevalence in patients with DLBCL and SMZL was 44% and 10%, respectively (7/16 vs. 2/20, p = 0.020). The pattern identified in this study is closer to that in Japan than in Italy. HCV seroprevalence in patients with early-stage (I/II) and late-stage (III/IV) DLBCL was 100% and 10%, respectively (6/6 vs. 1/10, p < 0.001). Early-stage DLBCL is clinically considered a form of primary splenic lymphoma rather than a systemic lymphoma with splenic involvement. High HCV seroprevalence in patients with early-stage DLBCL suggests a role of HCV in the pathogenesis of primary DLBCL.


BME Career Exploration: Examining Students' Connection with the Field.
A common perception of biomedical engineering (BME) undergraduates is that they struggle to find industry jobs upon graduation. While some statistics support this concern, students continue to pursue and persist through BME degrees. This persistence may relate to graduates' other career interests, though limited research examines where BME students go and why. Scholars are also pushing for research that examines engineering careers in a broader context, beyond traditional industry positions. This study adds to that conversation by asking: How do BME students describe their career interests and perceived job prospects in relation to why they pursue a BME degree? A qualitative study of BME students was performed at a public, R1 institution using semi-structured interviews at three timepoints across an academic year. An open coding data analysis approach explored careerperceptions of students nearing completion of a BME undergraduate degree. Findings indicated that students pursued a BME degree for reasons beyond BME career aspirations, most interestingly as a means to complete an engineering degree that they felt would have interesting enough content to keep them engaged. Participants also discussed the unique career-relevant skills they developed as a BME student, and the career-placement tradeoffs they associated with getting a BME undergraduate degree. Based on these results, we propose research that explores how students move through a BME degree into a career and how career-relevant competencies are communicated in job searches. Additionally, we suggest strategies for BME departments to consider for supporting students through the degree into a career.


Cognitive-behavioral therapy for migraine headaches: a minimal-therapist-contact approach versus a clinic-based approach.
The efficacy of a clinic-based cognitive-behavioral program for the treatment of common migraine was compared to the same approach using a minimal-therapist-contact format by means of a randomized controlled trial. Forty-eight subjects between 18 and 50 years of age completed the program. Following four weeks of recording headache activity, subjects were randomly assigned to a waiting list control condition or to one of the two treatment conditions. Treatment was followed by four weeks of recording of headache activity immediately posttreatment and again six months later. Multivariate analysis of variance indicated that there was a significant reduction in headache frequency, duration and peak intensity following treatment for both treated groups. These reductions were maintained at six months follow-up. Treatment for the minimal-contact group was significantly more cost-effective than for the clinic group.


Tetracycline. Another example of generic bioinequivalence.
Because of the Food and Drug Administration batch certification assurances, state government systems generally purchase antibiotics from the lowest bidder. A tetracycline hydrochloride tablet purchased in this manner is shown to be inferior to the innovator capsule product.


Assessment of the Utility of Gene Positioning Biomarkers in the Stratification of Prostate Cancers.
There is a pressing need for additional clinical biomarkers to predict the aggressiveness of individual cancers. Here, we examine the potential usefulness of spatial genome organization as a prognostic tool for prostate cancer. Using fluorescence in situ hybridization on formalin-fixed, paraffin embedded human prostate tissue specimens, we compared the nuclear positions of four genes between clinically relevant subgroups of prostate tissues. We find that directional repositioning of SP100 and TGFB3 gene loci stratifies prostate cancers of differing Gleason scores. A more peripheral position of SP100 and TGFB3 in the nucleus, compared to benign tissues, is associated with low Gleason score cancers, whereas more internal positioning correlates with higher Gleason scores. Conversely, LMNA is more internally positioned in many non-metastatic prostate cancers, while its position is indistinguishable from benign tissue in metastatic cancer. The false positive rates were relatively low, whereas, the false negative rates of single or combinations of genes were high, limiting the clinical utility of this assay in its current form. Nevertheless, our findings of subtype-specific gene positioning patterns in prostate cancer provides proof-of-concept for the potential usefulness of spatial gene positioning for prognostic applications, and encourage further exploration of spatial gene positioning patterns to identify novel clinically relevant molecular biomarkers, which may aid treatment decisions for cancer patients.


The electrocarboxylation of a series of benzophenones under galvanostatic conditions has been carried out in aprotic solvents using an undivided bulk electrolysis cell equipped with a Mg sacrificial anode. Systematic studies have been carried out in order to establish the qualitative relationships between the yield of carboxylation reaction and the operational and intrinsic parameters for the electrocarboxylation of benzophenones. For the diaryl ketones chosen for these studies, the yields of the target benzilic acids have been found to be strongly dependent on different parameters such as solvents, supporting electrolytes, cathode materials, current density, temperature and the nature of the substrates.


Unanticipated transient sciatic nerve deficits from intra-wound liposomal bupivacaine injection during total hip arthroplasty.
Liposomal bupivacaine (Exparel®) is a novel formulation of local anesthetic used to provide extended postoperative analgesia as part of a multimodal pain control regimen in patients undergoing total joint arthroplasty. In the three total hip arthroplasty cases described, all patients exhibited a transient loss of neurologic function in the sciatic nerve distribution of the operated extremity lasting between 24 and 72 h during the immediate postoperative period. Due to the nature and duration of the deficits, it was concluded that they likely occurred as a result of unintended injection of the medication in close proximity to the sciatic nerve. To the best of our knowledge, these events have yet to be reported in the current literature. We recommend orthopaedic surgeons pay special attention during infiltration of the medication at the surgical site to avoid postoperative neurological deficits.


Frequency specific patterns of resting-state networks development from childhood to adolescence: A magnetoencephalography study.
The present study investigated frequency dependent developmental patterns of the brain resting-state networks from childhood to adolescence. Magnetoencephalography (MEG) data were recorded from 20 healthy subjects at resting-state with eyes-open. The resting-state networks (RSNs) was analyzed at source-level. Brain network organization was characterized by mean clustering coefficient and average path length. The correlations between brain network measures and subjects' age during development from childhood to adolescence were statistically analyzed in delta (1-4Hz), theta (4-8Hz), alpha (8-12Hz), and beta (12-30Hz) frequency bands. A significant positive correlation between functional connectivity with age was found in alpha and beta frequency bands. A significant negative correlation between average path lengths with age was found in beta frequency band. The results suggest that there are significant developmental changes of resting-state networks from childhood to adolescence, which matures from a lattice network to a small-world network.


Risk factors and clinical indication of metastasis to lymph nodes posterior to right recurrent laryngeal nerve in papillary thyroid carcinoma: a single-center study in China.
Lymph nodes posterior to right recurrent laryngeal nerve (PRRLN) may be frequently overlooked during central compartment dissection (CCD) for papillary thyroid carcinoma (PTC). The purpose of this study was to investigate risk factors of lymph node PRRLN metastasis in right-sided PTC, thereby to identify the indications for lymph node PRRLN dissection. We conducted a retrospective study of patients with right-sided PTC who underwent a thyroidectomy plus lymph node PRRLN dissection during ipsilateral CCD. Overall, 108 patients (26.7%) had lymph node PRRLN metastases, including 26 (6.4%) who presented with solely lymph node PRRLN positivity. Factors of extrathyroidal extension, multifocality, larger tumor (≥1 cm), level VIa positivity (p < .0001 for each), and lateral compartments positivity (p = .0002) significantly predicted lymph node PRRLN metastasis in right-sided PTC. Lymph node PRRLN should be routinely explored during CCD because of the possibility of only involvement in PTC. Factors of tumors larger than 1 cm, multifocality, and extrathyroidal extension were independent predictors of lymph node PRRLN metastasis in right-sided PTC, and suggested the clinical indications of lymph node PRRLN dissection.


Cerebral perfusion is related to antidepressant effect and cognitive side effects of Electroconvulsive Therapy.
The mechanisms underlying the antidepressant effect and cognitive side effects of Electroconvulsive Therapy (ECT) remain elusive. The measurement of cerebral perfusion provides an insight into brain physiology. We investigated ECT-related perfusion changes in depressed patients and tested whether these changes correlate with clinical effects. A sample of 22 in-patients was examined at three time points: 1) within two days before, 2) within one week after, and 3) six months after an ECT series. Cerebral perfusion was quantified using arterial spin labeling magnetic resonance imaging. The primary regions of interest were the bilateral dorsolateral prefrontal cortices (DL-PFC) and hippocampi. The depression severity was assessed by the six-item Hamilton Depression Rating Scale, and cognitive performance by the Screen for Cognitive Impairment in Psychiatry. A linear mixed model and partial correlation were used for statistical analyses. Following an ECT series, perfusion decreased in the right (-6.0%, p = .01) and left DL-PFC (-5.6%, p = .001). Perfusion increased in the left hippocampus (4.8%, p = .03), while on the right side the increase was insignificant (2.3%, p = .23). A larger perfusion reduction in the right DL-PFC correlated with a better antidepressant effect, and a larger perfusion increase in the right hippocampus with worse cognitive impairment. ECT-induced attenuation of prefrontal activity may be related to clinical improvement, whereas a hippocampal process triggered by the treatment is likely associated with cognitive side effects.


O-glycomics: profiling and structural analysis of mucin-type O-linked glycans.
The great variability of O-glycan structures makes their analysis a challenging task, which can be solved by the use of several complementary methods. While chromatographic analysis of the fluorescently labeled oligosaccharides shows the quantitative amount of the different glycans in comparison to a standard, mass spectrometry analysis of permethylated oligosaccharides allows identification of new or uncommon glycan structures. In combination with liquid chromatography, all structures present in one sample can be identified. The linkage of the monosaccharides can be analyzed by GC-MS after further derivatization of the permethylated glycans.


Impact of single centre kidney paired donation transplantation to increase donor pool in India: a cohort study.
In a living donor kidney transplantation (LDKT) dominated transplant programme, kidney paired donation (KPD) may be a cost-effective and valid alternative strategy to increase LDKT in countries with limited resources where deceased donation kidney transplantation (DDKT) is in the initial stages. Here, we report our experience of 300 single-centre KPD transplantations to increase LDKT in India. Between January 2000 and July 2016, 3616 LDKT and 561 DDKT were performed at our transplantation centre, 300 (8.3%) using KPD. The reasons for joining KPD among transplanted patients were ABO incompatibility (n = 222), positive cross-match (n = 59) and better matching (n = 19). A total of 124 two-way (n = 248), 14 three-way (n = 42), one four-way (n = 4) and one six-way exchange (n = 6) yielded 300 KPD transplants. Death-censored graft and patient survival were 96% (n = 288) and 83.3% (n = 250), respectively. The mean serum creatinine was 1.3 mg/dl at a follow-up of 3 ± 3 years. We credit the success of our KPD programme to maintaining a registry of incompatible pairs, counselling on KPD, a high-volume LDKT programme and teamwork. KPD is legal, cost effective and rapidly growing for facilitating LDKT with incompatible donors. This study provides large-scale evidence for the expansion of single-centre LDKT via KPD when national programmes do not exist.


Treatment of radiation maculopathy and radiation-induced macular edema: A systematic review.
Radiation maculopathy and radiation-induced macular edema are common, sight-threatening complications after radiotherapy, especially that used for uveal melanoma. While many treatment and preventive strategies have been proposed, management of these conditions is still challenging. Initially, treatments were based on the use of retinal laser, but the outcomes were poor. Subsequently, management has shifted toward injection of intravitreal antivascular endothelial growth factor or corticosteroids. We reviewed current clinical evidence, which mostly relies on small sample-sized and retrospective studies, for the management of radiation maculopathy and, in particular, radiation-induced macular edema. At present, the first-line approach is usually intravitreal antivascular endothelial growth factor. Intravitreal dexamethasone implantation may be an option for those with suboptimal response or contraindications to antivascular endothelial growth factor agents. Possible preventive treatments that require future study are intravitreal bevacizumab and ranibizumab, peripheral laser photocoagulation, and subtenon triamcinolone acetonide.


Reply to 'Climate of doubt: a re-evaluation of Büntgen and Di Cosmo's environmental hypothesis for the Mongol withdrawal from Hungary, 1242 CE'.
In our 2016 article in Scientific Reports, we advanced a new hypothesis for the Mongol withdrawal from Hungary in 1242 CE, based on a joint analysis of climatic, environmental, and historical data. The re-evaluation now offered by Pinke et al. casts doubt on this hypothesis. However, their arguments are based on a level of generality that fails to appreciate the specific conditions of the Mongol invasion, do not offer new or different climatic data, and are supported by anachronistic production data and environmental information, which cannot be related to the period in question. While we acknowledge the importance of an open debate, we stand by our conclusions.


Poly(A) metabolism and aging: a current view.
Polyadenylation of mRNA is a key step in post-transcriptional control of gene expression. Therefore, age-dependent changes in poly(A) synthesis have to play a crucial role in the course of cellular aging. In this review, the importance of the signal sequence, poly(A), in determining mRNA stability and intracellular distribution of mRNA during aging is discussed.


Alpha-1-antitrypsin (Pi) types in multiple sclerosis and lack of interaction with immunoglobulin (Gm) markers.
Susceptibility to multiple sclerosis is thought to involve several genetic loci apart from the HLA region on chromosome 6. No Pi allotype nor phenotype was associated with the disease in 125 unrelated patients from the Grampian region of northeast Scotland. Despite a previously reported Gm-HLA association in this population there was no apparent interaction between Pi alleles and Gm type which influenced disease susceptibility.


Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomized clinical trials.
Our objective was to determine whether methotrexate is an effective steroid-sparing agent for patients with severe asthma. Published reports of controlled trials assessing the use of methotrexate in asthma were identified by a search of the MEDLINE, EMBASE, CINAHL, Biological Abstracts on CD, and Current Contents databases. Bibliographies from identified studies and from review articles were manually searched. Published and unpublished reports in any language were identified and assessed for inclusion in the meta-analysis. We selected randomized, double-blind, placebo-controlled trials in which low-dose methotrexate was administered to corticosteroid-dependent asthmatics, and oral steroids were subsequently tapered according to the patients' clinical status. Data were extracted independently by two reviewers. For all eligible trials, the mean reduction in oral corticosteroid dose, the mean change in FEV1, and the standard deviations, were calculated for the treatment and control groups. Data concerning side-effects of therapy were also extracted. Data from 12 studies, reporting on a total of 250 patients, were pooled using a weighted average method, with weights proportional to the inverse of the variance of the treatment effect. Compared to placebo, the use of methotrexate was associated with a pooled 6.0% improvement in FEV1 (95% CI, 1.0-11%) and an 18.2% reduction in oral steroid use (95% CI, 11.7-24.7%). This corresponded to a 3.3 mg day-1 greater reduction in oral steroid use for patients taking methotrexate than for those taking placebo (95% CI, 2.1-4.4 mg day-1). Gastrointestinal complications and transient increases in liver enzymes were more common in patients randomized to methotrexate. Three potentially life-threatening side-effects (two pneumonias and one liver dysfunction) occurred in 159 patients randomized to methotrexate vs. none in those patients on placebo. It was concluded that methotrexate allowed a modest reduction in oral corticosteroid compared to patients receiving placebo. The benefit is relatively small, however, and should be balanced against the potential for side-effects associated with the use of methotrexate.


Surgical correction of premature closure of the ulnar growth plate in the dog.
Successful correction of anterior bowing of the foreleg and severe lateral carpal valgus following on premature closure of the ulnar growth plate in a month old Great Dane bitch is described. The procedure involved stapling the radius across the distal growth plate and section of the ulna.


Chemical implications and time reduction of on-farm cocoa fermentation by Saccharomyces cerevisiae and Pichia kudriavzevii.
The use of starters during fermentation has been gaining momentum as it can warrant high-quality chocolate. The objective of this study was to investigate the influence of Saccharomyces cerevisiae (Sc) and Pichia kudriavzevii (Pk) during on-farm fermentation on physico-chemical and microbiological characteristics and levels of methylxanthines and bioactive amines of cocoa. Four treatments were used: ScPk (1:1), only Sc, only Pk, and no starter (control). The starters lead to changes throughout fermentation, but provided fermented cocoa with similar pH, titratable acidity, reducing sugars and phenolic compounds. ScPk shortened fermentation time by 24 h. The ScPk fermented and dried cocoa had higher levels of monomeric phenols, methylxanthines, phenylethylamine and lower levels of the putrefactive amines - putrescine and cadaverine (p < 0.05). The results were confirmed by multivariate analysis. Based on these results, the mixture of both yeasts species is a promising starter for cocoa fermentation decreasing duration time and modulating high-quality components.


Upregulation of ecto-5'-nucleotidase in human neuroblastoma SH-SY5Y cells on differentiation by retinoic acid or phorbolester.
Ecto-5'-nucleotidase has been suggested to play an important role in neural development and differentiation in situ and in vitro. In order to investigate whether neural differentiation is associated with an upregulation of ecto-5'-nucleotidase, we used all trans-retinoic acid or phorbol-12-myristate-13-acetate to induce a neural phenotype in the human neuroblastoma cell line SH-SY5Y. Both agents initiated a reduction in proliferation and an increase in polarity of SH-SY5Y cells as well as a time dependent increase in ecto-5'-nucleotidase activity. Non-specific ecto-phosphatase activity remained unaltered. Northern hybridization experiments suggest that the increase in ecto-5'-nucleotidase activity is due to increased enzyme synthesis rather than due to enzyme activation. The upregulation of ecto-5'-nucleotidase in differentiating neuroblastoma cells would be consisted with a functional role of ecto-5'-nucleotidase in neural development.


Characteristics of the tomato nuclear genome as determined by sequencing undermethylated EcoRI digested fragments.
A collection of 9,990 single-pass nuclear genomic sequences, corresponding to 5 Mb of tomato DNA, were obtained using methylation filtration (MF) strategy and reduced to 7,053 unique undermethylated genomic islands (UGIs) distributed as follows: (1) 59% non-coding sequences, (2) 28% coding sequences, (3) 12% transposons-96% of which are class I retroelements, and (4) 1% organellar sequences integrated into the nuclear genome over the past approximately 100 million years. A more detailed analysis of coding UGIs indicates that the unmethylated portion of tomato genes extends as far as 676 bp upstream and 766 bp downstream of coding regions with an average of 174 and 171 bp, respectively. Based on the analysis of the UGI copy distribution, the undermethylated portion of the tomato genome is determined to account for the majority of the unmethylated genes in the genome and is estimated to constitute 61+/-15 Mb of DNA (approximately 5% of the entire genome)--which is significantly less than the 220 Mb estimated for gene-rich euchromatic arms of the tomato genome. This result indicates that, while most genes reside in the euchromatin, a significant portion of euchromatin is methylated in the intergenic spacer regions. Implications of the results for sequencing the genome of tomato and other solanaceous species are discussed.


Genome sequence of a dissimilatory Fe(III)-reducing bacterium Geobacter soli type strain GSS01(T).
Strain GSS01(T) (=KCTC 4545=MCCC 1 K00269) is the type strain of the species Geobacter soli. G. soli strain GSS01(T) is of interest due to its ability to reduce insoluble Fe(III) oxides with a wide range of electron donors. Here we describe some key features of this strain, together with the whole genome sequence and annotation. The genome of size 3,657,100 bp contains 3229 protein-coding and 54 RNA genes, including 2 16S rRNA genes. The genome of strain GSS01(T)contains 76 predicted cytochrome genes, 24 pilus assembly protein genes and several other genes, which were proposed to be related to the reduction of insoluble Fe(III) oxides. The genes associated with the electron donors and acceptors of strain GSS01(T) were predicted in the genome. Information gained from its sequence will be relevant to the future elucidation of extracellular electron transfer mechanism during the reduction of Fe(III) oxides.


DePFth Perception in Clathrin-Mediated Endocytosis.
The earliest stages of clathrin-coated structure (CCS) assembly involve the recruitment and stabilization of clathrin-binding adaptor proteins and the clathrin coat. In this issue of Developmental Cell, Ma et al. (2016) now identify transient protein interactions that form the basis of AP-2 adaptor complex stabilization, key to initiating CCS formation.


The acyclic nucleoside phosphonate analogues, adefovir, tenofovir and PMEDAP, efficiently eliminate banana streak virus from banana (Musa spp.).
We report that the anti-retroviral and anti-hepadnavirus molecules, adefovir, tenofovir and 9-(2-phosphonomethoxyethyl)-2,6-diaminopurine (PMEDAP), efficiently eradicate the episomal form of Banana streak virus (BSV) from banana plants. Up to 90% of plants regenerated from BSV-infected highly proliferating meristems were virus free following a 6-month treatment period with 10 microg/ml (a non-phytotoxic concentration) of either compounds.


Tankyrase Inhibitors Target YAP by Stabilizing Angiomotin Family Proteins.
As the key effector in the Hippo pathway, YAP was identified as an oncoprotein whose expression is elevated in various human cancers. However, the development of potentially therapeutic compounds targeting YAP has been slow and limited. Here, we find that tankyrase inhibitors suppress YAP activity. This effect is mediated by anigomotin (AMOT) family proteins. Tankyrases associate with AMOT family proteins and promote their degradation through E3 ligase RNF146. By antagonizing tankyrase activity, tankyrase inhibitors stabilize AMOT family proteins, thereby suppressing YAP oncogenic functions. Together, our studies not only demonstrate the tankyrase-RNF146-AMOT axis as an upstream pathway regulating YAP but also reveal a therapeutic opportunity in targeting YAP for cancer treatment.


The influence of culture medium composition on the incidence of chromosomal breakage.
In patients with chromosomal instability and healthy subjects, significant differences were observed in the chromosomal breakage incidence in simultaneous lymphocyte cultures set up with TC medium 199, Eagle's Minimum Essential Medium, or RPMI, or RPMI 1629. The importance of the choice of culture medium for mutagenicity testing and studies of so-called spontaneous breakage is shown. Cultures incubated with TC Medium 199 showed the highest chromosomal breakage incidence.


In vivo imaging of therapy response to a novel pan-HER antibody mixture using FDG and FLT positron emission tomography.
Overexpression of the human epidermal growth factor receptor (HER) family and their ligands plays an important role in many cancers. Targeting multiple members of the HER family simultaneously may increase the therapeutic efficacy. Here, we report the ability to image the therapeutic response obtained by targeting HER family members individually or simultaneously using the novel monoclonal antibody (mAb) mixture Pan-HER. Mice with subcutaneous BxPC-3 pancreatic adenocarcinomas were divided into five groups receiving vehicle or mAb mixtures directed against either EGFR (HER1), HER2, HER3 or all three receptors combined by Pan-HER. Small animal positron emission tomography/computed tomography (PET/CT) with 2'-deoxy-2'-[(18)F]fluoro-D-glucose (FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) was performed at baseline and at day 1 or 2 after initiation of therapy. Changes in tumor uptake of tracers were quantified and compared to reduction in tumor size. Imaging results were further validated by immunohistochemistry and qPCR. Mean FDG and FLT uptake in the Pan-HER treated group decreased by 19 ± 4.3% and 24 ± 3.1%, respectively. The early change in FDG and FLT uptake correlated with tumor growth at day 23 relative to day 0. Ex vivo molecular analyses of markers associated with the mechanisms of FDG and FLT uptake confirmed the in vivo imaging results. Taken together, the study supports the use of FDG and FLT as imaging biomarkers of early response to Pan-HER therapy. FDG and FLT PET/CT imaging should be considered as imaging biomarkers in clinical evaluation of the Pan-HER mAb mixture.


Kinetics of adsorption from micellar solutions.
Previous studies on surfactant adsorption mostly deal with dilute systems without aggregation in the bulk phase. At the same time, micellar solutions can be more important from the point of view of applications. If one attempts to estimate the equilibrium adsorption, neglecting the influence of micelles can lead to reasonable results. The situation differs for non-equilibrium systems when the adsorption rate can increase by an order of magnitude at the increase of the surfactant concentration beyond the CMC. A critical survey of various models describing the influence of micelles on adsorption kinetics at the liquid-gas interface is given and the theoretical results are compared with existing experimental data. The theories proposed for the case of large deviations from the equilibrium are usually based on some unjustifiable assumptions and can describe the kinetic dependencies of adsorption in only a limited number of situations. Consequently, only rough estimates of the kinetic coefficients of micellization can be obtained from experimental data on dynamic surface tension. More rigorous equations can be derived if the system only deviates slightly from equilibrium. In the latter case, the agreement between theoretical and experimental results is essentially better and measurements of the dynamic surface elasticity of micellar solutions allow us to study the micellization kinetics.


Punitive school discipline as a mechanism of structural marginalization with implications for health inequity: A systematic review of quantitative studies in the health and social sciences literature.
Punitive school discipline deploys surveillance, exclusion, and corporal punishment to deter or account for perceived student misbehavior. Yet, education and legal scholarship suggests it fails to achieve stated goals and exacerbates harm. Furthermore, it is disproportionately imposed upon Black, Latinx, Native/Indigenous, LGBTQIA, and disabled students, concentrating its harms among marginalized young people. Its implications for health, however, are less clear. Using public health theories of sociostructural embodiment, we propose a framework characterizing pathways linking societal ideologies (e.g., racism) to punitive discipline with implications for health and health inequity and then present our systematic review of the punitive school discipline-health literature (N = 19 studies) conducted in accordance with PRISMA guidelines. Data were extracted on guiding theories, study characteristics, measurement, methods, and findings. This literature links punitive school discipline to greater risk for numerous health outcomes, including persistent depressive symptoms, depression, drug use disorder in adulthood, borderline personality disorder, antisocial behavior, death by suicide, injuries, trichomoniasis, pregnancy in adolescence, tobacco use, and smoking, with documented implications for racial health inequity. Using our adapted framework, we contextualize results and recommend avenues for future research. Our findings support demands to move away from punitive school discipline toward health-affirming interventions to promote school connectedness, safety, and wellbeing.


Constancy (the New Media "C") and Future Generations.
In the past, researchers would consider media's impact on youth in terms of three "Cs": consumption, content, and context. This article introduces a new construct-constancy-which supplants the previous terms. Constancy refers to the ubiquitous and continuous state of connected screens in the lives of children and adolescents. Constancy characterizes media content and use, which can be proactive, incidental, or contextual, exerting positive or negative effects on different users. Constancy can influence child development, as persistent access to smartphones and reception of messages will affect future generations' cognition and education, social interactions, emotions, and health. It will be important to address the developmental needs of the child or adolescent and not the smartphone in his or her pocket. Constancy requires pragmatic and innovative methodologies to understand the new circumstances around children, adolescents, and media. The landscape has changed and so must our approach to research and investigation of media effects.


Vibrio spp. from Macrobrachium amazonicum prawn farming are inhibited by Moringa oleifera extracts.
To investigate the in vitro antimicrobial potential of extracts of stem, leaves, flowers, pods and seeds of Moringa oleifera (M. oleifera) against Vibrio spp. from hatchery water and the prawn Macrobrachium amazonicum. The ethanol extracts of stem, leaves, pods and seeds and chloroform extract of flowers of M. oleifera were tested against Vibrio cholerae (V. cholerae) serogroups non-O1/non-O139 (n = 4), Vibrio vulnificus (n = 1) and Vibrio mimicus (n = 1). Escherichia coli (E. coli) (ATCC(®) 25922) was used as quality control. Vibrio species were obtained from Macrobrachium amazonicum prawns and from hatchery water from prawn farming. The Minimum Inhibitory Concentration (MIC) was determined by broth microdilution method. The best result was obtained with the ethanol extract of pods, which inhibited three strains of the V. cholerae, Vibrio vulnificus, Vibrio mimicus and E. coli (MIC range 0.312-5.000 mg/mL). The chloroform extract of flowers was effective against all V. cholerae strains and E. coli (MIC range 0.625-1.250 mg/mL). However, the ethanol extracts of stem and seeds showed low effectiveness in inhibiting the bacterial growth. The extracts of pods, flowers and leaves of M. oleifera have potential for the control of Vibrio spp. Further studies are necessary to isolate the bioactive compounds responsible for this antimicrobial activity.


Associations of sociodemographic and clinical factors with perinatal depression among Israeli women: a cross-sectional study.
Perinatal depression is a common problem that affects about 18% of women worldwide, though the heterogeneity between countries is great. The aims of this study were to assess the prevalence of perinatal depressive symptoms in a national sample of women in Israel, and to investigate associations of these symptoms with demographic, medical and lifestyle factors. The study included all members of Maccabi Health Services, the second largest health maintenance organization in Israel, who filled the Edinburgh Postnatal Depression Scale (EPDS) during 2015-2016. Crude odds ratios (ORs) and adjusted ORs (aORs) are presented for associations of sociodemographic, medical and lifestyle factors with perinatal depressive symptoms, according to a score ≥ 10 on the EPDS. Of 27,520 women who filled the EPDS, 1346 (4.9%) met the criteria for perinatal depression. In a logistic regression analysis we found the following factors associated with perinatal depression: the use of antidepressant medications (aOR = 2.34, 95% CI 1.94-2.82, P < 0.001 and aOR = 3.44; 95% CI 2.99-3.97, P < 0.001 for ≤3 months and > 3 months respectively), a diagnosis of chronic diabetes mellitus (aOR = 2.04; 95% CI 1.22-3.43, P = 0.007), Arab background (aOR = 2.28; 95% CI 1.82-2.86, P < 0.001), current and past smoking (aOR = 1.62; 95% CI 1.35-1.94, P < 0.001 and aOR = 1.36; 95% CI 1.05-1.76, P = 0.021, respectively), and anaemia (aOR = 1.17; 95% CI 1.04-1.32, P = 0.011). Orthodox Jewish affiliation and residence in the periphery of the country were associated with lower perinatal depression (aOR = 0.48; 95% CI 0.36-0.63, P < 0.001 and aOR = 0.72; 95% CI 0.57-0.92, P = 0.007, respectively). The prevalence of perinatal depression in this study was 4.9%. Perinatal depression was associated with a number of demographic, medical and lifestyle factors, including the use of antidepressant medication, chronic diabetes mellitus, Arab background, current or past smoking, and anaemia. These risk factors may help identify women at risk of perinatal depression.


SCLAREIN (SCLAREol contained in zeIN) nanoparticles: Development and characterization of an innovative natural nanoformulation.
Sclareol is a labdane diterpene which carries on a broad range of biological activities. However, its poor water solubility and bioavailability are the foremost drawbacks that limit its application in therapeutics. The purpose of this investigation was to develop a natural nanoformulation made up of a biopolymer i.e. zein and sclareol in order to address this issue and to enhance the pharmacological efficacy of the drug. The sclarein nanoparticles (sclareol-loaded zein nanosystems) showed a typical monomodal pattern, characterized by a mean diameter of ~120 nm, a narrow size distribution and a surface charge of ~-30 mV. The evaluation of the entrapment efficiency and the drug-loading capacity of the nanosystems demonstrated the noteworthy ability of the protein matrix to hold sclareol while allowing a gradual release of the compound over time. The nanosystems increased the cytotoxicity of sclareol at a drug concentration of ≥5 μM with respect to the free compound after just 24 h incubation against various cancer cell lines. Indeed, the interaction of tritiated sclarein formulations with cells showed a time-dependent cell uptake of the nanosystems commencing as early as 1 h from the onset of incubation, favouring a significant decrease of the efficacious concentration of the drug.


Southeastern US anesthesia providers' perspectives on abortion provision: Inductive findings from a qualitative study.
Health care providers, including anesthesia providers, hold varied personal views on abortion, which influences their involvement in multidisciplinary abortion care. We aimed to explore Southeastern US anesthesia providers' perspectives on abortion provision and factors impacting their decision to provide anesthesia for hospital-based induced abortion. We conducted in-depth, individual interviews with currently practicing anesthesia providers in the Southeastern United States. We recruited participants from regional anesthesiology conferences and via snowball sampling. A semistructured interview guide explored domains of obstetric experiences, standardized abortion cases, and personal abortion attitudes. We coded data iteratively and analyzed data thematically using inductive approaches with qualitative software. Fifteen participants completed interviews, at which point thematic saturation occurred. Participants represented a range of provider type and prior abortion experience. Participants weighed "personal and professional viewpoints" in considering their willingness to provide anesthesia care for hospital-based abortion. Many participants who personally disagreed with some abortion indications were still willing to provide anesthesia in those cases, some implicitly naming principles of medical ethics to justify differing professional and personal opinions. Participants also considered their "role in abortion decision-making": all participants reported that the abortion decision belongs to the patient or their obstetrician and not the anesthesia provider. Southeastern US anesthesia providers are influenced by multiple factors when considering their participation in hospital-based abortion care. Acknowledging differences in professional and personal viewpoints and identifying roles in abortion decision-making might be important to engaging anesthesia providers in abortion care, especially for high-risk medical or fetal indications. This original, qualitative study identified several inductive themes that characterize how Southeastern US anesthesia providers formulate their level of participation in hospital-based abortion care. Acknowledging differences in professional and personal viewpoints and identifying roles in abortion decision-making might facilitate interdisciplinary abortion care, especially for high-risk medical or fetal indications.


Successful treatment of bilateral deep femoral aneurysms and multiple iliac aneurysms associated with severe aortic valve disease: report of a case.
We report herein the case of a patient in whom aneurysms of the bilateral deep femoral arteries (DFA) and multiple iliac aneurysms associated with severe aortic valve disease were successfully treated by a two-staged operation. The patient was a 74-year-old man who had dense calcification of the ascending aorta and aortic arch. Prior to aortic valve replacement (AVR), the aneurysms of the DFA and internal iliac arteries were resected. The terminal end of the abdominal aorta and bilateral common iliac arteries were then reconstructed with a Y graft to be used as a possible alternative arterial input route in place of the ascending aorta for extracorporeal circulation during the AVR. The inferior mesenteric artery (IMA) was well developed, and the external iliac arteries and their branches were preserved at aneurysmectomy. Postoperatively, there was no ischemia of the pelvic organs or the hip muscles. The AVR was subsequently performed 5 weeks after the first operation, and the patient was discharged after an uneventful postoperative course.


Complications, readmission rates, and in-hospital lengths-of-stay in octogenarian vs. non-octogenarians following total knee arthroplasty: An analysis of over 1.7 million patients.
Studies investigating complications between octogenarians and non-octogenarians undergoing primary total knee arthroplasty (TKA) are limited. Therefore, we investigated whether octogenarians are at greater odds of: (1) in-hospital lengths of stay (LOS) (2) readmission rates, (3) medical complications, and (4) hardware complications compared to non-octogenarians following TKA. A retrospective query of the PearlDiver database isolated 1,775,460 patients who underwent primary TKA from 2005 to 2014. Patients aged 80 and above represented the study cohort (n = 295,908) and patients 65 to 79 represented the control cohort (n = 1,479,552). Study group patients were matched to controls in a 1:5 ratio according to gender and medical comorbidities. Pearson's Chi Square and logistic regression were used to analyze the primary outcomes of the study which included 90-day medical complications, 90-day readmission rates, 2-year implant-related complications, and in-hospital LOS. A p-value less than 0.001 was statistically significant. Octogenarians were found to have significantly higher incidence and odds of 90-day readmission rates (10.59 vs. 9.35%; OR: 1.15, p < 0.0001) and significantly longer in-hospital LOS (3.69 days ± 1.95 vs. 3.23 days ± 1.83, p < 0.0001) compared to controls. Octogenarians also had equal incidence and odds of developing any medical complication (1.26 vs. 1.26%; OR: 0.99, p = 0.99) and lower incidence and odds (1.67 vs. 1.93%; OR: 0.86, p < 0.001) of implant-related complications compared to controls. Octogenarians undergoing primary TKA have similar odds of medical related complications and lower odds of implant-related complications compared to non-octogenarian patients, whereas readmission rates and in-hospital LOS are greater.


Biomechanical comparison of three types of internal fixation in a type C zone II pelvic fracture model.
This study aimed to compare the stability of Tile C pelvic fractures fixed with two iliosacral (IS) screws, tension band plate (TBP), and minimally invasive adjustable plate (MIAP). Six embalmed specimens of adult pelvis were used. The soft tissue was removed from the specimens, but spines from the fourth lumbar vertebra to the proximal one-third of both femurs were retained. The pubic symphysis, bilateral sacroiliac joints and ligaments, bilateral hip joints, bilateral sacrotuberous ligaments, and bilateral sacrospinous ligaments were intact. Tile C pelvic fractures were created on the specimens. The symphysis pubis was fixed with a plate, and the fracture on the posterior pelvic ring was fixed with three types of internal fixation in a randomized block design. The specimens were placed in a biomechanical machine at a standing neutral posture. A cyclic vertical load of up to 500N was applied, and displacement was recorded. Shifts in the fracture gap were measured by a grating displacement sensor. Under different vertical loads, the shift in the fracture gap and displacement of the pelvic fractures fixed with two IS screws were similar to those in fractures fixed with MIAP. However, the shift in the fracture gap and displacement of fractures fixed with MIAP was significantly smaller than those of fractures fixed with TBP. The stability of the Tile C pelvic fractures fixed with MIAP was similar to that of fractures fixed with IS screws. MIAP performed better than TBP under vertical load.


Genome-wide association analysis reveals a novel pathway mediated by a dual-TIR domain protein for pathogen resistance in cotton.
Verticillium wilt is one of the most devasting diseases for many plants, leading to global economic loss. Cotton is known to be vulnerable to its fungal pathogen, Verticillium dahliae, yet the related genetic mechanism remains unknown. By genome-wide association studies of 419 accessions of the upland cotton, Gossypium hirsutum, we identify ten loci that are associated with resistance against Verticillium wilt. Among these loci, SHZDI1/SHZDP2/AYDP1 from chromosome A10 is located on a fragment introgressed from Gossypium arboreum. We characterize a large cluster of Toll/interleukin 1 (TIR) nucleotide-binding leucine-rich repeat receptors in this fragment. We then identify a dual-TIR domain gene from this cluster, GhRVD1, which triggers an effector-independent cell death and is induced by Verticillium dahliae. We confirm that GhRVD1 is one of the causal gene for SHZDI1. Allelic variation in the TIR domain attenuates GhRVD1-mediated resistance against Verticillium dahliae. Homodimerization between TIR1-TIR2 mediates rapid immune response, while disruption of its αD- and αE-helices interface eliminates the autoactivity and self-association of TIR1-TIR2. We further demonstrate that GhTIRP1 inhibits the autoactivity and self-association of TIR1-TIR2 by competing for binding to them, thereby preventing the resistance to Verticillium dahliae. We propose the first working model for TIRP1 involved self-association and autoactivity of dual-TIR domain proteins that confer compromised pathogen resistance of dual-TIR domain proteins in plants. The findings reveal a novel mechanism on Verticillium dahliae resistance and provide genetic basis for breeding in future.


Experimental transmission of atypical scrapie to sheep.
Active surveillance for transmissible spongiform encephalopathies in small ruminants has been an EU regulatory requirement since 2002. A number of European countries have subsequently reported cases of atypical scrapie, similar to previously published cases from Norway, which have pathological and molecular features distinct from classical scrapie. Most cases have occurred singly in flocks, associated with genotypes considered to be more resistant to classical disease. Experimental transmissibility of such isolates has been reported in certain ovinised transgenic mice, but has not previously been reported in the natural host. Information on the transmissibility of this agent is vital to ensuring that disease control measures are effective and proportionate. This report presents the successful experimental transmission, in 378 days, of atypical scrapie to a recipient sheep of homologous genotype with preservation of the pathological and molecular characteristics of the donor. This isolate also transmitted to ovinised transgenic mice (Tg338) with a murine phenotype indistinguishable from that of Nor 98. This result strengthens the opinion that these cases result from a distinct strain of scrapie agent, which is potentially transmissible in the natural host under field conditions.


The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells.
Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking in silico and binding to recombinant MEK by microscale thermophoresis in vitro. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer. A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest.


Direct asymmetric aldol-Tishchenko reaction of aliphatic ketones catalyzed by syn-aminoalcohol-Yb(III) complexes.
The asymmetric direct aldol condensation of aldehydes with ethyl- and propylketones is catalyzed by syn-alpha-aminoalcohol-Yb(OTf)3 complexes, yielding the anti-1,3-diol monoesters with high diastereocontrol and good enantioselectivity. Three adjacent stereogenic centers are created in a simultaneous aldol condensation and Evans-Tishchenko reduction in an acyclic system.


Twin tubular pinch effect in curving confined flows.
Colloidal suspensions of buoyancy neutral particles flowing in circular pipes focus into narrow distributions near the wall due to lateral migration effects associated with fluid inertia. In curving flows, these distributions are altered by Dean currents and the interplay between Reynolds and Dean numbers is used to predict equilibrium positions. Here, we propose a new description of inertial lateral migration in curving flows that expands current understanding of both focusing dynamics and equilibrium distributions. We find that at low Reynolds numbers, the ratio δ between lateral inertial migration and Dean forces scales simply with the particle radius, coil curvature and pipe radius as (Rp(3)R)/a(4). A critical value δc = 0.148 of this parameter is identified along with two related inertial focusing mechanisms. In the regime below δc, coined subcritical, Dean forces generate permanently circulating, twinned annuli, each with intricate equilibrium particle distributions including eyes and trailing arms. At δ > δc (supercritical regime) inertial lateral migration forces are dominant and particles focus to a single stable equilibrium position.


One-year study of the effect of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinaemia.
The effect of bezafibrate (2-(4-[2-(4-chlorobenzamido)-ethyl]-phenoxy)-2-methylporopionic acid) (450 mg daily) on serum lipoprotein concentrations was studied for 1 year in 14 subjects with hyperlipoproteinaemia (3 of type II A, 2 of type II B, 2 of type III and 7 of type IV). After 2 months serum cholesterol decreased from 7.12--6.08 mmoles/l (15% P less than 0.01), triglycerides from 2.52--1.96 mmoles/l (22%, P less than 0.01), very low density lipoprotein triglycerides from 1.48--0.86 mmoles/l (42%, P less than 0.01) and low density lipoprotein cholesterol from 5.00--3.81 mmoles/l (24%, P less than 0.01). While triglyceride concentrations of serum and lipoproteins remained constant for 1 year, serum and LDL cholesterol concentrations increased slightly after 6 and 12 months. The former rise was partly due also to a rise of the possibly beneficial high density lipoprotein cholesterol from 1.27--1.68 mmoles/l (32%, P less than 0.01) after 6 months, making the effect on total cholesterol less pronounced. Subjective side-effects were nausea in one patient. No severe biochemical side-effects were noted.


An analysis of factors influencing the establishment of a clinical pregnancy in an ultrasound-based ambulatory in vitro fertilization program.
In the study period (June 1984 to December 1986), 2232 cycles were stimulated in 1294 patients. Ultrasound-directed oocyte recovery (UDOR) was performed as an ambulatory procedure in 1737 (77.8%) cycles, resulting in 1375 embryos transfers (ET). Age, etiology, menstrual cycle length, number of oocytes collected, and number of embryos transferred were important determinants of the outcome. The number of attempts at in vitro fertilization did not affect the clinical pregnancy rate (CPR). In patients receiving four embryos, the CPR appeared to be highest when up to seven embryos were available for transfer. The fertilization rate in an individual cycle had a good prognostic value, the implantation rate being highest when 7 to 9 oocytes were retrieved and greater than 60% of these were fertilized. When 10 or more oocytes were collected, the implantation rate showed a progressive decline, regardless of the fertilization rate. Furthermore, multiple pregnancies failed to occur when greater than 12 oocytes were retrieved or more than eight embryos were available for transfer. These data suggest that, in excessively stimulated cycles, the quality of oocytes and embryos or uterine receptiveness may be suboptimal, and the transfer of more than four embryos is unlikely to increase the success rate.


Adrenal 21-hydroxylase deficiency in childhood: 25 years' experience.
To review past and present management of congenital adrenal hyperplasia at a single centre, as a guide to best practice. The records of 89 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency managed in a children's hospital in Australia over a period of 25 years were reviewed. The diagnosis was made in infancy in 66 patients (37 males and 29 females) and later in 23 (11 males and 12 females). The mean age for genitoplasty in females with ambiguous genitalia was 18 months before 1984 and 3 months thereafter. Significant differences were found between males and females presenting after infancy with regard to virilization, bone age advancement, risk of true precocious puberty and final height. The mean final height standard deviation scores for seven males and seven females treated from infancy were -1.32 and -1.26, respectively. The results emphasize the importance of early diagnosis and good control in ensuring a good outcome for patients with 21-hydroxylase deficiency.


C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence.
In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver haematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa-deficient adult HSCs underwent a pronounced increase in number with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa-deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover, we observed that age-specific Cebpa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically we identified N-Myc as a downstream target of C/EBPa, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs.


GABA synaptopathy promotes the elevation of caspases 3 and 9 as pro-apoptotic markers in Egyptian patients with autism spectrum disorder.
Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder characterized by reduced social communication as well as repetitive behaviors. Many studies have proved that defective synapses in ASD influence how neurons in the brain connect and communicate with each other. Synaptopathies arise from alterations that affecting the integrity and/or functionality of synapses and can contribute to synaptic pathologies. This study investigated the GABA levels in plasma being an inhibitory neurotransmitter, caspase 3 and 9 as pro-apoptotic proteins in 20 ASD children and 20 neurotypical controls using the ELISA technique. Analysis of receiver-operating characteristic (ROC) of the data that was obtained to evaluate the diagnostic value of the aforementioned evaluated biomarkers. Pearson's correlations and multiple regressions between the measured variables were also done. While GABA level was reduced in ASD patients, levels of caspases 3 and 9 were significantly higher when compared to neurotypical control participants. ROC and predictiveness curves showed that caspases 3, caspases 9, and GABA might be utilized as predictive markers in autism diagnosis. The present study indicates that the presence of GABAergic dysfunction promotes apoptosis in Egyptian ASD children. The obtained GABA synaptopathies and their connection with apoptosis can both relate to neuronal excitation, and imbalance of the inhibition system, which can be used as reliable predictive biomarkers for ASD.


Disruption of lmo1386, a putative DNA translocase gene, affects biofilm formation of Listeria monocytogenes on abiotic surfaces.
The distribution and survival of Listeria monocytogenes (L. monocytogenes) in food processing environment is linked to its ability to form biofilms, however the genetic mechanisms remain unclear. In our previous study, a Himar1 mariner-based transposon mutagenesis was performed and 42 mutants were confirmed to have reduced biofilm formation. Among the 42 biofilm deficient mutants, two isolates (s25-10C and s55-1D) harbored single insertion in lmo1386, a gene encoding a putative DNA translocase. The lmo1386 mutants had impaired biofilm formation in both static and flow conditions. The mutant strain s55-1D was complemented by cloning the entire lmo1386 gene into pPL2-gtcAP, a derivative of the integration vector pPL2 with the L. monocytogenes gtcA promoter. The genetically complemented mutant restored its biofilm phenotype, demonstrating the role of lmo1386 in the biofilm formation of L. monocytogenes. The lmo1386 mutant had reduced initial adhesion ability, which could at least partially contribute to the impaired biofilm phenotype. Additionally, the lmo1386 mutant formed elongated cell chains when grown in a nutrient TSBYE media, while no obvious cell morphology changes were observed when grown in the minimal MWB media. Overall, our findings suggest that the disruption of lmo1386, a putative DNA translocase gene affects the biofilm formation of L. monocytogenes on abiotic surfaces, which may further advance the understanding of the complicated process of biofilm formation.


Detection of myocardial dysfunction using global longitudinal strain with speckle-tracking echocardiography in patients with vs without rheumatoid arthritis: a systematic review and meta-analysis.
Rheumatoid arthritis (RA) is a systemic autoimmune disorder primarily involving the peripheral joints. Systemic involvement can occur, including myocardial dysfunction. Speckle tracking echocardiography (STE) is a novel diagnostic study which is recently being used to detect subclinical cardiac dysfunction. Global longitudinal strain (GLS) by STE is more sensitive than standard echocardiographic parameters to detect occult cardiac dysfunction. A systematic search of PUBMED, EMBASE, Cochrane, and Google Scholar databases was performed to identify studies comparing the STE parameters between RA and non-RA patients. Left ventricular (LV) GLS was significantly lower in patients with RA compared to non-RA patients with a standard mean difference (SMD) of -1.09 (-1.48--0.70, P < 0.001). LV Global Circumferential Strain (GCS) was reported in five studies, and it was found to be lower in RA patients with an SMD of -1.25 (-2.59--0.10; P < 0.0010). Meta regression analysis studies failed to show any significant impact of disease duration, activity, age, sex and BMI on LV GLS and RV GLS. RA patients have lower LV GLS and LV GCS compared to controls suggesting impaired myocardial dysfunction. Further studies need to be done to delineate the importance of lower GLS in asymptomatic rheumatoid patients to guide disease management and risk factor modification in this selected population.


Risk factors for loneliness: A literature review.
Increasingly, loneliness is being recognised as a serious problem with detrimental effects on health, as well as on social cohesion and community trust. To effectively tackle this complex issue, a clear understanding of the phenomenon and its main drivers is needed. Over years of scientific research on loneliness, many potential risk factors have emerged and been tested empirically. This narrative review of 109 studies provides a concise summary of empirical evidence on the main potential risk factors for loneliness and presents an additional section dedicated to the COVID-19 pandemic. Given the very large number of existing studies, emphasis is placed on recent meta-analyses and systematic literature reviews as well as longitudinal studies. Similarly, given the large number of possible risk factors for loneliness, which may differ based on the geographical and cultural context, this review focuses on studies from Europe and North America. The results show that demographic factors often correlate with loneliness, but in many cases the link becomes negligible when controlling for other factors. Often, physical and mental health problems are found to be associated with loneliness, and so are some psychological factors, such as neuroticism or extroversion. Loneliness also depends on the environment in which one lives, and possibly the broader socio-economic and socio-cultural contexts. Nevertheless, the review shows that ultimately everything comes down to the quantity and quality of social relationships. In particular, marital status, living arrangements and the characteristics of one's personal social network are quite consistently found to be among the strongest predictors of loneliness. These main findings about the risk factors for loneliness remained valid also during the COVID-19 pandemic. The findings of this review have implications for policy, as understanding who the most vulnerable groups are is key for designing targeted policy solutions that tackle loneliness.


Use of a Virus Gene Silencing Vector for Maize Functional Genomics Research.
Virus-induced gene silencing (VIGS) is a genetic technology that exploits the RNA-mediated defense against virus. The method has great potential for plant reverse genetics as it could knock down gene expression in a rapid way, which is triggered by a replicating viral genome engineered to carry a fragment of host gene to be silenced. A number of efficient VIGS vectors are available for dicots, such as for model plant Nicotiana benthamiana; however, only a few of VIGS vectors for monocotyledonous cereal crops. Here, we describe the method for the use of a newly developed VIGS vector based on a maize-infecting Cucumber mosaic virus (CMV) strain ZMBJ-CMV for maize. The RNA2 of ZMBJ-CMV was modified as a vector pCMV201-2bN81 having multiple cloning sites for the insert of 100-300 bp fragment of target gene. Using a method of vascular puncture inoculation of maize seeds with crude sap prepared from Agrobacterium-infiltrated N. benthamiana leaves, silencing of target genes could be obtained in 4 weeks.


Combined fluorescent seed selection and multiplex CRISPR/Cas9 assembly for fast generation of multiple Arabidopsis mutants.
Multiplex CRISPR-Cas9-based genome editing is an efficient method for targeted disruption of gene function in plants. Use of CRISPR-Cas9 has increased rapidly in recent years and is becoming a routine method for generating single and higher order Arabidopsis thaliana mutants. Low entry, reliable assembly of CRISPR/Cas9 vectors and efficient mutagenesis is necessary to enable a maximum of researchers to break through the genetic redundancy within plant multi-gene families and allow for a plethora of gene function studies that have been previously unachievable. It will also allow routine de novo generation of mutations in ever more complex genetic backgrounds that make introgression of pre-existing alleles highly cumbersome. To facilitate rapid and efficient use of CRISPR/Cas9 for Arabidopsis research, we developed a CRISPR/Cas9-based toolbox for generating mutations at multiple genomic loci, using two-color fluorescent seed selection. In our system, up-to eight gRNAs can be routinely introduced into a binary vector carrying either a FastRed, FastGreen or FastCyan fluorescent seed selection cassette. FastRed and FastGreen binary vectors can be co-transformed as a cocktail via floral dip to introduce sixteen gRNAs at the same time. The seeds can be screened either for red or green fluorescence, or for the presence of both colors. Importantly, in the second generation after transformation, Cas9 free plants are identified simply by screening the non-fluorescent seeds. Our collection of binary vectors allows to choose between two widely-used promoters to drive Cas enzymes, either the egg cell-specific (pEC1.2) from A. thaliana or the constitutive promoter from Petroselinum crispum (PcUBi4-2). Available enzymes are "classical" Cas9 codon-optimized for A. thaliana and a recently reported, intron-containing version of Cas9 codon-optimized for Zea mays, zCas9i. We observed the highest efficiency in producing knockout phenotypes by using intron-containing zCas9i driven under egg-cell specific pEC1.2 promoter. Finally, we introduced convenient restriction sites flanking promoter, Cas9 and fluorescent selection cassette in some of the T-DNA vectors, thus allowing straightforward swapping of all three elements for further adaptation and improvement of the system. A rapid, simple and flexible CISPR/Cas9 cloning system was established that allows assembly of multi-guide RNA constructs in a robust and reproducible fashion, by avoiding generation of very big constructs. The system enables a flexible, fast and efficient screening of single or higher order A. thaliana mutants.


Quantitative analysis of neovascular permeability in glioma by dynamic contrast-enhanced MR imaging.
This study was designed to quantitatively analyse neovascular permeability in glioma by dynamic contrast-enhanced MRI (DCE-MRI). Forty-four patients with glioma were included in this study. The highest value of volume transfer constant (K(trans)) and volume of extravascular extracellular space per unit volume of tissue (V(e)) were obtained and the differences in K(trans) and V(e) between low-grade glioma (LGG) and high-grade glioma (HGG) were analyzed. The correlations between K(trans), V(e) and glioma grade were performed. Receiver operating characteristic (ROC) curve analyses were conducted. The values of K(trans) and V(e) of LGG were significantly lower than those of HGG. The correlation analysis demonstrated statistically significant relationships between K(trans) and glioma grade, between V(e) and glioma grade, and between K(trans) and V(e). The ROC curve analyses of K(trans) (0.035/min) and V(e) (0.130) for differentiating LGG from HGG were statistically significant. Thus, DCE-MRI can be used to estimate neovascular permeability and for pre-operative grading of glioma.


Development of the Story Telling Examination for Early Mild Cognitive Impairment (Pre-Mild Cognitive Impairment) Screening.
Cognitive function prior to mild cognitive impairment (MCI) has become a burgeoning interest. Tools used to detect this early period before MCI are being pilot-tested. This study aimed to develop a new test to detect pre-MCI and to examine its content validity and feasibility. The Story Telling Examination for Early MCI Screening (STEEMS), an audio cognitive test, was developed. It covers ten cognitive domains, e.g., executive function, language fluency, abstract reasoning. Face and content validity were examined by experts in geriatric psychiatry and psychology. The content validity index was 1.00. STEEMS comprised 12 items with 2-4 types of scoring. The tool was further examined in 16 pilot samples for feasibility among healthy participants having no cognitive impairment (Montreal Cognitive Assessment [MoCA] test score ≥25, Mini-Cog ≥3) and no depressive symptoms (Geriatric Depression Scale <6). The 16 healthy older individuals aged 59-73 years, mean age was 65.06 ± 4.07 years, were predominantly males (68.8%). STEEMS scores ranged from 10 to 25, with a mean of 18.38 (SD = 4.2). Thirteen percent obtained 100% correct on the STEEMS, 63% scored 68-92% correct, and 25% scored 40-60% correct. The pre-MCI scores are illustrated by a bell curve's graphical depiction, suggesting a normal distribution probability distribution. Correlation between STEEMS and MoCA test scores was observed. STEEMS showed to be feasible for early elderly or late adults as being brief and easy to understand. The time spent to administer was predictably less than 7 min. STEEMS could potentially serve as a tool for pre-MCI screening. Further study and investigation in a larger population are required.


Evaluation of the pharmacokinetics of imipenem following regional limb perfusion using the saphenous and the cephalic veins in standing horses.
This prospective experimental study goal was to determine the pharmacokinetics of imipenem after intravenous regional limb perfusion (IV-RLP) in standing horses. Nine horses participated in the study; that was approved by the University Animal Care and Use Committee. One thoracic limb or one pelvic limb of each horse was randomly selected. After the veins were catheterized, an Esmarch bandage tourniquet was applied and the catheter was injected with a solution containing 500mg of imipenem. Synovial fluid samples were collected from the fetlock joint and blood samples were collected from the jugular vein. All samples were analyzed for imipenem concentration using liquid chromatography mass spectrometry. Cmax of imipenem in the fetlock joint using the cephalic and the saphenous vein was 87 and 60μg⁄mL, respectively. The results indicate that by performing IV-RLP using the cephalic/saphenous, one can achieve imipenem concentrations in the fetlock joint that are well above the MIC of most susceptible pathogens including resistant bacteria such as Methicillin Resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Thus, with selective; judicious use, RLP with imipenem can markedly increase treatment efficacy of severe distal limb infections in horses.


The contributions of plasma membrane Na+-Ca2+-exchange and the Ca2+-ATPase to the regulation of cytosolic calcium ([Ca2+]i) in a clonal pituitary cell line (AtT-20) of mouse corticotropes.
Single cell calcium microfluorimetry was used to examine the regulation of [Ca2+]i homeostasis in a clonal cell line of corticotropes (AtT-20 cells). Single cells, loaded with fura-2/AM, were exposed briefly to elevated potassium chloride (KCI, 40 mM, 5 sec). The time constant of decay of the [Ca2+]i signal was used as an index of [Ca2+]i extrusion and/or sequestration. Substitution of extracellular sodium with lithium, N-methyl-D-glucamine (NMDG), or Tris, increased resting levels of [Ca2+]i and significantly increased the time constant of [Ca2+]i decay by 40% compared to control indicating the participation of Na+-Ca2+-exchange. Prior exposure of single cells to thapsigargin (1 microM) or BuBHQ (10 microM). inhibitors of the SERCA Ca2+-ATPases, and/or the mitochondrial uncoupler FCCP (1 microM) did not significantly change the time constant of [Ca2+]i decay following KCl. Lanthanum ions (La3+), applied during the decay of the KCI-induced increase in [Ca2+]i, significantly increased the time constant of the return of [Ca2+]i to resting levels by 70% compared to control. Brief exposure of cells to sodium orthovanadate, an inhibitor of ATP-dependent pump activity, slowed and longer exposures prevented, the return of [Ca2+]i to resting levels. We conclude that neither intracellular SERCA pumps nor mitochondrial uptake contribute significantly to [Ca2+]i sequestration following a [Ca2+]i load and that the plasma membrane Ca2+-ATPase contributes to a greater extent than the Na+-Ca2+-exchanger to the return of [Ca2+]i to resting levels following a [Ca2+]i load under these experimental conditions.


The adenylate cyclase-cyclic AMP-phosphodiesterase system in pathological human thyroid.
The adenylate cyclase-cyclic AMP-phosphodiesterase system of human thyroid tissues adjacent to cold nodules (control), two follicular adenomas, one hyperplastic thyroid and one hyperfunctioning follicular carcinoma have been compared. In the hyperfunctional follicular carcinoma the basal adenylate cyclase is much higher than in control tissue, carcinoma adenylate cyclase does not respond to TSH and prostaglandin E1, whereas it responds normally to fluoride. In the hyperplastic, but hypofunctional thyroid the basal adenylate cyclase is higher than in normal tissue whereas the response to TSH, PGE1, and fluoride is normal. No difference between the follicular adenomas and normal thyroid stimulated and unstimulated adenylate cyclase was observed. Furthermore in various thyroid tissues no changes in the level of cyclic AMP phosphodiesterase was found. Our data indicate a greater change in the synthesis rather than in degradation of cyclic AMP in the human pathological thyroids studied.


Elevated FAM84B promotes cell proliferation via interacting with NPM1 in esophageal squamous cell carcinoma.
Family with sequence similarity 84, member B (FAM84B) is a significant copy number amplification gene in the 8q24.21 locus identified by our previous WGS study in esophageal squamous cell carcinoma (ESCC). However, its clinical relevance and potential mechanisms have been elusive. Here, we performed the association analyses between FAM84BAmp and clinicopathological features using 507 ESCC samples. The results indicated that, compared with the FAM84Bnon-Amp patients, the FAM84BAmp patients showed a more aggressive and a worse prognosis. A significant correlation was discovered between the expression level of FAM84B and FAM84BAmp in the ESCC cohort. Furthermore, we found that the forced expression change of FAM84B can influence ESCC cell proliferation and cell-cycle status, which is probably mediated by NPM1. A direct interaction between FAM84B and the C-terminal (189-294aa) of NPM1 was identified, which increased the NPM1 nuclear expression. Over-expression of NPM1 could inhibit the CDKN2A protein expression, which might affect the ESCC cell cycle. Our results indicate FAM84B CNA may be a potential diagnostic and therapeutic biomarker in ESCC, meanwhile, reveal a novel mechanism of FAM84B that promotes tumorigenesis via interacting with NPM1 and suppressing CDKN2A.


Ovulation induction with pulsatile gonadotropin-releasing hormone administration in patients with polycystic ovarian syndrome.
Gonadotropin-releasing hormone (0.025 microgram/kg) was administered intravenously in a pulsatile fashion to four subjects with polycystic ovary syndrome for a total of six cycles. Five of the six cycles culminated in ovulation, although in one course the response occurred too early to be attributed to the therapy alone. No pregnancies resulted. All luteal phases were of normal duration, but progesterone production as manifested by serum progesterone determination was deficient in some. If additional investigation confirms these preliminary findings, this form of therapy may offer a safe and economic alternative for anovulatory patients refractory to clomiphene citrate therapy. The response of the four subjects suggests that pulsatile gonadotropin-releasing hormone administration may override hypothalamic-pituitary dysfunction and result in ovulatory menstrual cycles.


Acridine orange staining as a replacement for subculturing of false-positive blood cultures with the BACTEC NR 660.
Despite the customization of growth index thresholds within individual laboratories, use of the BACTEC NR 660 automated blood culture system results in a number of false-positive cultures. The results of Gram staining, acridine orange staining, and subculturing to agar media were evaluated on 210 false-positive blood cultures over a 6-month period. Inclusion of acridine orange staining in the routine workup of false-positive blood cultures can eliminate the need for subculturing.


Somatic Versus Cognitive Depressive Symptoms as Predictors of Coronary Artery Disease among Women with Suspected Ischemia: The Women's Ischemia Syndrome Evaluation.
Depression is an established predictor of coronary artery disease (CAD) progression and mortality. "Somatic" symptoms of depression such as fatigue and sleep impairment overlap with symptoms of CAD and independently predict CAD events. Differentiating between "somatic" and "cognitive" depressive symptoms in at-risk patients may improve our understanding of the relationship between depression and CAD. The study utilized data from the Women's Ischemia Syndrome Evaluation. Participants (N = 641; mean age = 58.0 [11.4] years) were enrolled to evaluate chest pain or suspected myocardial ischemia. They completed a battery of symptom and psychological questionnaires (including the Beck Depression Inventory [BDI]) at baseline, along with quantitative coronary angiography and other CAD diagnostic procedures. The BDI provided scores for total depression and for cognitive and somatic depressive symptom subscales. Two hundred and fourteen (33.4%) women met criteria for obstructive CAD. Logistic regression models were used to examine relationships between depression symptoms and obstructive CAD. Neither BDI total scores (odds ratio [OR] =1.02, 95% confidence interval [CI], 0.99-1.05, P = 0.053) nor BDI cognitive scores (OR = 1.02, 95% CI, 1.00-1.04, P = 0.15) predicted CAD status. BDI somatic symptom scores, however, significantly predicted CAD status and remained statistically significant after controlling for age, race, and education (OR = 1.06, 95% CI, 1.01-1.12, P = 0.02). Among women with suspected myocardial ischemia, somatic but not cognitive depressive symptoms predicted an increased risk of obstructive CAD determined by coronary angiography. Consistent with prior reports, these results suggest a focus on somatic rather than cognitive depressive symptoms could offer additional diagnostic information.


Statistical Study of Risk Factors of End Stage Renal Failure in Peshawar, Pakistan.
End Stage Renal Failure (ESRD) is the last stage of the chronic renal failure in which kidneys become completely fail to function. The basic aim of this study was to discover the important risk factors of ESRD and to construct a model for prediction of the ESRD patients in various hospitals of Peshawar, Pakistan. The data were collected from the patients of renal diseases from three major hospitals of Peshawar. Brown method was used to obtain initial model, then backward elimination logistic regression analysis was performed to find the significant variables (risk factors). The response variable (ESRD) in this study is binary; therefore, logistic regression analysis is used to identify the significant variables. A Statistical Package GLIM and SPSS were used for fitting the model and for finding the significant variables. The backward elimination procedure selects predictor variables diabetic, hypertension, glomerulonephritis and heredity, for males. Thus, these variables are the main causes of ESRD. For females, the predictor variables selected are hypertension & (Diabetic*Hypertension), which means that hypertension and hypertensive diabetic are significant causes of ESRD. Our main conclusion from this analysis is that diabetic, hypertension and glomerulonephritis are the significant risk factors of ESRD.


Toxicity of minimal amounts of cadmium to the developing rat lung and pulmonary surfactant.
Pregnant rats were injected subcutaneously with 0, 1, 2, 4 or 8 mg cadmium chloride/kg each day during mid-gestation from day 12-15. Dams were sacrificed on day 21. The treatment resulted in a dose-related increase in prenatal mortality, and decreases in body weight, lung weight and saturated fatty acid containing lecithin content in the fetus but no change in pulmonary sphingomyelin. Although the lowest dose produced no changes in fetal viability, body weight or lung weight, a significant reduction in the amount of saturated fatty acid containing lecithin occurred. Since saturated fatty acid containing lecithin is a major component of pulmonary surfactant, fetuses from CdCl2-treated dams may be subject to respiratory distress postnatally.


The characteristics of psychiatric patients readmitted within a month of discharge.
From the Camberwell Register it was found that 9-14% of all admissions in the years 1965-70 were readmissions within a month of discharge. The characteristics of these patients were compared with the total population admitted. No particular diagnostic category was associated with rapid readmissions but the rapidly readmitted group contained a high proportion of young patients and divorced or separated patients. The case notes of rapidly readmitted patients were examined and compared with the case notes of a control group. The circumstance which predisposed patients to require rapid readmission was the degree of socially disruptive behaviour of the patient. Patients benefited from readmission and the reasons for this are discussed.