Stair negotiation as a rehabilitation intervention for enhancing recovery following total hip and knee replacement surgery.
Total hip replacement (THR) and total knee replacement (TKR) are common orthopaedic procedures. However, an optimal programme for post-operative rehabilitation has yet to be established. Stair negotiation is a challenging, habitual task, regularly used as a post-operative functional outcome measure; yet as a physical rehabilitation intervention it appears to be rarely used. The review purpose was to investigate the effectiveness of stair climbing as a rehabilitation intervention for THR and TKR patients. MEDLINE, PsycINFO, Science Citation Index, CINAHL, SPORTDiscus and the Cochrane Database of Systematic Reviews were searched. The systematic review targeted studies using stair negotiation as a rehabilitation intervention. Randomised and non-randomised controlled trials, pilot studies, and case studies were included; systematic reviews and meta-analyses were excluded. Of 650 articles identified, ten studies were eligible for review. A predefined data table to extract information from selected studies was used. Of the ten identified reports, two prehabilitation and eight rehabilitation studies included stair negotiation exercises as part of multi-modal physical interventions. Outcome measures were classified as: functional self-reported, perceptual, psychological and those relating to quality of life. Studies were methodologically heterogeneous and typically lacked adequate control groups. It was not possible to determine the impact of stair negotiation exercise on the positive outcomes of interventions. Stair negotiation warrants further investigation as a rehabilitation activity.


p16, Ki-67, and BD ProExC immunostaining: a practical approach for diagnosis of cervical intraepithelial neoplasia.
p16, Ki-67, and BD ProExC (TriPath Imaging, Inc., Burlington, NC) have each been shown to be helpful adjuncts in the diagnosis and grading of human papillomavirus-associated cervical intraepithelial neoplasia. However, no clear guidelines are available regarding their use in routine practice. This study was designed to evaluate the efficacy of the 3 stains alone and in combinations to determine the most useful strategy in the diagnosis of cervical intraepithelial neoplasia and provide guidance in instances with discordant staining patterns. Serial sections of 136 formalin-fixed paraffin-embedded cervical samples with consensus diagnoses of 39 benign-reactive, 46 low-grade cervical intraepithelial neoplasia (CIN I/human papillomavirus), and 51 high-grade cervical intraepithelial neoplasia (CINII/III) were immunostained using p16, Ki-67, and BD ProExC antibodies. Results of high-risk human papillomavirus testing were available in 70 cases. Immunostaining patterns were designated as negative, intermediate, and strongly positive based on the patterns observed most commonly in benign-reactive, low-grade cervical intraepithelial neoplasia, and high-grade cervical intraepithelial neoplasia lesions, respectively. A concordant staining pattern with all 3 stains correctly identified benign-reactive, low-grade cervical intraepithelial neoplasia, and high-grade cervical intraepithelial neoplasia cases. p16 was the most sensitive and specific individual stain (sensitivity, 33%; specificity, 93%; positive predictive value [PPV], 81%; negative predictive value [NPV], 58%). Performing all 3 immunostains and using concordant results of any 2 improved diagnostic accuracy (sensitivity, 35%; specificity, 98%; PPV, 93%; NPV, 67%). However, a significant proportion of low-grade cervical intraepithelial neoplasia cases showed aberrant staining patterns with 52% staining negative and 9% staining strongly positive. Low-grade cervical intraepithelial neoplasia cases with the negative staining pattern were more likely to be negative for high-risk human papillomavirus, whereas those showing the strongly positive staining pattern were high-risk human papillomavirus positive. Performing p16 and BD ProExC initially followed by Ki-67 only when p16 and BD ProExC yielded discordant results provided similar diagnostic accuracy at reduced cost because only one third of the cases required the additional stain.


Direct Granule Feeding of Thermal Droplet Deposition 3D Printing of Porous Pharmaceutical Solid Dosage Forms Free of Plasticisers.
To develop a new direct granule fed 3D printing method for manufacturing pharmaceutical solid dosage forms with porous structures using a thermal droplet deposition technology. Eudragit® E PO was used as the model polymer, which is well-known to be not FDM printable without additives. Wet granulation was used to produce drug loaded granules as the feedstock. The flow and feedability of the granules were evaluated. The physicochemical properties and in vitro drug release performance of the granules and the printed tablets were fully characterised. Using the method developed by this study, Eudragit E PO was printed with a model drug into tablets with infills ranging from 30-100%, without additives. The drug was confirmed to be molecularly dispersed in the printed tablets. The printing quality and performances of the porous tablets were confirmed to be highly compliant with the pharmacopeia requirement. The level of infill density of the porous tablets had a significant effect on their in vitro drug release performance. This is the first report of thermal droplet deposition printing via direct granule feeding. The results of this study demonstrated that this new printing method can be used as a potentially valuable alternative for decentralised pharmaceutical solid dosage form manufacturing.


Commentary: A Radiologist's Guide to Peer-Reviewing Manuscripts.
Reviewers play an important role in the publishing of radiology articles. When done well, reviewers help editors identify which articles to accept and improve them through their recommendations. In this commentary, we provide a step-by-step guide to reviewing both original science and review articles.


Evolution of the secondary structure of the rRNA internal transcribed spacer 2 (ITS2) in hard ticks (Ixodidae, Arthropoda).
ITS2 sequences are used extensively in molecular taxonomy and population genetics of arthropods and other animals yet little is known about the molecular evolution of ITS2. We studied the secondary structure of ITS2 in species from each of the six main lineages of hard ticks (family Ixodidae). The ITS2 of these ticks varied in length from 679 bp in Ixodes scapularis to 1547 bp in Aponomma concolor. Nucleotide content varied also: the ITS2 of ticks from the Prostriata lineage (Ixodes spp.) had 46-49% GC whereas ITS2 sequences of ticks from the Metastriata lineage (all other hard ticks) had 61-62% GC. Despite variation in nucleotide sequence, the secondary structure of the ITS2 of all of these ticks apparently has five domains. Stems 1, 3, 4 and 5 of this secondary structure were obvious in all of the species studied. However, stem 2 was not always obvious despite the fact that it is flanked by highly conserved sequence motifs in the adjacent stems, stems 1 and 3. The ITS2 of hard ticks has apparently evolved mostly by increases and decreases in length of the nucleotide sequences, which caused increases, and decreases in the length of stems of the secondary structure. This is most obvious when stems of the secondary structures of the Prostriata (Ixodes spp.) are compared to those of the Metastriata (all other hard ticks). Increases in the size of the ITS2 may have been caused by replication slippage which generated large repeats, like those seen in Haemaphysalis humerosa and species from the Rhipicepalinae lineage, and the small repeats found in species from the other lineages of ticks.


Predictive Value of Gross Extranodal Extension for Differentiated Thyroid Carcinoma Persistence/Recurrence.
We systematically investigated the predictive value of gross extranodal extension (gENE) for differentiated thyroid carcinoma persistence/recurrence. Retrospective study. A tertiary care hospital. This study was divided into 2 groups according to gENE status: the gENE group and non-gENE group. We compared the disease persistence/recurrence rates of these 2 groups in the entire cohort and by individual risk group (intermediate/high risk), analyzed whether gENE was an independent risk factor for disease persistence/recurrence, and explored the impact of gENE-specific features on disease persistence/recurrence. There were 989 patients who satisfied the inclusion criteria: 57 patients in the gENE group and 932 in the non-gENE group. The disease persistence/recurrence rate of the gENE group was higher than that of the non-gENE group in the entire cohort and by individual risk group (P < .05 for each). Unexpectedly, the outcomes of the gENE group with intermediate risk were similar to those of the non-gENE group with high risk (P = .72). For the entire cohort, gENE was an independent predictor for disease persistence/recurrence (odds ratio, 2.89; 95% CI, 1.39-6.00; P = .005). Specific features of gENE (P > .05 for each) were not related to disease persistence/recurrence. Patients with gENE and intermediate risk might be regraded as high risk. Specific features of gENE have no impact on disease persistence/recurrence.


Screening of the optimized prescription from Suqingwan in terms of its therapeutic effect on DSS-induced ulcerative colitis by its regulation of inflammatory and oxidative mediators.
Suqingwan (SQW), a traditional Chinese medicine used for treating ulcerative colitis (UC), is composed of 13 kinds of Traditional Chinese medicines (TCMs). According to TCM theory, we investigated whether a simplified prescription composed of the herbs with some functions, would have similar effects to SQW and examined its potential treatment mechanism of action. We categorized the herbs in SQW into four groups according to their traditional functions and used an orthogonal experimental design to obtain nine separated prescriptions (SPs) of SQW. A dextran sulfate sodium (DSS)-induced UC mouse model was used to evaluate the anti-ulcer colitis effects of the nine SPs and the calculated prescription (CP) was obtained based on the orthogonal t values of the disease activity index (DAI) of the nine SPs. The effect of the CP and SP8 were verified in the DSS-induced UC model, and the DAI and histopathology of the UC mice were examined. Myeloperoxidase (MPO), malondialdehyde (MDA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-4 and IL-10 of the mice in SP8 were investigated to explore the mechanism of action of the optimized prescription with regard to anti-inflammatory and anti-oxidation effects. Among the 9 SPs, separate prescription 6, 7 and 8 (SP6, SP7 and SP8) and the SQW formulation all significantly reduced the DAI of the UC mice and, in particular, SP8 had an effect similar to SQW, which consists of Sanguisorba officinalis L., Rehmannia glutinosa Libosch. and four other herbal medicines. In a further investigation, SP8 was found to improve the ulcerative colitis in mice in terms of both clinical symptoms and histopathology. The mortality of mice in the SP8 group was 33.3%, better than CP based on the orthogonal t values (83.3%). SP8 could also reduce the levels of TNF-α, IL-1β, IL-6, MPO and MDA and increase the levels of IL-4 and IL-10 in colon tissue of UC mice in comparison with those of the model group (p<0.05). An optimized prescription (SP8) from SQW was obtained based on an orthogonal experimental design, which involved 6 herbal medicines, with significantly fewer herbs than in the original prescription. SP8 displayed a similar anti-ulcerative colitis activity to SQW, and its in vivo mechanism of action is related to up-regulation of anti-inflammatory cytokines and down-regulation of pro-inflammatory and oxidative factors.


Assessing climate change mitigation and adaptation strategies and agricultural innovation systems in the Niger Delta.
Climate change and its impacts on agriculture have been widely discussed at national and global levels. An important aspect of the discussion has been adaptation/mitigation approaches. Consequently, several strategies have been suggested as measures to ensure agriculture remains productively profitable. However, food security especially in critical times, such as the lockdown during the COVID-19 pandemic proved to be a challenge even for regions naturally endowed for agriculture. The study evaluated research recommended strategies, and further examined the innovativeness of the strategies in fostering sustainable agricultural innovation system (AIS) in the Niger Delta. The study relied on both secondary and primary data; analysed 129 previous studies and gathered responses from 282 extension agents. The study introduces a method for assessing the innovativeness of strategies by calculating their rated values on five traits. Findings revealed the issues and implications of adopting most recommended strategies and the place of most strategies in fostering AIS. The study highlights the possible reasons why farmers fail to adopt most strategies as suggested by studies on climate change in the region. Based on the findings, recommendations were made on the way forward. The study adds to the scanty discussion of climate change and AIS at regional levels, particularly in the climate change prone and oil rich Niger Delta region. The study offers a novel approach for scoring innovations in agriculture.


Nrf2 modulated the restriction of lung function via impairment of intrinsic autophagy upon real-ambient PM2.5 exposure.
Compelling studies approve that fine particle matter (PM2.5) exposure was associated with high risk of respiratory disorders. However, the available data assessing the detailed influence of PM2.5 on lung was limited. To overcome the difficulty of inhalational PM2.5 exposure, the real-ambient PM2.5 exposure system was constructed. The mice were exposed to filtered air (FA) or real-ambient PM2.5 (PM2.5), and the adverse effect on lung was determined. Nuclear factor E2-related factor 2 (Nrf2) as a transcription factor, was reported to affect autophagy. Autophagy was proposed as a two-edge sword in respiratory disorders. Here, our data presented that PM2.5 exposure dramatically reduced the lung function of WT mice rather than Nrf2-/- mice. Consistently, thickened alveolar walls was observed in WT mice in PM2.5 exposure group, whereas the histological phenotype of Nrf2-/- mice exhibited no obvious alteration. Furthermore, PM2.5 exposure triggered low-grade production of inflammatory profile in WT and Nrf2-/- mice. Moreover, the protein levels of p62, Beclin1 and LC3B of WT mice rather than Nrf2-/- mice were also altered in PM2.5 exposure group. Taken together, the present study applied the real-ambient exposure system, revealed the adverse effect of air pollution on lung, and proposed the underlying mechanism.


Multimedia Technology Used to Supplement Patient Consent for Mohs Micrographic Surgery.
The patient consent process traditionally relies on conversations between the physician and the patient and rarely utilizes supplemental multimedia aids. To determine whether the addition of an educational video on Mohs micrographic surgery (MMS) can improve patient satisfaction with the consent process. This prospective observational quality improvement study compared the outcomes of traditional patient consent alone versus standard consent plus an educational video among patients undergoing their first MMS for a primary skin cancer. End points were patient satisfaction and preferences measured by postprocedure questionnaires. The addition of a supplemental video to the consent process did not affect overall patient satisfaction, which was very high in both video and control groups. However, specific components of patient satisfaction were improved such as patient perception of the opportunity to ask questions and understand the procedure. Multimedia aids can be effective tools in the patient consent process.


The Niemann-Pick type diseases - A synopsis of inborn errors in sphingolipid and cholesterol metabolism.
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.


Expression profile and role of prostacyclin receptor (PTGIR) in peri-implantation porcine conceptuses.
Prostacyclin (prostaglandin I2 [PGI2]) signaling system not only plays a pivotal role in vascular function in many species but is also important during early pregnancy in rodents and ruminants. Recently, abundant concentrations of PGI2 were found in the endometrium and uterine lumen of gilts at the time of implantation. In the present study, conceptuses collected on Days 10, 12, 14, 16, and 18 of pregnancy were examined for the expression of PGI2 receptors, PTGIR. Moreover, the effect of iloprost (a PGI2 analogue) on attachment, proliferation, and apoptosis in conceptus trophoblast (Tr) cells was investigated in vitro. Increased PTGIR mRNA expression was observed in Day 16 trophoblasts compared with Days 10, 12, and 14 conceptuses (P < 0.001) and Day 18 trophoblast tissue (P < 0.01). Embryos from Day 18 of gestation revealed greater PTGIR mRNA expression compared with Day 16 embryos (P < 0.01). In contrast to mRNA, PTGIR protein level in conceptus and trophoblast tissue was high on Days 12 and 14, followed by a decrease observed on Day 16. On Day 18 of pregnancy, PTGIR protein was detected in both trophoblast and embryonic tissue. Iloprost stimulated attachment and proliferation of Tr cells, but this effect was abolished by the addition of the PTGIR-specific antagonist, CAY10441, into culture medium. Addition of iloprost neither did affect the ratio of BAX/BCL-2 gene expression in cultured Tr cells nor did protect these cells from staurosporine-induced apoptosis. In summary, PTGIR is expressed in porcine conceptuses, and PGI2 acting through this receptor may promote the attachment and proliferation of Tr cells, thereby facilitating conceptus implantation.


Slow associative learning in alcohol dependence and the alcohol cue exposure treatment paradox.
To examine two explanations for the observation that cue-exposure treatment has not been clearly effective in the treatment of alcohol dependence: do alcohol-dependent individuals have either (1) slower extinction and/or (2) greater contextual specificity of extinction than non-dependent individuals? In two exploratory laboratory experiments we used mixed factorial designs with two-group between-subjects factors and within-subjects factors corresponding to performance in different parts of a computer-based learning task. University of Southampton psychology research laboratories and two addiction treatment services in the city of Southampton, UK. Experiment 1: 74 (54 female) undergraduates from the University of Southampton (age mean = 20.4 years). Experiment 2: 102 (40 female) participants from the University of Southampton, the local community, and from two Southampton alcohol treatment services (age mean = 41.3 years). The Alcohol Use Disorders Identification Test, a 1-week time-line follow-back alcohol consumption questionnaire, the Barratt Impulsiveness Scale (11th edn), and a computerized learning task. Experiment 2 additionally used the 44-item Big Five Inventory, a drug use history checklist, and the Hospital Anxiety and Depression Scale. Experiment 1: light and heavy drinkers did not differ significantly in extinction [extinction block × drinking status interaction, P = 0.761, ηp2=0.005 , 95% confidence interval (CI) = (0,0.028)] or on contextual control of extinction [recovery block × drinking status interaction, P = 0.514, ηp2=0.009 , 95% CI =(0, 0.084)]. Experiment 2: slower extinction in abstinent alcohol-dependent participants compared with light drinkers [extinction block × drinking status interaction, P = 0.023, ηp2=0.031 , 95% CI = 0, 0.069)] but no significant difference on contextual control of extinction [recovery block × drinking status interaction, P = 0.069, ηp2=0.033 , 95% CI = (0, 0.125)]. Abstinent alcohol-dependent people may have slower extinction learning for alcohol-related cues than non-dependent light drinkers.


[Pseudomigraine with transient neurological deficits and cerebrospinal fluid lymphocytosis].
Pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis is a rare syndrome resolving within less than 3 months. A young 17-year-old woman without previous medical history was admitted to the hospital because of right motor weakness and language disturbances. The symptoms resolved in a few hours and were followed by severe left headaches with important vegetative signs. Several similar episodes were noted in the previous 10 days. Cranial MRI was normal. EEG showed important slowing of the cerebral electrogenesis. More than 250 lymphocytic cells were found at CSF analysis. Outcome was spontaneously favorable, without similar symptoms after 6-month follow-up. Pseudomigraine with lymphocytic pleocytosis seems to be a particular syndrome of unknown origin. This is an elimination diagnosis, generally with a benign course.


Cimetidine in treatment of reflux oesophagitis with peptic stricture.
Twenty patients with reflux oesophagitis causing a tight peptic oesophageal stricture entered a randomised double-blind crossover trial in which they received cimetidine, 1.6 g daily, and matching placebo each for six months. The gross endoscopic appearances of oesophagitis, though not the grades of histopathological changes, showed significant improvement during treatment with cimetidine. The need for dilatation of the strictures, however, was not reduced.


Continuous feeding of antimicrobial growth promoters to commercial swine during the growing/finishing phase does not modify faecal community erythromycin resistance or community structure.
To investigate the effect of continuous feeding of antimicrobial growth promoters (tylosin or virginiamycin) on the swine faecal community. The study consisted of two separate on-farm feeding trials. Swine were fed rations containing tylosin (44 or 88 mg kg(-1) of feed) or virginiamycin (11 or 22 mg kg(-1) of feed) continuously over the growing/finishing phases. The temporal impact of continuous antimicrobial feeding on the faecal community was assessed and compared to nondosed control animals through anaerobic cultivation, the analysis of community 16S rRNA gene libraries and faecal volatile fatty acid content. Feeding either antimicrobial had no detectable effect on the faecal community. Erythromycin methylase genes encoding resistance to the macrolide-lincosamide-streptogramin B (MLS(B) ) antimicrobials are present at a high level within the faecal community of intensively raised swine. Continuous antimicrobial feeding over the entire growing/finishing phase had no effect on community erm-methylase gene copy numbers or faecal community structure. Antimicrobial growth promoters are believed to function by altering gut bacterial communities. However, widespread MLS(B) resistance within the faecal community of intensively raised swine likely negates any potential effects that these antimicrobials might have on altering the faecal community. These findings suggest that if AGP-mediated alterations to gut communities are an important mechanism for growth promotion, it is unlikely that these would be associated with the colonic community.


Growth of soil bacteria, on penicillin and neomycin, not previously exposed to these antibiotics.
There is growing evidence that bacteria, in the natural environment (e.g. the soil), can exhibit naturally occurring resistance/degradation against synthetic antibiotics. Our aim was to assess whether soils, not previously exposed to synthetic antibiotics, contained bacterial strains that were not only antibiotic resistant, but could actually utilize the antibiotics for energy and nutrients. We isolated 19 bacteria from four diverse soils that had the capability of growing on penicillin and neomycin as sole carbon sources up to concentrations of 1000 mg L(-1). The 19 bacterial isolates represent a diverse set of species in the phyla Proteobacteria (84%) and Bacteroidetes (16%). Nine antibiotic resistant genes were detected in the four soils but some of these genes (i.e. tetM, ermB, and sulI) were not detected in the soil isolates indicating the presence of unculturable antibiotic resistant bacteria. Most isolates that could subsist on penicillin or neomycin as sole carbon sources were also resistant to the presence of these two antibiotics and six other antibiotics at concentrations of either 20 or 1000 mg L(-1). The potentially large and diverse pool of antibiotic resistant and degradation genes implies ecological and health impacts yet to be explored and fully understood.


Uterine leiomyoblastoma (epithelioid leiomyoma) neoplasm of low-grade malignancy. A histopathologic study.
Uterine leiomyoblastomas are neoplasms of smooth muscle origin, which despite their benign histopathologic characteristics, have been shown to invade locally, metastasize, and recur, resulting in the patient's death. In an effort to define possible cellular changes that could explain the disparity between histopathologic features and biologic behavior, we have studied a series of three uterine leiomyoblastomas that, in routine sections, exhibited benign morphological characteristics. A detailed histopathologic study revealed, in all three cases, randomly distributed clusters of neoplastic cells with overt malignant features, such as cellular and nuclear atypia, abnormal mitoses, local infiltrating tendencies, and vascular invasion. These findings suggest that uterine leiomyoblastomas should be viewed as neoplasms of low-grade malignancy of a distinct clinicopathologic entity.


The synthesis of enantiomerically pure 4-substituted [2.2]paracyclophane derivatives by sulfoxide-metal exchange.
A general strategy for the synthesis of enantiomerically pure 4-substituted [2.2]paracyclophanes from a common sulfoxide precursor is described.


Changes in gut microbiome correlate with intestinal barrier dysfunction and inflammation following a 3-day ethanol exposure in aged mice.
Alcohol use among older adults is on the rise. This increase is clinically relevant as older adults are at risk for increased morbidity and mortality from many alcohol-related chronic diseases compared to younger patients. However, little is known regarding the synergistic effects of alcohol and age. There are intriguing data suggesting that aging may lead to impaired intestinal barrier integrity and dysbiosis of the intestinal microbiome, which could increase susceptibility to alcohol's negative effects. To study the effects of alcohol in age we exposed aged and young mice to 3 days of moderate ethanol and evaluated changes in gut parameters. We found that these levels of drinking do not have obvious effects in young mice but cause significant alcohol-induced gut barrier dysfunction and expression of the pro-inflammatory cytokine TNFα in aged mice. Ethanol-induced downregulation of expression of the gut-protective antimicrobial peptides Defa-rs1, Reg3b, and Reg3g was observed in aged, but not young mice. Analysis of the fecal microbiome revealed age-associated shifts in microbial taxa, which correlated with intestinal and hepatic inflammatory gene expression. Taken together, these data demonstrate that age drives microbiome dysbiosis, while ethanol exposure in aged mice induces changes in the expression of antimicrobial genes important for separating these potentially damaging microbes from the intestinal lumen. These changes highlight potential mechanistic targets for prevention of the age-related exacerbation of effects of ethanol on the gut.


Responses of isolated feline and human cerebral arteries to prostacyclin and some of its metabolites.
The effects of prostacyclin (PGI2) were studied in isolated cat basilar and middle cerebral arteries and in human pial arteries. In feline vessels with low resting tension, PGI2 had a contractile effect that reached a maximum of 132% (basilar artery) and 23% (middle cerebral artery) of the potassium-induced (127 mM) contraction. In potassium-contracted feline vessels, PGI2 caused a further contraction. When these vessels were contracted by PGF2 alpha, PGI2 induced relaxation, which was most marked in the middle cerebral artery. PGI2 consistently relaxed the middle cerebral artery contracted by the prostaglandin endoperoxide analogue U-44069, whereas the basilar artery was almost unaffected. In human pial arteries with low resting tension, PGI2 had no effects in concentrations below 10(-6) M, whereas higher concentrations induced contractions. In potassium-contracted (35 or 127 mM) preparations, PGI2 in concentrations below 10(-6) M produced relaxation; in higher concentrations further contraction was induced. Human pial arteries contracted by PGF2 alpha, U-44069, noradrenaline, or 5-hydroxytryptamine consistently relaxed in response to PGI2 (less than 10(-6) M). The PGI2 metabolite 6-keto-PGE1 had effects similar to those of PGI2, but proved to be less potent on human pial vessels. 6-Keto-PGF1 alpha was ineffective, whereas 6,15-diketo-PGF1 alpha had minor relaxant effects. The results suggest that consideration must be given to regional as well as species differences concerning the cerebrovascular effects of PGI2.


Development of a Carrier Free Dry Powder Inhalation Formulation of Ketotifen for Pulmonary Drug Delivery.
Pulmonary drug delivery route is gaining much attention because it enables to target the active ingredients directly to lung both for local and systemic treatments, which maximize the therapeutic effect and minimize unwanted systemic toxicity. Dry powder inhaler (DPI) systems for asthma therapy have shown several merits to the other pulmonary delivery systems such as nebulizers and metered dose inhalers. The present study aims to develop and optimize a DPI formulation for Ketotifen fumarate through spray drying technique. Particles size and morphology, crystallinity, and drug-excipient interaction of fabricated DPI formulations were evaluated by scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier Transform Infrared Spectroscopy methods, respectively. The aerosolization indexes and aerodynamic properties of dry powders were determined by next generation impactor. The powder flowability was assessed by measuring the Hausner ratio and compressibility index. Among solvent systems, ethanol-water mixture produced the most desirable powder property for inhalation after spray drying. Although co-spray dried formulations with ammonium bicarbonate resulted in the porous structure, it was not beneficial for DPI formulations due to the interaction with Ketotifen. DSC and XRD experiments proved the amorphous structure of prepared powders, which were stable for 12 months. The results of this study demonstrate the potential of Ketotifen DPI formulation and pave a way to use it easily in an industrial scale.


Race, Age, Gender, and Insurance Status: A Comparative Analysis of Access to and Quality of Gastrointestinal Cancer Care.
Socioeconomics, demographics, and insurance status play roles in healthcare access. Considering the limited resources available, understanding the relative impact of disparities helps prioritize programs designed to overcome them. This study evaluates gastrointestinal cancer care disparity by comparing the impact of different patient factors across oncologic care metrices. A multi-institutional prospectively maintained cancer database was reviewed retrospectively for gastrointestinal cancers (esophagus, stomach, liver, pancreas, colorectal, and hepato-pancreato-biliary) from 2007 to 2017 to assess quality of care provided. Quality of care was defined by clinical course following national guidelines for the respective cancer. This included surgical intervention, chemotherapy, palliative care, and minimal delay to treatment/diagnosis. Logistic regression was used to adjust for confounders and identify factors associated with quality of care. Kaplan-Meier survival curves were compared using log-rank test. One thousand seventy-two patients were identified. Survival improved in patients with private insurance compared to government-funded options [median overall survival (mOS) 57.8 vs. 21.2 months; P < .001]. Private insurance also correlated with earlier stage at diagnosis [stages I-II = 50.9% vs. 37.5%, stages III-IV = 37.7% vs. 49.1%, P < .001], increased chemotherapy use [44.2% vs. 37.1%, P < .001], and more surgical intervention [62.4% vs. 48.8%, P < .001]. Outcomes were inferior for Black Americans, including trend towards lower rate of surgical treatment [42% vs. 54%, P = .058] and worse survival in private insurance carriers [mOS 7.8 vs. 57.8 months, P = .021] and those with early stage disease [mOS 39.2 vs. 81.5 months, P = .045] compared to White counterparts. Insurance status has the strongest impact on the quality of gastrointestinal oncologic care with negative synergistic negative effect of race for Black Americans. While governmental programs aim to improve equality of care, there remains significant disparity compared to private insurance. Moreover, private insurance doesn't correct disparity for Black Americans, suggesting the need to address racial imbalances in cancer care.


Characteristics of macrofaunal assemblages and their relationships with environmental factors in a semi-enclosed bay.
Characteristics of macrofaunal assemblages and their relationships with environmental factors in a semi-enclosed bay were studied seasonally in China. A total of 251 species were identified, including polychaetes (104 species), crustaceans (73 species), mollusks (51 species), and other phyla (23 species). Mean values of macrofaunal abundance were 1210, 2483, 3209, 3600 ind./m2 while those of biomass were 56.88, 176.15, 136.28, 265.55 g/m2, respectively. Ranges of species richness index, evenness index, Shannon-Wiener index were 1.54-8.16, 0.17-0.90, 0.69-4.78, respectively. The diversity indices were affected by bottom water salinity and pH. BIOENV analysis showed that water depth, phaeophorbide, and silt-clay proportion had important impacts on macrofaunal assemblages while abundance and biomass were affected by bottom water temperature, salinity, and water depth. Compared with historical data, macrofaunal species number, abundance and biomass showed a slight increasing trend, which may be due to the water quality improvement of this bay.


Uropathogenic Escherichia coli pathogenicity islands and other ExPEC virulence genes may contribute to the genome variability of enteroinvasive E. coli.
Enteroinvasive Escherichia coli (EIEC) may be the causative agent of part of those million cases of diarrhea illness reported worldwide every year and attributable to Shigella. That is because both enteropathogens have many common characteristics that difficult their identification either by traditional microbiological methods or by molecular tools used in the clinical laboratory settings. While Shigella has been extensively studied, EIEC remains barely characterized at the molecular level. Recent EIEC important outbreaks, apparently generating more life-threatening cases, have prompted us to screen EIEC for virulence traits usually related to extraintestinal pathogenic E. coli (ExPEC). That could explain the appearance of EIEC strains presenting higher virulence potential. EIEC strains were distributed mainly in three phylogroups in a serogroup-dependent manner. Serogroups O124, O136, O144, and O152 were exclusively classified in phylogroup A; O143 in group E; and O28ac and O29 in group B1. Only two serogroups showed diverse phylogenetic origin as follows: O164 was assigned to groups A, B1, C, and B2 (one strain each), and O167 in groups E (five strains), and A (one strain) (Table 1). Eleven of 20 virulence genes (VGs) searched were detected, and the majority of the 19 different VGs combinations found were serogroup-specific. Uropathogenic E. coli (UPEC) PAI genetic markers were detected in all EIEC strains. PAIs IJ96 and IICFT073 were the most frequent (92.1 and 80.4%, respectively). PAI IV536 was restricted to some serogroups from phylogroups A, B1 and E. PAI ICFT073 was uniquely detected in phylogroups B2 and E. A total of 45 (88%) strains presented multiple PAI markers (two to four). PAIs IJ96 and IICFT073 were found together in 80% of strains. EIEC is a DEC pathovar that presents VGs and pathogenicity island genetic markers typically associated with ExPEC, especially UPEC. These features are distributed in a phylogenetic and serogroup-dependent manner suggesting the existence of stable EIEC subclones. The presence of phylogroups B2 and E strains allied to the presence of UPEC virulence-associated genes may underscore the ongoing evolution of EIEC towards a hypervirulent pathotype.


The Number of MRGPRX2-Expressing Cells Is Increased in Skin Lesions of Patients With Indolent Systemic Mastocytosis, But Is Not Linked to Symptom Severity.
Recently, the expression of the mast cell (MC) receptor Mas-related G protein-coupled receptor X2 (MRGPRX2) has been detected in lesional skin of adult patients with cutaneous mastocytosis. As of yet, little is known about the clinical relevance of MRGPRX2 and its agonists in patients with mastocytosis, including indolent systemic mastocytosis (ISM). MRGPRX2 and MRGPRX2 agonists, cortistatin (CST), and major basic protein (MBP) were analyzed in lesional and non-lesional skin of patients with ISM and skin of healthy controls by immunohistochemistry. Co-localization of MRGPRX2 and MRGPRX2-mRNA with the MC marker tryptase was assessed by immunofluorescence microscopy and in situ hybridization, respectively. We assessed clinical, demographic, and laboratory data, including mastocytosis activity score (MAS), serum tryptase, and KIT D816V allele burden. The number of MRGPRX2-expressing (MRGPRX2+) cells, MRGPRX2-mRNA+ MCs, and CST-expressing (CST+) and MBP-expressing (MBP+) cells was significantly higher in lesional skin as compared to non-lesional skin and/or skin of healthy controls (all p < 0.05). Increased numbers of MRGPRX2+ cells, MRGPRX2-mRNA+ MCs, and CST+ and MBP+ cells were not associated with clinical and laboratory features of ISM, including disease burden, symptom severity, evidence of anaphylaxis, and tryptase levels. Skin lesions of patients with ISM showed high numbers of MRGPRX2+ cells, although they were not linked to symptom severity. Clinical relevance of the MRGPRX2-mediated pathway of MC activation in ISM remains unclear and should be investigated in further studies.


Thienochromene derivatives inhibit pSTAT1 and pSTAT5 signaling induced by cytokines.
Furanocoumarins, particularly furo[3,2-c]coumarins, are found in many natural products. However, coumarins annulated to a thiophene ring have received scarce attention to date in the literature. Therefore, we synthesized 4-oxo-4H-thieno[3,2-c]chromene derivatives and tested in vitro their anti-inflammatory activity. Anti-inflammatory potential of the synthesized compounds (1, 2, 6-8, 9a-e and 10a-c) has been evaluated by measuring various pSTAT (signal transducer and activator of transcription) inhibition within the JAK (Janus-activated family kinase)/STAT signaling pathway. Ethyl 7-hydroxy-4-oxo-4H-thieno[3,2-c]chromene-2-carboxylate (7) showed best inhibition properties on pSTAT5 in GM-CSF (Granulocyte-macrophage colony-stimulating factor)-triggered PBMC assay, with IC50 value of 5.0 µM.


Association of CYP2E1, GST and mEH genetic polymorphisms with urinary acrylamide metabolites in workers exposed to acrylamide.
This study elucidates the association of acrylamide metabolites, N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA), N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-cysteine (GAMA2), and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-cysteine (GAMA3) in urine with genetic polymorphisms of the metabolic enzymes cytochrome P450 2E1 (CYP2E1), microsomal epoxide hydrolase (mEH) in exon 3 and exon 4, glutathione transferase theta (GSTT1) and mu (GSTM1), involved in the activation and detoxification of acrylamide (AA) in humans. Eighty-five workers were recruited, including 51 AA-exposed workers and 34 administrative staffs serve as controls. Personal air sampling was performed for the exposed workers. Each subject provided pre- and post-shift urine samples and blood samples. Urinary AAMA, GAMA2 and GAMA3 levels were simultaneously quantified using liquid chromatography-electronspray ionization/tandem mass spectrometry (LC-ESI-MS/MS). CYP2E1, mEH (in exon 3 and exon 4), GSTT1, and GSTM1 were analyzed using polymerase chain reaction (PCR). Our results reveal that AA personal exposures ranged from 4.37 × 10⁻³ to 113.61 μg/m³ with a mean at 15.36 μg/m³. The AAMA, GAMA2, and GAMA3 levels in the exposed group significantly exceeded those in controls. The GAMAs (the sum of GAMA2 and GAMA3)/AAMA ratios, potentially reflecting the proportion of AA metabolized to glycidamide (GA), varied from 0.003 to 0.456, and indicate high inter-individual variability in the metabolism of AA to GA in this study population. Multivariate regression analysis demonstrates that GSTM1 genotypes significantly modify the excretion of urinary AAMA and the GAMAs/AAMA ratio, exon 4 of mEH was significantly associated with the urinary GAMAs levels after adjustment for AA exposures. These results suggest that mEH and/or GSTM1 may be associated with the formation of urinary AAMA and GAMAs. Further study may be needed to shed light on the role of both enzymes in AA metabolism.


Action spectrum for lethality of near-UV light on Haemophilus influenzae and lack of mutation.
Mutation and inactivation of H. influenzae have been measured following irradiation at various near-UV wavelengths. Inactivation takes place most readily at 334 nm (but is unaffected by absence of excision or postreplication repair), and decreases markedly at longer wavelengths. No induced mutations to resistance to novobiocin or streptomycin or to ability to utilize protoporphyrin instead of hemin were detected at any of the wavelengths used. There were also no detectable induced mutations in an excision-defective strain after 334-nm irradiation. These results are in contrast to the in vitro mutation of purified transforming DNA we previously observed.


Assessment of the risk of bleeding from esophageal varices by continuous monitoring of portal pressure.
Portal pressure was monitored by means of an indwelling hepatic vein balloon catheter in patients with alcoholic cirrhosis and bleeding varices to determine the safety and feasibility of the technique and its value in predicting recurrence of bleeding. Forty patients were enrolled. Central venous access could not be achieved in 4 patients (10%). Hepatic vein catheterization was accomplished in the remaining 36 patients. Fourteen patients were either later found to have nonalcoholic liver disease or had already received treatment that excluded them from the protocol. The remaining 22 patients, who were treated with blood and fluid replacement, were monitored for up to 72 hours. Portal pressure was greater than 11 mm Hg in all patients (normal, less than 5 mm Hg) and did not change significantly over the 3 days of study. Portal pressure was significantly higher in the 9 patients who continued to bleed or rebled compared with the 13 patients who remained stable. The lowest pressure associated with continued bleeding or rebleeding was 16 mm Hg. Continuous monitoring of portal pressure in patients with bleeding esophageal varices due to alcoholic cirrhosis is safe and feasible and permits rapid stratification of the risk of continued bleeding or early rebleeding.


Natural alkaloid 8-oxo-epiberberine inhibited TGF-β1-triggred epithelial-mesenchymal transition by interfering Smad3.
Epithelial-mesenchymal transition (EMT), the transition of epithelial cells into mesenchymal cells, plays important roles in the metastasis of solid tumors. 8-Oxo-epiberberine (OPB) is a natural alkaloid extracted from the roots of Coptis chinensis Franch. In this study, The effect and the underlying mechanism of OPB on EMT in a TGF-β1-induced model and the inhibitory effect of OPB on lung metastasis were investigated. TGF-β1-stimulated lung cancer cells were co-treated with OPB, the morphological changes were examined. The protein expression of EMT biomarkers E-cadherin and N-cadherin was determined by Western blotting and immunofluorescence. The transcription activity of smad2/3 promoter was analyzed by a luciferase reporter assay. The effect of OPB on cell migration, invasion, and adhesion was detected by wound-healing, adhesion, and transwell assays. The in vivo anti-metastatic effect of OPB was evaluated using a 4 T1 cell xenograft mouse model. Results showed that OPB significantly reversed TGF-β1-triggered morphological changes, expression of EMT biomarkers, and migration, adhesion, and invasion. Furthermore, OPB suppressed TGF-β1-induced Smad2/3 activation, Smad3 phosphorylation and nuclear translocation, and interaction of Smad3 with Smad4. Besides, OPB dramatically decreased the metastatic nodules in the lung without affecting the growth of primary tumors. In conclusion, OPB inhibited TGF-β1-induced EMT possibly by interfering with Smad3. OPB might have therapeutic potentials for the treatment of metastatic cancers.


Radioimmunoassay of procollagen in serum of patients with Paget's disease of bone.
A new radioimmunoassay for human procollagen showed that the sera of 46 of 50 untreated patients with Paget's disease of bone contained increased concentrations of procollagen protein as compared to normal adults. After therapy with disodium etidronate, all the elevated serum procollagen concentrations decreased significantly, falling to normal levels in 33 of 40 patients. The procollagen levels before and after treatment were coordinate with the values for urinary total hydroxyproline and serum alkaline phosphatase activity. The data show that the radioimmunoassay for procollagen is a dependable and useful adjunct to the study of Paget's disease of bone.


Graphene oxide@Ce-doped TiO2 nanoparticles as electrocatalyst materials for voltammetric detection of hazardous methyl parathion.
A sensitive voltammetric sensor has been developed for hazardous methyl parathion detection (MP) using graphene oxide@Ce-doped TiO2 nanoparticle (GO@Ce-doped TiO2 NP) electrocatalyst. The GO@Ce-doped TiO2 NPs were prepared through the sol-gel method and characterized by various physicochemical and electrochemical techniques. The GO@Ce-doped TiO2 NP-modified glassy carbon electrode (GCE) addresses excellent electrocatalytic activity towards MP detection for environmental safety and protection. The developed strategy of GO@Ce-doped TiO2 NPs at GCE surfaces for MP detection achieved excellent sensitivity (2.359 μA μM-1 cm-2) and a low detection limit (LOD) 0.0016 μM with a wide linear range (0.002 to 48.327 μM). Moreover, the fabricated sensor shows high selectivity and long-term stability towards MP detection; this significant electrode further paves the way for real-time monitoring of environmental quantitative samples with satisfying recoveries.


Interhospital Sepsis Code in Catalonia (Spain): Territorial model for initial care of patients with sepsis.
Sepsis is a syndromic entity with high prevalence and mortality. The management of sepsis is standardized and exhibits time-dependent efficiency. However, the management of patients with sepsis is complex. The heterogeneity of the forms of presentation can make it difficult to detect and manage such cases, in the same way as differences in training, professional competences or the availability of health resources. The Advisory Commission for Patient Care with Sepsis (CAAPAS), comprising 7 scientific societies, the Emergency Medical System (SEM) and the Catalan Health Service (CatSalut), have developed the Interhospital Sepsis Code (CSI) in Catalonia (Spain). The general objective of the CSI is to increase awareness, promote early detection and facilitate initial care and interhospital coordination to attend septic patients in a homogeneous manner throughout Catalonia.


Pulmonary Alveolar Microlithiasis: A Unique Case of Familial PAM Complicated by Transplant Rejection.
Pulmonary alveolar microlithiasis (PAM) is a rare lung disease characterized by the deposition of calcium phosphate microliths or calcospherites, within the alveolar airspace. Typical imaging findings demonstrate a "sandstorm" appearance due to bilateral, interstitial sand-like micronodularities with basal predominance. We describe an unusual case of a 48-year-old male with severe, familial PAM ultimately treated with a bilateral lung transplant. PAM is a rare lung disease caused by a mutation in the SLC34A2 gene, which encodes for a sodium-phosphate cotransporter in type II alveolar cells, leading to accumulation of intra-alveolar phosphate causing microlith formation. PAM has an indolent course but can progress to chronic hypoxic respiratory failure, ultimately requiring lung transplant, the only known effective treatment.


QRFP in female rats: effects on high fat food intake and hypothalamic gene expression across the estrous cycle.
Pyroglutamylated arginine-phenylalanineamide peptide (QRFP) is a neuropeptide involved in feeding behavior. Central administration of QRFP selectively increases the intake of a high fat diet in male rats. QRFP administration also stimulates the hypothalamic-pituitary-gonadal axis via gonadotrophin-releasing hormone in male and female rats. Prepro-QRFP mRNA is expressed in localized regions of the mediobasal hypothalamus which are abundant in neurotransmitters, neuropeptides and receptor systems important for food intake regulation and reproductive behaviors. The current experiments were conducted to investigate the effects of centrally administered QRFP-26 on the intake of a high fat diet (HFD, 60%kcal from fat) in female rats and to investigate alterations in hypothalamic prepro-QRFP and its receptors, GPR130a and GPR103b, mRNA levels over the estrous cycle. In Experiment 1, female rats were administered QRFP-26 (intracerebroventricular; 0.3nmol, 0.5nmol, 1.0nmol) in rats consuming either a HFD or a low fat diet. All doses of QRFP-26 selectively increased the intake of the HFD in female rats. These data suggest that QRFP-26 regulates the intake of energy dense foods in female rats, which is similar to previous findings in male rats. In Experiment 2, hypothalamic levels of prepro-QRFP mRNA and its receptors were assessed during diestrus, proestrus, or estrus. The level of prepro-QRFP mRNA in the ventromedial/arcuate nucleus (VMH/ARC) of the hypothalamus was increased during proestrus, which suggests that endogenous estrogen levels regulate QRFP expression in the VMH/ARC. These data suggest that QRFP may play a role in coordinating feeding behaviors with reproductive function when energy demand is increased.


High-dose intravenous zidovudine with 5-fluorouracil and leucovorin. A phase I trial.
The inhibition of pyrimidine metabolism by 5-fluorouracil (5-FU) enhances the anti-cancer effects of zidovudine (formerly called AZT) in in vitro and in vivo model systems without additive toxicity. Zidovudine-induced DNA damage correlates with cytotoxicity. A Phase I trial of high-dose continuous-infusion intravenous zidovudine therapy in combination with 5-FU and leucovorin therapy was performed. Eighteen patients with advanced malignant tumors were treated with 43 courses of oral leucovorin (50 mg every 4 hours); continuous-infusion 5-FU (800 mg/M2/day) for 72 hours (3 days); and zidovudine, begun 24 hours after the start of 5-FU and leucovorin, for 48 hours, and terminating with the end of the 5-FU infusion. Zidovudine plasma levels and zidovudine-induced DNA damage were assessed. Zidovudine administered in doses of 2-20 g/M2/day, added no obvious toxicity to the basic chemotherapeutic treatment with 5-FU and leucovorin but resulted in a dose-dependent biologic effect manifested by an increase in DNA strand breaks in peripheral blood cells. At doses greater than 15 g/M2/day, altered plasma kinetics of zidovudine were observed; plasma zidovudine levels increased dramatically in relation to the dose of zidovudine. Limitations in drug administration restricted administration of higher intravenous doses without achieving a maximally tolerated dose. No responses were seen in this heavily pretreated population. Based on the results of preclinical studies, plasma zidovudine levels greater than those achieved at the maximal dose (133 microns) are required for increased anti-cancer activity with 5-FU. Additional studies using a bolus or rapid infusion as a method of achieving higher peak levels are indicated.


Master manipulator optimisation for robot assisted minimally invasive surgery.
In robot-assisted minimally invasive surgery, the surgeon controls a robot by operating a pair of master manipulators. Thus, the performance of a master manipulator directly affects the work of the surgeon physiologically and psychologically. In order to improve the operability and quality of operation, a structure optimisation method of master manipulator is proposed. The optimisation index of workspace and dexterity of main manipulator based on ergonomics and kinematics is established, and the reasonable weight coefficient of optimisation index is determined by using combination weighting method. Experiments verified that the proposed optimisation method ensures a large workspace and good kinematic performance for the master manipulator. This improves the comfort of the surgeon and can effectively avoid the problem of cutting off master-slave communication to adjust the position of the master manipulator owing to the small workspace.


Features of the Generalized Dynamics of Quasiparticles in Graphene.
The general dynamic properties of the electron, as quasiparticle in conduction band of graphene, were analyzed. It is shown that in graphene, these properties essentially differ from similar base properties for crystals with a simple lattice, despite insignificant, on the first sight, difference of dispersion law ε(p). Primarily, crystals with an elementary cell of arbitrary complexity of structure were considered. The obtained general relations were applied further to graphene. Herewith two-dimensional lattice of graphene has been considered as consisting of elementary cells with two atoms. Typically, graphene is considered as crystals consisting of two simple nested sublattices. It has been shown that both considerations lead to the analogous basic results. On the basis of obtained wave Hamiltonian, all the dynamic characteristics of the injected electron, considered as a quasiparticle, were found: speed, tensor of effective dynamic mass, and wave Lagrangian. Also, for some physically actual situations, the dynamic characteristics of an alternative description have been found: a mechanical momentum p m , mechanical Hamiltonian, and mechanical Lagrangian. For these situations, a generalized Louis de Broglie relationship between mechanical p m and wave p momenta was found also.


Relation of recurrence of atrial fibrillation after non-ST-elevation acute myocardial infarction to left atrial abnormality.
Atrial fibrillation (AF) is common during the course of acute myocardial infarction and is associated with left atrial (LA) dilatation. However, the role of LA depolarization abnormality on the electrocardiogram (ECG) in the setting of LA dilatation was not studied in this context. Patients admitted with non-ST-segment elevation myocardial infarction (NSTEMI) who developed new-onset AF (International Classification of Diseases, Ninth Revision code 427.31) were prospectively identified. Baseline ECGs and echocardiograms before the admission event were reviewed. Follow-up was directed toward pertinent cardiovascular events, atrial tachyarrhythmias, and death as end points. Of 101 patients with NSTEMI who had new-onset AF, 88 had current echocardiograms and 69 had LA dilatation (78%). Total follow-up was 24 months (mean 21.4). Prolonged P-wave duration (> or =110 ms) and decreased left ventricular fractional shortening were most significant in those with LA dilatation and were independently associated with AF. In those with LA dilatation, the prevalence of such abnormal atrial depolarization on ECGs was 56%. AF (43% vs 15%; p = 0.03) and heart failure (63% vs 35%; p = 0.03) occurred more often in this subset, but there was no difference in mortality. However, the overall prevalence of late cardiovascular complications in this subset was higher (71% vs 45%; p = 0.02) compared with that of immediate complications (20% vs 26%; p = 0.60). In conclusion, there is higher recurrence of AF in patients with NSTEMI who have a combination of electrocardiographic and echocardiographic LA abnormalities compared with those without.


Antibiotics and phagocytosis.
The influence of beta-lactam antibiotics, tetracyclines, aminoglycosides, erythromycin and clindamycin on the phagocytosis process is reviewed. The results of the studies published are summarized in tabular form.


Activation and discovery of tsukubarubicin from Streptomyces tsukubaensis through overexpressing SARPs.
Genome sequencing has revealed that each Streptomyces contains a wide range of biosynthetic gene clusters (BGCs) and has the capability to produce more novel natural products than what is expected. However, most gene clusters for secondary metabolite biosynthesis are cryptic under normal growth conditions. In Streptomyces tsukubaensis, combining overexpression of the putative SARPs (Streptomyces antibiotic regulatory proteins) and bioactivity-guided screening, the silent gene cluster (tsu) was successfully activated and a novel bioactive anthracycline tsukubarubicin was further isolated and identified. Biological activity assays demonstrated that tsukubarubicin possessed much better antitumor bioactivities against various human cancer cell lines (especially the breast cancer cell lines) than clinically used doxorubicin. Moreover, the previously unreported gene cluster (tsu) for biosynthesis of tsukubarubicin was first characterized and detailed annotations of this gene cluster were also conducted. Our strategy presented in this work is broadly applicable in other Streptomyces and will assist in enriching the natural products for potential drug leads. KEY POINTS: • Generally scalable strategy to activate silent gene clusters by manipulating SARPs. • The novel anthracycline tsukubarubicin with potent antitumor bioactivities. • Identification and annotation of the previously uncharacterized tsu gene cluster.


FRET-based glucose imaging identifies glucose signalling in response to biotic and abiotic stresses in rice roots.
Glucose is the primary energy provider and the most important sugar-signalling molecule, regulating metabolites and modulating gene expression from unicellular yeast to multicellular plants and animals. Therefore, monitoring intracellular glucose levels temporally and spatially in living cells is an essential step for decoding the glucose signalling in response to biotic and abiotic stresses. In this study, the genetically encoded FRET (Förster resonance energy transfer) nanosensors, FLIPglu-2μ∆13 and FLIPglu-600μΔ13, were used to measure cytosolic glucose dynamics in rice plants. First, we found that the FRET signal decreased in response to external glucose in a concentration-dependent manner. The glucose concentration at which the cytosolic level corresponded to the K0.5 value for FLIPglu-2μΔ13 was approximately 10.05μM, and that for FLIPglu-600μΔ13 was 0.9mM, respectively. The substrate selectivity of nanosensors for glucose and its analogues is D-Glucose>2-deoxyglucose>3-O-methylglucose>L-Glucose. We further showed that the biotic elicitors (flg22 and chitin) and the abiotic elicitors (osmotic stress, salinity and extreme temperature) induce the intracellular glucose increases in the detached root segments of transgenic rice containing FLIPglu-2μΔ13 in a stimulus-specific manner, but not in FLIPglu-600μΔ13 transgenic lines. These results demonstrated that FRET nanosensors can be used to detect increases in intracellular glucose within the physiological range of 0.2-20μM in response to various stimuli in transgenic rice root cells, which indicated that intracellular glucose may act as a potential secondary messenger to connect extracellular stimuli with cellular physiological responses in plants.


Intelligent computational techniques in marine oil spill management: A critical review.
Effective marine oil spill management (MOSM) is crucial to minimize the catastrophic impacts of oil spills. MOSM is a complex system affected by various factors, such as characteristics of spilled oil and environmental conditions. Oil spill detection, characterization, and monitoring; risk evaluation; response selection and process optimization; and waste management are the key components of MOSM demanding timely decision-making. Applying robust computational techniques based on real-time data (e.g., satellite and aerial observations) and historical records of oil spill incidents may considerably facilitate decision-making processes. Various soft-computing and artificial intelligence-based models and mathematical techniques have been used for the implementation of MOSM's components. This study presents a review of literature published since 2010 on the application of computational techniques in MOSM. A statistical evaluation is performed concerning the temporal distribution of papers, publishers' engagement, research subfields, countries of studies, and selected case studies. Key findings reported in the literature are summarized for two main practices in MOSM: spill detection, characterization, and monitoring; and spill management and response optimization. Potential gaps in applying computational techniques in MOSM have been identified, and a holistic computational-based framework has been suggested for effective MOSM.


Antiviral activity of lambda-carrageenan prepared from red seaweed (Gigartina skottsbergii) against BoHV-1 and SuHV-1.
The antiviral effect of polysaccharides has been known for many years. Carrageenans are considered a good alternative for the prevention of a wide range of diseases, mainly caused by enveloped viruses. The advantages lie on their high availability, low cost and low induction of resistance. The aim of this study was to evaluate the sensitivity of two viral pathogens of veterinary interest to the presence of lambda-carrageenan. This is the first report of a lambda-carrageenan having antiviral activity against animal viruses belonging to the Alphaherpesvirinae subfamily, BoHV-1 (bovine herpesvirus type 1) strain Cooper and SuHV-1 (suid herpesvirus type 1) strain Bartha. Lambda-carrageenan was able to reduce infectivity of both viruses with a more pronounced effect against BoHV-1. These results proved, as previously shown for human herpes virus type 1, that these compounds could be used as potential antiviral agents in the veterinary field.


Concurrent vinblastine and radiation therapy in bladder cancer.
Since mid-1987, 29 patients with invasive transitional cell carcinoma of the urinary bladder (T1-3 N0-X M0) were treated with concurrent radiation therapy (RT) (target dose [TD], 62-66 Gy) 1.8-2.0 Gy/day for 5 days a week with a break in the middle of treatment of 2-3 weeks and vinblastine weekly 2 mg/5-12 h intravenous infusion. Patients were divided into two groups: those had only the initial therapy (Group 1) and those who had both courses of RT combined with vinblastine (Group 2). Patients eligible for cystectomy were selected for full-dose RT, according to the results of treatment with a TD of 36 Gy. Tolerable toxicity rates were noted. No patient was excluded from the study. The authors report a clinical complete remission rate of 71% at early evaluation of treatment and a 3-year local progression-free survival of 66% (for Group 2 patients). These results are comparable to those obtained with more aggressive chemoradiation therapy regimens. The authors also noted improved local disease control in patients who received combination therapy in comparison with the 17 patients treated with RT alone. The authors suggest that concurrent RT and vinblastine therapy is an attractive alternative to other chemoradiation therapy regimens, and is especially superior to RT therapy alone in caring for old patients or patients in poor general condition.


Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hyperbilirubinemia in patients receiving tocilizumab.
Tocilizumab, a monoclonal antibody to interleukin-6 receptor, was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Two patients during clinical development met laboratory, but not clinical, criteria for Hy's law with bilirubin elevations suspected as a result of genetic variation in uridine diphosphoglucose glucuronosyltransferase (UGT1A1) typical of Gilbert syndrome. Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures. UGT1A1 single nucleotide polymorphism data were extracted from a genome-wide array database for 1187 patients from tocilizumab trials, and associations of UGT1A1 genotypes with bilirubin elevations were analyzed using logistic regression for associations with baseline and change from baseline in bilirubin levels as continuous variables. Bilirubin elevations were not associated with clinical adverse events. Both patients potentially meeting Hy's law carry homozygous UGT1A1*28 alleles and UGT1A1*60 alleles. UGT1A1*28 and three additional single nucleotide polymorphisms showed odds ratios greater than 25 for associations with elevated bilirubin. The presence of rs6742078 accounted for 32% of the total variance in bilirubin (P=2.2×10). Bilirubin increases occurring with tocilizumab appear to be related to anti-inflammatory effects extending to the liver. Thus, in the absence of other signs of hepatic dysfunction, bilirubin elevations after treatment with tocilizumab have a high probability of association with UGT1A1 polymorphism, which should alleviate concerns of serious hepatotoxicity. Our results underscore the value of genotyping in the clinical trial setting to avoid misinterpretations that could lead to terminating development of a promising new agent.


LV only pacing-mediated electrical storm with cardiac resynchronization therapy managed by simultaneous biventricular pacing.
Ventricular arrhythmia (VA) is a rare complication of cardiac resynchronization therapy (CRT). Little is known about ventricular proarrhythmia related to the pacing vector of CRT. This case report describes the elimination of ventricular arrythmia using biventricular pacing in a patient with VT-storm related to LV only pacing as part of the AdaptivCRT algorithm (Medtronic Inc). Simultaneous biventricular pacing was effective in eliminating polymorphic ventricular tachycardia. Changing the pacing vector is a noninvasive treatment strategy that should be considered to manage VA due to CRT.


Tension hydrothorax: roentgenographic characteristics and pathogenetic consideration.
We have described a 24-year-old diabetic woman with rapidly developing left-sided tension hydrothorax. The pleural effusion was characterized by high contents of protein and glucose. The chest roentgenogram exhibited massive pleural effusion, prominent air bronchograms, mediastinal shift, and diaphragmatic inversion. Prompt thoracocentesis proved to be life-saving.


A Quality by Design and green LC technique for the determination of mast cell stabilizer and histamine receptor antagonist (Olopatadine HCl) in multiple formulations.
Mast cell stabilizer and histamine receptor antagonist olopatadine hydrochloride (OPT) assay method predicated on LC have been established for the analysis in multiple formulations. The current method dealt with ophthalmic solution, nasal spray, and tablet formulation products. The isocratic chromatography method was optimized and validated with a Boston green C8 column (150 × 4.6 mm, 5 μm i.d.). Sodium dihydrogen phosphate buffer (pH 3.5) with acetonitrile in the ratio of 75:25 (v/v) was used as a mobile phase at a flow rate of 1.0 mL min-1 and at the column temperature of 30°C, and the detection was done at 299 nm. The method was validated as per International Council for Harmonisation (ICH) guidelines and United States Pharmacopoeia (USP). The accuracy results ranged from 99.9 to 100.7%, % relative standard deviation (RSD) from the precision was 0.5, and correlation coefficient from the linearity experiment was > 0.999. Solution stability was established for 24 h at room temperature and refrigerator conditions, and it was found that the solutions were stable. Using quality by design-based experiment designs, critical quality attributes were studied and it was found that the method was robust. In all the forced degradation studies peak purity was passed, and no interference was found at the retention time of the active component. The method validation data demonstrated that the developed method is linear, precise, accurate, specific, robust, and stable for the determination of OPT from multiple formulations. Analytical eco-scale tool, Green Analytical Procedure Index (GAPI) tool, and the National Environmental Method Index (NEMI) were used to evaluate the greenness of the method, and the analytical eco-score of 77 for the presented method was found to be excellent.


Genetic spectrum of Kallmann syndrome: Single-center experience and systematic review.
To study phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our center and systematically review the studies analyzing multiple congenital hypogonadotropic hypogonadism (CHH) genes in KS cohorts using next-generation sequencing. Five hundred twenty-two KS probands (our center n = 78, published studies n = 444) were included in this systematic review. Molecular diagnosis was considered if the likely pathogenic/pathogenic variant in known CHH gene/s was reported in the appropriate allelic state. Varsome prediction tool (following American College of Medical Genetics standards) was used to analyze the variants. For our center, the molecular diagnosis was seen in 20.5% of probands and was seen more often with severe than partial reproductive phenotype (28.3% vs. 4%, p = .0013). Our center data adds eight novel variants. The molecular diagnosis was seen in 31% as per the systematic review and analysis. It ranged from 16.6% to 72.2% at different centers. The affected genes were FGFR1 (9.8%), ANOS1 (7.5%), PROKR2 (6.1%), CHD7 (5.4%), oligogenic (2.1%), and others <1% each (FGF8, SOX10, PROK2, SEMA3A, IL17RD, and GNRHR). FGFR1 and ANOS1 were the commonly affected genes globally, whereas PROKR2 was commonest in studies from China and CHD7 from Japan, South Korea and Poland. This systematic review highlights that the genetic yield is 31% in KS probands, with distinct regional variations. The association of severe reproductive phenotype with the higher genetic yield needs further validation.


Open repair of thoracoabdominal aortic aneurysm in the modern surgical era: contemporary outcomes in 509 patients.
Recent technologic advances in endovascular devices have led to alternative approaches to thoracoabdominal aortic aneurysm (TAAA) repair; these innovative approaches must be compared with the "gold standard" of conventional open TAAA repair. To facilitate such comparisons, we evaluated contemporary outcomes of open TAAA repair. We retrospectively reviewed and analyzed data collected prospectively between May 2006 and October 2010 regarding 509 consecutive patients who underwent TAAA repair. Standard univariate statistical comparisons were performed, as well as multivariable modeling, to identify predictors of survival. A total of 305 patients (59.9%) had degenerative aneurysms without dissection, and 204 (40.1%) had aortic dissection. There were 104 (20.4%) urgent or emergent repairs and 26 (5.1%) ruptured aneurysms. Operative adjuncts were used selectively. Of the 290 patients (57.0%) who underwent extensive repairs (Crawford extents I and II), 282 (97.2%) had cerebrospinal fluid drainage, 257 (88.6%) had left heart bypass, and 213 (73.4%) had intercostal/lumbar artery reattachment. The overall operative survival rate was 92.1% (469 of 509), and survival was better after elective repairs (93.8% [380 of 405]) than after urgent or emergent operations (85.6% [89 of 104], p = 0.005). Renal failure necessitating hemodialysis at discharge developed in 30 patients (5.9%). Permanent paraplegia occurred in 13 patients (2.6%). Actuarial survival was 79.1% ± 2.0% at 2 years. Contemporary open TAAA repair is characterized by respectable early outcomes, particularly when repair is elective. Such results should be compared with those of evolving approaches, including endovascular and hybrid repairs.


Engineering and production of laccase from Trametes versicolor in the yeast Yarrowia lipolytica.
The lcc1 gene coding for the laccase from Trametes versicolor DSM11269 was cloned into the genome of Yarrowia lipolytica using either single or multiple integration sites. The levels of the recombinant laccase activity secreted in the culture media were 0.25 and 1 U ml(-1) for single and multiple integrations, respectively. The strain with a single integration was successfully used to express variant libraries which were screened on ABTS substrate. The strain encoding the double mutant L185P/Q214K (rM4A) showed a sixfold enhancement in secreted enzyme activity. The catalytic efficiency of the purified rM-4A laccase was respectively increased 2.4- and 2.8-fold towards ABTS and 2,6-dimethoxyphenol, compared to the rWT. Culture supernatants containing either rWT or rM-4A catalyzed the almost complete decolorization of an Amaranth solution (70 nMs(-1)). Taken together, our results open new perspectives for the use of Y. lipolytica as a molecular evolution platform to engineer laccases with improved properties.


The effectiveness of topical preparations for the treatment of earwax: a systematic review.
Earwax is a common problem in both primary and secondary care. There is uncertainty as to the most effective topical treatment. To assess the evidence concerning the efficacy of topical preparations used for treating earwax. Systematic review and meta-analysis. Searching for randomised controlled trials (RCTs) of relevant studies. Classification of preparations into three groups, enabling pooling of data and meta-analysis. Of the 18 RCTs included in the review, four were judged to be of high quality. Fifteen preparations including saline and plain water were studied. Oil-based and water-based preparations were equally effective at clearing earwax without syringing (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.4 to 2.3) and facilitating successful syringing (OR = 1.0, 95% CI = 0.6 to 1.6). A non-water-, non-oil-based preparation appeared more effective than an oil-based preparation at both clearing earwax without syringing, and facilitating successful syringing. Immediate syringing after application of a preparation may be as effective as using eardrops for several days and delaying syringing. On current evidence, there is little to choose between water-based and oil-based preparations; non-water-, non-oil-based preparations appear promising at both clearing earwax and facilitating successful syringing, but further large trials are needed. Although immediate ear syringing is effective and convenient for patients, it may be less cost-effective than using eardrops and perhaps avoiding syringing. Most of the evidence regarding such a common and time-consuming problem is not of high quality.


Report and abstracts of the 4th International Workshop on Chromosome 9. Williamsburg, Virginia, USA, April 23-25, 1995.
The Fourth International Workshop on Chromosome 9 was a highly successful endeavor in terms of the growth of the map, both genetic and physical, the amount of data entered into GDB, and the continued comradeship in the sharing of data and resources that was exemplified. SIGMA remained a stable and valuable part of the chromosome 9 mapping effort. A new subsection outlining the morbid anatomy of chromosome 9 was included. Finally, specific goals were set for the community to aim for over the upcoming months. These included extending the information about the ease of use of genetic markers, and coordinating across numerous groups the meiotic breakpoint mapping of many microsatellite markers. Workshop files are available by anonymous ftp from ftp.gene.ucl.ac.uk (188.8.131.52) in the subdirectory/pub/c9workshop/1995, or by using a World Wide Web browser (such as Mosaic or Netscape) via the Chromosome 9 Home Page (at the URL http:@www.gene.ucl.ac.uk/chr9home.html).


Management of meningococcemia.
Meningococcemia causes substantial morbidity and mortality worldwide, usually in the term of fulminant disease. This paper reviews the background, pathophysiology, clinical manifestations, and treatment of this entity, along with prevention measures and public health issues to be considered. The authors present updated information on breakthroughs in the understanding of genetic predisposition to invasive disease. The status of adjunctive treatment modalities such as monoclonal antibodies and activated protein C, and progress in conjugate vaccine development and implementation are also addressed.


Stimulation of thymocytes in vitro by serum of 2-acetylaminofluorene (AAF)-treated rats.
The serum of rats obtained at various time intervals after administration of AAF was tested for its action on the 3H-thymidine incorporation into the DNA of thymocytes in vitro. In comparison with untreated or solvent-treated controls, the sera of animals in the early phase after the AAF-treatment stimulate the incorporation of the nucleotide into the thymocytes of rats, mice and hamsters. This reaction shows an unequivocal dose-response relationship. The serum activity is dialysable and relatively thermostable. Spleen lymphocytes and peritoneal cells of rats are insensitve to the AAF-serum. A possible relationship between growth-stimulating serum activities in liver regeneration and in early carcinogen action is discussed.


Vaccine strategies: selective elicitation of cellular or humoral immunity?
The discovery of immunoregulatory cytokines and the fact that they modulate the cellular and humoral arms of the immune system, generally in opposing directions raises fundamental questions concerning vaccine development. Because antibiotic-resistance infectious organisms are appearing at an increasingly rapid rate, more emphasis will need to be placed on prevention of infection/disease via immunization and less on post-infection antibiotics. To accomplish this task effectively, immune regulation should be integrated into vaccine design. Here we consider the opposing potentials of cytokine-regulated cellular and humoral immunity, and question whether the "best of both worlds' is possible or desirable.


Genetically expressed HIV-1 viral proteins attenuate nicotine-induced behavioral sensitization and alter mesocorticolimbic ERK and CREB signaling in rats.
The prevalence of tobacco smoking in HIV-1 positive individuals is 3-fold greater than that in the HIV-1 negative population; however, whether HIV-1 viral proteins and nicotine together produce molecular changes in mesolimbic structures that mediate psychomotor behavior has not been studied. This study determined whether HIV-1 viral proteins changed nicotine-induced behavioral sensitization in HIV-1 transgenic (HIV-1Tg) rats. Further, we examined cAMP response element binding protein (CREB) and extracellular regulated kinase (ERK1/2) signaling in the prefrontal cortex (PFC), nucleus accumbens (NAc) and ventral tegmental area (VTA). HIV-1Tg rats exhibited a transient decrease of activity during habituation, but showed attenuated nicotine (0.35mg/kg, s.c.)-induced behavioral sensitization compared to Fisher 344 (F344) rats. The basal levels of phosphorylated CREB and ERK2 were lower in the PFC of HIV-1Tg rats, but not in the NAc and VTA, relative to the controls. In the nicotine-treated groups, the levels of phosphorylated CREB and ERK2 in the PFC were increased in HIV-1Tg rats, but decreased in F344 animals. Moreover, repeated nicotine administration reduced phosphorylated ERK2 in the VTA of HIV-1Tg rats and in the NAc of F344 rats, but had no effect on phosphorylated CREB, indicating a region-specific change of intracellular signaling. These results demonstrate that HIV-1 viral proteins produce differences in basal and nicotine-induced alterations in CREB and ERK signaling that may contribute to the alteration in psychomotor sensitization. Thus, HIV-1 positive smokers are possibly more vulnerable to alterations in CREB and ERK signaling and this has implications for motivated behavior, including tobacco smoking, in HIV-1 positive individuals who self-administer nicotine.


On the Identity of Smicridea (Smicridea) aequalis Banks, 1920 (Trichoptera: Hydropsychidae): Morphology of Adults and Immature Stages, Bionomics, Distribution, and Male Color Dimorphism.
After 100 years of its description, the morphological circumscription of Smicridea aequalis Banks, 1920 is provided in this study by the integration of morphological characters of adult, pupal, and larval stages. This fact facilitates its recognition in faunal inventory studies and allows its use in biomonitoring programs, mainly in the Amazon and Cerrado biomes, two biodiversity hotspots where this species is widely distributed. Adults of S. aequalis may have diurnal activity as they are found frequently and abundantly on the riparian vegetation of fast-flowing streams and rivers during the day. The remarkable color dimorphism observed in males of this species was not reported previously for caddisflies.


FISH analysis with a YAC probe improves detection of LAZ3/BCL6 rearrangement in non-Hodgkin's lymphoma.
Chromosomal translocations involving the chromosome 3q27 region are common in B-cell non-Hodgkin's lymphoma (NHL), mainly diffuse large cell lymphoma (DLCL) and less often in follicular lymphoma. Most of these rearrangements involve the same major translocation cluster (MTC) on the 3q27 region, disrupting the LAZ3/BCL6 gene. Some of those translocations are difficult to detect by cytogenetic analysis and/or Southern-blot analysis. In the present report we used a FISH assay to improve the detection of LAZ3/BCL6 rearrangements. We isolated a YAC clone (803g3), containing the BCL6 gene, in order to analyze by FISH 19 cases of B-cell non-Hodgkin's lymphoma with cytogenetically detectable 3q27 rearrangement, including reciprocal translocation in 11 cases, deletion in two cases, and addition of undefined chromosomal material on 3q27 in six cases. In the 11 cases with reciprocal translocation, FISH results confirmed cytogenetic data and showed disruption of the LAZ3 region: four t(3;4)(q27;p13), two t(3;11)(q27;q23.1), four t(3;14)(q27;q32) and one t(2;3)(p12;q27). In two of the cases, reciprocal t(3;14) was associated with other cytogenetically detectable abnormalities of 3q27, but FISH showed that they did not affect the LAZ3 gene region. FISH demonstrated a reciprocal translocation with LAZ3 gene rearrangement in two of the six patients with add 3q27: one t(3;11) and one t(3;14). In the two patients with del(3q27), one had two 3q27 FISH signals and one had only one 3q27 FISH signal, but no LAZ3 gene rearrangement was observed. We have identified a YAC containing the LAZ3/BCL6 gene. This YAC probe could be useful in clinical practice to demonstrate LAZ3 rearrangements by FISH analysis on tumor samples in NHL.


Peroral delivery systems based on superporous hydrogel polymers: release characteristics for the peptide drugs buserelin, octreotide and insulin.
Novel peroral peptide drug delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC) have recently been developed in our laboratory. In this report the following issues were studied: release of the peptide drugs buserelin, octreotide and insulin from SPH and SPHC polymers and the developed delivery systems, stability of these peptides during the release and the integrity of insulin in the polymeric matrix of SPHC. Release studies from SPH and SPHC polymers revealed that buserelin, octreotide and insulin were released almost completely from the polymers. Peptide release rates from SPH were faster than from SPHC, due to the more porous structure of SPH polymer. All peptides studied in contact with SPHC polymer were stable under different environmental conditions (ambient temperature, 37 degrees C, light and darkness and at pH values 3.2 and 7.2). FTIR studies demonstrated that no covalent binding occurred between insulin and the polymeric SPHC matrix. Release profiles of all peptides from the developed delivery systems showed a time-controlled release profile: after a short lag time of 10-15 min, a burst release of peptides occurred during which more than 80% of peptide was released within 30-45 min. In conclusion, the present delivery systems based on SPH and SPHC show appropriate in vitro properties for application in peroral peptide drug delivery of buserelin, octreotide and insulin, and are therefore promising for further in vivo evaluation.


The Impact of the COVID-19 Pandemic on Care Partners of People with Parkinson's Disease.
Since the onset of the coronavirus disease 2019 pandemic, the caregiving routine for care partners of people with Parkinson's disease (PwPD) changed substantially. To understand the nature and severity of burden in care partners of PwPD during the ongoing pandemic. We also sought to describe care partners' perceived change in burden and factors associated with increased burden. Cross-sectional online questionnaire-based study among care partners of PwPD, registered in the Fox Insight study. The questionnaire consisted of the Modified Caregiver Strain Index, whether an aspect of strain had changed over the course of the pandemic and additional pandemic-specific infection and lifestyle-related items. Two hundred seventy-three non-paid primary care partners responded to the questionnaire, 73% female with a median age at enrollment of 64 years, 56% reporting a household income greater than 75,000 USD per year, and 61% retired. An increase in burden compared to before the pandemic was prevalent, ranging from 33% to 63% for individual items. Emotional strain increased most frequently (63%). Decreases in burden were uncommon; work adjustments (7%) and time demands (6%) decreased most frequently. PD-related factors and care partner roles in personal care of the PwPD were the factors that were associated with strain in multivariable analysis, whereas social and pandemic-related factors were not. In this affluent and mostly retired cohort, increases in emotional strain during the pandemic were prevalent. Despite this, caregiving roles in personal care and severity of symptoms in the PwPD were more strongly associated with strain than social and pandemic-related factors.


Prostanoid production by rat aortic endothelial cells by bradykinin and histamine.
The present studies demonstrate that rat aortic endothelial cells, when stimulated with either bradykinin or histamine, caused the release of both PGI2 and PGE2. The method has also been used to characterize the histamine receptor involved which is H1-subtype. The findings suggest that prostanoid production by bradykinin and histamine constitutes an alternative mechanism to endothelium-derived relaxing factor in mediating vasodilatation.


Synthesis, characterization, and biological applications of pyrazole moiety bearing osmium(IV) complexes.
Osmium (IV) complexes with pyrazole nucleus containing ligands were synthesized. Os(IV) compounds were characterized using ESI-MS, ICP-OES, IR spectroscopy, electronic spectroscopy, conductance, and magnetic measurements. Whereas, ligands were characterized by heteronuclear spectroscopy, (1H and 13C), IR spectroscopy, and elemental analysis. All the compounds were tested for their potential to interact with HS-DNA by absorption titration, fluorescence spectroscopy, viscosity measurement, and docking study. The quenching constant and Stern Volmer constant values were calculated using fluorescence study. The synthesized compounds were studied for in-vitro bacteriostatic and cytotoxic activities. The cancer cell line studies of all the synthesized complexes were carried out on human lung cancer cells (A549).Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1921795 .


Evaluation of insulin secretory capacity in diabetes mellitus.
The capacity of the pancreatic beta cells to secrete insulin can be evaluated in vivo by measurement either of circulating immunoreactive insulin or of C peptide, a by-product of insulin synthesis. Evaluation of serum levels is complicated, however, by the variable degradation rates and distribution spaces of these peptides. Also, interpretation of peripheral vein concentrations of insulin, and perhaps C peptide, is more difficult because of hepatic catabolism. Quantitation of these peptides in the urine may provide an integrated measure of insulin secretion. In insulin treated diabetic patients who develop circulating insulin antibodies, beta cell secretory capacity may be assessed by C peptide measurement, or by techniques that allow separate determinations of "free" and "total" insulin. A variety of stimulatory tests may be used to investigate insulin secretory capacity.


Chiral Lead-Free Hybrid Perovskites for Self-Powered Circularly Polarized Light Detection.
Metal-halide perovskites are recently emerging as the promising alternative for CPL detection owing to their CPL-sensitive property induced by chiral organics and efficient charge transport of inorganic frameworks. However, most of these reported chiral perovskites involve high concentrations of toxic Pb which will become the potential bottleneck for their further application. Herein, we successfully developed two lead-free halide double perovskites, [(R)-β-MPA]4 AgBiI8 ((R)-β-MPA=(R)-(+)-β-methylphenethylammonium, 1-R), and [(S)-β-MPA]4 AgBiI8 ((S)-β-MPA=(S)-(-)-β-methylphenethylammonium, 1-S). Circular dichroism measurements reveal that these perovskites exhibit notable chirality induced by organic cations to distinguish different polarization states of CPL photons. Significantly, they present unique chiral polar photovoltaic, and resulting self-powered CPL detection without an external power source is unprecedentedly achieved. Furthermore, an anisotropy factor up to 0.3 is acquired for the self-powered CPL detection, reaching the highest value among reported chiral perovskites. This work suggests hybrid double perovskites are promising photoelectronic candidates, and provides a new approach for exploring new "green" circularly polarized light-sensitive materials with high performance.


Super adsorption performance of carboxymethyl cellulose/copper oxide-nickel oxide nanocomposite toward the removal of organic and inorganic pollutants.
A novel nanocomposite bead based on polymeric matrix of carboxymethyl cellulose and copper oxide-nickel oxide nanoparticles was synthesized, characterized, and applied for adsorptive removal of inorganic and organic contaminants at trace level of part per million (mgL-1) from aqueous sample. Carboxymethyl cellulose/copper oxide-nickel oxide (CMC/CuO-NiO) adsorbent beads were selective toward the removal of Pb(II) among other metal ions. The removal percentage of Pb(II) was more than 99% with 3 mgL-1. The waste beads after Pb (II) adsorption (Pb@CMC/CuO-NiO) and CMC/CuO-NiO nanocomposite beads were employed as adsorbents for removing of various dyes. It was found that Pb@CMC/CuO-NiO can be reused as adsorbent for the removal of Congo Red (CR), while CMC/CuO-NiO nanocomposite beads were more selective for removal of Eosin Yellow (EY) from aqueous media. The adsorption of CR and EY was optimized, and the removal percentages were 93% and 96.4%, respectively. The influence of different parameters was studied on the uptake capacity of Pb(II), CR, and EY, and lastly, the CMC/CuO-NiO beads exhibited responsive performance in relation to pH and other parameters. Thus, the prepared CMC/CuO-NiO beads were found to be a smart material which is effective and played super adsorption performance in the removal of Pb(II), CR, and EY from aqueous solution. These features make CMC/CuO-NiO beads suitable for numerous scientific and industrial applications and may be used as an alternative to high-cost commercial adsorbents.


A novel nonsense mutation in the DMP1 gene identified by a genome-wide association study is responsible for inherited rickets in Corriedale sheep.
Inherited rickets of Corriedale sheep is characterized by decreased growth rate, thoracic lordosis and angular limb deformities. Previous outcross and backcross studies implicate inheritance as a simple autosomal recessive disorder. A genome wide association study was conducted using the Illumina OvineSNP50 BeadChip on 20 related sheep comprising 17 affected and 3 carriers. A homozygous region of 125 consecutive single-nucleotide polymorphism (SNP) loci was identified in all affected sheep, covering a region of 6 Mb on ovine chromosome 6. Among 35 candidate genes in this region, the dentin matrix protein 1 gene (DMP1) was sequenced to reveal a nonsense mutation 250C/T on exon 6. This mutation introduced a stop codon (R145X) and could truncate C-terminal amino acids. Genotyping by PCR-RFLP for this mutation showed all 17 affected sheep were "T T" genotypes; the 3 carriers were "C T"; 24 phenotypically normal related sheep were either "C T" or "C C"; and 46 unrelated normal control sheep from other breeds were all "C C". The other SNPs in DMP1 were not concordant with the disease and can all be ruled out as candidates. Previous research has shown that mutations in the DMP1 gene are responsible for autosomal recessive hypophosphatemic rickets in humans. Dmp1_knockout mice exhibit rickets phenotypes. We believe the R145X mutation to be responsible for the inherited rickets found in Corriedale sheep. A simple diagnostic test can be designed to identify carriers with the defective "T" allele. Affected sheep could be used as animal models for this form of human rickets, and for further investigation of the role of DMP1 in phosphate homeostasis.


Moldless Printing of Silicone Lenses With Embedded Nanostructured Optical Filters.
Optical lenses are among the oldest technological innovations (3000 years ago) and they have enabled a multitude of applications in healthcare and in our daily lives. The primary function of optical lenses has changed little over time; they serve mainly as a light-collection (e.g. reflected, transmitted, diffracted) element, and the wavelength and/or intensity of the collected light is usually manipulated by coupling with various external optical filter elements or coatings. This generally results in losses associated with multiple interfacial reflections, and increases the complexity of design and construction. In this work we introduce a change in this paradigm, by integrating both light-shaping and image magnification into a single lens element using a moldless procedure that takes advantage of the physical and optical properties of mesoporous silicon (PSi) photonic crystal nanostructures. Casting of a liquid poly(dimethyl) siloxane (PDMS) pre-polymer solution onto a PSi film generates a droplet with contact angle that is readily controlled by the silicon nanostructure, and adhesion of the cured polymer to the PSi photonic crystal allows preparation of lightweight (10 mg) freestanding lenses (4.7 mm focal length) with an embedded optical component (e.g. optical rugate filter, resonant cavity, distributed Bragg reflector). Our fabrication process shows excellent reliability (yield 95%) and low cost and we expect our lens to have implications in a wide range of applications. As a proof-of-concept, using a single monolithic lens/filter element we demonstrate: fluorescence imaging of isolated human cancer cells with rejection of the blue excitation light, through a lens that is self-adhered to a commercial smartphone; shaping the emission spectrum of a white light emitting diode (LED) to tune the color from red through blue; and selection of a narrow wavelength band (bandwidth 5 nm) from a fluorescent molecular probe.


Implementation of Continuous Glucose Monitoring in Critical Care: A Scoping Review.
The aim of this review is to identify the implementation approaches, strategies, and outcomes for continuous glucose monitoring (CGM) in the intensive care unit (ICU). Medline and Web of Science databases were searched to report relevant literature published between September 12, 2016 and September 12, 2021. Implementation outcomes and strategies, defined by the Expert Recommendations for Implementing Change (ERIC) project, were extracted. Of the 324 titles reviewed, 16 articles were included in the review. While no studies were identified as implementation research, 14 of 16 identified implementation strategies that aligned with ERIC definitions. Included studies described a multi-disciplinary approach. Clinical outcomes included Mean Absolute Relative Difference (MARD), ranging from 7.5 to 15.3%, and 33-71% reduction in frequency of point-of-care (POC) blood glucose monitoring (BGM) using hybrid protocols. This scoping review provides valuable insight into the process of CGM implementation in the ICU. Continued research should include implementation outcomes to inform widespread utilization.