Complete nucleotide sequence and genome organization of Pelargonium flower break virus.
The complete nucleotide sequence of Pelargonium flower break virus (PFBV) has been determined. The genomic RNA is 3923 nucleotides (nt) long and contains five open reading frames (ORFs). The 5'-proximal ORF encodes a 27 kDa protein (p27) and terminates with an amber codon which may be read-through into an in-frame p56 ORF to generate a 86 kDa protein (p86) containing the viral RNA dependent-RNA polymerase motifs. Two small ORFs, located in the central part of the viral genome, encode polypeptides of 7 (p7) and 12 kDa (p12), respectively, which are very likely involved in virus movement. Interestingly, p12 presents a leucine zipper motif that has not been previously reported in related proteins. The 3'-proximal ORF encodes a 37 kDa capsid protein (CP). The p12 ORF is in-frame with the p86 ORF and a double read-through protein of 99 kDa (p99) may be produced. Amino acid sequence comparisons revealed that the proteins encoded by ORFs 2, 3 and 4 are more similar to the corresponding gene products of Carnation mottle virus than to those of other carmoviruses, whereas the p27 and the CP show higher identity with the equivalent proteins of Saguaro cactus virus. Phylogenetic analysis conducted with the different viral products confirmed the assignment of PFBV to the genus Carmovirus.


Multimodal echocardiography in the diagnosis of masses localized to the proximal portions of pulmonary arteries.
Proximal pulmonary artery masses are exceedingly rare, and their diagnosis and therapy are important and challenging for clinicians. This study reviews our experience exploring the value of a combination of transthoracic echocardiography and contrast echocardiography for the differential diagnosis of proximal pulmonary artery masses. Between January 2018 and June 2021, 44 patients diagnosed with a mass attached to the major pulmonary artery and straddling the bilateral pulmonary arteries or pulmonary valve on transthoracic echocardiography were referred to this study. Contrast echocardiography was performed in 17 patients. Masses were diagnosed based on their site of attachment, shape, size, mobility, hemodynamic consequences on transthoracic echocardiography, and tissue perfusion on contrast echocardiographic perfusion imaging. Pathological data were collected from medical records and analyzed. The most frequent location of proximal pulmonary artery masses was the major pulmonary artery trunk. Twelve patients underwent complete mass resection, whereas nine patients underwent percutaneous pulmonary artery biopsy puncture and had a pathological diagnosis. Another 24 patients were confirmed with the validation methods. Contrast echocardiography has good sensitivity and specificity for differentiating thrombi from pulmonary artery sarcomas (PAS). The mass types were distributed as follows: thrombi (19, 43%), PAS (15, 34%), metastatic tumors (6, 14%), vegetations (3, 7%), and primary benign lesions (1, 2%). The majority of proximal pulmonary artery masses were thrombi or PAS. A combination of transthoracic echocardiography and contrast echocardiography offers advantages in the early identification of proximal pulmonary masses and provides clinically important information about the characteristics of masses, especially for differentiating thrombi from PAS.


Development of loop mediated isothermal amplification (LAMP): A new tool for rapid diagnosis of cotton leaf curl viral disease.
Cotton leaf curl disease (CLCuD) ranks top among all endemic diseases transmitted by whitefly (Bemisia tabaci) affecting cotton (Gossypium hirsutum) causing severe economic losses to the cotton growers in the Indian subcontinent. For its effective management, robust tools for detection are a prerequisite and it is important to diagnose the virus titre in early stage of infection in plants as well as in the disease transmitting vector. Considering the limitations in current PCR-based techniques we have standardised rapid and sensitive Loop Mediated Isothermal Amplification (LAMP) protocol for the diagnosis of cotton leaf curl virus (CLCuV) in cotton leaves and in its transmitting vector whitefly. Perhaps, this is the first report of use of LAMP tool for rapid diagnosis of CLCuV in cotton and its transmitting vector the whitefly. Further, the colorimetric detection for diagnostic simplicity of amplified LAMP product by using different dyes lead to enhanced applicability of this technique in the field of disease diagnostics. The merit of present study is that the diagnostic failure of PCR and LAMP due to low virus titre in the infected leaf has been circumvented through the combination of rolling circle amplification (RCA) with LAMP. Thus RCA-LAMP can be an option for ultra-sensitive detection of samples with low virus titre. The potential applications of this advanced diagnostic tool in laboratory research on diagnosis of CLCuV, an important viral pathogen of cotton have been discussed.


Kunitz-type protease inhibitor BmSPI51 plays an antifungal role in the silkworm cocoon.
The protease inhibitors found in silkworm cocoons can be divided into several families, a majority of which contain serpin, TIL, or Kunitz domains. Previously, it has been reported that TIL-type protease inhibitors have antimicrobial activity. To date, however, it has not been determined whether the Kunitz-type protease inhibitor BmSPI51, the most abundant of cocoon protease inhibitors, plays an antimicrobial role. Thus, in this study, we sought to determine the biological role of BmSPI51 in silkworm cocoons. Our results obtained from real-time quantitative reverse transcription PCR and immunofluorescence analyses indicate that BmSPI51 is expressed exclusively in the silk glands during the larval fifth instar stage and is subsequently secreted into cocoon silk. Moreover, at a molar ratio of 1:1, BmSPI51 produced via prokaryotic expression exhibited inhibitory activity against trypsin and also proved to be highly stable over wide ranges of temperature and pH values. The expression of BmSPI51 was also found to be significantly upregulated in the larval fat body after infection with three species of fungi, namely, Candida albicans, Beauveria bassiana, and Saccharomyces cerevisiae. In vitro inhibition tests revealed that BmSPI51 significantly inhibited the sporular growth of all three of these fungal species. Further, results obtained from a binding assay showed that BmSPI51 binds to β-d-glucan and mannan on the surface of fungal cells. In this study, we, thus, revealed the antimicrobial activity of BmSPI51 and its underlying mechanism in silkworm, thereby contributing to our present understanding of defense mechanisms in silkworm cocoons.


In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test.
Patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) are often exposed simultaneously to a few potentially culprit drugs. However, both the standard lymphocyte transformation tests (LTT) with proliferation as the assay end-point as well as skin tests, if done, are often negative. As provocation tests are considered too dangerous, there is an urgent need to identify the relevant drug in SJS/TEN and to improve sensitivity of tests able to identify the causative drug. Fifteen patients with SJS/TEN with the ALDEN score ≥ 6 and 18 drug-exposed controls were included. Peripheral blood mononuclear cells (PBMC) were isolated and cultured under defined conditions with drugs. LTT was compared to the following end-points: cytokine levels in cell culture supernatant, number of granzyme B secreting cells by ELISpot and intracellular staining for granulysin and IFNγ in CD3(+) CD4(+), CD3(+) CD8(+) and NKp46(+) cells. To further enhance sensitivity, the effect of IL-7/IL-15 pre-incubation of PBMC was evaluated. Lymphocyte transformation tests was positive in only 4/15 patients (sensitivity 27%, CI: 8-55%). Similarly, with granzyme B-ELISpot culprit drugs were positive in 5/15 patients (sensitivity 33%, CI: 12-62%). The expression of granulysin was significantly induced in NKp46(+) and CD3(+) CD4(+) cells (sensitivity 40%, CI: 16-68% and 53%, CI: 27-79% respectively). Cytokine production could be demonstrated in 38%, CI: 14-68% and 43%, CI: 18-71% of patients for IL-2 and IL-5, respectively, and in 55%, CI: 23-83% for IFNγ. Pre-incubation with IL-7/IL-15 enhanced drug-specific response only in a few patients. Specificities of tested assays were in the range of 95 (CI: 80-99%)-100% (CI: 90-100%). Granulysin expression in CD3(+) CD4(+) , Granzyme B-ELISpot and IFNγ production considered together provided a sensitivity of 80% (CI: 52-96%) and specificity of 95% (80-99%). Thus, this study demonstrated that combining different assays may be a feasible approach to identify the causative drug of SJS/TEN reactions; however, confirmation on another group of patients is necessary.


Dopamine involvement in ACTH-induced grooming behavior.
Low doses of dopamine agonists and antagonists were tested for their effects on the excessive grooming behavior induced by intracerebroventricular (ICV) injections of ACTH1-24. Grooming scores were significantly depressed at doses of haloperidol, metoclopramide, pimozide, and butaclamol that did not decrease locomotor activity. In fact at two doses of haloperidol (0.067 and 0.10 mg/kg), grooming scores were decreased while locomotor activity was increased significantly. Metoclopramide increased grooming scores at a dose reported to block presynaptic dopamine receptors. Apomorphine potentiated the grooming induced by low doses of ACTH. These data support the hypothesis that dopaminergic neurotransmission is necessary for the display of ACTH-induced grooming behavior.


Analysis of inpatient use of fresh frozen plasma and other therapies and associated outcomes in patients with major bleeds from vitamin K antagonism.
We conducted an observational study of outcomes and costs associated with fresh frozen plasma (FFP) use in patients receiving warfarin with intracerebral, gastrointestinal, or musculoskeletal bleeding. Patients who had at least 1 International Classification of Diseases, Ninth Revision code indicative of anticoagulation history, received ≥ 1 unit FFP, and had patient costs >$0 were identified from a database of >600 US hospitals. The main outcome was transfusion of additional blood products (eg, cryoprecipitate, red blood cells, or platelets) or vitamin K. Further outcomes included administration of other bleeding-related therapies (eg, recombinant activated factor VII, albumin, or crystalloids), incidence of fluid overload, days in the intensive care unit, discharge status, and total hospital costs. The most frequently administered products were vitamin K and red blood cells, given to 55.6% to 61.0% and 19.2% to 29.3% of patients, respectively. The number of FFP units transfused correlated highly with fluid overload (r > 0.91) and was associated with inpatient mortality, nonhome discharge, and intensive care unit admittance. For both inpatient mortality and nonhome discharge, the odds ratio was significant when ≥ 4 units FFP were transfused (P < 0.05). A dose of >2 units FFP was associated with an increased probability of an intensive care unit stay (P < 0.05). Total costs were greater among patients receiving >2 units FFP compared with patients who received 1 unit FFP (P < 0.001), with a substantial increase in costs incurred when ≥ 4 units FFP were transfused. In patients with warfarin-related bleeding, inpatient mortality, nonhome discharge, intensive care unit admission, and hospital costs were associated with the number of units of FFP transfused.


Validation of the bowel urgency numeric rating scale in patients with Crohn's disease: results from a mixed methods study.
Bowel urgency (BU) is an important symptom of Crohn's disease (CD), however there is no patient-reported outcome (PRO) scale validated in this population to assess BU severity. Here we evaluated the content validity and psychometric properties of the Urgency Numeric Rating Scale (NRS). Qualitative interviews were conducted with moderate-to-severe CD participants to confirm importance and relevance of BU in this population, cognitively debrief the Urgency NRS, and explore score interpretation and CD remission. A quantitative web survey study was conducted to explore the measurement properties of the urgency NRS. Qualitative Interview: 34 of 35 participants reported BU. It was most bothersome for 44%, 47% reported it daily, 18% with every bowel movement. BU had a severe impact on daily activities, causing many participants to stay home more than preferred. Patients confirmed the relevance, appropriateness, comprehensibility of the item, recall period, response options, and instructions of the Urgency NRS. Small reductions on the Urgency NRS score reflected meaningful improvements. Quantitative survey: The study sample comprised 76 participants (65.8% female). Mean Urgency NRS score was 4.7 (SD 2.26; N = 76) at Week 1, with no floor/ceiling effect. Test-retest reliability was acceptable. Construct and known-groups validity against selected PROs were overall strong and within ranges hypothesized a priori. The Urgency NRS is a valid and reliable instrument to assess BU severity in CD.


Metal Nanoparticles-Polymers Hybrid Materials II.
Despite the pandemic, the last five years have been marked by an extraordinary development of new advanced technologies, based not only on new materials but also on modeling, information technology and artificial intelligence, which have allowed for great leaps forward in various research fields [...].


The Haskins pediatric atlas: a magnetic-resonance-imaging-based pediatric template and atlas.
Spatial normalization plays an essential role in multi-subject MRI and functional MRI (fMRI) experiments by facilitating a common space in which group analyses are performed. Although many prominent adult templates are available, their use for pediatric data is problematic. Generalized templates for pediatric populations are limited or constructed using older methods that result in less ideal normalization. The Haskins pediatric templates and atlases aim to provide superior registration and more precise accuracy in labeling of anatomical and functional regions essential for all fMRI studies involving pediatric populations. The Haskins pediatric templates and atlases were generated with nonlinear methods using structural MRI from 72 children (age range 7-14 years, median 10 years), allowing for a detailed template with corresponding parcellations of labeled atlas regions. The accuracy of these templates and atlases was assessed using multiple metrics of deformation distance and overlap. When comparing the deformation distances from normalizing pediatric data between this template and both the adult templates and other pediatric templates, we found significantly less deformation distance for the Haskins pediatric template (P<0.0001). Further, the correct atlas classification was higher using the Haskins pediatric template in 74% of regions (P<0.0001). The Haskins pediatric template results in more accurate correspondence across subjects because of lower deformation distances. This correspondence also provides better accuracy in atlas locations to benefit structural and functional imaging analyses of pediatric populations.


Aspects of morphogenesis and cytodifferentiation of endoderm offered by organ culture techniques.
In this article, I will summarize the results obtained in my laboratory from the study of organogenesis since 1970. The results have shown region-specific directive influence of mesenchymes and reactivity of endoderms including those of the allantois, yolk sac, digestive tract and urogenital sinus. It was also shown that morphogenesis can take place without coupling cytodifferentiation in heterologous recombination experiments.


A systematic review of microRNAs in patients with hypertrophic cardiomyopathy.
Several microRNAs (miRNA) have been associated with hypertrophic cardiomyopathy (HCM), but studies differ regarding methods employed. In an attempt to understand their role in the disease, we performed a systematic review of studies assessing miRNAs and their association with HCM. The literature search was based on The Medical Subject Headings (MeSH) terms "Hypertrophic Cardiomyopathy" and "MicroRNA" combined with other synonyms on Embase, Medline and LILACS databases in April 2020. The selected studies and data extraction were independently evaluated. Only human reports with a clear definition of HCM diagnosis were included. The search found 68 studies, 13 fulfilled the selection criteria, with a total of 329 patients. Eighty-seven miRNA were differentially expressed in HCM patients, being mir-21, mir-29a and mir-133 the most reported. The miRNA were mainly up-regulated, where mir-29a was up-regulated in 6 studies, followed by mir-133 in 4 and mir-21 in 3. The other miRNAs were mainly up-regulated. Blood samples were evaluated in the majority of patients (86%), but a greater number of miRNAs (79%) were assessed in myocardium. Six studies evaluating the phenotype correlation demonstrated that several miRNAs, mainly mir-1-3p, mir-19b, mir-21, mir-29a, mir-155, and mir-221, were related to either hypertrophy or fibrosis. Mir-29a showed a more consistent phenotypic correlation. Eighty-seven miRNAs were differentially expressed in HCM patients, the majority in up-regulation. Mir-21, mir-29a and mir-133 were the most reported. Correlation with left ventricular hypertrophy and fibrosis was evaluated in six studies for several miRNAs, nevertheless, mir-29a showed more consistent findings and seems to be a promising biomarker.


Determination of amines and phenolic acids in wine with benzoyl chloride derivatization and liquid chromatography-mass spectrometry.
Amine and phenolic metabolites are important contributors to the flavor and health effects of many foods, including wine. Determination of these metabolites often involves UV detection following separation by liquid chromatography. While this is sufficient for some applications, chemical derivatization with LC-MS provides greater sensitivity and selectivity relative to LC-UV. We have developed an assay for 56 amine and phenolic metabolites in wine using benzoyl chloride derivatization and LC-MS. Isotopically labeled benzoyl chloride was used to prepare internal standards for each metabolite. Nanomolar limits of detection were achieved for all metabolites. To demonstrate the application of this assay, we compared metabolite profiles from Merlot and Cabernet Sauvignon wines from California and Australia. We found five metabolites which were significantly different when grouped by varietal, while twenty-four were different when grouped by location of production. This shows that the method can identify differences between various wines.


An estimate of the amount of genetic variation in the common mussel Mytilus edulis.
Allozyme variation in a population of the common mussel Mytilus edulis in Mumbles, South Wales, has been studied by starch gel electrophoresis. On the basis of data obtained for 34 loci, we estimate the proportion of loci polymorphic to be 30%. Using only the 29 loci for which individual genotypes can be accurately typed, the average heterozygosity is estimated to be 9.5 +/- 3.6%. The calculated expected average heterozygosity based on Hardy-Weinberg expectations is identical with the observed value. Allele frequency data at six polymorphic loci are given for several other British populations. There is no significant geographic heterogeneity. The results are discussed in relation to genetic adaptive strategies and are shown to be inconsistent with the predictions of the neutral hypothesis.


Human neuroblastoma stem cells.
Human neuroblastoma is an embryonic cancer of the neural crest. Cellular heterogeneity is a characteristic feature of both tumors and derived cell lines. Recent studies have revealed that both cell lines and tumors contain cancer stem cells. In culture, these cells are self-renewing, multipotent, and highly malignant; in tumors their frequency correlates with a worse prognosis. Their identification and characterization should now permit a targeted approach to more effective treatment of this often fatal childhood cancer.


Real-life comparison of mortality in patients with SARS-CoV-2 infection at risk for clinical progression treated with molnupiravir or nirmatrelvir plus ritonavir during the Omicron era in Italy: a nationwide, cohort study.
Comparative data on mortality in COVID-19 patients treated with molnupiravir or with nirmatrelvir plus ritonavir are inconclusive. We therefore compared all-cause mortality in community-dwelling COVID-19 patients treated with these drugs during the Omicron era. Data collected in the nationwide, population-based, cohort of patients registered in the database of the Italian Medicines Agency (AIFA) were used. To increase completeness of the recorded deaths and date correctness, a cross-check with the National Death Registry provided by the Ministry of the Interior was performed. We included in this study all patients infected by SARS-CoV-2 treated within 5 days after the test date and symptom onset between February 8 and April 30, 2022. All-cause mortalities by day 28 were compared between the two treatment groups after balancing for baseline characteristics using weights obtained from a gradient boosting machine algorithm. In the considered timeframe, 17,977 patients treated with molnupiravir and 11,576 patients with nirmatrelvir plus ritonavir were included in the analysis. Most patients (25,617/29,553 = 86.7%) received a full vaccine course including the booster dose. A higher crude incidence rate of all-cause mortality was found among molnupiravir users (51.83 per 100,000 person-days), compared to nirmatrelvir plus ritonavir users (22.29 per 100,000 person-days). However, molnupiravir-treated patients were older than those treated with nirmatrelvir plus ritonavir and differences between the two populations were found as far as types of co-morbidities were concerned. For this reason, we compared the weight-adjusted cumulative incidences using the Aalen estimator and found that the adjusted cumulative incidence rates were 1.23% (95% CI 1.07%-1.38%) for molnupiravir-treated and 0.78% (95% CI 0.58%-0.98%) for nirmatrelvir plus ritonavir-treated patients (adjusted log rank p = 0.0002). Moreover, the weight-adjusted mixed-effect Cox model including Italian regions and NHS centers as random effects and treatment as the only covariate confirmed a significant reduced risk of death in patients treated with nirmatrelvir plus ritonavir. Lastly, a significant reduction in the risk of death associated with nirmatrelvir plus ritonavir was confirmed in patient subgroups, such as in females, fully vaccinated patients, those treated within day 2 since symptom onset and patients without (haemato)-oncological diseases. Early initiation of nirmatrelvir plus ritonavir was associated for the first time with a significantly reduced risk of all-cause mortality by day 28 compared to molnupiravir, both in the overall population and in patient subgroups, including those fully vaccinated with the booster dose. This study did not receive funding.


Carotid artery stenting: clinical and procedural implications for near-occlusion stenosis.
The advisability of implanting a stent in carotid near-occlusion stenosis is a controversial topic. We have assessed procedural and clinical implications of stent implantation for carotid artery disease with near occlusion. We included 205 patients who underwent carotid artery revascularisation with a stent. The group of patients with near-occlusion stenosis (n=54)was compared to the rest of the population (n=151). No differences were found between groups for age, sex, and the percentage of symptomatic patients (three-quarters of the population). Carotid stent revascularisation for near-occlusion stenosis presented a high procedural success rate (96%) similar to that of revascularisation processes for other lesions (98%). Stenting in cases of near-occlusion stenosis required increased use of proximal protection (54% vs. 20.5%, P<.001) and predilation (33% vs. 17%, P=.01). The process to repair near-occlusion stenosis cause increased detachment of plaque, as shown by higher percentages of macroscopic plaque captured by protection devices (18.5% vs. 7%, P=.01) and of perioperative ischaemic brain lesions (47% vs 31%, P = .07). At 30 days of follow-up, the tendency toward adverse neurological events (death, major and minor stroke) was higher in the near-occlusion group (9.2% vs. 3.2%, P=.08). Stent revascularisation for near-occlusion carotid stenosis has a high procedural success rate; however, its higher plaque load was responsible for the increased rate of ischaemic brain lesions and adverse neurovascular events at 30 days post-procedure.


Mutation and copy number analysis of LNX1 and Numbl in nervous system tumors.
Alterations at chromosome locus 4q12 are frequently found in gliomas; this locus contains the receptor tyrosine kinase--encoding genes KIT, PDGFRA, and KDR (alias VEGFR2). Notable among the genes at this locus is LNX1, the ligand of Numb protein X. LNX1 encodes a PDZ domain containing protein, which interacts with the cell fate determinant Numbl, a Numb homolog-like gene involved in the maintenance of neural progenitor cells during embryonic neurogenesis. We performed a mutation analysis for LNX1 and Numbl genes. In addition, gene copy numbers of LNX1, Numbl, and KIT in human nervous system tumors were analyzed by chromogenic in situ hybridization. Tissue samples from 90 patients were screened for LNX1 and Numbl mutations, and tissue sections from 56 samples were analyzed for gene amplification status. Our analysis revealed missense mutations in LNX1 exons 3 and 5 and a single-nucleotide polymorphism in Numbl exon 6. In addition, polyglutamine repeat polymorphism was found in Numbl exon 10. Chromogenic in situ hybridization showed gene amplification of LNX1 in 10%, Numbl in 5%, and KIT in 6% of nervous system tumors. Both gene sequence alterations and amplifications of LNX1 and Numbl are present in a subset of human gliomas, and the role of these genes in neurogenesis suggests that they may contribute to development of glial tumors.


Development and feasibility of the Help to Overcome Problems Effectively (HOPE) self-management intervention for people living with multiple sclerosis.
To describe the development and feasibility of a self-management intervention called the Help to Overcome Problems Effectively (HOPE: MS), aimed at improving the physical and psychological wellbeing of people living with Multiple Sclerosis (MS). HOPE: MS is an innovative, 6-week group-based, manualised self-management intervention combining positive psychology theory and practice, and cognitive behavioural therapy (CBT). Participants (N = 21) recruited via a local East Midlands branch of the MS Society attended one of three HOPE: MS interventions and completed self-reported outcome measures in week 1 and week 6. The following outcome measures were used: The Multiple Sclerosis Impact Scale; Multiple Sclerosis Fatigue Severity Scale; The Multiple Sclerosis Self-Efficacy Scale; The Adult State Hope Scale; The Hospital Anxiety and Depression Scale; The Positive and Negative Affect Scale. Post-intervention (6 weeks) mean scores decreased in the physical impact (baseline M = 65.6, SD = 17.4; 6 weeks M = 55.1, SD = 17.9, 95% CI [-4.39, -16.47] and the psychological impact of MS (baseline M = 24.0, SD = 7.3; 6 weeks M = 18.9; SD = 6.3, 95% CI [-2.54, -7.66]). There was also a decrease mean fatigue severity scores (baseline 49.4, SD = 13.3, 6 weeks M = 41.1, SD = 14.4, 95% CI [-2.65, -13.44]). There was a mean decrease in depression scores (baseline M = 6.9, SD = 3.5; 6 weeks M = 4.2, SD = 2.8, 95% CI [-1.43, -4.00]). There were smaller mean decreases in anxiety (baseline M = 7.6, SD = 3.4; 6 weeks M = 6.7 (4.0), 95% CI [0.69, -2.50]) and negative affect (baseline M = 22.9, SD = 6.8; 6 weeks M = 20.8 (8.1), 95% CI [0.69, -2.50]) refer Table 3 ). Mean MS self-efficacy scores (baseline 21.7, SD = 4.2; 6 weeks M = 24.1, SD = 4.7, 95% CI [0.23, 4.53]), mean total hope scores (baseline M = 23.3, SD = 10.7; 6 weeks M = 32.2 (10.6), 95% CI [4.91, 12.9]), hope agency scores (baseline M = 10.5, SD = 5.7; 6 weeks M = 15.7 (6.2), 95% CI [2.37, 8.01]), hope pathways (baseline M = 12.9, SD = 6.0; 6 weeks M = 16.6 (4.9), 95% CI [2.00, 5.43]) and positive affect scores increased (baseline M = 27.3, SD = 7.1; 6 months M = 32.2, SD = 8.4, 95% CI [0.42, 9.39]). Participants positively rated the intervention quality and delivery. This feasibility study showed that the HOPE: MS was acceptable and useful to people living with MS. Further robust evaluations using a randomised controlled trial design with longer follow ups are needed to confirm early promising results of the HOPE: MS. Implications for rehabilitation Living with MS requires constant adjustments to cope with unpredictable symptoms. Self-management interventions have the potential to help people living with MS to improve their quality of life. A feasibility study of the HOPE: MS self-management group-based intervention showed that it was acceptable and useful to people living with MS.


Public-private differences in short-term neonatal outcomes following birth by prelabour caesarean section at early and full term.
Prelabour caesarean section (CS) at early term (370 -386 weeks) is associated with higher rates of adverse short-term neonatal outcomes and higher costs than those performed at full term (390 -406 weeks). Prelabour CS is more common in private than in public hospitals in Australia, particularly at early term. To evaluate the impact of hospital sector (public or private) and timing of delivery on short-term neonatal outcomes following prelabour CS at term. A retrospective cohort study of 22 954 viable singleton prelabour CS births at term (370 -406 weeks) at a single centre encompassing co-located public and private hospitals during 1998-2013 was undertaken. Propensity score analysis was used to adjust for confounding differences between sectors. The primary outcome was Neonatal Critical Care Unit (NCCU) admission with serious morbidity. Secondary outcomes included respiratory distress, vigorous resuscitation and jaundice. The private hospital performed prelabour CS at over double the rate of the public hospital (33.7% of all private births vs 14.7% public) and more private than public prelabour CSs occurred at early term (66.8% vs 47.9%). Public babies were more than twice as likely as private babies to require admission to NCCU with serious morbidity (adjusted odds ratio (AOR) 2.54, 95% CI 1.77-3.65) but were less likely to need vigorous resuscitation (AOR 0.53, 95% CI 0.45-0.62). Disparities in outcomes between public and private cohorts were accentuated at full term. Despite early-term prelabour CSs occurring more often in the private hospital, public babies had more adverse outcomes and treatment escalations.


Food security, poverty and household resilience to COVID-19 in Burkina Faso: Evidence from urban small traders' households.
Analyses of the effects of the COVID-19 pandemic on food security of urban households and their resilience are increasingly receiving scholarly interest. In Burkina Faso, urban households whose primary activity is trade were the most immediately impacted by COVID-19 due to the closure of markets. The objective of this research was to analyze the effect of income loss due to COVID-19 on food security and poverty among urban small traders' households by considering their resilience capacity. A survey was performed on 503 households of small traders operating in 5 markets in Ouagadougou. Objective and subjective indicators of food security were calculated, as well as several indices of resilience capacity. A simple logit model and ordered logit model were used for the socioeconomic analysis. Three main results emerge. First, COVID-19 has increased the likelihood of households being food insecure due to their lower food consumption scores. Second, estimates show that COVID-19 has reduced households' incomes by increasing their likelihood of entering poverty. Finally, at all levels of analysis, households with adaptive capacity were able to adjust to the shock, but social security was not a mitigating factor. Implications in terms of economic policies are discussed.


Identification of human liver cytochrome P450 isoforms involved in autoinduced metabolism of the antiangiogenic agent (Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid (TSU-68).
(Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid (TSU-68) is a new anticancer drug that inhibits angiogenic receptor tyrosine kinases, which play a crucial role in tumor-induced vascularization. TSU-68 undergoes hepatic oxidation and glucuronidation. Incubation of TSU-68 with human liver microsomes in the presence of NADPH resulted in the formation of three major metabolites: 5-, 6-, and 7-hydroxyindolinone derivatives. The 5-, 6-, and 7-hydroxylation followed simple Michaelis-Menten kinetics with V(max)/K(m) values (an indicator of intrinsic clearance) of 13, 25, and 6 microl/min/mg, respectively. Of the 10 cDNA-expressed human cytochrome P450 isoforms examined, only CYP1A1 and CYP1A2 exhibited appreciable TSU-68 hydroxylation activity. Inhibition studies with alpha-naphthoflavone (a selective CYP1A2 inhibitor) and anti-CYP1A2 antibody also indicated the almost exclusive role of CYP1A2 in microsomal TSU-68 hydroxylation. Treatment of human hepatocytes with 10 microM TSU-68 resulted in a 28- to 140-fold increase in CYP1A1/2-mediated ethoxyresorufin O-deethylase activity. The protein levels of CYP1A2 were increased in TSU-68-treated hepatocytes, and those of CYP1A1, which were undetectable in control hepatocytes, were also increased to detectable levels in the TSU-68-treated hepatocytes. Thus, TSU-68 was shown to induce CYP1A1/2 expression, which was responsible for its hydroxylation. The observation that TSU-68 treatment resulted in a 10- to 45-fold increase in 5-, 6-, and 7-hydroxylation directly demonstrated the autoinduced hydroxylation of TSU-68. In conclusion, TSU-68 has the potential to cause induction of its own CYP1A1/2-mediated oxidative metabolism in humans. This autoinductive effect provides a clear explanation for the clinically observed decrease in TSU-68 plasma concentrations during repeated administration of the drug.


Study-related health and behavior patterns of medical students: A longitudinal study.
Little is known about specific health risks and resources and their development influencing medical students' stress. To evaluate the development of quality of life and study-related behavior and experience patterns among medical students. Data were collected in the first (n = 112 of 182 in 2006) and the fourth semesters (n = 164 of 176 in 2008). The instruments "Work-Related Behavior and Experience Patterns" (AVEM, including four main patterns: "Health", "Unambitious," "Overexertion," "Burnout") and "Short Form-12 Health Survey (SF-12)" were used at both points in time. The medical students scored significantly lower on mental health compared with reference samples of young adults. The proportion of students with a healthy pattern decreased from 47.3% (95% CI 38.1-56.5%) in the first semester to 36.9% (29.4-44.4%) in the fourth semester. This corresponded to an increase in the proportion of students at risk for burnout from 7.1% (2.3-11.9%) to 20% (13.8-26.2%). At both time points, female students had a higher risk for overexertion and a lower prevalence of a healthy pattern than male students. Our data provide evidence for a decrease in the healthy pattern and an increase in the burnout pattern. Intervention is needed, especially for students at risk for burnout.


How Far Can We Go with Laparoscopic Liver Resection for Hepatocellular Carcinoma? Laparoscopic Sectionectomy of the Liver Combined with the Resection of the Major Hepatic Vein Main Trunk.
Although the reports of laparoscopic major liver resection are increasing, hepatocellular carcinomas (HCCs) close to the liver hilum and/or major hepatic veins are still considered contraindications. There is virtually no report of laparoscopic liver resection (LLR) for HCC which involves the main trunk of major hepatic veins. We present our method for the procedure. We experienced 6 cases: 3 right anterior, 2 left medial, and 1 right posterior extended sectionectomies with major hepatic vein resection; tumor sizes are within 40-75 (median: 60) mm. The operating time, intraoperative blood loss, and postoperative hospital stay are within 341-603 (median: 434) min, 100-750 (300) ml, and 8-44 (18) days. There was no mortality and 1 patient developed postoperative pleural effusion. For these procedures, we propose that the steps listed below are useful, taking advantages of the laparoscopy-specific view. (1) The Glissonian pedicle of the section is encircled and clamped. (2) Liver transection on the ischemic line is performed in the caudal to cranial direction. (3) During transection, the clamped Glissonian pedicle and the peripheral part of hepatic vein are divided. (4) The root of hepatic vein is divided in the good view from caudal and dorsal direction.


Assessment of Neutrophil Apoptosis.
The process of neutrophil apoptosis has an important role in the resolution of acute inflammation. Apoptotic cell death is characterized by a coordinated sequence of cellular alterations that serve to uncouple neutrophil effector functions whilst maintaining plasma membrane integrity. In this way the release on neutrophil intracellular contents, including proteases, glycosidases, and reactive oxygen species, is limited during apoptosis. In addition, plasma membrane alterations associated with neutrophil apoptosis provide molecular cues that enable recognition by phagocytic cells, including macrophages. The recognition and uptake of apoptotic neutrophils by macrophages dampens proinflammatory responses to pathogen- or damage-associated molecular patterns and triggers release of proresolution mediators, that further promote resolution of inflammation. The key cellular and molecular events that act to control neutrophil apoptosis and subsequent macrophage phagocytosis have been characterized by in vitro studies, unveiling potential therapeutic targets for the manipulation of these regulatory pathways. In this chapter, we outline some of the key assays that are used to assess neutrophil apoptosis in vitro, together with methods to assess activation of the apoptotic machinery and phagocytic clearance of apoptotic neutrophils.


Development and in vitro evaluation of buccal mucoadhesive films for photodynamic inactivation of Candida albicans.
Candidiasis is one of the most common diseases that occur in the oral cavity, caused mainly by the species Candida albicans. Methylene blue (MB) has a potential for microbial photoinactivation and can cause the destruction of fungi when applied in Photodynamic Therapy (PDT). Mucoadhesive films are increasingly being studied as a platform for drug application due to their advantages when compared to other pharmaceutical forms. The aim of this work was to develop mucoadhesive buccal film containing poloxamer 407 (P407), alcohol polyvinyl (PVA) and polyvinylpyrrolidone (PVP) for the release of MB aiming the photoinactivation of Candida albicans in buccal infections. Different amounts of P407 were added to the binary polymeric blends composed PVA and PVP. Formulations were characterized as morphology, thickness, density, bending strength, mechanical properties, water vapor transmission, disintegration time, mucoadhesion, DSC, ATR-FTIR, in vitro drug release profile and photodynamic inactivation. The films displayed physicochemical characteristics dependent of polymeric composition, mucoadhesive properties, fast MB release and were effective in photo inactivate the local growth of Candida albicans isolates. The formulation containing the lowest PVA and P407 amounts displayed the best performance. Therefore, data obtained from the film system show its potentially useful role as a platform for buccal MB delivery in photoinactivation of C. albicans, showing its potential for in vivo evaluation.


Dietary components and risk of total, cancer and cardiovascular disease mortality in the Linxian Nutrition Intervention Trials cohort in China.
Although previous studies have shown that dietary consumption of certain food groups is associated with a lower risk of cancer, heart disease and stroke mortality in western populations, limited prospective data are available from China. We prospectively examined the association between dietary intake of different food groups at baseline and risk of total, cancer, heart disease and stroke mortality outcomes in the Linxian Nutrition Intervention Trials(NIT) cohort. In 1984-1991, 2445 subjects aged 40-69 years from the Linxian NIT cohort completed a food frequency questionnaire. Deaths from esophageal and gastric cancer, heart disease and stroke were identified through up to 26 years of follow-up. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for associations between intake of groups of food items and these mortality endpoints. We concluded that higher intake of certain food groups was associated with lower risk of gastric cancer, heart disease and stroke mortality in a prospective cohort in rural China. Our findings provide additional evidence that increasing intake of grains, vegetables, beans, fruits and nuts may help reduce mortality from these diseases.


New functions of small nucleolar RNAs.
Small nucleolar RNAs (snoRNAs) are one of the most abundant and well-studied groups of non-coding RNAs. snoRNAs are mostly engaged in processing of rRNA. However, recent data indicate that snoRNAs are also involved in other processes including regulation of alternative splicing, translation and oxidative stress. snoRNAs are also involved in pathogenesis of some hereditary diseases and cancer. Therefore, the range of snoRNAs' functions is significantly wider than it has been assumed earlier.


The influence of androgens on the development of a sex difference in the vasopressinergic innervation of the rat lateral septum.
The vasopressinergic innervation of the lateral septum is much denser in male than in female rats. The present study demonstrates that, under physiological conditions, the development of this sex difference is dependent on the presence of androgens around the seventh postnatal day. It was possible, however, to induce in female or neonatally castrated male rats a fiber density as high as in control males by high doses of testosterone, given in the first, second or even third week of life.


Outcomes of obese patients undergoing less invasive LVAD implantation.
Obesity and heart failure rates continue to rise, confronting heart failure centers with challenging left ventricular assist device (LVAD) implantations. Although less invasive approaches to implantation have been successfully implemented by many centers, this surgical approach has not yet been well evaluated in the obese population. Therefore, we sought to describe our experience with less invasive device implantation in this patient cohort. All implants of centrifugal ventricular assist devices were retrospectively reviewed. Patients implanted with a less invasive approach via a left thoracotomy and upper hemisternotomy were included. Patients were stratified by body mass index (<30 vs ≥30 kg/m2 ). Perioperative and short-term outcomes were evaluated. Forty-two patients implanted with the less invasive approach (BMI <30: 27 vs. BMI ≥30 kg/m2 : 15) were identified. The obese cohort was significantly younger (58.5 vs 46.1 years, P = .022), while other preoperative demographics were similar. Postoperative mechanical ventilator time was longer in the obese cohort (22.9 vs 46.1 hour, P = .045). However, other perioperative and short-term outcomes were comparable. Wound dehiscence occurred in one obese patient. Six-month survival was also comparable between cohorts (96.3% vs 86.7%, P = .264). In this limited patient series, outcomes appear to be comparable in nonobese and obese patients undergoing less invasive LVAD implantation. Therefore, obesity should perhaps not be viewed as a lone contraindication to the application of this surgical approach.


BCL10 nuclear expression and t(11;18)(q21;q21) indicate nonresponsiveness to Helicobacter pylori eradication of Chinese primary gastric MALT lymphoma.
The eradication of Helicobacter pylori (H. pylori) with antibiotics induces complete remission in 75% of patients with gastric MALT lymphoma. We investigated the efficacy of H. pylori eradication and assessed the predictive value of BCL10 nuclear expression and t(11;18)(q21;q21) regarding resistance to H. pylori eradication in primary gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients from mainland China. Twenty-two gastric MALT cases (Stage I(E)) underwent H. pylori eradication with antibiotics, and sequential endoscopic-bioptic follow-ups were performed and assessed with regular morphologic and immunohistochemical examinations. BCL10 nuclear expression and interphase fluorescence in situ hybridization (FISH) for MALT1 and API2/MALT1 were tested. Thirteen out of the 22 cases (59.1%) achieved complete regression (CR) after the eradication of H. pylori. The longest follow-up period in the 22 patients was 68 months, with 12 patients longer than 24 months. For the 13 CR patients, the longest follow-up period after H. pylori eradication was 53 months, with 6 patients longer than 24 months. BCL10 nuclear expression was detected by immunohistochemical staining in 9 cases, including 7 (77.8%) of 9 cases who showed no response (NR) and 2 (15.4%) of 13 patients who achieved CR following eradication therapy (P < 0.05). t(11;18)(q21;q21) was evaluated by interphase FISH in 18 cases including 11 CR and 7 NR patients after H. pylori eradication. t(11;18)(q21;q21) was found in 4 (57.1%) of 7 patients who showed NR following H. pylori eradication, but one in 11 CR patients (P < 0.05). A total of 59.1% of patients with early gastric MALT lymphoma recruited in this study achieved CR after H. pylori eradication. BCL10 nuclear expression and t(11;18)(q21;q21)-positive gastric MALT lymphomas are likely to be related to a failure to respond to H. pylori eradication in Chinese patients.


Expression of inducible nitric oxide synthase and cyclooxygenase-2 in ovarian cancer: correlation with clinical outcome.
Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) play a critical role in cancer development. We investigated iNOS and COX-2 expression in relation to clinical outcome in 78 International Federation of Gynecology and Obstetrics (FIGO) stage III ovarian serous carcinoma with a low grade of differentiation (G3). Disease-free interval and cause-specific survival rates (Kaplan-Meier method) were compared using the log rank test. A multivariate analysis (Cox-proportional hazards models) was used to determine the independent effect of each variable on prognosis. Fisher's exact test was used to analyze the distribution of iNOS and COX-2 expression according to clinical complete response to chemotherapy and to the presence of a brief disease-free interval (< or =12 months). Overall 60 and 125 months cause-specific survival rates were 32% and 11%, respectively. In univariate analysis, iNOS (P=0.005 and P=0.003, respectively), COX-2 (P=0.002 and P=0.007, respectively), residual disease after surgery (P=0.017 and P=0.032, respectively), and FIGO stage (P=0.008 and P=0.025, respectively) were associated with survival and a disease-free interval. In multivariate analysis (Cox proportional hazards models), the factors that were found to be significantly independent predictors of disease relapse as well as survival were iNOS (P=0.014 and P=0.001, respectively), COX-2 expression (P=0.007 and P=0.029, respectively), and FIGO stage (P=0.026 and P=0.05, respectively). iNOS and COX-2 expressions were correlated with a brief disease-free interval (P=0.001) and clinical complete response to first-line chemotherapy (P=0.038 and P=0.033, respectively). The evaluation of iNOS and COX-2 expression may give additional prognostic information concerning the clinical outcome of patients with ovarian carcinoma and may encourage them to select more tailored therapies.


Detection of glial fibrillary acidic protein and neurofilaments in the cerebrospinal fluid of patients with neurocysticercosis.
Neurocysticercosis (NCC) is an infection caused by Taenia solium larval metacestodes in the central nervous system. The glial fibrillary acidic protein (GFAP) and neurofilaments (NFs) can be used as markers of glial and neuronal damage, respectively. We studied the GFAP and NFs of 68, 160 and 200 kDa in the cerebrospinal fluid (CSF) of patients with NCC by Western blotting. Our results showed that patients with NCC had significantly elevated GFAP levels in the CSF compared with the control, whereas NFs of 68, 160 and 200 kDa were not detected in the CFS of NCC patients. We concluded that GFAP could be used as a marker of glial damage in the CFS of NCC patients.


Synthesis and photophysics of an octathioglycosylated zinc(II) phthalocyanine.
A water soluble zinc(II) phthalocyanine symmetrically appended with eight thioglucose units was synthesized from commercially available hexadecafluorophthalocyaninatozinc(II) by controlled nucleophilic substitution of the peripheral fluoro groups. The photophysical properties and cancer cell uptake studies of this nonhydrolyzable thioglycosylated phthalocyanine are reported. The new compound has amphiphilic character, is chemically stable, and can potentially be used as a photosensitizer in photodynamic therapy.


Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance.
We aimed to investigate the efficacy of pegvisomant in patients with acromegaly resistant to long-term (> or = 24-month), high-dose treatment with octreotide-LAR (40 mg/month) or lanreotide (120 mg/month). This was an open, prospective study. We studied 16 patients with acromegaly (nine women; aged 28-61 years). The main outcome measures were IGF-I levels, blood pressure, glucose tolerance and safety (liver function and tumor size). Pegvisomant was given at doses of 10-40 mg s.c. daily. Dose titration was performed every month by IGF-I assay. Three patients spontaneously stopped pegvisomant treatment after 6-9 months because of poor compliance; from the measurement of serum pegvisomant, another patient was found not to inject herself properly. After 6 months, IGF-I levels decreased by 63 +/- 19% (767.8 +/- 152.9 vs 299.8 +/- 162.9 microg/l, P < 0.0001, t-test); serum IGF-I levels normalized in 57%. After 12 months, IGF-I levels normalized in nine (75%) patients and were reduced by over 50% in another three (25%). The mean tumor volume remained stable during the study (1198 +/- 1234 vs 1196 +/- 1351 mm(3), P = 0.37): it did not change ( +/- 25% vs basal) in nine patients, increased by 39.4% and 40.8% in two and decreased by 30.8-46.5% in four. The total/high-density lipoprotein (HDL):cholesterol ratio (from 4.4 +/- 1.0 to 3.7 +/- 0.6, P = 0.0012), glucose levels (from 5.6 +/- 1.2 to 4.4 +/- 1.4 mmol/l, P = 0.026), insulin levels (from 12.4 +/- 6.7 to 8.1 +/- 3.0 mUl/l, P = 0.0023) and homeostasis model assessment (HOMA) index (from 3.4 +/- 2.1 to 1.9 +/- 1.0, P = 0.0017) decreased. Treatment for 12 months with pegvisomant normalized IGF-I levels, and improved cardiovascular risk parameters and insulin sensitivity in patients with acromegaly resistant to long-term, high-dose treatment with somatostatin analogs. The tolerance of treatment was good.


Phospholipid composition of cultured human endothelial cells.
Detailed analyses of the phospholipid compositions of cultured human endothelial cells are reported here. No significant differences were found between the phospholipid compositions of cells from human artery, saphenous and umbilical vein. However, due to the small sample sizes, relatively large standard deviations for some of the phospholipid classes were observed. A representative composition of endothelial cells is: phosphatidylcholine 36.6%, choline plasmalogen 3.7%, phosphatidylethanolamine 10.2%, ethanolamine plasmalogen 7.6%, sphingomyelin 10.8%, phosphatidylserine 7.1%, lysophosphatidylcholine 7.5%, phosphatidylinositol 3.1%, lysophosphatidylethanolamine 3.6%, phosphatidylinositol 4,5-bisphosphate 1.8%, phosphatidic acid 1.9%, phosphatidylinositol 4-phosphate 1.5%, and cardiolipin 1.9%. The cells possess high choline plasmalogen and lysophosphatidylethanolamine contents. The other phospholipids are within the normal biological ranges expected. Phospholipids were separated by high-performance liquid chromatography and quantified by lipid phosphorus assay.


Antioxidant vitamins in prevention.
The authors are aware that there is still a need for much research to elucidate the possible preventive effects of antioxidant vitamins with regard to degenerative and neoplastic diseases. There must also be vigorous examination of the evidence that antioxidant vitamins can play a crucial part in a large number of other disorders (Alzheimer's disease, Parkinson's disease, diabetes, chronic and acute inflammations, airway disorders, reperfusion syndrome). The aim of prevention-oriented medical research must be to develop suitable measures able to make a considerable contribution to the overall prevention policy. Although there is still uncertainty about the mode of action and the optimal dosage of antioxidant nutrients and dietary constituents, particularly because of the safety when the dosage is correct, more information must be provided about early prevention of an inappropriate, low antioxidant intake; intake in the diet should definitely be preferred to supplementation because of the other beneficial effects of the recommended foodstuffs.


Pasieka's parathyroid symptoms scores correlate with SF-36 scores in patients undergoing surgery for primary hyperparathyroidism.
Parathyroidectomy for primary hyperparathyroidism (PHPT) is expected to trigger an improvement in the quality of life. This has been demonstrated previously by using the SF-36 questionnaire, whose interpretation is difficult in routine clinical practice. As an alternative, the 13-item questionnaire developed by Pasieka et al. can be used to assess the severity of symptoms on a visual analogue from which a parathyroid assessment of symptoms score (PAS) can be calculated. The purpose of this study was to correlate results of these two assessment tools. Prospective case-series study recruiting consecutive unselected patients who underwent successful parathyroidectomy for PHPT. SF-36(v2) and Pasieka's questionnaires were collected before parathyroidectomy and at 3, 6, and 12 months postoperatively. Between November 2005 and December 2006, 101 patients were diagnosed with PHPT (30 men; aged 18-89 years). Preoperative PAS ranged 0-1040 and did not correlate with the severity of hypercalcemia (2.91+/-0.25; range, 2.56-3.4 mmol/l). Scores from the SF-36 questionnaire were under the 50th percentile for the normal population in three domains (vitality, emotional role, and physical role). Minimally invasive parathyroidectomy was performed in 69 patients and bilateral cervical exploration in 32 patients. All were found to have a single parathyroid adenoma and were normocalcemic at 3-12 months after parathyroidectomy. At follow-up, there was a significant reduction of PAS from 460+/-257 preoperatively to 254+/-234 at 3 months postoperatively (n=72), to 245+/-215 at 6 months (n=50), and 249+/-212 at 12 months (n=63) (p<0.05, Student's t-test). There was a significant and persistent improvement in five domains of SF-36 questionnaire: bodily pain, general health, vitality, social functioning and mental health. Overall analysis of 244 assessments using both questionnaires demonstrated a negative correlation between increasing PAS and decreasing mental component scores and physical component scores of the SF-36 assessment (r2=0.372 and 0.301, respectively). Pasieka's parathyroid assessment of symptom scores (PAS) correlate with SF-36 questionnaire scores. Because PAS allows easier and faster analysis, we advocate that Pasieka's questionnaire should be integrated into the assessment of patients with PHPT as a reliable tool to identify symptomatic changes that correlate with improved quality of life.


Some microbial, chemical and sensorial properties of gamma irradiated sesame (Sesamum indicum L.) seeds.
The effect on microbial, chemical and sensorial properties of sesame seeds was determined after irradiation and storage. The sesame seeds were analyzed before and after irradiation with 3, 6 and 9 kGy of gamma irradiation, and after 6 and 12 months of storage. The results showed that gamma irradiation had no significant (p>0.05) effect on the moisture, ash and fat content on sesame seeds. While, small differences, but sometimes significant (p<0.05), on protein and sugar contents were recorded between irradiated and non-irradiated samples. Total acidity percentage decreased significantly (p<0.05), while total volatile basic nitrogen (TVBN) increased significantly (p<0.05) due to irradiation. During storage, total acidity increased (p<0.05) and TVBN decreased (p<0.05). Gamma irradiation reduced the microorganisms of sesame seeds. Samples treated with 3 kGy or more remained completely free of fungi throughout the storage. While, only the samples treated with 9 kGy remained completely free of bacteria at the end of storage period (after 12 months). The scores for taste, flavor, color and texture of irradiated samples were higher, but not significantly (p>0.05) than those of non-irradiated samples.


Determination of fatty acids in bio-samples based on the pre-column fluorescence derivatization with 1,3,5,7-tetramethyl-8-butyrethylenediamine-difluoroboradiaza-s-indacene by high performance liquid chromatography.
1,3,5,7-Tetramethyl-8-butyrethylenediamine-difluoroboradiaza-s-indacene (TMBB-EDAN) has been designed and synthesized as a highly fluorescent labeling reagent for carboxylic acids. By using TMBB-EDAN, a sensitive and rapid method based on high performance liquid chromatography-fluorescence detection for the determination of twelve fatty acids (FAs) in bio-samples has been developed. Under optimized conditions, these FAs were tagged with TMBB-EDAN in the presence of 1-ethyl-3-(3-dimethyla-minopropyl) carbodiamide at 20°C for 30min and then the baseline separation was achieved on a C18 column with a linear gradient elution in 26min. With fluorescence detection at λex/λem=490nm/510nm, the linear ranges of FAs were from 3.0 to 300nM and the detection limits with a signal-to-noise ratio of 3 were in the 0.2-0.4nM range. The proposed method offers advantages of milder derivatization condition and much better sensitivity for the determination of FAs, when compared to the reported fluorescence derivatization-based methods.


Gene-expression profiling in Chinese patients with colon cancer by coupling experimental and bioinformatic genomewide gene-expression analyses: identification and validation of IFITM3 as a biomarker of early colon carcinogenesis.
Expression microarrays are widely used for investigating the nature and extent of global gene-expression changes in human cancer. Accurate genomewide gene-expression profiles have not been conducted in colon tumor and normal colon tissue specimens obtained from Chinese patients. In the present study a pure population of colon cancer and normal colon cells was obtained and the global gene-expression differences were compared in the 2 cell types using combined experimental and bioinformatic approaches. Various categories of genes that were differentially expressed in those 2 types of cells were identified, including a novel candidate tumor marker, IFITM3. Elevated IFITM3 expression in colon cancer cells was first confirmed using quantitative real-time polymerase chain reaction. IFITM3 protein expression in human colon cancer specimens was further analyzed using both tissue microarray and standard tissue sections by immunostaining analyses. It was found that there was a significant IFITM3 increase in adenoma as compared with that in normal colon tissue. The data suggest that IFITM3 plays an important role in early colon cancer development.


CAR-T Therapy in Clinical Practice: Technical Advances and Current Challenges.
Chimeric antigen receptors (CAR) redirect T cells to specifically recognize and eliminate tumor cells. CAR-T therapy has achieved successful clinical outcomes, and it has been transformed into commercially available products to treat acute lymphoblastic leukemia and B cell lymphoma. These breakthroughs have motivated hundreds of CAR-T clinical trials initiated each year, with ≈900 cases registered on the ClinicalTrials website till 2021. Accumulating clinical experiences have highlighted some limitations of this strategy, e.g., relapse after complete response, poor efficacy in solid tumors, on-target off-tumor toxicities, lack of persistence, and tumor resistance. These challenges limit the therapeutic application of CAR-T cells. Multidisciplinary approaches are actively investigated to address these issues. In this review, the antigens, CAR designs, and cell sources are summarized in clinical trials from 2020 to 2021. The innovative modular and programmable designs in CAR-T cells, including advances in signaling domains, antigen-recognition domains, T cell engineering, and cell resources, are further discussed. Integrative genetic and chemical engineering strategies are promising to improve the versatility, antitumor efficacy, persistence, and safety of CAR-T cells. In the future, the next generation of CAR-T cell therapies will offer more options for patients who are refractory to standard tumor therapies.


Thiol diffusion and the role of humidity in "Dip Pen Nanolithography".
The radii of octadecanethiol spots deposited by an atomic force microscope tip onto a gold surface were studied as a function of contact time and humidity. The deposition is well described by two-dimensional diffusion from an annular source of constant concentration, with a surface diffusion coefficient of 8400 nm(2) s(-1), independent of humidity. Facile transfer is observed even after near continuous deposition for more than 24 h in a dry N2 environment, indicating that a water meniscus is not required.


Axonal transport of glycerophospholipids in regenerating sciatic nerve of the rat during aging.
The effect of age upon the axoplasmic transport of glycerophospholipids has been studied using as a model the regenerating sciatic nerve of young (2-month-old), young adult (6-month-old), middle-aged (16-month-old), and aged (20-month-old) male rats. The right sciatic nerve was crushed 0.5 mm down the incisura ischiadica. Four and nine days after the lesion, a mixture of [2-3H] glycerol and [methyl-14C] choline was bilaterally injected into the spinal cord, at a level of the L4-L5 vertebrae. The animals were killed 18 hr after the isotope injection. Proximal and distal portions of crushed nerve and of contralateral sham-operated ones were dissected and consecutive 5-mm segments were subjected to lipid extraction and analysis. The findings of the present study are summarized as follows: (1) The accumulation of labeled lipid material axonally transported four days after nerve injury was mainly located at the crush site in young, young adult, middle-aged, and aged rats. The accumulation of both 3H-glycerolipids and 14C-choline phospholipids in postcrush segments was markedly higher for young and young adult than for aged rats, four and nine days after crush; (2) the average rate of axonal regeneration, determined between days 4 and 9 following crush injury was 3.6 and 4.2 mm/day for 2-month-old and 6-month-old rats, respectively; it decreased to the value of 2.5 mm/day for 16-20-month-old rats.


Toxicological effects of chronic low doses of aflatoxin B(1) and fumonisin B(1)-containing Fusarium moniliforme culture material in weaned piglets.
The effects of chronic oral exposure (28 days) to aflatoxin B(1) (AFB(1)) and fumonisin B(1) (FB(1)) were studied in weaned piglets. Six experimental groups, each comprising two neutered males and two females, were fed ad libitum with rations containing: (A) 0 mg of FB(1) and 0 mg of AFB(1)/kg of feed (control); (B) 10 mg of FB(1)/kg of feed; (C) 30 mg of FB(1)/kg of feed; (D) 50 microg of AFB(1)/kg of feed; (E) 10 mg of FB(1) plus 50 microg of AFB(1)/kg of feed; (F) 30 mg of FB(1) plus 50 microg of AFB(1)/kg of feed. The animals were inspected twice daily and their body weight and feed consumption were recorded weekly and daily, respectively. Samples of feces and urine were collected 24 h after the start of the experiment, to check for fumonisin residues by HPLC analysis. Blood samples were drawn at the start of the experiment and after 28 days for quantification of hematological and biochemical parameters. Necropsies were performed after 28 days; at necropsy, the organs were weighed, inspected macroscopically and processed for histopathological and toxicological analyses. All piglets from groups C and F presented typical signs of pulmonary edema, with reduced feed consumption and body weight gain as well as pathological alterations. FB(1) was detected in feces and urine at 24 h of intoxication and in liver after 28 days of intoxication. Increases were detected regarding the following hematological and biochemical parameters in animals from treatments C and F: erythrocyte number; hematocrit; total bilirubin; total protein; activity of serum alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Cholesterol levels were significantly aumented only in animals from groups C and F, whereas albumin concentrations increased in groups C, F, B and E. The average organ/body weight ratio of piglets (hearth, liver and lung) were significantly greater in groups C and F. The only joint effects of FB(1) and AFB(1) detected (group F) were a decrease in feed consumption during the last week of intoxication and in feed conversion throughout the 28 days of intoxication. Chronic intoxication of piglets with AFB(1) and FB(1) leads to important losses of productivity.


Combining oxidative N-heterocyclic carbene catalysis with click chemistry: a facile one-pot approach to 1,2,3-triazole derivatives.
A combination of the oxidative N-heterocyclic carbene catalysis and click chemistry has been explored for the direct, one-pot synthesis of 1,2,3-triazole derivatives from aromatic aldehydes. This procedure was found to be very efficient and a variety of 1,2,3-triazole derivatives could be accessed through their corresponding propargyl esters in moderate-to-good yields under mild conditions.


Recognition of the mRNA AU-rich element by the zinc finger domain of TIS11d.
The tandem zinc finger (TZF) domain of the protein TIS11d binds to the class II AU-rich element (ARE) in the 3' untranslated region (3' UTR) of target mRNAs and promotes their deadenylation and degradation. The NMR structure of the TIS11d TZF domain bound to the RNA sequence 5'-UUAUUUAUU-3' comprises a pair of novel CCCH fingers of type CX(8)CX(5)CX(3)H separated by an 18-residue linker. The two TIS11d zinc fingers bind in a symmetrical fashion to adjacent 5'-UAUU-3' subsites on the single-stranded RNA via a combination of electrostatic and hydrogen-bonding interactions, with intercalative stacking between conserved aromatic side chains and the RNA bases. Sequence specificity in RNA recognition is achieved by a network of intermolecular hydrogen bonds, mostly between TIS11d main-chain functional groups and the Watson-Crick edges of the bases. The TIS11d structure provides insights into the RNA-binding functions of this large family of CCCH zinc finger proteins.


Copper(I)-Catalyzed Asymmetric Vinylogous Aldol-Type Reaction of Allylazaarenes.
A vinylogous aldol-type reaction of allylazaarenes and aldehydes is disclosed that affords a series of chiral γ-hydroxyl-α,β-unsaturated azaarenes in moderate to excellent yields with high to excellent regio- and enantioselectivities. With (R,RP )-TANIAPHOS and (R,R)-QUINOXP* as the ligand, the carbon-carbon double bond in the products is generated in (E)-form. With (R)-DTBM-SEGPHOS as the ligand, (Z)-form carbon-carbon double bond is formed in the major product. In this vinylogous reaction, aromatic, α,β-unsaturated, and aliphatic aldehydes are competent substrates. Moreover, a variety of azaarenes, such as pyrimidine, pyridine, pyrazine, quinoline, quinoxaline, quinazoline, and benzo[d]imidazole are well-tolerated. At last, the chiral vinylogous product is demonstrated as a suitable Michael acceptor towards CuI-catalyzed nucleophilic addition with organomagnesium reagents.


A longitudinal study of body fatness in childhood and adolescence.
Data from the United States Health Examination Surveys were analyzed to determine changes in body fatness between childhood and adolescence. A national probability sample (2,177 children) was examined in both Cycle II (6 to 11 years) and Cycle III (12 to 17 years) of these surveys and comprised the study cohort. The interval between examinations was three or four years. Adiposity was measured as skinfold thickness and correlations between childhood and adolescent adiposity were explored. High rank-order correlations were found between the two examinations for each race-sex group (P less than 0.001). The relationship between childhood and adolescent fatness was independent of stature, skeletal and sexual maturation, and economic status. Childhood fatness was the most predictive factor for adolescent fatness. This strong relationship indicates that the potentially obese adolescent can be identified during childhood.


To make a difference: nursing presence.
Nursing presence in clinical practice. To explore the concept of presence within the nursing literature. Published literature. True presence creates the opportunity for nurses to go where the patient is in life, to learn about the experience of health as it is defined and lived, and to work with patients as they choose the meaning of the situation.


Robotic balance assessment in community-dwelling older people with different grades of impairment of physical performance.
Impaired physical performance is common in older adults and has been identified as a major risk factor for falls. To date, there are no conclusive data on the impairment of balance parameters in older subjects with different levels of physical performance. The aim of this study was to investigate the relationship between different grades of physical performance, as assessed by the Short Physical Performance Battery (SPPB), and the multidimensional balance control parameters, as measured by means of a robotic system, in community-dwelling older adults. This study enrolled subjects aged ≥ 65 years. Balance parameters were assessed by the hunova robot in static and dynamic (unstable and perturbating) conditions, in both standing and seated positions and with the eyes open/closed. The study population consisted of 96 subjects (62 females, mean age 77.2 ± 6.5 years). According to their SPPB scores, subjects were separated into poor performers (SPPB < 8, n = 29), intermediate performers (SPPB = 8-9, n = 29) and good performers (SPPB > 9, n = 38). Poor performers displayed significantly worse balance control, showing impaired trunk control in most of the standing and sitting balance tests, especially in dynamic (both with unstable and perturbating platform/seat) conditions. For the first time, multidimensional balance parameters, as detected by the hunova robotic system, were significantly correlated with SPPB functional performances in community-dwelling older subjects. In addition, balance parameters in dynamic conditions proved to be more sensitive in detecting balance impairments than static tests.


Utility of a screening tool for haemostatic defects in a multicentre cohort of adolescents with heavy menstrual bleeding.
Heavy menstrual bleeding (HMB) may be expected for many adolescents after menarche. Accurate assessment of HMB, a key component in the diagnosis of a haemostatic defect (HD), is a well-recognized challenge. Our objective was to determine the diagnostic accuracy of an HMB-specific screening tool for HDs in adolescents with HMB, presenting to a secondary care setting. Adolescents with HMB were evaluated for a HD at 4 US centres. A screening tool, the Philipp Tool, developed and validated in adult women with HMB, was administered. We modified the tool by assigning a score based on the number of affirmative responses. Sensitivity, specificity and likelihood ratios (LRs) of a positive tool, modified tool, with a pictorial blood assessment chart (PBAC) score >185, and with serum ferritin ≤20 ng/mL were calculated for HDs. Among 248 adolescents with HMB, 29% were diagnosed with HDs. Sensitivity, specificity and LR of a positive screening tool for HDs were 95% (range 88-99), 14% (9-21) and 1.1 (1-1.2), respectively. A score of ≥2, addition of a PBAC score >185 and ferritin ≤20 ng/mL changed the sensitivity, specificity and LR of the tool to 72% (61-81), 94% (83-99), 76% (65-85); 60% (53-68), 24% (16-34) and 39% (31-47) and 1.8 (1.4-2.2), 1.2 (1.1-1.4) and 1.2 (1-1.4), respectively. Although sensitive, the discriminative ability of the tool to identify adolescents with HDs from those without, who presented with HMB, was low. Further research is needed to optimize or develop an adolescent-specific HMB tool for secondary care settings.


Postoperative adhesion prevention using a statin-containing cellulose film in an experimental model.
Intraperitoneal adhesions are a common problem in abdominal surgery. The aim of this study was to compare the effectiveness of Statofilm, a novel antiadhesive film based on cross-linked carboxymethylcellulose and atorvastatin, with that of sodium hyaluronate-carboxymethylcellulose (Seprafilm(®)) in the prevention of postoperative intraperitoneal adhesions in rats. One hundred male Wistar rats underwent a laparotomy and adhesions were induced by caecal abrasion. The animals were allocated to five groups: a control group with no adhesion barrier, Seprafilm(®) group, placebo group with a film containing carboxymethylcellulose without atorvastatin, and low- and high-dose groups with films containing carboxymethylcellulose and atorvastatin 0·125 and 1 mg per kg bodyweight respectively. Adhesions were classified by two independent surgeons 2 weeks after surgery. Caecal biopsies were obtained for histological evaluation of fibrosis, inflammation and vascular proliferation. All antiadhesive film groups (Seprafilm(®), placebo, low-dose and high-dose) had statistically significant adhesion reduction compared with the control group (P < 0·001, P = 0·015, P < 0·001 and P < 0·001 respectively). The low-dose Statofilm was superior to Seprafilm(®) in terms of adhesion prevention (P = 0·001). Adhesions were present in three-quarters of rats in the Seprafilm(®) group, but only one-quarter in the low-dose Statofilm group. The data suggest that the newly developed adhesion barrier Statofilm has better results than Seprafilm(®) in preventing postoperative adhesions in rats. A low-dose atorvastatin-containing film, such as Statofilm, could be evaluated for future clinical application.


Spectral features of resting-state EEG in Parkinson's Disease: A multicenter study using functional data analysis.
This study aims 1) To analyse differences in resting-state electroencephalogram (rs-EEG) spectral features of Parkinson's Disease (PD) and healthy subjects (non-PD) using Functional Data Analysis (FDA) and 2) To explore, in four independent cohorts, the external validity and reproducibility of the findings using both epoch-to-epoch FDA and averaged-epochs approach. We included 169 subjects (85 non-PD; 84 PD) from four centres. Rs-EEG signals were preprocessed with a combination of automated pipelines. Sensor-level relative power spectral density (PSD), dominant frequency (DF), and DF variability (DFV) features were extracted. Differences in each feature were compared between PD and non-PD on averaged epochs and using FDA to model the epoch-to-epoch change of each feature. For averaged epochs, significantly higher theta relative PSD in PD was found across all datasets. Also, higher pre-alpha relative PSD was observed in three of four datasets in PD patients. For FDA, similar findings were achieved in theta, but all datasets showed consistently significant posterior pre-alpha differences across multiple epochs. Increased generalised theta, with posterior pre-alpha relative PSD, was the most reproducible finding in PD. Rs-EEG theta and pre-alpha findings are generalisable in PD. FDA constitutes a reliable and powerful tool to analyse epoch-to-epoch the rs-EEG.


Solid-phase extraction based on hydrophilic interaction liquid chromatography with acetone as eluent for eliminating matrix effects in the analysis of biological fluids by LC-MS.
Analysis of drugs and metabolites in biological matrices such as blood or plasma by LC-MS is routinely challenged by the presence of large quantities of competing molecules for ionization in soft ionization sources, such as proteins and phospholipids. While the former can easily be removed by protein precipitation, pre-analytical extraction of the latter is necessary because they show very high retention in reversed-phase LC resulting in long analysis times or in ion suppression effects when not eluted before the next runs. A novel HILIC-based SPE approach, making use of silica cartridges and of acetone as organic solvent, is introduced as a potent alternative to current commercial methods for phospholipid removal. The methodology was developed and tested for a broad polarity range of pharmaceutical solutes (log P from 0 to 6.6) and broad applicability can therefore be envisaged.


Never too little: Grip and lift forces following probabilistic weight cues in patients with writer's cramp.
Planning of voluntary object-related movements requires the estimation of the most probable object properties. We investigated how 14 writer's cramp (WC) patients compared to 14 controls use probabilistic weight cues in a serial grip-lift task. In every grip-lift trial, an object of either light, medium or heavy weight had to be grasped and lifted after a visual cue gave a probabilistic prediction of the object weights (e.g. 32.5% light, 67.5% medium, 0 % heavy). We determined peak (1) grip force GF, (2) load force LF, (3) grip force rate GFR, (4) load force rate LFR, while we registered brain activity with functional magnetic resonance imaging. In both groups, GFR, LFR and GF increased when a higher probability of heavy weights was announced. When a higher probability of light weights was indicated, controls reduced GFR, LFR and GF, while WC patients did not downscale their forces. There were no inter-group differences in blood oxygenation level dependent activation. WC patients could not utilize the decision range in motor planning and adjust their force in a probabilistic cued fine motor task. The results support the pathophysiological model of a hyperfunctional dopamine dependent direct basal ganglia pathway in WC.


Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice.
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of viral hepatitis in the pre- and post-transplant period. The current guidelines reflect the declining need for hepatitis B immunoglobulin following liver transplant, now replaced with nucleos(t)ide analogues that effectively suppress viral replication for the long term with minimal risk for drug resistance. It describes the limitations of pegylated interferon alpha in the treatment for chronic hepatitis D. The guidelines feature the paradigm shift in the treatment arena of chronic hepatitis C, now consisting of highly effective direct-acting antiviral (DAA) medications that effect a cure almost universally. Its safety profile and easy tolerance have permitted its use in patients with decompensated cirrhosis and/or end-stage renal disease. The high potency of the DAA's has fueled the rapidly expanding utilization of hepatitis C-exposed grafts in non-hepatitis C-infected liver, heart, or kidney recipients within structured protocols, followed by viral eradication with DAA therapy in the peri- or post-transplant period. Chronic hepatitis E has become more recognized in the solid-organ transplant recipients, and the therapeutic approach has been streamlined to start with reduction of immunosuppression, and if indicated afterward, ribavirin monotherapy.


Effects of minimal dose aprotinin on blood loss and fibrinolytic system-complement activation in coronary artery bypass grafting surgery.
To determine whether 500,000 KIU aprotinin is effective to reduce blood loss in coronary artery bypass grafting (CABG) and to evaluate the effects of this regimen on hematologic parameters. Forty-four patients scheduled for primary CABG were randomly assigned to the aprotinin (n = 24) or control group (n = 20). In aprotinin group, aprotinin was administered in two equal doses (before skin incision and added to the pump prime). Ventilation time, intensive care unit stay, mediastinal tube drainage, hospitalization, transfusion requirements, and postoperative morbidities and mortality were noted. Hematologic markers of fibrinolytic activity and complement activation were also measured pre- and postoperatively. Although less mediastinal drainage occurred in aprotinin group, the difference was not statistically significant. Other postoperative variables like transfusion requirements, morbidities, and mortality were also found to be similar between groups. Among hematologic parameters, only postoperative levels of alpha2-antiplasmin and plasminogen activator inhibitor-1 were significantly higher in aprotinin group. Although plasmin inhibitors begin to rise at this very low aprotinin dosage, it is not advisable to use this aprotinin regimen in CABG patients.


The use of an early postoperative CRH test to assess adrenal function after transsphenoidal surgery for pituitary adenomas.
Transsphenoidal surgery (TS) is the treatment of choice for many pituitary tumors. Because TS may cause pituitary insufficiency in some of these patients, early postoperative assessment of pituitary function is essential for appropriate endocrine management. The aim of our study was to evaluate the clinical relevance of the CRH-stimulation test in assessing postoperative pituitary-adrenal function. We performed a retrospective analysis of 144 patients treated by TS between January 1990 and November 2009, in whom a CRH-test and a second stimulation test was performed to assess adrenal function during follow-up. Patients with Cushing's disease were excluded. Hydrocortisone substitution was started if peak cortisol levels were <550 nmol/L. The cortisol response was insufficient in 42(29%) and sufficient in 102 patients at the postoperative CRH-test. Thirteen of 42(30%) demonstrated a normal cortisol response during a second cortisol stimulation test. In 75 of the 102 patients with a sufficient response to CRH repeat testing revealed an insufficient cortisol response in 14 patients (14%). All but one had concomitant pituitary hormone deficits. There were no cases of adrenal crises during follow-up. Additional pituitary insufficiency was significantly more present (P < 0.001) in the group of patients with an abnormal response to CRH directly after surgery. In this study a substitution strategy of hydrocortisone guided by the postoperative cortisol response to CRH appeared safe and did not result in any case of adrenal crises. However, the early postoperative CRH-test does not reliably predict adrenal function after TS for pituitary adenomas in all patients and retesting is mandatory.


Evaluation of the role of timolol 0.1% gel in myopic regression after laser in situ keratomileusis.
To evaluate the efficacy of the concomitant administration of antiglaucoma medications namely timolol 0.1% gel in cases with myopic regression after myopic laser in situ keratomileusis (LASIK). Prospective observational clinical trial. Ninty five eyes of 75 patients were included in this study prospectively. The mean myopic regression was -1.29 ± 0.83 diopters (range -0.5 to -4.62) after myopic LASIK. The eyes were divided into two groups: 50 eyes administrated timolol 0.1% gel once daily for 12 months (treated group), and 45 eyes were age matched (control group). We assessed the amounts of myopic regression in terms of changes in the refraction (spherical equivalent and astigmatism), intraocular pressure (IOP), pachymetry and the refractive power of the cornea measurements for all participants. The refractive error and visual acuity were similar between the two groups at baseline. The treated group had an improvement in spherical equivalent significantly from -1.29 ± 0.83 to -0.94 ± 1.07 diopters (P = 0.012). Astigmatism was changed from -0.94 ± 0.53 to -0.86 ± 0.60 diopters but this change was not statistically significant (P = 0.20). The IOP was decreased significantly from 12.6 ± 1.9 to 9.0 ± 1.1 mm Hg (P < 0.001). Central corneal thickness was changed from 425.6 ± 19.86 to 429 ± 18.1 μm but not statistically significant (P = 0.56). The central corneal power decreased significantly from 37.2 ± 1.8 to 36.4 ± 1.3 diopters (P < 0.05). Timolol 0.1% gel was effective for reduction and improvement of myopic regression especially the spherical errors after myopic LASIK.


Calculation of cerebral tissue and cerebrospinal fluid space volumes from computer tomograms.
The volumes of the cerebral tissue, and internal and external cerebrospinal fluid spaces were calculated from the computer tomograms of 28 patients. On the basis of their different absorption coefficients, cerebral tissue and CSF space were outlines and their volumes calculated by computer. The ratio of cerebral tissue volume to CSF space volume was expressed as an index. This correlated well with an objective grading of severity of hydrocephalus. The index in patients without pathology was between 10.5 and 18.4. In cerebral atrophy the index was between 2.1 and 6.7 depending upon the severity. In occlusive hydrocephalus it was between 1.0 and 5.6. The changes in the volume of the CSF space after treatment can easily by demonstrated by appropriate changes in the index.


Effects of lesions of the Locus coeruleus and the ventral noradrenergic bundle on the antinociceptive action of clonidine in rats.
Effects of electrolytic lesions of noradrenergic brain systems on clonidine-induced analgesia were tested in rats by tail-compression method. Bilateral lesions of the locus coereleus decreased clonidine analgesia whilst lesions involving the ventral noradrenergic bundle produced no significant effect. These data demonstrate that antinociceptive effect of clonidine is related to action upon the noradrenergic system of the locus coeruleus.


Trends in tobacco smoking and smoking cessation in Russia with a focus on Indigenous populations: A narrative review.
Tobacco smoking is one of the main preventable causes of illness and premature death. Globally, more than 7 million people die annually from diseases associated with smoking, and this number is projected to increase to 8 million per year by 2030. Wide disparities in smoking prevalence exist by gender, age, socioeconomic status, rurality and ethnicity. In several countries, smoking is disproportionately high among the Indigenous populations. This review assesses the prevalence and harm of smoking and current trends in smoking cessation among the diverse multi-ethnic populations of Russia, with a particular emphasis on Indigenous populations. We systematically searched health, nursing, social science and grey literature databases and bibliographies for relevant studies. Search strings combined keywords related to smoking prevalence and smoking cessation with keywords related to Russia and the Indigenous populations of Russia. Studies were included if they were published between 1 January 2005 and 14 October 2020, and if they reported prevalence of tobacco smoking and/or activities and outcomes of a smoking cessation programme or ban in the Russian Federation. Tobacco smoking is significant in the entire Russian population, a higher prevalence of smoking in Indigenous populations compared to the dominant Russian (Slavic) ethnic group is common. Smoking prevalence data for most of the Indigenous ethnic groups of Russia remains unclear. Tobacco control interventions for Indigenous groups are underdeveloped even though they have the potential to deliver proportionately greater reduction in smoking harm.


Synthesis and bioassay of a boron-dipyrromethene derivative of estradiol for fluorescence imaging in vivo.
C7α-substituted estradiols bind to estrogen receptors in cell nuclei, yet these derivatives remain little used in bioimaging. Here, we describe a fluorescent derivative of estradiol (E2) with a boron-dipyrromethene (BODIPY) moiety attached to C7α, synthesized by olefin metathesis reaction of 7α-allylestradiol and 9-decenyl-BODIPY. In ovariectomized rats and non-ovariectomized mice, E2-BODIPY promoted the growth of uterine tissue similar to the effect of estradiol. Twenty-four hours after subcutaneous injection of E2-BODIPY in non-ovariectomized mice, we observed fluorescence of E2-BODIPY in the nuclei of uterine epithelial cells. Our findings suggest that fluorescence microscopy can localize this derivative in E2-responsive cells during normal development and tumorigenesis in vivo.


Interactions of 1,10-phenanthroline and its copper complex with Ehrlich cells.
Mechanistic details of the interaction of 1,10-phenanthroline and its copper complex with Ehrlich ascites tumor cells were examined, using inhibition of cell proliferation, DNA breakage, and increased membrane permeability as indices of cellular damage. The metal chelating agent, 1,10-phenanthroline (OP), the 1:0.5 complex of 1,10-phenanthroline and CuCl2 [(OP)2Cu], and CuCl2 inhibited growth of Ehrlich ascites tumor cell monolayers during 48-h treatments by 50% at about 3.5, 2, and 70 nmol/10(5) cells/mL, respectively. (OP)2Cu at 10 nmol/10(5) cells also enhanced uptake of trypan blue dye during 6 h of treatment, while dye uptake in OP- and CuCl2-treated cells remained similar to controls. DNA breakage, measured by DNA alkaline elution, was produced during 1-h treatments with (OP)2Cu at drug/cell ratios similar to those producing growth inhibition. Copper uptake was similar for both (OP)2Cu and CuCl2. Electron spin resonance (ESR) spectroscopy suggested that cellular ligands bind copper added as (OP)2Cu or CuCl2 and then undergo time-dependent reductions of Cu(II) to Cu(I) for both forms. Inhibition of (OP)2Cu-induced single-strand scission and trypan blue uptake by scavengers of activated oxygen is consistent with participation of superoxide and H2O2 in both processes. In contrast, superoxide dismutase (SOD) did not reduce the magnitude of the fraction of cellular DNA appearing in lysis fractions prior to alkaline elution of (OP)2Cu-treated cells. Dimethyl sulfoxide (DMSO) inhibited uptake of trypan blue dye but did not inhibit DNA strand scission produced by (OP)2Cu. Thus, multiple mechanisms for generation of oxidative damage occur in (OP)2Cu-treated cells. Growth inhibition produced by OP or (OP)2Cu, as well as the low levels of strand scission produced by OP, was not reversed by scavengers.


Multistep skin cancer in mice as a model to study the evolution of cancer cells.
Although much of cancer research relies on Nowell's clonal evolution hypothesis as a conceptual framework, large gaps remain in understanding how tumors develop. The multistage skin cancer model in mice provides continuing insight on fundamental aspects of tumor evolution. In this model, mutation of the oncogene Hras is frequently the initiating event while mutation of the tumor suppressor p53 is a late event, associated with malignant progression. Recent evidence demonstrates that intracellular signaling from the initial Hras mutation leads directly to the activation of p53, creating selective pressure in favor of cells with mutant p53. Thus, selection for subsequent mutations is mechanistically linked to the initial mutation, explaining the preferred order of mutational events observed. Analysis of this model also reveals that a diverse array of signals can selectively impair or enhance clonal expansion of Ras mutant cells into a visible neoplasm. These modifiers can be genetic, physiological, or environmental and are often highly specific to tumor cells. This indicates that tumor cells have an inherent reduced capacity to buffer against perturbations. Reduced buffering may play an important role in both tumor evolution and therapy response and may be a hallmark of cancer cells.


Prevalence of Depression, Anxiety, Post-Traumatic Stress, and Insomnia Symptoms Among Frontline Healthcare Workers in a COVID-19 Hospital in Northeast Mexico.
Frontline healthcare workers (FHCWs) exposed to COVID-19 patients are at an increased risk of developing psychological burden. This study aims to determine the prevalence of mental health symptoms and associated factors among Mexican FHCWs attending COVID-19 patients. FHCWs, including attending physicians, residents/fellows, and nurses providing care to COVID-19 patients at a private hospital in Monterrey, Mexico, were invited to answer an online survey between August 28, and November 30, 2020. Symptoms of depression, anxiety, post-traumatic stress, and insomnia were evaluated with the Patient Health Questionnaire (PHQ)-9, Generalized Anxiety Disorder (GAD)-7, Impact of Event Scale-Revised (IES-R), and Insomnia Severity Index (ISI). Multivariate analysis was performed to identify variables associated with each outcome. 131 FHCWs, 43.5% attending physicians, 19.8% residents/fellows, and 36.6% nurses were included. The overall prevalence of depression, anxiety, post-traumatic stress, and insomnia was 36%, 21%, 23%, and 24% respectively. Multivariate analysis revealed that residents/fellows and nurses reported more depression and insomnia than attending physicians. Although not significant, residents/fellows were more likely to experience all symptoms than nurses. Mexican FHCWs, especially nurses and residents/fellows, experienced a significant psychological burden while attending to COVID-19 patients. Tailored interventions providing support to FHCWs during future outbreaks are required.


Combined orthotopic liver transplantation and caesarean section for the Budd-Chiari syndrome.
Fulminant hepatic failure is a rare complication of pregnancy. We describe a case of Budd-Chiari syndrome that resulted in the need for combined liver transplantation and Caesarean section at 32 weeks' gestation. The anaesthetic and perioperative management are discussed.


Human gastric lipase: a sulfhydryl enzyme.
One sulfhydryl group was modified per mol of native human gastric lipase after incubation at pH 8.0 with 5,5'-dithiobis(2-nitrobenzoic acid) for 18 h or with 4,4'-dithiopyridine for 100 min. With both reagents a direct correlation was found between the modification of one sulfhydryl group and the loss of human gastric lipase activity. Incubation of human gastric lipase with a new hydrophobic sulfhydryl reagent dodecyldithio-5-(2-nitrobenzoic acid) in 30-fold molar excess, at pH 3.0, 5.0, and 8.0, induced immediate and complete human gastric lipase inactivation. Unlike 5,5'-dithiobis(2-nitrobenzoic acid) and 4,4'-dithiopyridine, dodecyldithio-5-(2-nitrobenzoic acid) almost instantaneously stopped the course of tributyrin hydrolysis by human gastric lipase. Human gastric lipase can thus be said to be a sulfhydryl enzyme.


Age-related attenuation of the evening circadian arousal signal in humans.
The human circadian pacemaker maintains timing and consolidation of sleep-wake behavior by opposing the build-up of homeostatic sleep pressure during the wake episode, particularly in the evening during the 'wake maintenance zone'. We tested whether age-related changes in sleep are a consequence of a weaker circadian arousal signal in the evening. Circadian rhythms and spectral components of the sleep EEG were investigated in 17 young (20-31 year) and 15 older (57-74 year) volunteers under constant posture conditions during a 40-h nap protocol (75/150 min sleep/wake schedule). Quantitative evidence for a weaker circadian arousal signal in aging arose from significantly more sleep occurring during the wake maintenance zone and higher subjective sleepiness ratings in the late afternoon and evening in the older group. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep together with less pronounced day-night differences in the lower alpha and spindle range of sleep EEG activity in the older group. Thus, our data indicate that age-related changes in sleep propensity are clearly related to a reduced circadian signal opposing the homeostatic drive for sleep.