Effects of natural flavones and flavonols on the kinase activity of Cdk5.
A number of natural and synthetic flavonoids have been assessed previously with regard to their effects on the activity of cyclin-dependent kinases (Cdk1 and -2) related to the inhibition of cell cycle progression. On the other hand, the Cdk5/p35 system is of major importance in neuronal migration phenomena and brain development, and its deregulation is implicated in neurodegenerative diseases, particularly Alzheimer's. Here we show that some natural flavonoids inhibit the activity of the Cdk5/p35 system in the micromolar range, while others are practically inactive. Ring B-unsubstituted and highly methoxylated flavones were inactive or gave irreproducible results, and 6-methoxyapigenin and 6-methoxyluteolin were the most potent Cdk5 complex inhibitors within this series, while the common flavonols kaempferol and quercetin showed intermediate behavior. The reported crystal structure of the Cdk5 complex with its activator p25 was used for docking studies, which also led to the identification of the two 6-methoxyflavones, kaempferol and quercetin, as well as the untested 6-methoxy derivatives of kaempferol and quercetin and the corresponding 6-hydroxy analogues as compounds exhibiting a good fit to the active site of the enzyme.


Ischaemic colitis associated with oral contraceptive and bisacodyl use.
A woman with a history of hip replacement presented 3 days prior to revision of the hip with abdominal pain, diarrhoea and haematochezia. These symptoms began 6 h after she began taking bisacodyl in preparation for her upcoming surgery. She was on low-dose estradiol for hormone replacement therapy (HRT). Subsequent colonoscopy and biopsies were consistent with acute colonic ischaemia (CI). She was treated with intravenous fluids and antibiotics and discharged and told to stop HRT and bisacodyl. Follow-up colonoscopy 1 month after discharge was normal. This case adds to the three other previously reported cases of bisacodyl-associated CI.


Omalizumab: a review of its use in the management of allergic asthma.
Omalizumab (Xolair) is a humanized monoclonal antibody used in the treatment of adolescent and adult patients with moderate to severe allergic asthma inadequately controlled with inhaled corticosteroids (ICS). It selectively binds to circulating immunoglobulin E (IgE) and, thereby, prevents binding of IgE to mast cells and other effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, thus preventing cellular activation by antigens and the subsequent allergic/asthmatic symptoms. Omalizumab decreases free serum IgE levels in a dose-dependent manner, reduces IgE receptor density on effector cells, and significantly improves airway inflammation parameters. Omalizumab is slowly absorbed after subcutaneous administration, and mean elimination half-life is 26 days, thus allowing infrequent administration of the drug. Omalizumab dosage is determined by bodyweight and pretreatment serum total IgE levels. Patients treated with subcutaneous omalizumab in clinical trials received a dosage that was approximately equal to 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Thus, patients received 150 or 300 mg every 4 weeks, or 225, 300, or 375 mg every 2 weeks. In adults and adolescents (> or =12 years of age) with moderate to severe allergic asthma, subcutaneous administration of omalizumab as add-on therapy with ICS improved the number of asthma exacerbations, rescue medication use, asthma symptom scores, and quality-of-life (QOL) scores compared with placebo during 28- and 32-week double-blind trials. In addition, concomitant ICS use was significantly decreased in patients receiving omalizumab, and in the two largest double-blind trials approximately 40% of omalizumab recipients completely withdrew from ICS therapy while maintaining effective asthma control. In general, results of extension studies showed that the beneficial effects of omalizumab were maintained over a total period of 52 weeks. Omalizumab was well tolerated as add-on therapy with ICS during treatment for up to 52 weeks. Common adverse events in clinical trials included injection site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis, although the incidence of adverse events with omalizumab was similar to that with placebo. Omalizumab, as add-on therapy with ICS, is an effective and well tolerated agent for the treatment of moderate to severe allergic asthma in adolescents and adults. In addition to its symptomatic and QOL benefits, omalizumab therapy allows ICS dosage reduction or discontinuation of ICS in many patients. Comparisons of omalizumab with other asthma therapies have yet to be conducted; however, clinical efficacy and tolerability data indicate that omalizumab is a valuable option in the treatment of allergic asthma.


Phase 2 Study of Lutetium 177-Labeled Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab in Patients with Advanced Renal Cell Carcinoma.
Despite advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC), there is still an unmet need in the treatment of this disease. A phase 2 radioimmunotherapy (RIT) trial with lutetium 177 ((177)Lu)-girentuximab was initiated to evaluate the efficacy of this approach. In this nonrandomized single-arm trial, patients with progressive metastatic ccRCC who met the inclusion criteria received 2405 MBq/m(2) of (177)Lu-girentuximab intravenously. In the absence of persistent toxicity and progressive disease, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. A total of 14 patients were included. After the first therapeutic infusion, eight patients (57%) had stable disease (SD) and one (7%) had a partial regression. The treatment was generally well tolerated but resulted in grade 3-4 myelotoxicity in most patients. After the second cycle, continued SD was observed in five of six patients, but none were eligible for retreatment due to prolonged thrombocytopenia. In conclusion, RIT with (177)Lu-girentuximab resulted in disease stabilization in 9 of 14 patients with progressive metastatic ccRCC, but myelotoxicity prevented retreatment in some patients. We investigated the efficacy of lutetium 177-girentuximab radioimmunotherapy in patients with metastatic kidney cancer. The treatment resulted in disease stabilization in 9 of 14 patients. The main toxicity was prolonged low blood cell counts. ClinicalTrials.gov identifier: NCT02002312 (https://clinicaltrials.gov/ct2/show/NCT02002312).


Introducing COCOS: codon consequence scanner for annotating reading frame changes induced by stop-lost and frame shift variants.
Reading frame altering genomic variants can impact gene expression levels and the structure of protein products, thus potentially inducing disease phenotypes. Current annotation approaches report the impact of such variants in the context of altered DNA sequence only; attributes of the resulting transcript, reading frame and translated protein product are not reported. To remedy this shortcoming, we present a new genetic annotation approach termed Codon Consequence Scanner (COCOS). Implemented as an Ensembl variant effect predictor (VEP) plugin, COCOS captures amino acid sequence alterations stemming from variants that produce an altered reading frame, such as stop-lost variants and small insertions and deletions (InDels). To highlight its significance, COCOS was applied to data from the 1000 Genomes Project. Transcripts affected by stop-lost variants introduce a median of 15 amino acids, while InDels have a more extensive impact with a median of 66 amino acids being incorporated. Captured sequence alterations are written out in FASTA format and can be further analyzed for impact on the underlying protein structure. COCOS is available to all users on github: https://github.com/butkiem/COCOS. firstname.lastname@example.com.


Moiré patterns as a probe of interplanar interactions for graphene on h-BN.
By atomistic modeling of moiré patterns of graphene on a substrate with a small lattice mismatch, we find qualitatively different strain distributions for small and large misorientation angles, corresponding to the commensurate-incommensurate transition recently observed in graphene on hexagonal BN. We find that the ratio of C-N and C-B interactions is the main parameter determining the different bond lengths in the center and edges of the moiré pattern. Agreement with experimental data is obtained only by assuming that the C-B interactions are at least twice weaker than the C-N interactions. The correspondence between the strain distribution in the nanoscale moiré pattern and the potential energy surface at the atomic scale found in our calculations makes the moiré pattern a tool to study details of dispersive forces in van der Waals heterostructures.


Amanida: an R package for meta-analysis of metabolomics non-integral data.
The combination, analysis and evaluation of different studies which try to answer or solve the same scientific question, also known as a meta-analysis, plays a crucial role in answering relevant clinical relevant questions. Unfortunately, metabolomics studies rarely disclose all the statistical information needed to perform a meta-analysis. Here, we present a meta-analysis approach using only the most reported statistical parameters in this field: P-value and fold-change. The P-values are combined via Fisher's method and fold-changes by averaging, both weighted by the study size (n). The amanida package includes several visualization options: a volcano plot for quantitative results, a vote plot for total regulation behaviours (up/down regulations) for each compound, and a explore plot of the vote-counting results with the number of times a compound is found upregulated or downregulated. In this way, it is very easy to detect discrepancies between studies at a first glance. Amanida code and documentation are at CRAN and https://github.com/mariallr/amanida. Supplementary data are available at Bioinformatics online.


Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin.
Heterochronic blood sharing rejuvenates old tissues, and most of the studies on how this works focus on young plasma, its fractions, and a few youthful systemic candidates. However, it was not formally established that young blood is necessary for this multi-tissue rejuvenation. Here, using our recently developed small animal blood exchange process, we replaced half of the plasma in mice with saline containing 5% albumin (terming it a "neutral" age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity. Comparative proteomic analysis on serum from NBE, and from a similar human clinical procedure of therapeutic plasma exchange (TPE), revealed a molecular re-setting of the systemic signaling milieu, interestingly, elevating the levels of some proteins, which broadly coordinate tissue maintenance and repair and promote immune responses. Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation. Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE. A model of action (supported by a large body of published data) is that significant dilution of autoregulatory proteins that crosstalk to multiple signaling pathways (with their own feedback loops) would, through changes in gene expression, have long-lasting molecular and functional effects that are consistent with our observations. This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.


Microglia and Perivascular Macrophages Act as Antigen Presenting Cells to Promote CD8 T Cell Infiltration of the Brain.
CD8 T cell infiltration of the central nervous system (CNS) is necessary for host protection but contributes to neuropathology. Antigen presenting cells (APCs) situated at CNS borders are thought to mediate T cell entry into the parenchyma during neuroinflammation. The identity of the CNS-resident APC that presents antigen via major histocompatibility complex (MHC) class I to CD8 T cells is unknown. Herein, we characterize MHC class I expression in the naïve and virally infected brain and identify microglia and macrophages (CNS-myeloid cells) as APCs that upregulate H-2Kb and H-2Db upon infection. Conditional ablation of H-2Kb and H-2Db from CNS-myeloid cells allowed us to determine that antigen presentation via H-2Db, but not H-2Kb, was required for CNS immune infiltration during Theiler's murine encephalomyelitis virus (TMEV) infection and drives brain atrophy as a consequence of infection. These results demonstrate that CNS-myeloid cells are key APCs mediating CD8 T cell brain infiltration.


Contribution of the phenolic fraction to the antioxidant activity and oxidative stability of olive oil.
Antioxidant activity of the phenolic fraction of extra virgin olive oil (EVOO) was measured by means of a chemical and an electrochemical method. Both methods were tested in predicting the oxidative spoilage and stability to oxidation of 22 EVOO samples and resulted correlated with peroxide values and oxidative stability measured by Rancimat. The main phenolic compounds of EVOOs were detected by HRGC. To study the contribution of single polyphenols (PPs) to antioxidant activity of phenolic fraction and oxidative stability of EVOOs, multivariate statistical analyses were applied on HRGC data. An isomer of oleuropein aglycon was shown to affect significantly antioxidant activity of phenolic fraction but not oil stability to oxidation. No individual compounds was identified as the main cause of the overall antioxidant activity, and the total polyphenol determination by the Folin reagent was better correlated to antioxidant activity and oxidative stability than each tested PP or PPs groups such as o-diphenols.


Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer.
(Aim) Bacterial infection underlies the pathogenesis of many human diseases, including acute and chronic inflammation. Here, we investigated a possible role for bacterial infection in the progression of chronic pancreatitis. (Materials and Methods) Pancreatic juice was obtained from patients with pancreatic cancer (n = 20) or duodenal cancer/bile duct cancer (n = 16) and subjected to PCR using universal primers for the bacterial 16S ribosomal RNA gene. Bacterial species were identified by PCR using bile samples from four pancreatic cancer patients. PCR products were subcloned into T-vectors, and the sequences were then analyzed. Immunohistochemical and serologic analyses for Enterococcus faecalis infection were performed on a large cohort of healthy volunteers and patients with chronic pancreatitis or pancreatic cancer and on mice with caerulein-induced chronic pancreatitis. The effect of E. faecalis antigens on cytokine secretion by pancreatic cancer cells was also investigated. (Results) We found that 29 of 36 pancreatic juice samples were positive for bacterial DNA. Enterococcus and Enterobacter species were detected primarily in bile, which is thought to be a pathway for bacterial infection of the pancreas. Enterococcus faecalis was also detected in pancreatic tissue from chronic pancreatitis and pancreatic cancer patients; antibodies to E. faecalis capsular polysaccharide were elevated in serum from chronic pancreatitis patients. Enterococcus-specific antibodies and pancreatic tissue-associated E. faecalis were detected in mice with caerulein-induced chronic pancreatitis. Addition of Enterococcus lipoteichoic acid and heat-killed bacteria induced expression of pro-fibrotic cytokines by pancreatic cancer cells in vitro. (Conclusion) Infection with E. faecalis may be involved in chronic pancreatitis progression, ultimately leading to development of pancreatic cancer.


An In Vivo Study on Load Distribution in Different Implant Configurations for Supporting Fixed Partial Dentures.
The aims of this study were to develop a device for in vivo measurement of three-dimensional (3D) loads on implants and to investigate the effects of implant configuration on the load distribution under a three-unit fixed partial denture (FPD). A 67-year-old female patient with three implants (in the mandibular left second premolar, first molar, and second molar regions) was recruited. Four implant configurations for a three-unit FPD depending on the number and position of the implants were considered in this study. They included a three-implant prosthesis and three types of two-implant prosthesis: a central pontic, posterior cantilever, and anterior cantilever, with the same superstructure (splinted three crowns) for the same occlusal contact. Customized abutments and 3D piezoelectric force transducers were fixed to the implants of the four configurations with the superstructure. The loads on the implants were recorded during maximum voluntary clenching (MVC-test) and when chewing a piece of chewing gum (GUMtest). The occlusal forces on the dental arch during MVC-test with the four implant configurations did not exhibit significant differences. In the three-implant prosthesis, there were no significant differences in the mean maximum resultant load on each implant in both tests. In the central pontic, the load on the second premolar was significantly greater than that on the second molar in the MVC-test but there were no significant differences in the GUM-test. High loads were detected on the first molar in both the posterior cantilever and anterior cantilever. The highest load was detected on the first molar in the posterior cantilever during the GUMtest. The in vivo 3D load-measuring device using the piezoelectric force transducers enabled the measurement of the functional load on implants supporting a FPD. The results suggested, within the limitations of this study, that a three-implant prosthesis and central pontic provide biomechanically beneficial designs compared with the posterior cantilever and anterior cantilever in terms of the equal distribution of loads on supporting implants.


Hypomorphic Rag mutations can cause destructive midline granulomatous disease.
Destructive midline granulomatous disease characterized by necrotizing granulomas of the head and neck is most commonly caused by Wegener granulomatosis, natural killer/T-cell lymphomas, cocaine abuse, or infections. An adolescent patient with myasthenia gravis treated with thymectomy subsequently developed extensive granulomatous destruction of midface structures, palate, nasal septum, airways, and epiglottis. His lymphocyte numbers, total immunoglobulin G level, and T-cell receptor (TCR) repertoire appeared normal. Sequencing of Recombination activating gene-1 (Rag1) showed compound heterozygous Rag1 mutations; a novel deletion with no recombinase activity and a missense mutation resulting in 50% Rag activity. His thymus was dysplastic and, although not depleted of T cells, showed a notable absence of autoimmune regulator (AIRE) and Foxp3(+) regulatory T cells. This distinct Rag-deficient phenotype characterized by immune dysregulation with granulomatous hyperinflammation and autoimmunity, with relatively normal T and B lymphocyte numbers and a diverse TCR repertoire expands the spectrum of presentation in Rag deficiency. This study was registered at www.clinicaltrials.gov as #NCT00128973.


Therapeutic targeting of Polo-like kinase-1 and Aurora kinases in T-cell acute lymphoblastic leukemia.
Polo-like kinases (PLKs) and Aurora kinases (AKs) act as key cell cycle regulators in healthy human cells. In cancer, these protein kinases are often overexpressed and dysregulated, thus contributing to uncontrolled cell proliferation and growth. T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy arising in the thymus from T-cell progenitors. Primary chemoresistant and relapsed T-ALL patients have yet a poor outcome, therefore novel therapies, targeting signaling pathways important for leukemic cell proliferation, are required. Here, we demonstrate the potential therapeutic effects of BI6727, MK-5108, and GSK1070916, three selective inhibitors of PLK1, AK-A, and AK-B/C, respectively, in a panel of T-ALL cell lines and primary cells from T-ALL patients. The drugs were both cytostatic and cytotoxic to T-ALL cells by inducing G2/M-phase arrest and apoptosis. The drugs retained part of their pro-apoptotic activity in the presence of MS-5 bone marrow stromal cells. Moreover, we document for the first time that BI6727 perturbed both the PI3K/Akt/mTORC2 and the MEK/ERK/mTORC1 signaling pathways, and that a combination of BI6727 with specific inhibitors of the aforementioned pathways (MK-2206, CCI-779) displayed significantly synergistic cytotoxic effects. Taken together, our findings indicate that PLK1 and AK inhibitors display the potential for being employed in innovative therapeutic strategies for improving T-ALL patient outcome.


Identity confusion and depression in groups of adolescents having psychiatric and physical symptoms.
The aim of this study was to investigate the identity status of adolescents having psychiatric and physical symptoms and the relation of depression with identity problems in adolescence. Three groups of university students were given a sociodemographic questionnaire, Beck Depression Inventory (BDI) and Sense of Identity Assessment Form (SIAF). The first group consisted of 31 students who were seen by the consultant psychiatrist at the Student Health Center of a university in Ankara. The second group included 37 students who applied to the same center with various physical complaints but did not need to be consulted by the psychiatrist. The third group was a group of 50 healthy students at the same university. The analysis revealed that only those with psychiatric complaints had identity confusion and that for the males in this group depressive symptoms are significant predictors of identity confusion.


Comparative evaluation of three laparoscopic cholecystectomy techniques in rabbit's model.
The aim of this randomized study was to compare the complications and perioperative outcome of three different techniques of laparoscopic cholecystectomy (LC). Changes in the liver function test after LC techniques were investigated. Also, we compared the degree of postoperative adhesions and histopathological changes of the liver bed. Thirty rabbits were divided into three groups: group A) Fundus-first technique by Hook dissecting instrument and Roeder Slipknot applied for cystic duct (CD) ligation; group B) conventional technique by Maryland dissecting forceps and electrothermal bipolar vessel sealing (EBVS) for CD seal; group C) conventional technique by EBVS for gallbladder (GB) dissection and CD seal. Group A presented a longer GB dissection time than groups B and C. GB perforation and bleeding from tissues adjacent to GB were similar among tested groups. Gamma-glutamyl transferase and alkaline phosphatase levels increased (p ≤ 0.05) on day 3 postoperatively in group A. By the 15th postoperative day, the enzymes returned to the preoperative values. Transient elevation of hepatic transaminases occurred after LC in all groups. Group A had a higher adherence score than groups B and C and was associated with the least predictable technique. LC can be performed using different techniques, although the use of EBVS is highly recommended.


American Society of Clinical Oncology Road to Recovery Report: Learning From the COVID-19 Experience to Improve Clinical Research and Cancer Care.
This report presents the American Society of Clinical Oncology's (ASCO's) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.


The streptothricin acetyltransferase (sat) gene as a positive selectable marker for methanogenic archaea.
A repertoire of sophisticated genetic tools has significantly enhanced studies of Methanosarcina genera, yet the lack of multiple positive selectable markers has limited the types of genetic experiments that can be performed. In this study, we report the development of an additional positive selection system for Methanosarcina that utilizes the antibiotic nourseothricin and the Streptomyces rochei streptothricin acetyltransferase (sat) gene, which may be broadly applicable to other groups of methanogenic archaea. Nourseothricin was found to inhibit growth of four different methanogen species at concentrations ≤300 μg/ml in liquid or on solid media. Selection of nourseothricin resistant transformants was possible in two genetically tractable Methanosarcina species, M. acetivorans and M. barkeri, using the sat gene as a positive selectable marker. Additionally, the sat marker was useful for constructing a gene deletion mutant strain of M. acetivorans, emphasizing its utility as a second positive selectable marker for genetic analyses of Methanosarcina genera. Interestingly, two human gut-associated methanogens Methanobrevibacter smithii and Methanomassillicoccus luminyensis were more sensitive to nourseothricin than either Methanosarcina species, suggesting the nourseothricin-sat gene pair may provide a robust positive selection system for development of genetic tools in these and other methanogens.


Mouse DNA polymerase beta gene promoter: fine mapping and involvement of Sp1-like mouse transcription factor in its function.
The promoter of mouse DNA polymerase beta gene was analyzed by combining 5'-upstream region of this gene with chloramphenicol acetyltransferase (CAT) gene and by introduction of the recombinant plasmid DNA into mouse NIH/3T3 cells. Serial deletion of the mouse DNA sequence revealed that the promoter function resides within a 33 base pair region from the nucleotide position -48 to -15 with respect to the transcription initiation site, and is highly active without enhancer sequence. The promoter region was separated into two subregions: one (-48 to -35) contains a GC-box and the other contains a 10 base pair palindrome, whose sequence is similar to one of promoter consensus sequences found in a number of promoters including adenovirus promoters. The DNA polymerase beta promoter-directed CAT expression was competitively inhibited by the simultaneous transfection of plasmid DNA containing SV40 early promoter sequence. The viral sequences which are competitive to the GC-box of DNA polymerase beta gene promoter were the GC-boxes of SV40 promoter. Therefore, it is concluded that transcription of mouse DNA polymerase beta gene is regulated by mouse trans-acting factors equivalent to human Sp1 which is known to be trans-acting protein factor acting on SV40 GC-box sequences.


Distinction of the phenotypes of in vitro anchorage-independent soft-agar growth and in vivo tumorigenicity in the nude mouse.
The growth characteristics of LT-2 cells, an epithelial squamous cell carcinoma, clearly separate the phenotypes of anchorage-independent growth in soft agar and tumor formation in vivo. LT-2 readily grows and forms tumor nodules in the nude mouse but does not proliferate anchorage independently in soft agar. This distinction is confirmed by the observation that cells explanted from nude mouse tumor nodules and cultured in vitro still do not clone in soft agar. The human origin of tumor nodule cells was confirmed by karyotyping. LT-2 cells have an aneuploid karyotype which has persisted for 4.5 years in culture with considerable variation in chromosomal number. Passage through the nude mouse did not select for any "tumor" clone since marked chromosomal variation was still noted by cells explanted from tumor nodules. Tumor cells formed a well-differentiated skin with keratin formation in the nude mouse despite wide karotypic variations of cells and years of in vitro culture. Strict monolayer growth was noted by LT-2 cells when grown in culture flasks and also by cells explanted from tumor nodules, indicating that monolayer growth and nude mouse tumorigenicity are also separate phenotypes.


Robust estimation of mean-variance relation.
Accurate assessment of the mean-variance relation can benefit subsequent analysis in biomedical research. However, in most biomedical data, both the true mean and the true variance are unavailable. Instead, raw data are typically used to allow forming sample mean and sample variance in practice. In addition, different experimental conditions sometimes cause a slightly different mean-variance relation from the majority of the data in the same data set. To address these issues, we propose a semiparametric estimator, where we treat the uncertainty in the sample mean as a measurement error problem, the uncertainty in the sample variance as model error, and use a mixture model to account for different mean-variance relations. Asymptotic normality of the proposed method is established and its finite sample properties are demonstrated by simulation studies. The data application shows that the proposed method produces sensible results compared with methods either ignoring the uncertainty in the sample means or ignoring the potential different mean-variance relations.


5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats.
We previously demonstrated a change in the receptors mediating 5-hydroxytryptamine (5-HT)-induced contraction in arteries of deoxycorticosterone acetate (DOCA)-salt-hypertensive rats. Specifically, contraction to 5-HT is mediated primarily by 5-HT2A receptors in arteries from normotensive sham rats and by both 5-HT2A and 5-HT2B receptors in arteries from hypertensive rats. We hypothesized that the 5-HT2B receptor may play a role in maintaining the high blood pressure of DOCA-salt-hypertensive rats, and herein we provide data connecting in vitro and in vivo findings. The endothelium-denuded isolated superior mesenteric artery of DOCA-salt rats displayed a marked increase in maximum contraction to the newly available 5-HT2B-receptor agonist BW-723C86 compared with that of arteries from sham rats, confirming that the 5-HT2B receptor plays a greater role in 5-HT-induced contraction in arteries from DOCA-salt rats. In chronically instrumented rats, the 5-HT2B-receptor antagonist LY-272015 (0.3, 1.0, and 3.0 mg/kg iv at 30-min intervals) was given cumulatively 1 time/wk during 4 wk of continued DOCA-salt treatment. LY-272015 did not reduce blood pressure of the sham-treated rats at any time or dose. However, LY-272015 (1.0 and 3. 0 mg/kg) significantly reduced mean blood pressure in a subgroup of week 3 (-20 mmHg) and week 4 DOCA-salt (-40 mmHg) rats that had extremely high blood pressure (mean arterial blood pressure approximately 200 mmHg). Blockade of 5-HT2B receptors by in vivo administration of LY-272015 (3.0 mg/kg) was verified by observing reduced 5-HT-induced contraction in rat stomach fundus, the tissue from which the 5-HT2B receptor was originally cloned. These data support the novel hypothesis that 5-HT2B-receptor expression is induced during the development of DOCA-salt hypertension and contributes to the maintenance of severe blood pressure elevations.


[Chronic mercury poisoning from cosmetic creams (author's transl)].
Two cases of chronic mercury poisoning are reported. Both patients had used a skin cream containing mercury for years which contained the latter substance in various strengths (3%-50%). The creams are commercially available, usually in 20 g tin as a skin whitener or skin care preparation. According to the regulations in force, preparations containing not more than 5% Hg in the form of white precipitate can be freely obtained without prescription in drug-stores and perhaps also in shops dealing in cosmetics. The limits of tolerance at which the first symptoms of mercury poisoning may appear may perhaps have been already reached by the regular use of freely purchasable preparations.


Assessment of Aflatoxin M1 in human breast and powdered milk in Tehran, Iran.
Aflatoxins, produced by Aspergillus flavus and Aspergillus parasiticus, are among the most toxic mycotoxins. Aflatoxin M1 (AFM1) is a hydroxylated metabolite of aflatoxin B1 (AFB1), found in milk and dairy products from animals fed AFB1-contaminated feed. Consumption of AFM1 has related adverse effects on human health. Breast milk can be a source of contamination for infants due to the presence of AFM. AFM1 can also contaminate powdered milk, a significant product of the milk industry. Consequently, monitoring dairy products for these toxins is imperative. A total of 50 samples (25 samples of breast milk and 25 samples of powdered infant milk formula) were collected in Tehran from December 2021 to February 2022. HPLC method was used for the determination of AFM1 in samples. and Discussion: AFM1 was detected in 72% of breast milk samples and 96% of powdered milk samples. AFM1 levels varied significantly between the two sample types (p < 0.05). The average amount of AFM1 in breast milk samples was 25.82 ± 4.72 ng/kg, while the average amount in powdered milk samples was 40.59 ± 7.76 ng/kg. Moreover, 44% of the breast and 68% of powdered milk samples exceeded the AFM1 content limit of the European Union and the Iranian national standard. This study concludes that given the importance of breast milk and formula to maternal and infant health, monitoring and regulating the toxin levels in these products in Tehran is crucial.


[Celiac disease in adults: histological and morphometric data].
A morphologic and morphometric study of duodenal mucosal biopsies obtained from 90 patients suffering of celiac sprue was done. The results were compared with clinical, serological features as well as with information on inheritance. The diagnosis of celiac sprue was made when there was a combination of both specific clinical and serological signs with chronic atrophic mucosal changes in the duodenum correlating with morphometrical data. It was concluded that the lack of one of the mentioned parameters makes the diagnosis invalid and the patient needs further observation.


Stem cell-derived islet cells for transplantation.
The promise of islet transplantation for type 1 diabetes has been hampered by the lack of a renewable source of insulin-producing cells. However, steadfast advances in the field have set the stage for stem cell-based approaches to take over in the near future. This review focuses on the most intriguing findings reported in recent years, which include not only progress in adult and embryonic stem cell differentiation, but also the direct reprogramming of nonendocrine tissues into insulin-producing beta cells. In spite of their potential for tumorigenesis, human embryonic stem (hES) cells are poised to be in clinical trials within the next decade. This situation is mainly due to the preclinical success of a differentiation method that recapitulates beta cell development. In contrast, adult stem cells still need one such gold standard of differentiation, and progress is somewhat impeded by the lack of consensus on the best source. A concerted effort is necessary to bring their potential to clinical fruition. In the meantime, reported success in reprogramming might offer a 'third way' towards the rescue of pancreatic endocrine function. Here we discuss the important strategic decisions that need to be made in order to maximize the therapeutic chances of each of the presented approaches.


Is there a nonadherent subtype of hypertensive patient? A latent class analysis approach.
To determine subtypes of adherence, 636 hypertensive patients (48% White, 34% male) reported adherence to medications, diet, exercise, smoking, and home blood pressure monitoring. A latent class analysis approach was used to identify subgroups that adhere to these five self-management behaviors. Fit statistics suggested two latent classes. The first class (labeled "more adherent") included patients with greater probability of adhering to recommendations compared with the second class (labeled "less adherent") with regard to nonsmoking (97.7% versus 76.3%), medications (75.5% versus 49.5%), diet (70.7% versus 46.9%), exercise (63.4% versus 27.2%), and blood pressure monitoring (32% versus 3.4%). Logistic regression analyses used to characterize the two classes showed that "more adherent" participants were more likely to report full-time employment, adequate income, and better emotional and physical well-being. Results suggest the presence of a less adherent subtype of hypertensive patients. Behavioral interventions designed to improve adherence might best target these at-risk patients for greater treatment efficiency.


Shared care for open heart surgery: 21 years' experience.
To determine whether patients undergoing open heart surgery, the majority coronary artery bypass grafting (CABG), can safely be returned early to the smaller nonspecialized hospital that referred them for postoperative care by a cardiological team. Another objective is to determine what benefits might accrue from this practice and to whose credit. All 1696 patients, 1512 having coronary bypass alone or with ventricular aneurysm repair in 6%, referred from a military hospital with investigative facilities from November 1971 to November 1992 were studied with attention to length of postoperative stay in both hospitals, perioperative mortality and major complications mandating return to the surgical centre (which was almost always for reoperation). Time between initial coronary angiography and CABG was examined to see whether it related to the early return policy. After the first two years, postoperative care at the surgical hospital following CABG was reduced from a mean of 10.4 to 2.4 days, with an 18% reduction in the combined time spent at both hospitals, an estimated reduction of some 48 patient-years at the surgical hospital. A perceived need for active in-patient-rehabilitation and formal postoperative assessment explains the somewhat higher than average 23-day combined hospital stay after CABG. There have been no cardiovascular problems associated with the process of patient transfer and the three postoperative deaths that occurred in the referring hospital do not appear related to early transfer. Most of the 29 patients (2%) returned to the surgical hospital during the postoperative phase to have reoperations; there were three deaths, inevitable in one, scarcely preventable in two and unrelated to the early transfer in all three. Overall perioperative mortality was 2.7%; it was 1.3% for isolated primary CABG, 7.7% for reoperation. Delay between angiography and CABG was less than one day in 9%, less than four weeks in 69% and less than 12 weeks in 96%. It is believed that rapid access to surgical treatment was facilitated by cardiologists' willingness to undertake postoperative care and by the amicable trusting relationship between staff of the two hospitals. It is possible to transfer patients safely after open heart surgery to a smaller, nonspecialized hospital for postoperative care; there are no significant ill effects from the practice and obvious benefits accrue to several involved parties. This model of shared care may have lessons for those designing or modifying cardiac surgical care programs.


Optimizing viable leukocyte sampling from the female genital tract for clinical trials: an international multi-site study.
Functional analysis of mononuclear leukocytes in the female genital mucosa is essential for understanding the immunologic effects of HIV vaccines and microbicides at the site of HIV exposure. However, the best female genital tract sampling technique is unclear. We enrolled women from four sites in Africa and the US to compare three genital leukocyte sampling methods: cervicovaginal lavages (CVL), endocervical cytobrushes, and ectocervical biopsies. Absolute yields of mononuclear leukocyte subpopulations were determined by flow cytometric bead-based cell counting. Of the non-invasive sampling types, two combined sequential cytobrushes yielded significantly more viable mononuclear leukocytes than a CVL (p<0.0001). In a subsequent comparison, two cytobrushes yielded as many leukocytes (∼ 10,000) as one biopsy, with macrophages/monocytes being more prominent in cytobrushes and T lymphocytes in biopsies. Sample yields were consistent between sites. In a subgroup analysis, we observed significant reproducibility between replicate same-day biopsies (r = 0.89, p = 0.0123). Visible red blood cells in cytobrushes increased leukocyte yields more than three-fold (p = 0.0078), but did not change their subpopulation profile, indicating that these leukocytes were still largely derived from the mucosa and not peripheral blood. We also confirmed that many CD4(+) T cells in the female genital tract express the α4β7 integrin, an HIV envelope-binding mucosal homing receptor. CVL sampling recovered the lowest number of viable mononuclear leukocytes. Two cervical cytobrushes yielded comparable total numbers of viable leukocytes to one biopsy, but cytobrushes and biopsies were biased toward macrophages and T lymphocytes, respectively. Our study also established the feasibility of obtaining consistent flow cytometric analyses of isolated genital cells from four study sites in the US and Africa. These data represent an important step towards implementing mucosal cell sampling in international clinical trials of HIV prevention.


The effect of topical medications on radial artery spasm in patients undergoing transradial coronary procedures: a systematic review.
The objective of this review was to identify the effectiveness of topical medications on radial artery spasm (RAS) in patients undergoing transradial percutaneous coronary procedures. Percutaneous coronary procedures were traditionally carried out via the femoral artery; however, over the last 20 years there has been a global increase in the number of proceduralists carrying out percutaneous coronary procedures via the transradial approach. Radial artery spasm remains an issue for the transradial approach, potentially leading to procedural failure. Topical medications have been suggested to reduce the occurrence of RAS during transradial percutaneous coronary procedures. This review considered papers that included participants aged 18 years and over undergoing non-emergency transradial percutaneous coronary procedures. This review considered papers on the utilization of topical medications prior to commencing the transradial approach for percutaneous coronary procedures to reduce RAS. Topical medications were compared to other medications. The primary outcome was the incidence of RAS as assessed by angiography or ultrasound or resistance felt by the operator while manipulating the catheter. Other outcomes of interest included change in radial artery diameter, measured by angiography or ultrasound, change in radial artery patency and side effects of medications administered. Randomized and quasi-randomized controlled trials were considered. A three-step search strategy was utilized in this review. A search of various databases was carried out followed by a search for unpublished literature between 1989 to January 2017. Only papers published in English were included in the review. Papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instrument from the Joanna Briggs Institute (JBI). There was no need for a third reviewer. Quantitative data was extracted from papers included in the review using the JBI data extraction instrument and entered in to RevMan5 (Copenhagen: The Nordic Cochrane Centre, Cochrane). All results were subject to double data entry. Effect sizes were expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals were calculated for analysis. Only three studies involving 697 participants met the inclusion criteria. There was a statistically significant reduction in the incidence of RAS in patients treated with a eutectic mixture of local anesthetics compared to subcutaneous lidocaine (OR 0.26; 95%CI 0.07,0.96). However there were no significant differences in RAS in studies that compared eutectic mixture of local anesthetics and placebo or a combinations of lidocaine with nitroglycerine compared to placebo. It is difficult to draw a valid conclusion, given the low number of studies, small sample sizes and heterogeneity between the studies.


Perceived Security Risk Based on Moderating Factors for Blockchain Technology Applications in Cloud Storage to Achieve Secure Healthcare Systems.
Due to the high amount of electronic health records, hospitals have prioritized data protection. Because it uses parallel computing and is distributed, the security of the cloud cannot be guaranteed. Because of the large number of e-health records, hospitals have made data security a major concern. The cloud's security cannot be guaranteed because it uses parallel processing and is distributed. The blockchain (BC) has been deployed in the cloud to preserve and secure medical data because it is particularly prone to security breaches and attacks such as forgery, manipulation, and privacy leaks. An overview of blockchain (BC) technology in cloud storage to improve healthcare system security can be obtained by reading this paper. First, we will look at the benefits and drawbacks of using a basic cloud storage system. After that, a brief overview of blockchain cloud storage technology will be offered. Many researches have focused on using blockchain technology in healthcare systems as a possible solution to the security concerns in healthcare, resulting in tighter and more advanced security requirements being provided. This survey could lead to a blockchain-based solution for the protection of cloud-outsourced healthcare data. Evaluation and comparison of the simulation tests of the offered blockchain technology-focused studies can demonstrate integrity verification with cloud storage and medical data, data interchange with reduced computational complexity, security, and privacy protection. Because of blockchain and IT, business warfare has emerged, and governments in the Middle East have embraced it. Thus, this research focused on the qualities that influence customers' interest in and approval of blockchain technology in cloud storage for healthcare system security and the aspects that increase people's knowledge of blockchain. One way to better understand how people feel about learning how to use blockchain technology in healthcare is through the United Theory of Acceptance and Use of Technology (UTAUT). A snowball sampling method was used to select respondents in an online poll to gather data about blockchain technology in Middle Eastern poor countries. A total of 443 randomly selected responses were tested using SPSS. Blockchain adoption has been shown to be influenced by anticipation, effort expectancy, social influence (SI), facilitation factors, personal innovativeness (PInn), and a perception of security risk (PSR). Blockchain adoption and acceptance were found to be influenced by anticipation, effort expectancy, social influence (SI), facilitating conditions, personal innovativeness (PInn), and perceived security risk (PSR) during the COVID-19 pandemic, as well as providing an overview of current trends in the field and issues pertaining to significance and compatibility.


Clinical spectrum of Wilson's disease (hepatolenticular degeneration).
Fifty-eight patients with Wilson's disease are reviewed, of whom 25 symptomatic patients experienced liver disease first and 28, brain disease. Ten of these patients presented with liver disease alone, 19 with brain disease alone, and 24 with evidence of both liver and brain disease. The remaining five were discovered as asymptomatic siblings of known patients. Three of the patients with hepatic presentation and one with neurologic presentation later experienced the other type of symptomatology, bringing the total number of patients with mixed disease to 28. Of the 44 patients with brain disease, 12 presented primarily with extrapyramidal findings, 6 with cerebellar findings, and 17 with both; pseudobulbar findings were noted in 9 patients, all of whom had other symptoms of severe nervous system disease. In addition to these presentations, in an appreciable number of patients the first symptoms were of a mental or emotional disorder. Disease of other organ systems, such as the joints and kidneys, also occurred but infrequently. Where adequate family information was available, 13 of 65 siblings (20%) were known to have had or were suspected of having had Wilson's disease. This is consistent with the autosomal-recessive pattern of inheritance.


[The effects of bito on the rate of burn surface healing and the content of molecular products of lipid peroxidation during burn injury].
The effects of an intravenously infused biological inhibitor of toxic oligopeptides (blood alpha-, beta-globulins) were studied on the rate burn surface epithelization, the levels of primary, secondary and end products of lipid peroxidation in different periods after experimental thermal injury. The agent was shown to accelerate the epithelization of a burn wound, to be able to lower the levels of molecular products of lipid peroxidation.


Clients' experiences of living at home with a mechanical ventilator.
This paper reports on a study of how clients experience living with home mechanical ventilation and how they experience care and supervision of healthcare personnel. The number of people living at home with mechanical ventilators is increasing, and this is considered a successful approach to reducing incapacity and mortality. Qualitative interviews were conducted with 10 service users in 2006. The informants were 18-75 years old and had varying diagnoses and levels of functioning. The interviews were tape recorded, transcribed and analysed by qualitative content analysis. Two main themes emerged: Theme 1. Having a home ventilator enhances quality of life--a life worth living. The ventilator treatment builds up strength and improves well-being. Participants emphasized that it was important to feel in control of their own situation and had an overriding wish to live a normal and active life; Theme 2. Competence and continuity of healthcare personnel are factors for success. The experience was that competence and follow-up by healthcare personnel varied, and that good quality teaching and information were important. Users of home mechanical ventilators should be active partners in their own care so that their experience is taken into account. It is important for clients having home mechanical ventilation to be empowered and have control in their daily lives, as well as having competent caregivers and continuity of care.


Contrasting Residency Training in Japan and the United States From Perspectives of Japanese Physicians Trained in Both Systems.
International medical graduates (IMGs) have significant exposure to clinical training in their home country, which provides opportunity for international comparison of training experiences. One relevant IMG population is Japanese physicians who have completed some training before entering residency programs in the United States and desire to improve medical education in Japan. We examined Japanese IMGs' perceptions of the respective attributes of residency in the United States and Japan. Individual semistructured interviews were conducted with 33 purposively sampled Japanese IMGs who had completed training. We used exploratory thematic analysis, iterative data collection, and thematic analyses with constant comparison. Comments were organized into 3 categories: (1) attributes of US residency preferable to Japanese residency; (2) attributes of residency training with no clear preference for the US or Japanese systems; and (3) attributes of Japanese residency preferable to US residency. Within each category, we matched themes to residency program requirements or culture of medical training. Main themes include high regard for Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements, with emphasis on efficient achievement of clinical competency through graded responsibility, contrasted with preference expressed for a Japanese training culture of increased professional commitment facilitated by a lack of work hour limits and development of broad clinician skills, including bedside procedures and radiology interpretation. Japanese training culture contrasts with a US model that is increasingly focused on work-life balance and associated compartmentalization of patient care. These findings enhance our understanding of the global medical education landscape and challenges to international standardization of training.


Sex-linked inheritance in macaque monkeys: implications for effective population size and dispersal to Sulawesi.
Sex-specific differences in dispersal, survival, reproductive success, and natural selection differentially affect the effective population size (N(e)) of genomic regions with different modes of inheritance such as sex chromosomes and mitochondrial DNA. In papionin monkeys (macaques, baboons, geladas, mandrills, drills, and mangabeys), for example, these factors are expected to reduce N(e) of paternally inherited portions of the genome compared to maternally inherited portions. To explore this further, we quantified relative N(e) of autosomal DNA, X and Y chromosomes, and mitochondrial DNA using molecular polymorphism and divergence information from pigtail macaque monkeys (Macaca nemestrina). Consistent with demographic expectations, we found that N(e) of the Y is lower than expected from a Wright-Fisher idealized population with an equal proportion of males and females, whereas N(e) of mitochondrial DNA is higher. However, N(e) of 11 loci on the X chromosome was lower than expected, a finding that could be explained by pervasive hitchhiking effects on this chromosome. We evaluated the fit of these data to various models involving natural selection or sex-biased demography. Significant support was recovered for natural selection acting on the Y chromosome. A demographic model with a skewed sex ratio was more likely than one with sex-biased migration and explained the data about as well as an ideal model without sex-biased demography. We then incorporated these results into an evaluation of macaque divergence and migration on Borneo and Sulawesi islands. One X-linked locus was not monophyletic on Sulawesi, but multilocus data analyzed in a coalescent framework failed to reject a model without migration between these islands after both were colonized.


Hemoglobin and Change in Hemoglobin Status Predict Mortality, Cardiovascular Events, and Bleeding in Stable Coronary Artery Disease.
Anemia is a predictor of adverse outcomes in acute myocardial infarction. We studied the relationship of hemoglobin, or its change over time, and outcomes in patients with stable coronary artery disease. The ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease is a prospective, cohort study of outpatients with stable coronary artery disease (32,901 in 45 countries 2009-2010): 21,829 with baseline hemoglobin levels. They were divided into hemoglobin quintiles and anemia status (anemic or normal at baseline/follow-up: normal/normal; anemic/normal; normal/anemic; anemic/anemic. All-cause mortality, cardiovascular events, and major bleeding at 4-year follow-up were assessed. Low baseline hemoglobin was an independent predictor of all-cause, cardiovascular, and noncardiovascular mortality, the composite of cardiovascular death/myocardial infarction or stroke and major bleeds (all P <.001; unadjusted models). Anemia at follow-up was independently associated with all-cause mortality (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.55-2.33 for anemic/anemic; 1.87; 1.54-2.28 for normal/anemic; both P <.001), noncardiovascular mortality (P <.001), and cardiovascular mortality (P = .001). Patients whose baseline anemia normalized (anemic/normal) were not at increased risk of death (HR, 1.02; 95% CI, 0.77-1.35), although the risk of major bleeding was greater (HR, 2.06; 95% CI, 1.23-3.44; P = .013) than in those with normal hemoglobin throughout. Sensitivity analyses excluding patients with heart failure and chronic kidney disease at baseline yielded qualitatively similar results. In this large population with stable coronary artery disease, low hemoglobin was an independent predictor of mortality, cardiovascular events, and major bleeds. Persisting or new-onset anemia is a powerful predictor of cardiovascular and noncardiovascular mortality.


Elimination of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol when normalized to urinary creatinine.
Gas chromatography mass/spectrometry quantitative analysis of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THCCOOH), the major metabolite of delta-9-tetrahydrocannabinol (THC) found in urine following marijuana use, was performed on serial urine specimens collected from an inpatient adolescent population of marijuana users. Creatinine normalization of THCCOOH was used to compensate for dilute or concentrated urine specimens. The urinary terminal elimination rate constant and terminal half-life was calculated for each subject. The mean urinary elimination rate constant for THCCOOH normalized to creatinine was 0.08433 days(-1) (range 0.05408-0.16544) reflecting a 8.22 day terminal half-life. A half-life of 1.15 days was observed for the initial decline phase of THCCOOH corrected by creatinine suggesting that reuse of marijuana can be detected after this phase ends. The creatinine normalized THCCOOH level was a better indicator for predicting reuse of marijuana than urinary concentrations of THCCOOH. The Mean Residence Time (MRT) of THCCOOH/Cr (5.7 days) correlated well with the length of time a subject will have detectable urinary THCCOOH concentrations (20.8 days).


Carbon monoxide is not responsible for the cigarette smoke-induced changes in the pulmonary metabolism of arachidonic acid and prostaglandin E2.
Cigarette smoke is known to interfere with the pulmonary metabolism of arachidonic acid and prostaglandin E2 (PGE2). We investigated the possible role of carbon monoxide in these cigarette smoke-induced alterations. 14C-Arachidonic acid (50 nmol) was infused into the pulmonary circulation of isolated perfused hamster lungs, and the radioactive metabolites in the perfusion effluent, as well as the distribution of incorporated radioactive arachidonic acid within the lung lipids, were analysed. Carbon monoxide, added into the ventilatory air, had no effect on the oxidative metabolism of arachidonic acid or on the distribution of radioactive arachidonic acid within the lung. In addition, carbon monoxide had no effect on the metabolism of PGE2 following infusion of 100 nmol of 14C-PGE2 into the rat pulmonary circulation. The present study suggests that carbon monoxide is not responsible for the cigarette smoke-induced changes in the pulmonary metabolism of arachidonic acid and PGE2.


Changes in physical activity across a 6-month weight loss intervention in adolescents with intellectual and developmental disabilities.
Adolescents and young adults with intellectual and developmental disabilities (IDD) have high rates of obesity and low levels of physical activity. This analysis examined changes in light, moderate-to-vigorous physical activity (MVPA) and sedentary time, and the association between changes in MVPA and weight loss in adolescents and young adults with IDD and overweight and obesity participating in a 6-month multi-component weight loss intervention. Adolescents and young adults with IDD and overweight or obesity (body mass index ≥ 85 percentile, n = 110, age ~16 years, 52.7% female) and a parent were randomised to one of three intervention groups: face-to-face delivery/conventional reduced energy diet (n = 36), remote delivery (RD)/conventional reduced energy diet (n = 39), or RD/reduced energy enhanced stop light diet (eSLD) (n = 35.) Participants were asked to engage in 60 min/day of MVPA on 5 or more days/wk. Participants and a parent attended twice monthly education/behavioural counselling sessions with a health educator to assist participants in complying with dietary and MVPA recommendations. Education/counselling in the RD arms was delivered remotely using video conferencing, and self-monitoring of MVPA and daily steps was completed using a wireless activity tracker. Education/counselling in the face-to-face arm was delivered during home-visits and self-monitoring of MVPA and daily steps was completed by self-report using paper tracking forms designed for individuals with IDD. MVPA, light activity, and sedentary time were assessed over 7 days at baseline and 6 months using a portable accelerometer (ActiGraph wGT3x-BT). Mixed modelling analysis completed using participants with valid accelerometer data (i.e. ≥4-10 h days) at baseline (n = 68) and 6 months (n = 30) revealed no significant changes in light, moderate- MVPA, or sedentary time across the 6-month intervention (all P > 0.05). Participants obtained 15.2 ± 21.5 min/day of MVPA at baseline and 19.7 ± 19.7 min/day at 6 months (P = 0.119). Mixed modelling indicated no significant effects of group (P = 0.79), time (P = 0.10), or group-by-time interaction (P = 0.21) on changes in MVPA from baseline to 6 months. Correlational analysis conducted on participants with valid accelerometer data at both baseline and 6 months (n = 24) revealed no significant associations between baseline sedentary time (r = 0.10, P = 0.40) and baseline MVPA (r = -0.22, P = 0.30) and change in MVPA across the 6-month intervention. Additionally, attendance at education/counselling sessions (r = 0.26, P = 0.22) and frequency of self-monitoring of MVPA were not significantly associated with change in MVPA from baseline to 6 months (r = 0.26, P = 0.44). Baseline MVPA (r = 0.02, P = 0.92) and change in MVPA from baseline to 6 months (r = 0.13, P = 0.30) were not associated with changes in body weight across the 6-month intervention. We observed a non-significant increase in MVPA (30%), which was not associated with the magnitude of weight loss in a sample of adolescents and young adults with IDD who participated in a 6-month multi-component weight loss intervention. Additional strategies to increase MVPA in adolescents and young adults with IDD participating in weight loss interventions need to be developed and evaluated.


Developing standards for institutional ethics committees: lessons from The Netherlands.
This article presents standards for setting up and educating institutional ethics committees (IECs). These standards are based on experiences in the Netherlands, where IECs have been established in a large number of health care institutions. Though the IEC has become a generally accepted institution within Dutch health care, there are concerns over its effectiveness regarding the improving of the moral quality of clinical decision making. Health care practitioners and members of IECs too, experience a gap between the IEC and the reality of the clinical environment. At this moment, there is interest in developing programmes which educate practitioners in moral issues and how to deal with them, using the method of a structured debate on the ward. The IEC will not be made obsolete by this development, but can play a guiding role in the implementation of such programmes. Current concerns are the lack of patient representation in the Dutch IEC, and the loss of contact with the local community of health care practitioners because of the merger of hospitals into bodies similar to UK National Health Service (NHS) trusts.


Intraocular lens exchange through a 3.2-mm corneal incision for opacified intraocular lenses.
The aim was to evaluate visual and refractive results and complications of intraocular lens (IOL) exchange through a 3.2 mm corneal incision for opacified IOLs. This retrospective study comprised 33 eyes of 32 patients with IOL opacification requiring an IOL exchange between July 2003 and March 2007. Exchange surgery was performed through a 3.2-mm temporal clear corneal incision followed by implantation of a new foldable hydrophobic IOL. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), topographical astigmatism, and refractive cylinder were evaluated. Surgically induced astigmatism (SIA) was calculated and complications were recorded. Opacification was observed in 25 eyes (76%) with Aqua-Sense, 3 eyes (9%) with Hydroview, 3 eyes (9%) with MemoryLens IOLs, and 2 eyes (6%) with DgR. The mean follow-up period was 36.54 months. An uneventful IOL exchange was achieved in 18 eyes (55%). Zonular dehiscence occurred in 9 eyes (27%), and posterior capsule tear developed in 4 eyes (12%). The mean preoperative BSCVA (mean ± standard deviation, decimal scale) was 0.13 ± 0.08 (mean: 20/150, range 20/2000 to 20/60) and improved to 0.63 ± 0.18 (mean: 20/32, range 20/60 to 20/20, P < 0.001). The mean SIA was 0.70 D. Seven eyes (21%) had 0.5 D or lower SIA. IOL exchange is a technically challenging procedure with potential risks of reversing the advantages of a prior small-incision cataract surgery. The use of a small corneal incision for IOL exchange could preserve the advantages of modern phacoemulsification surgery with acceptable SIA related to the procedure.


Wars between microbes on roots and fruits.
Microbes in nature often live in unfavorable conditions. To survive, they have to occupy niches close to food sources and efficiently utilize nutrients that are often present in very low concentrations. Moreover, they have to possess an arsenal of attack and defense mechanisms against competing bacteria. In this review, we will discuss strategies used by microbes to compete with each other in the rhizosphere and on fruits, with a focus on mechanisms of inter- and intra-species antagonism. Special attention will be paid to the recently discovered roles of volatile organic compounds. Several microbes with proven capabilities in the art of warfare are being applied in products used for the biological control of plant diseases, including post-harvest control of fruits and vegetables.


Psychological outcomes following sexual assault: Differences by sexual assault setting.
Sexual assault is associated with increased psychological distress. It is possible that military sexual assault (MSA) is associated with heightened psychological distress compared to adult sexual assault that occurs pre- or postmilitary service due to the nature of the military setting. Veterans and service members (N = 3,114; 19.6% women) who participated in the Post-Deployment Mental Health Study completed self-report measures of sexual assault history, symptoms of posttraumatic stress disorder (PTSD), symptoms of depression, hazardous alcohol use, drug use, and suicidal ideation. Women who reported a history of MSA endorsed higher levels of all types of psychological distress than women who did not experience adult sexual assault. Women who reported a history of MSA also endorsed higher levels of PTSD and depression symptoms than women who experienced pre- or postmilitary adult sexual assault. Men who reported a history of adult sexual assault, regardless of setting, reported higher levels of PTSD and depression symptoms than individuals who did not experience adult sexual assault. MSA was associated with higher psychological distress than pre- or postmilitary adult sexual assault among women. Among men, distress associated with MSA was comparable to sexual assault outside the military. Women may face unique challenges when they experience sexual assault in the military, and men may face additional stigma (compared to women) when they experience sexual assault, regardless of setting. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland.
Elevated circulating estrogen levels are associated with increased risk of breast cancer in obese postmenopausal women. Following menopause, the biosynthesis of estrogens through CYP19 (aromatase)-mediated metabolism of androgen precursors occurs primarily in adipose tissue, and the resulting estrogens are then secreted into the systemic circulation. The potential links between obesity, inflammation, and aromatase expression are unknown. In both dietary and genetic models of obesity, we observed necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS) in the mammary glands and visceral fat. The presence of CLS was associated with activation of NF-κB and increased levels of proinflammatory mediators (TNF-α, IL-1β, Cox-2), which were paralleled by elevated levels of aromatase expression and activity in the mammary gland and visceral fat of obese mice. Analyses of the stromal-vascular and adipocyte fractions of the mammary gland suggested that macrophage-derived proinflammatory mediators induced aromatase and estrogen-dependent gene expression (PR, pS2) in adipocytes. Saturated fatty acids, which have been linked to obesity-related inflammation, stimulated NF-κB activity in macrophages leading to increased levels of TNF-α, IL-1β, and Cox-2, each of which contributed to the induction of aromatase in preadipocytes. The discovery of the obesity → inflammation → aromatase axis in the mammary gland and visceral fat and its association with CLS may provide insight into mechanisms underlying the increased risk of hormone receptor-positive breast cancer in obese postmenopausal women, the reduced efficacy of aromatase inhibitors in the treatment of breast cancer in these women, and their generally worse outcomes. The presence of CLS may be a biomarker of increased breast cancer risk or poor prognosis.


Expression of the Lhx genes apterous and lim1 in an errant polychaete: implications for bilaterian appendage evolution, neural development, and muscle diversification.
Arthropod and vertebrate appendages appear to have evolved via parallel co-option of a plesiomorphic gene regulatory network. Our previous work implies that annelids evolved unrelated appendage-forming mechanisms; we therefore found no support for homology of parapodia and arthropodia at the level of the whole appendage. We expand on that study here by asking whether expression of the LIM homeobox (Lhx) genes apterous and lim1 in the annelid Neanthes arenaceodentata supports homology of the dorsal branches as well as the proximodistal axes of parapodia and arthropodia. In addition, we explore whether the neural expression of apterous and lim1 in Neanthes supports the putative ancestral function of the Lhx gene family in regulating the differentiation and maintenance of neuronal subtypes. Both genes exhibit continuous expression in specific portions of the developing central nervous system, from hatching to at least the 13-chaetiger stage. For example, nerve cord expression occurs in segmentally iterated patterns consisting of diffuse sets of many lim1-positive cells and comparatively fewer, clustered pairs of apterous-positive cells. Additionally, continuous apterous expression is observed in presumed neurosecretory ganglia of the posterior brain, while lim1 is continuously expressed in stomatogastric ganglia of the anterior brain. apterous is also expressed in the jaw sacs, dorsal parapodial muscles, and a presumed pair of cephalic sensory organs, whereas lim1 is expressed in multiple pharyngeal ganglia, the segmental peripheral nervous system, neuropodial chaetal sac muscles, and parapodial ligules. The early and persistent nervous system expression of apterous and lim1 in Neanthes juveniles supports conservation of Lhx function in bilaterian neural differentiation and maintenance. Our results also suggest that diversification of parapodial muscle precursors involves a complementary LIM code similar to those generating distinct neuronal identities in fly and mouse nerve cords. Expression of apterous and lim1 in discrete components of developing parapodia is intriguing but does not map to comparable expression of these genes in developing arthropod appendages. Thus, annelid and arthropod appendage development apparently evolved, in part, via distinct co-option of the neuronal regulatory architecture. These divergent patterns of apterous and lim1 activity seemingly reflect de novo origins of parapodia and arthropodia, although we discuss alternative hypotheses.


Early detection of lung cancer: clinical perspectives of recent advances in biology and radiology.
Lung cancer is the most common cause of cancer death in developed countries. The prognosis is poor, with less than 15% of patients surviving 5 years after diagnosis. The poor prognosis is attributable to lack of efficient diagnostic methods for early detection and lack of successful treatment for metastatic disease. Most patients (>75%) present with stage III or IV disease and are rarely curable with current therapies. Within the last decade, rapid advances in molecular biology, pathology, bronchology, and radiology have provided a rational basis for improving outcome. These advancements have led to a better documentation of morphological changes in the bronchial epithelium before development of clinical evident invasive carcinomas. This has changed our concept of lung carcinogenesis and emphasized the multistep carcinogenesis approach on several levels. Combined with the technical developments in bronchoscopic techniques, e.g., laser-induced fluorescence endoscope (LIFE) bronchoscopy, we now have improved methods to localize preinvasive and early-invasive bronchial lesions. With the LIFE bronchoscope, a new morphological entity (angiogenic squamous dysplasia) has been recognized, which might be an important biomarker and target for antiangiogenic chemopreventive agents. To reduce the mortality of lung cancer, these new technologies have been taken into the clinic in different scientific settings. The use of low-dose spiral computed tomography in the screening of a high-risk population has demonstrated the possibility of diagnosing small peripheral tumors that are not seen on conventional X-ray. A shift in the therapeutic paradigm from targeting advanced clinically manifest lung cancer toward asymptomatic preinvasive and early-invasive cancer is occurring. The present article reviews the recent advances in the diagnosis of preinvasive and early-invasive cancer to identify biomarkers for early detection of lung cancer and for chemoprevention studies.


Structural and functional insights into Saccharomyces cerevisiae Tpa1, a putative prolylhydroxylase influencing translation termination and transcription.
Efficiency of translation termination relies on the specific recognition of the three stop codons by the eukaryotic translation termination factor eRF1. To date only a few proteins are known to be involved in translation termination in eukaryotes. Saccharomyces cerevisiae Tpa1, a largely conserved but uncharacterized protein, has been described to associate with a messenger ribonucleoprotein complex located at the 3' end of mRNAs that contains at least eRF1, eRF3, and Pab1. Deletion of the TPA1 gene results in a decrease of translation termination efficacy and an increase in mRNAs half-lives and longer mRNA poly(A) tails. In parallel, Schizosaccharomyces pombe Ofd1, a Tpa1 ortholog, and its partner Nro1 have been implicated in the regulation of the stability of a transcription factor that regulates genes essential for the cell response to hypoxia. To gain insight into Tpa1/Ofd1 function, we have solved the crystal structure of S. cerevisiae Tpa1 protein. This protein is composed of two equivalent domains with the double-stranded β-helix fold. The N-terminal domain displays a highly conserved active site with strong similarities with prolyl-4-hydroxylases. Further functional studies show that the integrity of Tpa1 active site as well as the presence of Yor051c/Ett1 (the S. cerevisiae Nro1 ortholog) are essential for correct translation termination. In parallel, we show that Tpa1 represses the expression of genes regulated by Hap1, a transcription factor involved in the response to levels of heme and oxygen. Altogether, our results support that Tpa1 is a putative enzyme acting as an oxygen sensor and influencing several distinct regulatory pathways.


Localization of the N-terminal domain in light-harvesting chlorophyll a/b protein by EPR measurements.
The conformational distribution of the N-terminal domain of the major light-harvesting chlorophyll a/b protein (LHCIIb) has been characterized by electron-electron double resonance yielding distances between spin labels placed in various domains of the protein. Distance distributions involving residue 3 near the N terminus turned out to be bimodal, revealing that this domain, which is involved in regulatory functions such as balancing the energy flow through photosystems (PS) I and II, exists in at least two conformational states. Models of the conformational sub-ensembles were generated on the basis of experimental distance restraints from measurements on LHCIIb monomers and then checked for consistency with the experimental distance distribution between residues 3 in trimers. Only models where residue 3 is located above the core of the protein and extends into the aqueous phase on the stromal side fit the trimer data. In the other state, which consequently is populated only in monomers, the N-terminal domain extends sideways from the protein core. The two conformational states may correspond to two functional states of LHCIIb, namely trimeric LHCIIb associated with PSII in stacked thylakoid membranes and presumably monomeric LHCIIb associated with PSI in nonstacked thylakoids. The switch between these two is known to be triggered by phosphorylation of Thr-6. A similar phosphorylation-induced conformational change of the N-terminal domain has been observed by others in bovine annexin IV which, due to the conformational switch, also loses its membrane-aggregating property.


Vitamin D Deficiency in Community-Dwelling Elderly Is Not Associated with Age-Related Macular Degeneration.
Elderly persons are at elevated risk of vitamin D deficiency, which is involved in various health problems. However, its relation with age-related macular degeneration (AMD) is debated. We investigated factors associated with plasma 25-hydroxyvitamin D [25(OH)D] deficiency and the associations between plasma 25(OH)D concentrations and AMD in elderly subjects. Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes (ALIENOR) is a population-based study on eye diseases performed in elderly residents of Bordeaux, France. Plasma 25(OH)D concentrations were assessed from blood samples and categorized as <25 nmol/L (deficiency), 25-49 nmol/L (insufficiency), or ≥50 nmol/L (sufficiency). AMD was classified as: no AMD, early AMD, and late AMD. Associations between baseline characteristics and plasma 25(OH)D status were examined with multinomial logistic regression analysis. Associations between AMD and plasma 25(OH)D status were estimated using generalized estimating equation logistic regressions. Six hundred ninety-seven subjects with complete data were included. The prevalence of plasma 25(OH)D deficiency and insufficiency were 27.3% and 55.9%, respectively. In multivariate analysis, 25(OH)D deficiency was significantly associated with older age (P = 0.0007), females (P = 0.0007), absence of physical activity (P = 0.01), absence of vitamin D supplementation (P < 0.0001), higher plasma total cholesterol (P = 0.007), use of fibrates (P < 0.0001), lower alcohol consumption (P = 0.02), and season of blood sampling (P < 0.0001). After adjustment for these covariates and dietary omega-3 polyunsaturated fatty acid intake, smoking, and body mass index, no significant associations were found between early AMD and 25(OH)D insufficiency or deficiency (OR: 0.71, P = 0.12; OR: 0.73, P = 0.23, respectively) or with late AMD (OR: 1.04, P = 0.93; OR: 0.74, P = 0.59, respectively). These findings underline the very high prevalence of plasma 25(OH)D deficiency in this elderly population but do not support a specific role for vitamin D in AMD.


An On-Device Learning System for Estimating Liquid Consumption from Consumer-Grade Water Bottles and Its Evaluation.
A lightweight on-device liquid consumption estimation system involving an energy-aware machine learning algorithm is developed in this work. This system consists of two separate on-device neural network models that carry out liquid consumption estimation with the result of two tasks: the detection of sip from gestures with which the bottle is handled by its user and the detection of first sips after a bottle refill. This predictive volume estimation framework incorporates a self-correction mechanism that can minimize the error after each bottle fill-up cycle, which makes the system robust to errors from the sip classification module. In this paper, a detailed characterization of sip detection is performed to understand the accuracy-complexity tradeoffs by developing and implementing a variety of different ML models with varying complexities. The maximum energy consumed by the entire framework is around 119 mJ during a maximum computation time of 300 μs. The energy consumption and computation times of the proposed framework is suitable for implementation in low-power embedded hardware that can be incorporated in consumer grade water bottles.


[Two molecular forms of pea ferredoxin in the electron transport chain of chloroplasts].
The effects of two molecular forms of water-soluble ferredoxin (Fd I and Fd II) on the kinetics of electron transport in bean chloroplasts (class B) were studied. The light-induced redox transitions of the photosystem I reaction center P700 were measured by the intensity of the EPR signal I produced by P700+. Both forms of ferredoxin, Fd I and Fd II, when added to the chloroplasts in catalytic amounts, stimulate the light-induced electron transfer from P700 to NADP+. Nevertheless, Fd I is a better mediator of the back reactions from NADPH to P700+. This electron transfer pathway is sensitive to the cyclic electron transport inhibitor, antimycin A, and to DCMU inhibitor of electron transport between photosystem II and plastoquinone. It may be concluded that the two molecular forms of ferredoxin, Fd I and Fd II, differ in their ability to catalyze cyclic electron transport in photosystem I. The role of Fd I and Fd II in regulation of electron transport at the acceptor site of photosystem I is discussed.


Body size and mortality in women: a 29 year follow up of 12,000 pregnant women in northern Finland.
To examine the association between body height, body mass index (BMI), and mortality in fertile women of childbearing age. A prospective cohort study with a 29 year mortality follow up. A cohort of women (n = 11,997) expected to deliver during 1966 in two northern provinces of Finland. Data on height and pre-pregnancy weight, collected with those on sociodemographic characteristics and smoking by questionnaire at the third trimester, were provided by 91% of the participants. Follow up for mortality using national registries was from delivery until the end of 1994. Height had a 'U' shaped association with total mortality over the whole follow up time. In women who were shorter than average, the death rate from cardiovascular diseases was increased and in taller women this was true for tumours. Compared with the women of 'normal weight' (BMI 21 to < 25 kg/m2), the obese subjects (BMI at least 29) did not have increased mortality during the first 20 years, but had a relative risk of 1.7 during the final nine years of follow up, primarily as a result of cardiovascular diseases. The lean women (BMI < 21) experienced a similar rate overall, but moderately overweight women (BMI 25 to < 29) had a consistently lower mortality than women of normal weight. Among fertile women of childbearing age, both the short and tall seem to have an increased total mortality compared with those of average body height, resulting from opposite trends in major causes of death. Obesity is associated with raised long term total mortality.


Immunoglobulin light chains activate tubular epithelial cells through redox signaling.
The renal proximal tubule metabolizes circulating low-molecular-weight proteins such as Ig free light chains. In the setting of plasma cell dyscrasias, the burden of filtered protein can be very high. Endocytosis of certain nephrotoxic light chains induces H(2)O(2) production and monocyte chemoattractant protein-1 (MCP-1) release, leading to recruitment of inflammatory cells and interstitial fibrosis, but how these processes are linked mechanistically is not well understood. This study investigated the relationship between H(2)O(2) generated after light chain endocytosis by human proximal tubular (HK-2) cells and activation of c-Src, a redox-sensitive tyrosine kinase. HK-2 cells exposed to two different light chains upregulated c-Src activity, which increased the production of MCP-1. In parallel, we observed a time-dependent oxidation of c-Src. Inhibition of c-Src activity and silencing c-Src expression abrogated the light chain-induced MCP-1 response, but had no effect on H(2)O(2), indicating that production of H(2)O(2) is upstream of c-Src in the signaling cascade. Silencing megalin and cubilin expression inhibited the MCP-1 response, whereas extracellular catalase did not, indicating that endocytosis is required and that intracellular generation of reactive oxygen species activates c-Src. These data show that intracellular H(2)O(2) induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, which promotes release of MCP-1.


Mortality of short-term workers in two international cohorts.
The purpose of this study was to compare the pattern of mortality of blue-collar workers employed less and more than 1 year in the man-made vitreous fiber (MMVF) and the reinforced plastic industries, the latter group being exposed to styrene. We conducted an analysis among 21,784 workers with less than 1 year of employment (short-term workers) and 19,117 workers with 1 or more years of employment (long-term workers) employed in eight European countries. We conducted analyses based on external as well as internal comparisons. In both cohorts, the standardized mortality ratio for all causes among short-term workers was approximately 40% higher, compared with that for longer-term workers. In internal comparisons, the difference was reduced to 9% in the MMVF cohort and 11% in the styrene cohort. Workers with less than 1 month of employment displayed an increased mortality in both cohorts and in most countries. The increased mortality among short-term workers was not concentrated shortly after they quit employment. In both cohorts, short-term workers had a higher mortality from external causes, while little difference was seen in mortality from ischemic heart disease and malignant neoplasms. Although extra-occupational factors may contribute to increase the mortality of short-term workers and, in particular, of those employed for less than 1 month, the difference observed in analyses adjusted for characteristics of employment suggested a relatively small difference in mortality from most causes.


Advertising and Environmental Stewardship: Evidence from the BP Oil Spill.
This paper explores whether private markets can incentivize environmental stewardship. We examine the consumer response to the 2010 BP oil spill and test how BP's investment in the 2000-2008 "Beyond Petroleum" green advertising campaign affected this response. We find evidence consistent with consumer punishment: BP station margins and volumes declined by 2.9 cents per gallon and 4.2 percent, respectively, in the month after the spill. However, pre-spill advertising significantly dampened the price response, and may have reduced brand switching by BP stations. These results indicate that firms may have incentives to engage in green advertising without investments in environmental stewardship.


Post-translational modifications of proteins in antiphospholipid antibody syndrome.
Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombosis and/or pregnancy morbidity. The incidence is around five new cases/100,000 persons per year and the prevalence is around 40-50 cases/100,000. The prevalence is higher (about 30%) among patients with systemic lupus erythematosus. APS is associated with circulating antiphospholipid antibodies (aPLs), a heterogeneous group of autoantibodies directed against negatively charged molecules and a combination of protein-complexed phospholipids. The predominant protein antigen in this disorder is beta 2-glycoprotein I (β2GPI). Despite the discovery of "new" antigenic targets and development of "new" methodological approaches, the laboratory diagnosis of APS is still an evolving field and studies to identify further antigenic target(s) as potential diagnostic markers and risk predictors are in progress. In particular, recent studies were aimed at analyzing the pathogenic role of post-translational modifications (PTMs) of proteins induced by inflammation and/or oxidative stress as modulators of protein structure and function and possibly as a source of antigenic epitopes. The present review is focused on PTMs of self-proteins responsible for autoimmune reactions in patients with APS. At present, the known PTMs in APS involve β2GPI. In particular, the PTM of β2GPI via thiol-exchange reactions is a highly specific phenomenon that makes the protein more antigenic. Other PTMs, including sialylation and acetylation, may affect β2GPI antigenicity. Moreover, the addition or loss of carbohydrate chains affects β2GPI immunoreactivity since carbohydrates are determining factors for β2GPI conformation. In addition to β2GPI, PTMs of other self proteins such as vimentin and annexins may play a role in the immune response during APS. The study of PTMs is useful to clarify the role of modified proteins in the pathogenesis of APS as well as to design more efficient diagnostic/prognostic tools and more targeted therapeutic approaches.


Substance and psychiatric disorders among men and women repeat driving under the influence offenders who accept a treatment-sentencing option.
Driving under the influence (DUI) continues to be a serious public health concern in the United States. Research suggests that the substance use/abuse and psychiatric histories of repeat offenders might contribute to the persistence of this phenomenon. Because psychiatric histories could be important to recovery and likely differ substantially between men and women, the present study examined psychiatric and substance-use histories of male and female DUI repeat offenders in treatment. Seven hundred twenty-nine residents at the Middlesex Driving Under the Influence of Liquor program in Tewksbury, MA, a licensed residential facility providing treatment and education to repeat DUI offenders, participated in the current study during the course of 12 months. These participants completed a standardized diagnostic interview-12 modules of the Composite International Diagnostic Interview-as part of their intake interview. Female repeat offenders in this study were substantially different from male repeat offenders in lifetime and past-year psychiatric comorbidity patterns. Women had more extensive histories of psychiatric morbidity (i.e., psychiatric disorder in addition to substance abuse/dependence, alcohol abuse/dependence, and pathological gambling) and were more likely than men to report a history of multiple morbidities (i.e., multiple psychiatric disorders in addition to substance-related or gambling disorders). Both male and female repeat DUI offenders have extensive but different psychiatric histories that might play a significant role in DUI recidivism. These differences in psychiatric and substance-use histories among men and women could have important implications for treatment and prevention of DUI.


Combination therapy of cholesterol reduction and L-arginine supplementation controls accelerated vein graft atheroma.
Hyperlipidemia contributes to the development of intimal hyperplasia and accelerated atheroma in vein bypass grafts. Dietary cholesterol reduction and oral supplementation with L-arginine have been shown to reduce accelerated atheroma in experimental vein grafts. This study extends these observations by examining the effect of the combination therapy of cholesterol reduction and L-arginine supplementation on the development of intimal hyperplasia in vein grafts in hypercholesterolemic animals. Thirty New Zealand White rabbits had a carotid vein bypass graft performed and were sacrificed at 28 days postoperatively either for morphology (light and electron microscopy) and videomorphometry, or for in vitro contractile studies. Twenty animals received a 1% cholesterol diet for 4 weeks prior to surgery. This diet was continued until harvest in ten animals. Ten cholesterol-fed animals received L-arginine supplementation (2 g/kg/day, p.o.) for 7 days preoperatively and thereafter until harvest and in addition were returned to a normal diet on the day of surgery. The last ten animals were controls (normal diet). Combined cholesterol reduction and L-arginine supplementation prevented accelerated atheroma in vein grafts, halted the change in enhanced smooth muscle cell contractility, and improved endothelial cell function. Early postoperative therapy targeting atheroma development in the high-risk patient could offer significant morphological and functional benefits.


Aromatic donor-acceptor interaction promoted catalyst assemblies for hydrolytic kinetic resolution of epichlorohydrin.
Three generations of Co(iii)-salen complexes containing electron-deficient aromatic moieties (acceptors) have been synthesized. When electron-rich aromatic compounds (donors) were introduced, these complexes were designed to form catalyst assemblies through aromatic donor-acceptor interaction. For all three generations of complexes, the addition of a proper donor led to higher catalytic efficiency in the hydrolytic kinetic resolution (HKR) of epichlorohydrin. The reaction rates are in the following order: Generation 3 > Generation 2 > Generation 1. The aromatic donor-acceptor interaction was verified by NMR spectroscopy and UV-vis absorption spectroscopy studies. These results demonstrated that aromatic donor-acceptor interaction can be a valuable driving force in the assembly of supramolecular catalysts.


Terahertz Spectroscopy for Non-Destructive Solid-State Investigation of Norfloxacin in Paper Tablets after Wet Granulation.
(1) Background: Amorphous drug systems are an intensively studied approach to overcome the insufficient bioavailability of poorly soluble drugs. Here, paper tablets were studied, which were made from cellulose-based paper matrices loaded with norfloxacin. Moreover, wet granulation was introduced as an additional processing step for improving the flowability of the solids, which is necessary when considering production on an industrial scale. (2) Methods: The possible impact of the wet granulation on the crystallinity of norfloxacin was studied by examining granulated and non-granulated samples. Crystallinity investigations were performed using X-ray powder diffraction (XRD) and terahertz time-domain spectroscopy (THz TDS). (3) Results: THz TDS allowed for a more straightforward crystallinity assessment than XRD. Moreover, using THz TDS, it was possible to detect minor changes in the crystallinity of the API after the granulation, whereas this was not possible with the XRD analysis. (4) Conclusions: THz TDS results indicate a partial crystallization of norfloxacin due to the wet granulation. Depending on the formulation, THz TDS can serve as a beneficial and advantageous tool to determine the crystallinity of an API.