Cost per response for abatacept versus adalimumab in rheumatoid arthritis by ACPA subgroups in Germany, Italy, Spain, US and Canada.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to disability and reduced quality of life. Effective treatment with biologic DMARDs poses a significant economic burden. The Abatacept versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) trial was a head-to-head, randomized study comparing abatacept in serum anti-citrullinated protein antibody (ACPA)-positive patients, with increasing efficacy across ACPA quartile levels. The aim of this study was to evaluate the cost per response accrued using abatacept versus adalimumab in ACPA-positive and ACPA-negative patients with RA from the health care perspective in Germany, Italy, Spain, the US and Canada. A cost-consequence analysis (CCA) was designed to compare the monthly costs per responding patient/patient in remission. Efficacy, safety and resource use inputs were based on the AMPLE trial. A one-way deterministic sensitivity analysis (OWSA) was also performed to assess the impact of model inputs on the results for total incremental costs. Cost per response in ACPA-positive patients favoured abatacept compared with adalimumab (ACR20, ACR90 and HAQ-DI). Subgroup analysis favoured abatacept with increasing stringency of response criteria and serum ACPA levels. Cost per remission (DAS28-CRP) favoured abatacept in ACPA-negative patients, while cost per CDAI and SDAI favoured abatacept in ACPA-positive patients. Abatacept was consistently favoured in ACPA-Q4 patients across all outcomes and countries. Cost savings were greater with abatacept when more stringent response criteria were applied and also with increasing ACPA levels, which could lead to a lower overall health care budget impact with abatacept compared with adalimumab.


Completion of advance directives by older health maintenance organization members: the role of attitudes and beliefs regarding life-sustaining treatment.
This study examined whether older health maintenance organization (HMO) members' attitudes and beliefs regarding life-sustaining treatment were associated with their completion of advance directives (ADs). A mailed survey of 1,247 subjects, aged 75 and older, participating in a randomized trial comparing two educational interventions designed to increase AD completion: mailed written materials versus written materials plus a videotape. AD completion was documented by medical record review. The initial trial took place in October 1994 at a large group-model HMO in the Denver metropolitan area. The survey was mailed to participants 3 months after the trial. All HMO members aged 75 and older who received medical care at one of the medical offices (n = 1247) were mailed the survey. Participants were the 735 members who returned the survey. AD completers were compared with noncompleters on survey items pertaining to attitudes and beliefs regarding life-sustaining treatment. Of survey respondents, AD completers (n = 313) differed from noncompleters (n = 422) in their agreement with the following attitudinal/belief statements: (1) Putting my wishes for life-sustaining treatment in writing is too binding (completers = 12, noncompleters = 35); (2) I prefer that my family decide what kind of medical care is best for me if I should become unable to communicate my wishes (completers = 69, noncompleters = 88); and (3) My physician clearly understands my wishes for life-sustaining treatment (completers = 76, noncompleters = 43; all values, P< .0001). Completers were more likely to believe that their physicians understood their wishes and less likely to think that ADs are too binding. More noncompleters wanted their family to decide, even though an AD would increase their families' ability to do so. AD completion rates might increase if they were characterized as a way to preserve flexibility in a complex medical system, help families reach amicable decisions on behalf of their loved ones, and increase patients' confidence that their physician understands their wishes for life-sustaining treatment.


Differential expression of MEK1 and MEK2 during mouse development.
Map/Erk kinase 1 (MEK1) and MEK2 activate the Erk/ MAP kinases and have been implicated in cell growth and differentiation. To investigate the role of MEKs during mouse development, we have examined their expression and activity in various murine tissues during embryonic development and in the adult mouse. MEK2 RNA message is expressed at high levels in all embryonic tissues examined, including all neural tissues, and liver. This can be observed by in situ hybridization of tissue sections of 14.5-day-old mouse embryos, as well as by Northern blot analyses. MEK1, on the other hand, is expressed at very low levels in most embryonic murine tissue but can be detected in developing skeletal muscle. It is expressed at higher levels in adult tissue, particularly in brain, where it is expressed at high levels. Western blot analyses of MEK1 and MEK2 in 14.5-day-old embryonic and adult mouse tissue confirm the RNA analysis. Levels of MEK1 kinase activity are particularly high in adult brain tissues as well. These findings suggest that MEK2 may be the primary Erk/MAP kinase activator during development and that MEK1 may play a role in the proliferative or mitogenic response in adult mouse tissues. This study also raises the possibility that MEK1 and MEK2 might not have redundant functions in cells but may possess unique specificity in their interactions with upstream activators or downstream targets.


Abusive Supervision and Creativity: Investigating the Moderating Role of Performance Improvement Attribution and the Mediating Role of Psychological Availability.
The existing studies have indicated that abusive supervision affects creativity; however, the specific impact mechanism is still unclear due to the uncertain relationship between leadership and employee creativity. Based on the resource perspective, this study examines the influence of abusive supervision on creativity through psychological availability (PA) and the moderating of this mediation by performance improvement attribution (PIA). Based on a survey of 234 employees', the hypotheses have been tested and the results reveal that abusive supervision had a detrimental effect on employee creativity partially mediated by employee PA, and employees' PIA moderated the mediation. This study offers new insights into the mechanisms associated with the relationship between abusive supervision and creativity.


Can renal leukemic infiltration cause hypertension in children?
Out of 334 children with acute lymphoblastic leukemia who were treated with St Jude Total XI and Total XIII chemotherapy protocols were investigated and 21 (6.3%) were hypertensive. The incidence of tumor lysis syndrome was higher in the hypertensive group than in the nonhypertensive group (28.6% vs. 11.5%) (P = 0.035). There were no differences between patients treated with high-dose methylprednisolone and prednisolone St Jude Total XI and Total XIII, St Jude Total XIII LR and St Jude Total XIII HR groups in respect of the above-mentioned parameters. Central nervous system involvement, skeletal system involvement, abdominal lymphadenopathy, elevated lactate dehydrogenase and leukocyte count, French-American-British types and immunophenotypes were not found to be statistically significant to the development of hypertension (P > 0.05). We found that renal leukemic infiltration is a risk factor in hypertension development (P = 0.04) and hypertension is a risk factor for renal parenchymal disorder in the follow-up period (P = 0.0001). Six patients presenting with hypertension in the first week of disease therapy were evaluated for renal parenchymal disorder and glomerular filtration rate abnormality in the follow-up period. Glomerular filtration rate abnormality was found in 1 and renal scintigraphic dimercaptosuccinic acid abnormalities (reduced uptake and dilated hypoactivity) were found in 4 patients. Hypertension was also found to be a risk factor for renal parenchymal disorder in the follow-up period.


Current Insights into Research on Rice stripe virus.
Rice stripe virus (RSV) is one of the most destructive viruses of rice, and greatly reduces rice production in China, Japan, and Korea, where mostly japonica cultivars of rice are grown. RSV is transmitted by the small brown plant-hopper (SBPH) in a persistent and circulative-propagative manner. Several methods have been developed for detection of RSV, which is composed of four single-stranded RNAs that encode seven proteins. Genome sequence data and comparative phylogenetic analysis have been used to identify the origin and diversity of RSV isolates. Several rice varieties resistant to RSV have been selected and QTL analysis and fine mapping have been intensively performed to map RSV resistance loci or genes. RSV genes have been used to generate several genetically modified transgenic rice plants with RSV resistance. Recently, genome-wide transcriptome analyses and deep sequencing have been used to identify mRNAs and small RNAs involved in RSV infection; several rice host factors that interact with RSV proteins have also been identified. In this article, we review the current statues of RSV research and propose integrated approaches for the study of interactions among RSV, rice, and the SBPH.


The mGlu2/3 agonist LY379268 reduces sucrose taking, seeking, and motivation in male and female rats.
The mGlu2/3 receptor agonist LY379268 reduces sucrose-seeking, but not sucrose-taking, in male rats. This study explored the generality of this effect across the sexes. In addition, the effect of the drug on motivation to receive sucrose was assessed. Adult male and female Long-Evans rats ( N = 91) were challenged with LY379268 in three experiments: (1) a fixed ratio (FR) schedule of reinforcement (taking), (2) extinction of responding previously reinforced on the FR (seeking) or (3) responding reinforced on a progressive ratio (PR) schedule of reinforcement (motivation). For each experiment, rats first responded to 10% liquid sucrose on an FR in 10 daily 2-h sessions. For the PR study, this was followed by training on a PR for 7 daily 3-h sessions. Rats were then challenged in a counterbalanced order with LY379268 (0, 1.5, 3 and 6 mg/kg; IP; 30-min pretreatment) on test days, followed by either three reacquisition days of FR (experiments 1 and 2) or PR (experiment 3) responding. Female rats responded more to sucrose on the FR and PR. LY379268 reduced responding in all three experiments. LY379268 challenge to sucrose taking on the FR produced an inverted U-shaped function while extinction responding and responding for sucrose on the PR were decreased dose-dependently, with PR responding insensitive to the 1.5 mg/kg dose. There were no sex-dependent effects of the drug on sucrose-directed responding. The sucrose anti-taking, -seeking, and -motivation effects of LY379268 across male and female rats support further evaluation of glutamate modulation as an antiaddiction pharmacotherapy.


Development of auditory asymmetry in transient evoked otoacoustic emissions in pre-term infants.
We previously reported that transient evoked otoacoustic emissions (TEOAEs) continue to develop after the onset of cochlear function in pre-term infants from 34 to 39 weeks of conceptional age (Morlet et al., 1996). The time-course of development differed between genders. Reported here are findings of further analysis of data from the study cohort, comprising 1020 ears of 510 pre-term neonates (conceptional age ranging from 34 to 39 weeks), demonstrating developmental differences between right and left ears. The left ear of female pre-term infants showed enhancement of TEOAE amplitude at low and medium frequencies with age, whereas differences were less dramatic in the right ear. In male infants, TEOAE amplitude decreased in several frequency bands at high frequencies, above 4 kHz, between 34 and 39 weeks conceptional age; most developmental differences were found to be more dramatic in the right than in the left ear. It is tempting to speculate that these developmental features underlie well-known inter-aural asymmetries that have been demonstrated in the adult human.


COVID-19 and rheumatology: is shielding really necessary?
Rheumatology patients who are taking immunosuppressants are considered to be at 'high risk' from COVID-19, hence have been self-isolating or shielding. However, they may be protected from the features of hyperinflammation driven by a 'cytokine storm', so may have better clinical outcomes if infected. This editorial discusses whether it may not be necessary to advise these patients to shield.


Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy.
M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitro and in vivo experiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.


The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.
Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409. Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29.6 months [95% CI 27.9-36.0] for the palbociclib plus letrozole group and 27.9 months [25.5-31.1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10.2 months (95% CI 5.7-12.6) for the letrozole group and 20.2 months (13.8-27.5) for the palbociclib plus letrozole group (HR 0.488, 95% CI 0.319-0.748; one-sided p=0.0004). In cohort 1 (n=66), median progression-free survival was 5.7 months (2.6-10.5) for the letrozole group and 26.1 months (11.2-not estimable) for the palbociclib plus letrozole group (HR 0.299, 0.156-0.572; one-sided p<0.0001); in cohort 2 (n=99), median progression-free survival was 11.1 months (7.1-16.4) for the letrozole group and 18.1 months (13.1-27.5) for the palbociclib plus letrozole group (HR 0.508, 0.303-0.853; one-sided p=0.0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. Pfizer.


Mapping of the conserved antigenic domains shared between potato apyrase and parasite ATP diphosphohydrolases: potential application in human parasitic diseases.
Evolutionary and closer structural relationships are demonstrated by phylogenetic analysis, peptide prediction and molecular modelling between Solanum tuberosum apyrase, Schistosoma mansoni SmATPase 2 and Leishmania braziliensis NDPase. Specific protein domains are suggested to be potentially involved in the immune response, and also seem to be conserved during host and parasite co-evolution. Significant IgG antibody reactivity was observed in sera from patients with American cutaneous leishmaniasis (ACL) and schistosomiasis using potato apyrase as antigen in ELISA. S. mansoni adult worm or egg, L. braziliensis promastigote (Lb) and Trypanosoma cruzi epimastigote (EPI) have ATP diphosphohydrolases, and antigenic preparations of them were evaluated. In ACL patients, IgG seropositivity was about 43% and 90% for Lb and potato apyrase, respectively, while IgM was lower (40%) or IgG (100%) seropositivity for both soluble egg (SEA) and adult worm (SWAP) antigens was higher than that found for potato apyrase (IgM=10%; IgG=39%). In Chagas disease, IgG seropositivity for EPI and potato apyrase was 97% and 17%, respectively, while the IgM was low (3%) for both antigens. The study of the conserved domains from both parasite proteins and potato apyrase could lead to the development of new drug targets or molecular markers.


Pelvic floor muscle biofeedback in the treatment of urinary incontinence: a literature review.
Biofeedback is efficacious in the training of the pelvic floor musculature in order to enhance continence. This article reviews the anatomy and physiology of micturition as the underlying rationale for pelvic floor muscle biofeedback in the treatment of urinary incontinence. It critically reviews 28 studies published in peer reviewed journals from 1975 to 2005 that were prospective, randomized studies with parametric statistical analyses, operationally defined patient selection criteria, treatment protocols and outcome measures. The overall mean treatment improvement for patients undergoing biofeedback for urinary incontinence was 72.61%. In 21 of 35 (60%) paired comparisons, biofeedback demonstrated superior symptomatic outcome to control or alternate treatment groups. Larger studies and a standardization of technology and methodology are required for more conclusive determinations.


Isoprenoid-independent pathway is involved in apoptosis induced by risedronate, a bisphosphonate, in which Bim plays a critical role in breast cancer cell line MCF-7.
Bisphosphonates cause apoptosis to various types of cancer cells including breast cancer. Inhibition of the mevalonate pathway was reported to be involved in the apoptosis induced by bisphosphonates, but its precise mechanism has not been unveiled. In the present study, we investigated the molecular mechanism of risedronate, a bisphosphonate, in the apoptosis of the breast cancer cell line MCF-7 in comparison with that of cerivastatin, an HMG CoA reductase inhibitor (statin), since statin has been known to induce apoptosis through an isoprenoid-dependent pathway in these cells. We found that i) risedronate induced MCF-7 cells into apoptosis in a manner similar to cerivastatin with the activation of caspase-9 followed by caspase-6 and -7, that ii) bisphosphonate-induced apoptosis was significantly, but not fully, recovered by the addition of GGOH, an isoprenoid, which completely rescued in case of cerivastatin-induced apoptosis, that iii) risedronate induced G2 arrest with the induction of Bim (BH3-only protein), but that statin induced G1 arrest without it, and that iv) the down-regulation of Bim protein by siRNA significantly attenuated the risedronate-induced apoptosis. These data clearly indicate that both isoprenoid-dependent and -independent pathways might be involved in the apoptosis induced by bisphosphonate, and Bim might be a critical component for the isoprenoid-independent apoptotic pathway.


[Biologically active compounds and methods of their removal through biocatalysis].
Pharmaceuticals and other biologically active substances are produced in increasing numbers. Because of increased usage and improper storage, they pass into surface water, ground water and drinking water directly or through wastewaters. This is a threat to many living organisms, including humans, because of hormonal imbalances primarily related to reproductive processes or the problem of microbial drug resistance. Due to the scale of the emission and limited possibilities of decomposition of these pollutants by physico-chemical methods it is necessary to develop new efficient processes. One of the proposed solutions is the use of tools offered by biocatalysis. Thanks to the biocatalysis process, a wide range of biologically active compounds can be removed, by using of enzymes with low substrate specificity and operating in environmentally friendly conditions. Recent studies indicate the effectiveness of those methods used in the removal of pollutants of different chemical structure, with the formation of non-toxic metabolites.


An off-the-shelf integrated microfluidic device comprising self-assembled monolayers for protein array experiments.
Microfluidic-based protein arrays are promising tools for life sciences, with increased sensitivity and specificity. One of the drawbacks of this technology is the need to create fresh surface chemistry for protein immobilization at the beginning of each experiment. In this work, we attempted to include the process of surface functionalization as part of the fabrication of the device, which would substitute the time consuming step of surface functionalization at the beginning of each protein array experiment. To this end, we employed a novel surface modification using self-assembled monolayers (SAMs) to immobilize biomolecules within the channels of a polydimethylsiloxane (PDMS) integrated microfluidic device. As a model, we present a general method for depositing siloxane-anchored SAMs, with 1-undecyl-thioacetate-trichlorosilane (C11TA) on the silica surfaces. The process involved developing PDMS-compatible conditions for both SAM deposition and functional group activation. We successfully demonstrated the ability to produce, within an integrated microfluidic channel, a C11TA monolayer with a covalently conjugated antibody. The antibody could then bind its antigen with a high signal to background ratio. We further demonstrated that the antibody was still active after storage of the device for a week. Integration of the surface chemistry into the device as part of its fabrication process has potential to significantly simplify and shorten many experimental procedures involving microfluidic-based protein arrays. In turn, this will allow for broader dissemination of this important technology.


Characterization of two novel antimicrobial peptides from the cuticular extracts of the ant Trichomyrmex criniceps (Mayr), (Hymenoptera: Formicidae).
Antimicrobial peptides (AMPs) from cuticular extracts of worker ants of Trichomyrmex criniceps (Mayr, Hymenoptera: Formicidae) were isolated and evaluated for their antimicrobial activity. Eight peptides ranging in mass from 804.42 to 1541.04 Da were characterized using a combination of analytical and bioinformatics approach. All the eight peptides were novel with no similarity to any of the AMPs archived in the Antimicrobial Peptide Database. Two of the eight novel peptides, the smallest and the largest by mass were named Crinicepsin-1 and Crinicepsin-2 and were chemically synthesized by solid phase peptide synthesis. The two synthetic peptides had antibacterial and weak hemolytic activity.


Pyrazine functionalized Ag(I) and Au(I)-NHC complexes are potential antibacterial agents.
Antimicrobial resistance is an ever-increasing problem throughout the world and has already reached severe proportions. Bacteria can develop ways to render traditional antibiotics ineffective, raising a crucial need to find new antimicrobials with novel mode of action. We demonstrate here a novel class of pyrazine functionalized Ag(I) and Au(I)-NHC complexes as antibacterial agents against human pathogens that are resistant to several antibiotics. Complete synthetic and structural studies of Au(I) and Ag(I) complexes of 2-(1-methylimidazolium) pyrimidinechloride (L-1), 2,6-bis(1-methylimidazol)pyrazinechloride (L-2) and 2,6-bis(1-methyl imidazol) pyrazinehexa-fluorophosphate (L-3) are reported herein. Chloro[2,6-bis(1-methyl imidazol)pyrazine]gold(I), 2b and chloro [2,6-bis(1-methyl imidazol)pyrazine]silver(I), 2a complexes are found to have more potent antimicrobial activity than other synthesized compounds and several conventionally used antibiotics. Complexes 2b and 2a also inhibit the biofilm formation by Gram-positive bacteria, Streptococcus mutans and Gram-negative bacteria, Escherichia coli, causing drastic damage to the bacterial cell wall and increasing membrane permeability. Complexes 2b and 2a strongly binds to both Lys and Dap-Type peptidoglycan layers, which may be the reason for damage to the bacterial cell wall. Theoretical studies of all the complexes reveal that 2b and 2a are more reactive than other complexes, and this may be the cause of differences in antibacterial activity. These findings will pave the way towards developing a new class of antibiotics against different groups of conventional antibiotic-resistant bacteria.


Absence of methylation at HpaII sites in three human genomic tRNA sequences.
It has been known since the development of nearest neighbor analysis that the frequency of the dinucleotide CpG is markedly suppressed in vertebrate DNA (i.e. less than %C x %G). This suppression appears to be heterogeneous since it was shown some years ago that three vertebrate tRNA genes did not exhibit CpG suppression. We have analyzed 13 different human tRNA genes and found that they also do not exhibit CpG suppression. Because CpG suppression has been linked, to some extent at least, to the methylation-deamination process by which a methylated CpG is mutated to TpG, we investigated whether the lack of suppression of CpG in tRNAs could originate from an absence of methylation. Three human tRNA genes were selected from Genbank (lysine, Proline, and Phenylalanine) and examined for methylation at HpaII sites by polymerase chain reaction (PCR) and Southern blot analysis. The observed patterns were consistent with the absence of methylation at the seven HpaII sites analyzed in and around the tRNA genes, and we predict that the remaining CpGs in these genes will be unmethylated. Since GC-rich promoter regions also escape CpG suppression and since they are generally unmethylated, avoidance of methylation may be a general explanation for the absence of CpG suppression in selected regions of vertebrate genomes.


Comparative Genomics of Potato Common Scab-Causing Streptomyces spp. Displaying Varying Virulence.
Common scab of potato causes important economic losses worldwide following the development of necrotic lesions on tubers. In this study, the genomes of 14 prevalent scab-causing Streptomyces spp. isolated from Prince Edward Island, one of the most important Canadian potato production areas, were sequenced and annotated. Their phylogenomic affiliation was determined, their pan-genome was characterized, and pathogenic determinants involved in their virulence, ranging from weak to aggressive, were compared. 13 out of 14 strains clustered with Streptomyces scabiei, while the last strain clustered with Streptomyces acidiscabies. The toxicogenic and colonization genomic regions were compared, and while some atypical gene organizations were observed, no clear correlation with virulence was observed. The production of the phytotoxin thaxtomin A was also quantified and again, contrary to previous reports in the literature, no clear correlation was found between the amount of thaxtomin A secreted, and the virulence observed. Although no significant differences were observed when comparing the presence/absence of the main virulence factors among the strains of S. scabiei, a distinct profile was observed for S. acidiscabies. Several mutations predicted to affect the functionality of some virulence factors were identified, including one in the bldA gene that correlates with the absence of thaxtomin A production despite the presence of the corresponding biosynthetic gene cluster in S. scabiei LBUM 1485. These novel findings obtained using a large number of scab-causing Streptomyces strains are challenging some assumptions made so far on Streptomyces' virulence and suggest that other factors, yet to be characterized, are also key contributors.


Prognostic Significance of Treatment Strategies for the Recurrent Hepatocellular Carcinomas After Radical Resection.
The high rate of recurrence and repetitive features of hepatocellular carcinoma (HCC) require specific treatment strategies. This study aimed to evaluate the long-term outcomes of recurrent HCC focusing on clinicopathological factors. A total of 104 patients who were treated with re-hepatectomy, radiofrequency ablation (RFA) or transcatheter arterial chemoembolization for recurrent HCC were analyzed. Post-recurrent prognoses were compared between each treatment group based on the presence of adverse prognostic factors (APFs) identified. In the hepatectomy group, the prognosis of patients with APFs was significantly worse compared to those without APFs. By contrast, the survival rate of patients who underwent RFA was not significantly different from those with and without APFs. Our results demonstrate the heterogeneity that exists in terms of the long-term survival of patients with recurrent HCC. The treatment strategy for recurrent HCC should be based on the assessment of presence of APFs to improve long-term prognosis.


Area-under-the-curve monitoring of prednisolone for dose optimization in a stable renal transplant population.
Renal transplant recipients were noted to appear cushingoid while on low doses of steroid as part of a triple therapy immunosuppression of cyclosporin A (CsA), prednisolone, and azathioprine. The study group comprised adult renal transplant recipients with stable graft function who had received their renal allograft a minimum of 1 year previously (43 studies undertaken in 22 men and 20 women) with median daily prednisone dose of 7 mg (range 3-10). The control group was healthy nontransplant subjects [median dose 10 mg (10-30)]. Prednisolone bioavailability was measured using a limited 6-hour area under the curve (AUC), with prednisolone measured using specific HPLC assay. The median prednisolone AUC/mg dose for all transplant recipients was significantly greater than the control group by approximately 50% (316 nmol x h/L/mg prednisolone versus 218). AUC was significantly higher in female recipients (median 415 versus 297 for men) and in recipients receiving cyclosporin (348 versus 285). The highest AUC was in women on estrogen supplements who were receiving cyclosporin (median 595). A significantly higher proportion of patients on triple therapy had steroid side effects compared with those on steroid and azathioprine (17/27 versus 4/15), more women than men had side effects (14/16 versus 7/22), and the AUC/mg prednisone was greater in those with side effects than without (median 377 versus 288 nmol x h/L/mg). The results are consistent with the hypothesis that CsA increases the bioavailability of prednisolone, most likely through inhibition of P-glycoprotein. The increased exposure to steroid increased the side-effect profile of steroids in the majority of patients. Because the major contributor to AUC is the maximum postdose concentration, it may be possible to use single-point monitoring (2 hours postdose) for routine clinical studies.


Mental health nurses' experience of challenging workplace situations: A qualitative descriptive study.
Mental health nursing is acknowledged internationally as being a demanding profession; however, little is known about the range of experience and complexity of workplace challenges or their impacts on mental health nurses (MHN). This qualitative descriptive study aimed to examine and describe the range of challenging workplace situations experienced by MHN and is reported according to the Standards for Reporting Qualitative Research. An online cross-sectional survey collected demographic data and open-ended descriptions of workplace challenges experienced by n = 374 Australian MHN. Using a modified a priori framework, four categories of experience were derived through content analysis: consumer-related, colleague-related, nursing role-related, and organizational service-related challenges. Many accounts described a complex interplay of challenges. The findings extend prior knowledge on MHN experiences. Frequent workplace challenges included violence and aggression from consumers, bullying from colleagues, low staffing levels, and poor skill mix. Further extending the evidence, key challenges rarely described in prior literature were the psychological impacts of suicides and murder; the personal nature of threats from consumers; moral distress and concerns with colleagues' quality of practice; and exacerbation of practice-related issues by lack of support from colleagues and/or the organization. These have important implications for the profession and can inform targeted strategies to reduce stressors where possible, build staff well-being, support workforce retention, and improve the provision of quality care. The implementation of targeted policy and initiatives that focus on reducing key stressors and supporting practice are vital to staff retention and ensuring a high standard of practice in complex mental health workplaces.


Visible-Light-Mediated Thiol-Ene Reactions through Organic Photoredox Catalysis.
Synthetically useful radical thiol-ene reactions can be initiated by visible-light irradiation in the presence of an organic photocatalyst, 9-mesityl-10-methylacridinum tetrafluoroborate. The key thiyl radical intermediates are generated upon quenching of the photoexcited catalyst with a variety of thiols. The success of this method requires only the use of near-stoichiometric levels of alkene coupling partners. Using these highly efficient metal-free conditions, thiol-ene reactions between carbohydrates and peptides can be accomplished in excellent yields.


Long-Term Follow-Up of Inpatients with Cervical Myelopathy Who Received Integrative Korean Medicine Treatment: A Retrospective Analysis and Questionnaire Survey Study.
Cervical myelopathy (CM) is generally considered an indication for surgery in Western medicine. Case reports have indicated that Korean medicine (KM) treatments are effective in improving CM-associated symptoms. We investigated the effectiveness of non-surgical KM treatment of CM patients through a retrospective chart review and follow-up survey. We retrospectively analyzed the medical records and surveyed follow-up data of CM patients with neurological symptoms admitted to KM hospitals between January 2011 and January 2018. The admission and discharge assessments included the numeric rating scale (NRS) for neck and arm pain, neck disability index (NDI), and 5-level EuroQol 5-dimension (EQ-5D-5L). A follow-up survey was conducted about whether surgery was subsequently performed or recommended, symptom recurrence, discomfort in daily living, current treatment, as well as NRS, NDI, EQ-5D-5L, and patient global impression of change (PGIC) scores. The NRS for neck pain decreased from 4.88 ± 2.03 (95% CI: 4.23‒5.52) at admission to 3.23 ± 1.64 (95% CI: 2.70‒3.75) at discharge and 2.24 ± 1.84 (95% CI: 1.43‒3.05) at follow-up. The NRS for radiating arm pain decreased from 5.42 ± 1.55 (95% CI: 4.93‒5.92) to 3.77 ± 1.54 (95% CI: 3.28‒4.27) at discharge and 2.43 ± 1.60 (95% CI: 1.72‒3.13) at follow-up. The NDI decreased significantly from 36.24 ± 18.79 (95% CI: 30.24‒42.24) at admission to 30.89 ± 15.54 (95% CI: 25.93‒35.86) at discharge and 13.35 ± 11.95 (95% CI: 8.08‒18.63) at follow-up. The EQ-5D score improved significantly from 0.70 ± 0.21 (95% CI: 0.63‒0.77) to 0.78 ± 0.17 (95% CI: 0.73‒0.84) at discharge and 0.84 ± 0.08 (95% CI: 0.80‒0.88) at follow-up. At the follow-up, four patients experienced persistent pain and were undergoing treatment (19.1%), while 20 patients (95.8%) reported symptom improvement. From a long-term perspective, integrative KM treatment may help to reduce pain and improve function, and improve quality of life of CM patients.


Retrospective Analysis of Presentation, Treatment, and Outcomes of Multiple Myeloma at a Large Public Referral Hospital in Eldoret, Kenya.
Treatment patterns and survival outcomes of patients with multiple myeloma (MM) in Kenya have not been adequately characterized. The objectives of this study were to describe the clinical, laboratory, and imaging findings at diagnosis, to describe the treatment offered, and to determine the survival outcomes of patients with MM over an 11-year period. A retrospective chart review was carried out for all patients who were diagnosed and treated for MM at Moi Teaching and Referral Hospital from 2009 to 2019. The Kaplan-Meier method was used to estimate survival. Factors affecting survival were identified using univariate and multivariate analyses. A total of 221 patient charts were analyzed of which 124 belonged to male patients (56.1%). The median age at diagnosis was 61 years. Bone pain was the most common presenting complaint observed in 69.6% of 194 patients assessed. Out of 102 patients who received imaging studies, 60 (58.8%) had lytic lesions, 30 (29.4%) had fractures, whereas 30 (29.4%) had spinal cord compression. Anemia, renal failure, and hypercalcemia were observed in 87/187 (46.5%), 22/161 (13.7%), and 23/42 (54.8%) patients, respectively. Thalidomide and dexamethasone (65.2%); bortezomib, thalidomide, and dexamethasone (14.6%); and melphalan and prednisolone (11.9%) were the most prescribed initial chemotherapy regimens among 219 patients analyzed. Overall survival at 1 and 5 years was 70% and 21%, respectively; median overall survival was 29.0 months. In multivariate analysis, male sex (hazard ratio [HR] 1.9), baseline anemia (HR 1.8), and baseline renal failure (HR 3.2) were associated with significantly shorter survival. Survival outcomes were poor despite increased use of multiagent-based chemotherapy regimens. Greater access to available diagnostics and treatments is required to achieve rational treatment and increased survival.


Analysis of public food procurement in relation to dairy products and their quality criteria.
Public procurement of food is key to ensuring proper nutrition with high-quality products in public institutions such as schools and kindergartens. However, it should not be considered a mandatory expenditure from public finances but rather an investment in health promotion. A total of 1,126 public procurement orders processed by schools and kindergartens in Poland during the period from November 2022 to March 2023 were analyzed. Ultimately, 197 public procurement orders meeting the inclusion criteria were considered for analysis. Based on these orders, 2,753 food products classified as dairy and its derivatives were extracted. The ordered quantities of individual products were analyzed, as well as their descriptions (quality characteristics). Criteria related to composition were most commonly described, the most common criterion was the fat content and the absence of preservatives. On the second places were organoleptic characteristics, where taste and consistency expectations were most frequently specified. Sustainable public procurement criteria were the least frequently mentioned and were treated as highly marginal. Introducing minimum standards for the descriptions of dairy products in terms of organoleptic characteristics, composition features, and sustainability criteria will improve the quality of dairy products supplied to public institutions, particularly schools and kindergartens.


The prevalence of Campylobacter pylori gastritis among asymptomatic adults.
To determine the prevalence of Campylobacter pylori colonization in the healthy population we studied 54 asymptomatic volunteers and 65 patients referred because of gastrointestinal symptoms. All subjects underwent gastroscopy and gastric biopsy. C. pylori was isolated from 6 volunteers (11%) and 36 patients (55%). Histologic evidence of inflammation was present in 98% of the culture-positive subjects. Linear regression analysis revealed that the prevalence of C. pylori colonization increased with age. There was no difference in the isolation rate between the two groups when adjusted for age. Four of the six culture-positive volunteers underwent repeat endoscopy and gastric biopsy 1 year later; despite remaining asymptomatic, all still had positive culture results and histologic evidence of gastritis. We conclude that the prevalence of C. pylori-associated gastritis among symptomatic patients increases with age and that the organism may be present in the gastrointestinal tract for prolonged periods without symptoms or evidence of disease progression.


Recovery of hearing in Cisplatin-induced ototoxicity in the Guinea pig with intratympanic dexamethasone.
The purpose of this study was to investigate the effectiveness of intratympanic dexamethasone injection as a therapeutic agent against cisplatin-induced ototoxicity. Animals were randomly divided into three groups. Group one received intraperitoneal cisplatin alone, group two, received intratympanic dexamethasone after cisplatin ototoxicity had been demonstrated. Group three, which is control group, received intratympanic dexamethasone.Then we made three measurements. First we measured the baseline distortion product otoacustic emission (DPOAEs) of all the guine pigs. Second we injected cisplatin intraperitoneal group one and two the same day. Third we measured DPOAEs after 72 h of group one and two. Moreover DPOAEs were measured at the end of the first and second week only in group two. Cochleae were harvested and processed for electron microscopy after then. Values of The DPOAEs amplitudes and signal-to-noise ratio (SNR) at 1-6 kHz frequencies for group 1 after the injections significantly decreased over those before injections (P < 0.05). In group 3, there were no significant differences in DPOAE amplitude and SNR values When they are compare before and after their intratympanic dexamethasone injections (P > 0.05). In group 2, the DPOAEs measurements were close to significance at the end of the second week (P = 0.056). Intratympanic dexamethasone injection did not cause any ototoxic effect. Although intratympanic dexamethasone did not reach the statistically significant results, the measurements were close to significance. Intratympanic dexamethasone might have a significant therapeutic effect after cisplatin ototoxicity with different dose and application regimens.


Detection of a tadalafil analogue as an adulterant in a dietary supplement for erectile dysfunction.
Several cases of adulteration of dietary supplements with tadalafil, sildenafil, and vardenafil, or their unapproved analogues have been reported worldwide. Mainly, the presence of the latter represents a serious health risk to consumers as their efficacy and toxic effects have not been assessed and may result in unpredictable adverse effects. To investigate the suspected adulteration with synthetic phosphodiesterase type 5 (PDE-5) inhibitors in a dietary supplement marketed in Argentina for the treatment of erectile dysfunction (ED). The content of the capsules of the dietary supplement (sample A) was analyzed by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) diode-array detection. From the organic extract of sample A, a major compound was purified by column chromatography (CC). The isolated compound was identified by proton nuclear magnetic resonance (1H NMR) and carbon NMR (13C NMR), heteronuclear single quantum coherence, distortionless enhancement by polarization transfer (DEPT 135), electrospray ionization mass spectrometry, and ultraviolet, and infrared (Fourier transform infrared spectroscopy) spectroscopy. Proof of adulteration of herbal products with synthetic PDE-5 inhibitors. By TLC and HPLC analysis, a major compound was detected in sample A organic extract. The purification of this extract by CC led to the isolation of a pure compound which was identified according to its spectral data as (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b] indole-1,4-dione or aminotadalafil. An unapproved PDE-5 inhibitor analogue, which was identified as aminotadalafil, has been detected in a dietary supplement. This study represents the first report in Latin America and one of the few independent studies of an adulteration with an unapproved PDE-5 inhibitor of an herbal product for ED treatment.


Annual smoking-attributable mortality, years of potential life lost, and economic costs--United States, 1995-1999.
Cigarette smoking is the leading cause of preventable death in the United States and produces substantial health-related economic costs to society. This report presents the annual estimates of the disease impact of smoking in the United States during 1995-1999. CDC calculated national estimates of annual smoking-attributable mortality (SAM), years of potential life lost (YPLL), smoking-attributable medical expenditures (SAEs) for adults and infants, and productivity costs for adults. Results show that during 1995-1999, smoking caused approximately 440,000 premature deaths in the United States annually and approximately $157 billion in annual health-related economic losses. Implementation of comprehensive tobacco-control programs as recommended by CDC could effectively reduce the prevalence, disease impact, and economic costs of smoking.


How developing world concerns need to be part of drug development plans: a case study of four emerging antiretrovirals.
Clinical trials are usually designed to meet registration requirements in developed countries, and do not always address key concerns for use in developing countries. Four late-stage investigational new drugs - rilpivirine, etravirine, raltegravir and maraviroc - show potential to improve antiretroviral therapy. However, a number of issues could limit their use in developing countries, including dose selection, treatment strategy, combination with other drugs, use in specific populations and reliance on expensive tests. Key research questions relevant for developing countries need to be answered early in the drug development process to ensure maximum benefit for the majority.


Testing an mHealth momentary assessment Routine Outcome Monitoring application: a focus on restoration of daily life positive mood states.
Routine Outcome Monitoring (ROM) is used as a means to enrich the process of treatment with feedback on patient outcomes, facilitating patient involvement and shared decision making. While traditional ROM measures focus on retrospective accounts of symptoms, novel mHealth technology makes it possible to collect real life, in-the-moment ambulatory data that allow for an ecologically valid assessment of personalized and contextualized emotional and behavioural adjustment in the flow daily life (mROM). In a sample of 34 patients with major depressive disorder, treated with antidepressants, the combined effect of treatment and natural course was examined over a period of 18 weeks with Ecological Momentary Assessment (EMA). EMA consisted of repeated, within-subject, mini-measurements of experience (eg positive affect, negative affect, medication side effects) and context (eg stressors, situations, activities) at 10 unselected semi-random moments per day, for a period of six days, repeated three times over the 18-week period (baseline, week 6 and week 18). EMA measures of emotional and behavioural adjustment were sensitive to the effects of treatment and natural course over the 18-week period, particularly EMA measures focussing on positive mood states and the ability to use natural rewards (impact of positive events on positive mood states), with standardized effect sizes of 0.4-0.5. EMA measures of activities, social interaction, stress-sensitivity and negative mood states were also sensitive to change over time. This study supports the use of mROM as a means to involve the patient in the process of needs assessment and treatment. EMA data are meaningful to the patient, as they reflect daily life circumstances. Assessment of treatment response with mROM data allows for an interpretation of the effect of treatment at the level of daily life emotional and social adjustment--as an index of health, obviating the need for an exclusive focus on traditional measures of 'sickness'.


Holmium laser enucleation for prostatic adenoma: analysis of learning curve over the course of 70 consecutive cases.
We elucidate the learning curve, efficacy and safety of holmium laser enucleation of prostatic adenomas. We retrospectively reviewed data on 70 patients who had undergone holmium laser enucleation for prostatic adenoma. All patients were assessed preoperatively and at an interval of 6 months postoperatively based on the International Prostate Symptom Score, quality of life index, peak urinary flow rate and post-void residual urine measurement. All complications were noted. The relationship between the number of procedures performed and treatment efficacy was analyzed. The learning curve with regard to efficiency for tissue enucleation and morcellation was assessed. Holmium laser enucleation of the prostate resulted in a significant improvement in subjective symptoms and urodynamic parameters. The ratio of improvement in the preoperative-to-postoperative peak urinary flow rate, post-void residual urine, International Prostate Symptom Score and quality of life index did not change significantly as experience increased. However, the efficiency of enucleation increased significantly as experience increased. Complications included short-term stress urinary incontinence in 8 cases and postoperative urethral stricture in 5. Bladder injury during morcellation was observed in 2 cases. Holmium laser enucleation of the prostate is an effective treatment option for benign prostatic adenoma, providing good treatment efficacy and minimal bleeding even if the surgeon has minimal experience. It requires more time to perform than traditional surgery but there is a learning curve for the enucleation technique as experience increases. Technical improvement in tissue morcellation may be necessary if the prevalence of this treatment is to increase dramatically.


Pathologic conditions of the plantar fascia.
Plantar heel pain in adults is commonly seen in the office of the podiatric foot and ankle specialist. These symptoms may have developed acutely or over a period of time. Often the plantar fascia is the source of the pain, which is caused by a traumatic event or a biomechanical flaw. It is imperative that the podiatric physician understands the multiple causes of plantar foot pain and is able to differentiate the multiple causes of heel pain to confirm a specific diagnosis and formulate a proper treatment plan. A thorough history and physical examination are necessary to obtain this information, and diagnostic procedures are sometimes needed.


Beyond ejection fraction: an integrative approach for assessment of cardiac structure and function in heart failure.
Left ventricular ejection fraction (LVEF) has been the central parameter used for diagnosis and management in patients with heart failure. A good predictor of adverse outcomes in heart failure when below ∼45%, LVEF is less useful as a marker of risk as it approaches normal. As a measure of cardiac function, ejection fraction has several important limitations. Calculated as the stroke volume divided by end-diastolic volume, the estimation of ejection fraction is generally based on geometric assumptions that allow for assessment of volumes based on linear or two-dimensional measurements. Left ventricular ejection fraction is both preload- and afterload-dependent, can change substantially based on loading conditions, is only moderately reproducible, and represents only a single measure of risk in patients with heart failure. Moreover, the relationship between ejection fraction and risk in patients with heart failure is modified by factors such as hypertension, diabetes, and renal function. A more complete evaluation and understanding of left ventricular function in patients with heart failure requires a more comprehensive assessment: we conceptualize an integrative approach that incorporates measures of left and right ventricular function, left ventricular geometry, left atrial size, and valvular function, as well as non-imaging factors (such as clinical parameters and biomarkers), providing a comprehensive and accurate prediction of risk in heart failure.


Cellular telephone interference with medical equipment.
To assess the potential electromagnetic interference (EMI) effects that new or current-generation cellular telephones have on medical devices. For this study, performed at the Mayo Clinic in Rochester, Minn, between March 9, 2004, and April 24, 2004, we tested 16 different medical devices with 6 cellular telephones to assess the potential for EMI. Two of the medical devices were tested with both new and old interface modules. The 6 cellular telephones chosen represent the different cellular technology protocols in use: Code Division Multiple Access (2 models), Global System for Mobile communications, Integrated Digital Enhanced Network, Time Division Multiple Access, and analog. The cellular telephones were tested when operating at or near their maximum power output. The medical devices, connected to clinical simulators during testing, were monitored by observing the device displays and alarms. Of 510 tests performed, the incidence of clinically important interference was 1.2%; EMI was Induced in 108 tests (21.2%). Interference occurred in 7 (44%) of the 16 devices tested. Cellular telephones can interfere with medical equipment. Technology changes in both cellular telephones and medical equipment may continue to mitigate or may worsen clinically relevant interference. Compared with cellular telephones tested in previous studies, those currently in use must be closer to medical devices before any interference is noticed. However, periodic testing of cellular telephones to determine their effects on medical equipment will be required.


Replicative senescence of hematopoietic stem cells during serial transplantation: does telomere shortening play a role?
Hematopoietic stem cells (HSC) have a finite proliferative lifespan, based upon the limited number of times they can be serially transplanted in mice. Telomeres have been shown to shorten during the division of many normal somatic cells in humans, and the attrition of telomeres has been shown to ultimately cause replicative senescence in vitro for a number of different human cell strains. Whereas most human cell types have little to no detectable levels of telomerase activity, hematopoietic cells, including HSC, express low to moderate levels of telomerase, and yet telomeres shorten considerably during replicative aging of these cells. Here we consider the role telomerase may play in the hematopoietic system as well as the effect that over-expression of telomerase reverse transcriptase may have on the replicative capacity of hematopoietic stem cells during transplantation.


Predictors for Prolonged Drainage following Tissue Expander-Based Breast Reconstruction.
A closed-suction drain is usually inserted during tissue expander-based breast reconstruction. Prolonged duration of drain retention can disturb patients' daily lives and affect overall sociomedical costs. This study aimed to investigate factors that may influence the drainage and to identify predictors of unusually prolonged drain duration. Patients who underwent delayed-immediate, two-stage breast reconstruction using a tissue expander between January of 2013 and July of 2017 were reviewed. Prolonged drain duration was defined as drain duration for longer than the 75th percentile of that for the entire cohort. Effects of patient- and operation-related variables on drainage and prolonged drain duration were evaluated. A total of 1056 cases (1002 patients) were analyzed. The median drain duration was 10 days. Drain placement for more than 12 postoperative days was observed in 256 cases (24.2 percent), classified as prolonged drain duration. Multivariate analyses demonstrated that old age, high body mass index, neoadjuvant chemotherapy, insertion of large Siltex textured tissue expanders, and greater volume of initial inflation were independent risk factors of prolonged drain duration. The size and texture of the tissue expanders and initial inflation volume retained their influence, regardless of mastectomy specimen weight. Use of acellular dermal matrix had contradictory effects according to breast size, being protective against prolonged drain duration in cases with mastectomy specimen weight greater than 400 g, and being a significant predictor for it in cases with mastectomy specimen weight less than or equal to 400 g. Several factors, including reconstructive operation-related factors, might influence drain duration following tissue expander-based breast reconstruction. Risk, III.


An Atypical Case of Mucocutaneous Blastomycosis in the Greater Toronto Area.
Blastomycosis is an uncommon infection caused by Blastomyces dermatitidis. While management is fairly straightforward, diagnosis can be quite challenging. We describe a case of a healthy 37-year-old man who presented with progressive mucocutaneous lesions, without lung or other systemic involvement. Treatment with itraconazole resulted in complete resolution of signs and symptoms. This case showcases the variety of blastomycosis clinical presentation and the importance of blastomycosis in the differential diagnosis of verrucous and papillomatous mucocutaneous lesions.


Using single-cell sequencing technology to detect circulating tumor cells in solid tumors.
Circulating tumor cells are tumor cells with high vitality and high metastatic potential that invade and shed into the peripheral blood from primary solid tumors or metastatic foci. Due to the heterogeneity of tumors, it is difficult for high-throughput sequencing analysis of tumor tissues to find the genomic characteristics of low-abundance tumor stem cells. Single-cell sequencing of circulating tumor cells avoids interference from tumor heterogeneity by comparing the differences between single-cell genomes, transcriptomes, and epigenetic groups among circulating tumor cells, primary and metastatic tumors, and metastatic lymph nodes in patients' peripheral blood, providing a new perspective for understanding the biological process of tumors. This article describes the identification, biological characteristics, and single-cell genome-wide variation in circulating tumor cells and summarizes the application of single-cell sequencing technology to tumor typing, metastasis analysis, progression detection, and adjuvant therapy.


Rituximab in chronic lymphocytic leukemia.
Rituximab is a class I chimeric anti-CD20 antibody that has shown efficacy in chronic lymphocytic leukemia (CLL), both as a single agent and in combination with traditional chemotherapies. The modest activity demonstrated in early studies evaluating rituximab in relapsed CLL was improved with higher doses or more dose-intensive regimens that overcame the unfavorable pharmacokinetic features commonly found in CLL. These studies led to a variety of combination trials of rituximab with chemotherapy, where both phase II and later phase III studies have shown great promise for the advancement of CLL therapy. Despite the therapeutic success of rituximab in CLL, studies demonstrating the definitive relative mechanism of tumor clearance are still lacking and this requires further investigation. In addition to being used as a therapy for CLL, rituximab is an effective treatment for autoimmune CLL complications such as hemolytic anemia and immune thrombocytopenia (ITP). Patients with CLL may experience early infusion-related side effects that can be diminished with corticosteroid pretreatment and stepped-up dosing. Risk factors for infusion-related toxicity may relate to atypical CLL expressing bright CD20 antigen expression, although several different studies have not clearly implicated elevated white blood cell count as a risk factor. Other adverse events, including delayed cytopenias, reactivation of hepatitis B, and development of progressive multifocal leukoencephalopathy, are rare. Future efforts focusing on novel combination-based strategies will be required to fully appreciate the benefit of this therapy in CLL.


Phototherapy with Light Emitting Diodes: Treating a Broad Range of Medical and Aesthetic Conditions in Dermatology.
Within the field of dermatology, advances in the use of light emitting diodes (LEDs) have led to their clinical application for a variety of medical and cosmetic uses. Of note, one phototherapy device has demonstrated beneficial effects over a range of clinical applications (Omnilux™; GlobalMed Technologies, Glen Ellen, California). The study included a literature review of published studies. Using LEDs with frequencies of 415nm (blue), 633nm (red), and 830nm (infrared), this device has demonstrated significant results for the treatment of medical conditions, including mild-to-moderate acne vulgaris, wound healing, psoriasis, squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, actinic keratosis, and cosmetic applications. Although photodynamic therapy with the photosensitizer 5-aminolevulinic acid might cause stinging and burning, phototherapy is free of adverse events. We determined that phototherapy using LEDs is beneficial for a range of medical and aesthetic conditions encountered in the dermatology practice. This treatment displays an excellent safety profile.


Linear low-density polyethylene and zirconium phosphate nanocomposites: evidence from thermal, thermo-mechanical, morphological and low-field nuclear magnetic resonance techniques.
Lamellar alpha-zirconium phosphate was synthesized by direct precipitation and also directly expanded with octadecylamine, through alcoholic solution. To produce a nanocomposite, it was incorporated in linear low-density polyethylene in the molten state, using a counterrotating twin-screw extruder set at 170-190 degrees C and 100 rpm. The differential scanning calorimetry analysis revealed a decrease in the polyolefin melting temperature and crystallinity degree. The higher onset temperature of the zirconium phosphate modified with octadecylamine and linear low density polyethylene composite indicated an increasing of thermal stability and it suggests that some polyethylene chains entered into the filler's spacing. Dynamic-mechanical analysis evidenced an increase in both moduli (storage and loss). Wide-angle X-ray diffraction showed additional peaks--diffraction angles appeared in the region beneath 12 degrees--which were attributed to partial intercalation of polyethylene chains between filler interlamellar spacing. By hydrogen low-field nuclear magnetic resonance, the two low intensity relaxation time peaks shifted to higher values, strongly suggesting interaction between the octadecylamine and polymer matrix into the filler galleries. From these results, it may be postulated that a partially intercalated and/or exfoliated nanostructure in the zirconium phosphate modified with octadecylamine and linear low density polyethylene composite was achieved.


Range-intensity-profile prior dehazing method for underwater range-gated imaging.
This paper is concerned with the mitigation of backscatter effects in a single gated image. A range-intensity-profile prior dehazing method is proposed to estimate scene depth and finely remove water backscatter at different depths for underwater range-gated imaging. It is based on the prior that the target intensity is distributed with range intensity profiles in gated images. The depth transmission and depth-noise map are then calculated from the scene depth. A high-quality image is restored by subtracting the depth-noise map and dividing the depth transmission. The simulation and experimental results show that the proposed method works well even if a portion of the estimated depth may be smaller than its real value, and the peak signal-to-noise ratio of dehazing images gets up to a doubled increase.


Efficacy of Anaerobic Soil Disinfestation for Control of Prunus Replant Disease.
Prunus replant disease (PRD) is an important soilborne complex that suppresses growth and productivity of replanted stone fruit and nut orchards. It is effectively managed with preplant soil fumigation but, due to regulatory challenges, nonfumigant-based control strategies for PRD and other soilborne disease problems may become increasingly important, especially in California. We examined the potential of preplant anaerobic soil disinfestation (ASD) for control of PRD in four repeated orchard replant trials on sandy loam soil near Parlier, CA. After removal of the old orchard trees, alternative ASD treatments, all using rice bran as the main carbon source, were implemented, starting in late September. The alternative treatments incorporated rice bran at (i) 20 t ha-1, alone, in 3.0-m-wide row strips; (ii) 20 t ha-1, preceded by incorporation of a sudangrass cover crop and followed by drip application of molasses (10 t ha-1), in 3.0-m-wide row strips; (iii) 20 t ha-1, alone, in 1.8-m-wide strips; or (iv) 12 t ha-1, alone, in 1.8-m-wide strips. All ASD-treated areas were covered with clear tarp and drip irrigated with 25 cm of water. Tarps remained for 6 weeks, during which the soil moisture level was kept at or above field capacity by drip irrigation. All trials included nontreated control and fumigated standard treatments. ASD raised temperature and reduced redox potential in soil at 15- and 46-cm depths for 6 weeks. Fumigation and ASD treatments both nearly eradicated bioassay inoculum of Pythium ultimum in the soil before almond trees were replanted and significantly affected almond tree root communities of fungi and oomycetes after planting. Fumigation treatments and ASD treatments with rice bran at 20 t ha-1 in 3.0-m strips increased tree growth significantly and by similar magnitudes. Among repeated experiments, mean increases in trunk cross-sectional area growth due to fumigation ranged from 137 to 264%, while the increases due to ASD at 20 t ha-1 in 3.0-m strips ranged from 148 to 214%, compared with controls. ASD offers effective control of PRD and is worthy of further optimization and testing for management of PRD and additional orchard replant problems.


Insulin Resistance and Microalbuminuria in Patients with Impaired Fasting Glucose versus Hemoglobin A1c-Defined Prediabetes.
This study investigated differences among patients with impaired fasting glucose (IFG) and hemoglobin A1c (HbA1c)-defined prediabetes (A1c-PDM); we compared insulin resistance and the prevalence of microalbuminuria (MAU) in these individuals. A total of 982 patients with newly diagnosed PDM and 455 non-PDM healthy individuals were evaluated. Serum insulin, HbA1c, fasting plasma glucose (FPG), and urine albumin excretion (UAE) levels were measured. The homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) was calculated. MAU was more prevalent in patients with IFG than in those with A1c-PDM (13.2% versus 6.4%, p=0.003). Patients with MAU had significantly higher FPG than those with normoalbuminuria (99.8 mg/dL versus 97.1 mg/dL, p=0.008). However, there was no significant difference in HbA1c levels between the two groups. Patients with IFG had significantly higher HOMA-IR values than those with A1c-PDM (2.31 versus 2.04, p=0.009). In contrast, there was no significant difference in the HOMA-B between the two groups. After adjusting for potential confounders, UAE was significantly correlated with FPG, but not with HbA1c. An elevated FPG level ≥113 mg/dL led to a 2.1-fold increase in the prevalence of MAU (odds ratio, 2.107; 95% confidence interval, 1.010-4.193; p=0.015). However, an elevated HbA1c level ≥6.1% was not significantly associated with the prevalence of MAU. Patients with IFG may be at a greater risk of insulin resistance and possible progression to diabetic nephropathy than patients with A1c-PDM.


Penicillin-binding proteins of Haemophilus ducreyi.
The penicillin-binding protein (PBP) profile of Haemophilus ducreyi was determined by a whole-cell-labeling assay. Only two major PBPs, of molecular weights 90,000 (PBP 1) and 38,500 (PBP 2), were detected in six of eight strains studied. Competition binding experiments and the attendant morphological effects suggested that PBP 1 was either a functional amalgamation or a lack of resolution of two proteins equivalent to PBPs 1 and 3 of Escherichia coli.


[The causes and management of ischemic mitral regurgitation].
Ischemic mitral regurgitation (IMR) is recognized as one of the complications of coronary artery disease. The aim of this study is to evaluate the causes and surgical management of IMR. From October 1986 to March 1995, 443 of patients underwent isolated coronary artery bypass grafting (CABG). In forty-four of the patients (9.9%) who underwent isolated CABG, the severity of postoperative IMR was reduced by two or more grades by the Sellers index. Hemodynamic parameters of these patients included: left ventricle ejection fraction, left ventricle end-diastolic volume index and left ventricle regional wall motion. They were assessed by left ventriculography (LVG). In addition, cardiac index and pulmonary artery wedge pressure were assessed by S-G catheterization and mitral annulus diameter by ultrasonic echocardiography. Twenty-nine patients experienced an increase in IMR severity after CABG, one of whom required mitral valve replacement for cardiac failure, and later died due to low output syndrome postoperative. On the other hand, fifteen patients experience a reduction in IMR severity after CABG. We conclude that the causes of IMR were regional asynergy at the site of papillary muscle, mitral annulus dilation and left ventricle dilation. Our findings suggest that severe IMR patients required concomitant mitral valve surgery with CABG. Patients with mild or moderate IMR patients with mitral annulus dilation or regional asynergy at the site of mitral papillary muscle may require the same surgery.


Status of exercise stress testing after myocardial infarction.
The use and current limitations of early exercise testing of the patient with a postmyocardial infarction (MI) is reviewed. The test provides useful information in identifying patients at high risk of a second coronary event, thereby helping direct possible interventional therapy. It also furnishes information regarding the patient's capacity for physical exertion, detection of ventricular arrhythmias, and extent of coronary artery disease. Angina, ST segment responses, BP, and ventricular arrhythmias during early exercise testing are evaluated for their importance in determining prognosis. The concomitant use of thallium scintigraphy and radionuclide ventriculography seems to augment detection of multivessel disease and left-ventricular dysfunction. A practical strategy for the use of early exercise testing in the evaluation of post-Mis is provided.


Identification of a novel signal in the cytoplasmic tail of the Na+:HCO3- cotransporter NBC1 that mediates basolateral targeting.
The Na(+):HCO(3)(-) cotransporter NBC1 (SLC4A4, variant A, kidney specific) is located exclusively on the basolateral membrane of epithelial cells, implying that this molecule has acquired specific signals for targeting to the basolateral membrane. A motif with the sequence QQPFLS (positions 1010-1015) in the cytoplasmic tail of NBC1 was recently demonstrated to mediate targeting of NBC1 to the basolateral membrane. Here, we demonstrate that mutating the amino acid F (phenylalanine) or L (leucine) at positions 1013 or 1014 to alanine, respectively, resulted in the retargeting of NBC1 to the apical membrane. Furthermore, mutation of the FL motif to FF showed similar properties as the wild-type; however, mutation of the FL motif to LL showed significant intracellular retention of NBC1. Mutating the amino acids Q-Q-P and S (positions 1010-1011-1012 and 1015) to A-A-A and A, respectively, did not affect the membrane targeting of NBC1. Functional studies in oocytes with microelectrode demonstrated that the apically targeted mutants, as well as basolaterally targeted mutants, are all functional. We propose that the FL motif in the COOH-terminal tail of NBC1 is essential for the targeting of NBC1 to the basolateral membrane but is distinct from the membrane-targeting di-leucine motif identified in other membrane proteins.


Production of tense morphology by Afrikaans-speaking children with and without specific language impairment.
To establish whether the predictions of the extended optional infinitive (EOI) hypothesis (Rice, Wexler, & Cleave, 1995) hold for the language of Afrikaans-speaking children with specific language impairment (SLI) and whether tense marking is a possible clinical marker of SLI in Afrikaans. Production of tense morphology was examined in 3 groups of Afrikaans-speaking children-15 with SLI who were 6 years old, 15 typically developing (TD) 4-year-olds matched on mean length of utterance, and 15 TD 6-year-olds-using both elicited and spontaneously produced verb forms. On the sentence completion task, children with SLI fared on par with 4-year-olds and worse than age-matched peers. However, in terms of spontaneous production of morphemes pertaining to tense, children with SLI fared worse than both TD groups. Furthermore, children with SLI mostly made the same types of errors as 4-year-olds, although some errors were unique to the SLI group. Most errors entailed omissions, of modal and temporal auxiliaries as well as of copula be. The errors offer support for the EOI hypothesis. Tense marking has the potential to be a clinical marker of SLI in Afrikaans, but further research with larger groups of Afrikaans-speaking children, including children of other ages, is needed to confirm this.


Pestiviruses infection: Interferon-virus mutual regulation.
Pestiviruses are a class of viruses that in some cases can cause persistent infection of the host, thus posing a threat to the livestock industry. Interferons (IFNs) are a group of secreted proteins that play a crucial role in antiviral defense. In this review, on the one hand, we elaborate on how pestiviruses are recognized by the host retinoic acid-inducible gene-I (RIG-I), melanoma-differentiation-associated protein 5 (MDA5), and Toll-like receptor 3 (TLR3) proteins to induce the synthesis of IFNs. On the other hand, we focus on reviewing how pestiviruses antagonize the production of IFNs utilizing various strategies mediated by self-encoded proteins, such as the structural envelope protein (Erns) and non-structural protein (Npro). Hence, the IFN signal transduction pathway induced by pestiviruses infection and the process of pestiviruses blockade on the production of IFNs intertwines into an intricate regulatory network. By reviewing the interaction between IFN and pestiviruses (based on studies on BVDV and CSFV), we expect to provide a theoretical basis and reference for a better understanding of the mechanisms of induction and evasion of the innate immune response during infection with these viruses.


The effects of social capital on entrepreneurial resilience of SME from China: A moderated mediation model of entrepreneurial passion and Confucian traditional golden-mean thinking.
Small and medium-sized startups play a crucial role in a country's sustainable development. SMEs are at an early development stage, which means weaker institutional norms and successful paradigms, tending to suffer from exceptionally high failure rates because of many constraints, including a lack of resources and credit to access the core information. The higher the environmental uncertainty, the more likely that new start-ups rely on all kinds of social links for acquiring resources. As a critical ability to withstand and overcome obstacles, entrepreneurial resilience is an essential personal characteristic to ensure the sustainability of new ventures. The purpose of this study is to investigate the internal mechanism through which SME entrepreneurs' social capital affects entrepreneurial resilience. To reveal the internal mechanism, we propose a moderated and mediation model. Using survey data from SEM entrepreneurs in China, hierarchical regression analysis and bootstrapping model are adapted to test and verify mediation and moderation effects. The results show that social capital indeed positively influences entrepreneurial resilience directly and partly through the mediating effect of harmonious entrepreneurial passion and obsessive entrepreneurial passion. Moreover, findings suggest golden-mean thinking negatively moderates the relationship between obsessive entrepreneurial passion and entrepreneurial resilience yet positively moderates the relationship between social capital and entrepreneurial resilience. Based on these findings, we conclude that entrepreneurial resilience may be achieved more effectively through the complex internal process of social capital, entrepreneurial passion, and golden-mean thinking. Finally, the study proposes the theoretical and practical implications and suggestions for follow-up research.


Initial specification of the epibranchial placode in zebrafish embryos depends on the fibroblast growth factor signal.
In vertebrates, cranial sensory ganglia are mainly derived from ectodermal placodes, which are focal thickenings at characteristic positions in the embryonic head. Here, we provide the first description of the early development of the epibranchial placode in zebrafish embryos using sox3 as a molecular marker. By the one-somite stage, we saw a pair of single sox3-expressing domains appear lateral to the future hindbrain. The sox3 domain, which is referred to here as the early lateral placode, is segregated during the early phase of segmentation to form a pax2a-positive medial area and a pax2a-negative lateral area. The medial area subsequently developed to form the otic placode, while the lateral area was further segregated along the anteroposterior axis, giving rise to four sox3-positive subdomains by 26 hr postfertilization. Given their spatial relationship with the expression of the markers for the epibranchial ganglion, as well as their positions and temporal changes, we propose that these four domains correspond to the facial, glossopharyngeal, vagal, and posterior lateral line placodes in an anterior-to-posterior order. The expression of sox3 in the early lateral placode was absent in mutants lacking functional fgf8, while implantation of fibroblast growth factor (FGF) beads restored the sox3 expression. Using SU5402, which inhibits the FGF signal, we were able to demonstrate that formation of both the early lateral domains and later epibranchial placodes depends on the FGF signal operating at the beginning of somitogenesis. Together, these data provide evidence for the essential role of FGF signals in the development of the epibranchial placodes.


[Evaluation of the treatment tactics in patients with stage II malignant neoplasms].
The paper deals with an analysis of the schemes of treatment of patients suffering from malignant tumors of the intestinal and respiratory tract, breast, cervix and corpus uteri in different Union Republics of the USSR within 1970-1980. This period witnessed noticeable improvements including increased effectiveness of the said schemes, extension of indications for surgery and development and integration of new drugs with practice.


In vitro progesterone and testosterone production by the rat placenta during pregnancy.
In vitro placental production of progesterone, testosterone, 20 alpha-hydroxy-4-pregen-3-one, and 17 beta-estradiol (E2) was investigated throughout pregnancy in the rat by RIA. Incubations of minced placental preparations with the steroidogenic enzyme inhibitors aminogluthethimide phosphate [2-(p-aminophenyl)2-ethyl-glutarimide phosphate] and cyanoketone (2 alpha-cyano-4,4,17 beta-trimethyl-17 beta-hydroxy-5-androsten-3-one resulted in a dose-related inhibition of progesterone and testosterone production. Progesterone production (picograms per mg tissue) from 2-h incubations of minced placental preparations was low on day 10 of pregnancy (day 1 = morning sperm are found in vaginal washings), peaked on day 12 (mean +/- SE, 281 +/- 32), decreased on day 14 (183 +/- 20), and returned to low levels (less than 80 pg/mg tissue X 2 h) from day 16 to term. Testosterone production (picograms per mg tissue/2 h) was not detectable on day 10, progressively increased to a peak of 46 +/- 7 on day 18, and decreased to term. Production of 20 alpha-hydroxy-4-pregnen-3-one or E2 was negligible in these minced placental preparations. Addition of androstenedione to placental incubates did not result in E2 production. Total steroid production per placenta was calculated as a function of the average placental weight for a given day. Total placental progesterone production was low on day 10 and rose to high levels (greater than 12 ng/placenta X 2 h) from day 12 to term. Total testosterone production progressively increased to a peak of 19 +/- 3 ng/placenta X 12 h on day 18 and decreased to term. These results demonstrate that throughout pregnancy, the rat placenta is an active steroidogenic tissue.


Shallot-enriched amaranth-based extruded snack influences blood glucose levels, hematological parameters, and carbohydrate degrading enzymes in streptozotocin-induced diabetic rats.
Diabetes mellitus affects different age groups, and it is popularly managed using synthetic drugs; however, recent research efforts focus on dietary intervention especially the use of fiber rich crops to circumvent the effects of drugs. Developed shallot-enriched amaranth-based extruded snacks, namely: GCB, Amaranth: shallot: soy cake (55:25:20) %; TYD, Amaranth: shallot: soy cake (75:14.81:10.19)%; DZU, Amaranth: shallot: soy cake (60.43:25:14.57)%; and JKL, Amaranth: shallot: soy cake (70:25:5)%, were evaluated for proximate composition, total phenol and flavonoid contents. Snacks ability to modulate carbohydrate hydrolyzing enzymes in streptozotocin induced diabetic rats were also investigated. AMT (100% amaranth grain extrudate) and CCS (commercial shallot-enriched snack) served as control. Protein contents of snacks provided up to 25% of daily protein requirements for adult. Snacks exhibited high total phenol and flavonoid contents. Animals fed with snacks showed ameliorative effects on hematological parameters, attenuates elevation of enzyme activities in kidney and liver homogenates, and displayed decreased α-glucosidase/α-amylase activities. PRACTICAL APPLICATIONS: Dietary intervention is capable of circumventing the adverse effects of synthetic drugs in the management of diabetes mellitus. The study established that developed shallot-enriched amaranth-based extruded snacks possess significant ability to hamper the activities of key carbohydrate hydrolyzing enzymes in streptozotocin induced diabetic rats, hence, has potential as a functional nutritious snack to curtail hyperglycemia and prevent diabetic complications.


Successful Management of Right Ventricular Failure After Emergent Transcatheter Mitral Valve Edge-to-Edge Repair With Inhaled Nitric Oxide: A Case Report.
Mitral regurgitation (MR) induces left ventricular failure and pulmonary hypertension (PH) and can lead to right ventricular (RV) failure. Inhaled nitric oxide (iNO) decreases pulmonary vessel resistance. iNO has been used in patients with PH and RV failure. We present a case with cardiogenic shock due to severe degenerative MR. The patient underwent emergent transcatheter mitral valve edge-to-edge repair (TEER). Despite TEER had been successfully performed, hemodynamics did not improve due to RV failure. Administration of iNO improved hemodynamics. This case suggests administration of iNO could be an effective option for RV failure after TEER.


Cerebrospinal fluid catecholamines in delirium and dementia.
Dopamine and noradrenaline are functionally connected to delirium and have been targets for pharmacological interventions but the biochemical evidence to support this notion is limited. To study the CSF levels of dopamine, noradrenaline and the third catecholamine adrenaline in delirium and dementia, these were quantified in three patient cohorts: (i) cognitively normal elderly patients (n = 122); (ii) hip fracture patients with or without delirium and dementia (n = 118); and (iii) patients with delirium precipitated by another medical condition (medical delirium, n = 26). Delirium was assessed by the Confusion Assessment Method. The hip fracture cohort had higher CSF levels of noradrenaline and adrenaline than the two other cohorts (both P < 0.001). Within the hip fracture cohort those with delirium (n = 65) had lower CSF adrenaline and dopamine levels than those without delirium (n = 52, P = 0.03, P = 0.002). Similarly, the medical delirium patients had lower CSF dopamine levels than the cognitively normal elderly (P < 0.001). Age did not correlate with the CSF catecholamine levels. These findings with lower CSF dopamine levels in hip fracture- and medical delirium patients challenge the theory of dopamine excess in delirium and question use of antipsychotics in delirium. The use of alpha-2 agonists with the potential to reduce noradrenaline release needs further examination.


Genetic mapping of the amphotropic murine leukemia virus receptor on mouse chromosome 8.
Southern blotting with a molecular clone of the amphotropic murine leukemia virus receptor identified restriction enzyme length polymorphisms among different taxonomic groups of mice. Analysis of the progeny of two interspecies genetic crosses was used to establish the genetic map location of the mouse gene encoding this receptor, Ram1, within the proximal region of chromosome 8.


[Intestinal pneumatosis and portomesenteric gas: a case review].
Intestinal pneumatosis (presence of gas in the intestinal wall and in the portomeseteric veins) is an infrequent clinical situation that has been associated with extended bowel necrosis and fatal outcome. However, there are other reasons that can justify these findings without such an outcome. Recent advances in diagnostic imaging techniques, especially multislice computerized tomography (MSCT), have allowed precise and quick diagnosis of these entities. In this article, we review the MSCT radiological manifestations of intestinal pneumatosis, as well as the different diagnoses related with the findings observed in a patient diagnosed with esophageal carcinoma under chemotherapy treatment.


Zoning changes and social diversity in New York City, 1990-2015.
The writings of Jane Jacobs led urbanists to advocate for increased social diversity in neighborhoods as a method of promoting vitality in public spaces. Since then, New York City has become both a role model and a testing ground for zoning changes that support this objective. However, since the 2000s community activists and scholars have argued that these zoning changes have led to the dislocation of communities of color and incentivized gentrification. This project analyzed panel social and housing census data from 1990 and 2015 to assess the validity of these arguments. Results suggest that zoning changes have limited and differentiated effects on the different dimensions of social diversity. For instance, they have strong effects on household income diversity, a nuanced effect on race diversity, and slightly negative effects on family type diversity.


GERONIMO: A tool for systematic retrieval of structural RNAs in a broad evolutionary context.
While web-based tools such as BLAST have made identifying conserved gene homologs appear easy, genes with variable sequences pose significant challenges. Functionally important noncoding RNAs (ncRNA) often show low sequence conservation due to genetic variations, including insertions and deletions. Rather than conserved sequences, these RNAs possess highly conserved structural features across a broad phylogenetic range. Such features can be identified using the covariance models approach, which combines sequence alignment with a secondary RNA structure consensus. However, running standard implementation of that approach (Infernal) requires advanced bioinformatics knowledge compared to user-friendly web services like BLAST. The issue is partially addressed by RNAcentral, which can be used to search for homologs across a broad range of ncRNA sequence collections from diverse organisms but not across the genome assemblies. Here, we present GERONIMO, which conducts evolutionary searches across hundreds of genomes in a fully automated way. It provides results extended with taxonomy context, as summary tables and visualizations, to facilitate analysis for user convenience. Additionally, GERONIMO supplements homologous sequences with genomic regions to analyze promoter motifs or gene collinearity, enhancing the validation of results. GERONIMO, built using Snakemake, has undergone extensive testing on hundreds of genomes, establishing itself as a valuable tool in the identification of ncRNA homologs across diverse taxonomic groups. Consequently, GERONIMO facilitates the investigation of the evolutionary patterns of functionally significant ncRNA players, whose understanding has previously been limited to individual organisms and close relatives.


A quantitative heterogeneity analysis approach to molecular subtype recognition of breast cancer in dynamic contrast-enhanced magnetic imaging images from radiomics data.
Breast cancer is a major cause of mortality among women worldwide. Dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) is a good imaging technique that can show temporal information about the kinetics of the contrast agent in suspicious breast lesions as well as acceptable spatial resolution. Computer-aided detection systems assist in the detection of lesions through medical image processing techniques combined with computerized analysis and calculation, which in turn helps radiologists recognize molecular subtypes of breast lesions that will be beneficial for better treatment plan decisions. In this paper, a computer-aided diagnosis method is proposed to automatically locate breast cancer lesions and identify molecular subtypes of breast cancer with heterogeneity analysis from radiomics data. A fast region-based convolutional network (Faster R-CNN) framework is first applied to images to detect breast cancer lesions. Then, the heterogeneous regions of every breast cancer lesion are extracted. Based on the multiple visual and kinetic radiomics features extracted from the heterogeneous regions, a temporal bag of visual word model is proposed, which takes into account the dynamic characteristics of both lesion and heterogeneous regions in images over time. The recognition task of molecular subtypes of breast lesions is realized based on a stacking classification model. At the genetic level, breast cancer is divided into four molecular subtypes, namely, luminal epithelial type A (Luminal A), luminal epithelial type B (Luminal B), HER-2 overexpression and basal cell type. The experimental results show that the precision of the four subtypes is 93%, 94%, 83%, 86%; the recall is 96%, 80%, 91%, 94%; and the F1-score is 95%, 86%, 87%. The experimental results denote the influence of heterogeneous regions on the recognition task. The DCE-MRI-based approach to identify molecular typing of breast cancer for noninvasive diagnosis will contribute to the development of breast cancer treatment, improved outcomes and reduced mortality.


Comparison of coagulant activity of factor VII and activated factor VII activity assays when used for determination of recombinant activated factor VII levels in plasma.
Two assays [coagulant activity of factor VII (FVII:C) and activated factor VII (FVIIa) activity] are currently available for the assessment of factor VII and FVIIa pharmacokinetics. This article presents the results of a comparison of the two assays when applied both in vitro as well as during clinical pharmacokinetic trials of recombinant FVIIa (rFVIIa) administered to healthy individuals and haemophilia patients. The in-vitro data showed that, for the FVII:C assay, plasma samples do not dilute in parallel. For the FVIIa activity assay, dilutions of samples are both parallel and linear with different dilutions of the calibrator. Moreover, intra-assay variation was found to be smaller for the FVIIa activity assay than for the FVII:C assay. When adding different amounts of rFVIIa (0-6 microg/ml) to normal plasma, a mean specific activity of rFVIIa of 48.6 U/mug was observed on applying the FVII:C assay; however, the specific activity decreased with increasing levels of rFVIIa. For the FVIIa activity assay, the mean specific activity was 45.4 IU/mug. Direct comparison of the two activity assays showed that no simple conversion between FVII:C and FVIIa activity measurements are possible. When applying the two assays for pharmacokinetic assessments in two clinical trials, statistically significant different estimates for the area under the curve, half-life, clearance and volume of distribution were obtained. In conclusion, for evaluation of rFVIIa pharmacokinetic properties, activity should be measured with the FVIIa activity assay - which is a more specific and reliable assay of the two available factor VII activity assays, especially when assessing low activity levels.


[Screening for the familial form of medullary cancer of the thyroid].
Several questions concerning the diagnosis of medullary carcinoma of the thyroid (MCT) arise from two studies of kindred of a patient with MCT carried out in 1977 and 1983. Diagnosis is based on calcitonin level determination after stimulation by pentagastrine. This method should be proposed for all kindred every time a positive diagnosis of MCT has been made for the first time in a given family. When calcitonin levels are normal it is necessary to repeat this test once a year in all individuals over 5 years of age with a high risk of MCT. Surgical removal should be proposed in cases where calcitonin levels are high. But in practice, this may be difficult and screening must be adapted to each individual case.


Anaesthetic management of a patient with Freeman Sheldon syndrome.
We present a case of Freeman Sheldon (Whistling Face) syndrome. The anaesthetic management of an additional cervical kyphoscoliosis is discussed.