Current Reproductive Technologies Impacting Equine Embryo Production.
Numerous reproductive technologies have been developed in the past several decades, which have dramatically changed the way mares are bred. This review will focus on embryo recovery and transfer, cooled-shipped embryos, embryo freezing, oocyte freezing, oocyte collection and transfer, intracytoplasmic sperm injection (ICSI), and sexed semen. Embryo transfer procedures have been constant for many years and the costs have not changed. The major change has been the ability to store embryos at 5 C for 12-24 hours and transport them to recipient stations. Embryo freezing has become more common using the technique of vitrification of embryos >300 μm or deflating embryos >300 μm before freezing. Oocyte vitrification has resulted in poor pregnancy rates although the technique works well in women. The ability to collect oocytes from mares and fertilize them by sperm injection has revolutionized the veterinarian's approach to infertility in the mare and/or stallion. A transvaginal approach can be used to collect oocytes from preovulatory follicles and unstimulated follicles 5-25 mm in size. Although traditional in vitro fertilization does not work well in the horse, ICSI can be used to produce blastocysts which, upon nonsurgical transfer into recipients, provide a pregnancy rate similar to fresh embryos collected from donor mares. Sorting sperm by flow cytometry into X- and Y-bearing spermatozoa has been shown to provide about a 50% pregnancy rate with freshly sorted sperm but only 12% with sorted, frozen/thawed stallion sperm. It is likely that more advanced reproductive techniques will be developed in the future. Their acceptance will depend on how well they work, perceived need, cost, and, to some extent, the breed associations.


On the functional neuroanatomy of visual word processing: effects of case and letter deviance.
This functional magnetic resonance imaging study contrasted case-deviant and letter-deviant forms with familiar forms of the same phonological words (e.g., TaXi and Taksi vs Taxi) and found that both types of deviance led to increased activation in a left occipito-temporal regions, corresponding to the visual word form area (VWFA). The sensitivity of the VWFA to both types of deviance may suggest that this region represents well-known visual words not only as sequences of abstract letter identities but also includes information on the typical case-format pattern of visual words. Case-deviant items, in addition to increased activation in a right occipito-temporal region and in a left occipital and a left posterior occipito-temporal region, which may reflect increased demands on the letter processing posed by the case-deviant forms.


Hyaluronate metabolism undergoes an ontogenic transition during fetal development: implications for scar-free wound healing.
Wound healing in the fetus occurs by a different process from that in the adult. Instead of healing with scar formation, fetal cutaneous wounds heal by regeneration that results in complete restoration of normal skin architecture. The mechanisms responsible for this remarkable phenomenon involve factors in the fetal environment and properties intrinsic to fetal cells. Hyaluronic acid (HA) is a major component of the fetal extracellular matrix (ECM) and is believed to play an important role in this process. In this study, HA and HA-stimulating activity (HASA) in fetal and adult wound fluid were examined using sensitive, newly developed assays. In an ovine model, higher levels of HA and HASA were observed in fetal as compared with adult wound fluid. This difference was most prominent in wound fluid from fetal lambs at 75 and 100 days gestation (term = 145 days); these samples contained persistently elevated HA and HASA levels for up to 2 weeks after wounding (HA peak levels 145 micrograms/mL and 110 micrograms/mL, respectively). In contrast, wound fluid from 120-day-gestation fetuses had significantly lower levels (P < .001) that were transient and similar to that in the adult (HA peak levels 70 micrograms/mL and 10 micrograms/mL, respectively). These observations confirm an ontogenic transition in wound HA metabolism from a fetal to an adult-like phenotype. Levels of HASA as a function of time after wounding correlated with levels of HA, suggesting a role for HASA in controlling HA deposition during tissue repair. Two patterns of HASA and HA synthesis were noted.(ABSTRACT TRUNCATED AT 250 WORDS)


A Bayesian approach to estimate skeletal age-at-death utilizing dental wear.
In the forensic context, teeth are often recovered in mass disasters, armed conflicts, and mass graves associated with human rights violations. Therefore, for victim identification, techniques utilizing the dentition to estimate the first parameters of identity (e.g., age) can be critical. This analysis was undertaken to apply a Bayesian statistical method, transition analysis, based on the Gompertz-Makeham (GM) hazard model, to estimate individual ages-at-death for Balkan populations utilizing dental wear. Dental wear phases were scored following Smith's eight-phase ordinal scoring method and chart. To estimate age, probability density functions for the posterior distributions of age for each tooth phase are calculated. Transition analysis was utilized to generate a mean age-of-transition from one dental wear phase to the next. The age estimates are based on the calculated age distribution from the GM hazard analysis and the ages-of-transition. To estimate the age-at-death for an individual, the highest posterior density region for each phase is calculated. By using a Bayesian statistical approach to estimate age, the population's age distribution is taken into account. Therefore, the age estimates are reliable for the Balkan populations, regardless of population or sex differences. The results showed that a vast amount of interpersonal variation in dental wear exists within the current sample and that this method may be most useful for classifying unknown individuals into broad age cohorts rather than small age ranges.


CircPOSTN competes with KIF1B for miR-185-5p binding sites to promote the tumorigenesis of glioma.
The involvement of certain circular RNAs (circRNAs) in the development of glioma has been revealed. CircRNA periostin (circPOSTN) was validated to be positively associated with glioma cell growth and metastasis. However, the mechanism underlying circPOSTN in glioma tumorigenesis remain vague. The expression of circPOSTN, KIF1B (Kinesin Family Member 1B) and miR-185-5p was detected using quantitative real-time polymerase chain reaction and Western blot. In vitro assays were conducted using cell counting kit-8 assay, colony formation assay, EdU assay, flow cytometry, Western blot, and transwell assay, respectively. The direct interactions between miR-185-5p and circPOSTN or KIF1B was confirmed by using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. CircPOSTN was highly expressed in glioma tissues and cells. Knockdown of circPOSTN restrained glioma cell proliferation, migration and invasion in vitro, as well as hindered glioma xenograft growth in vivo. Mechanistically, circPOSTN acted as miR-185-5p sponge to up-regulate the expression of its target KIF1B. Moreover, miR-185-5p inhibition reversed the anticancer effects of circPOSTN knockdown on glioma tumorigenesis, and miR-185-5p re-expression suppressed the malignant phenotype of glioma cells via targeting KIF1B. CircPOSTN acted as an oncogene to expedite glioma tumorigenesis via targeting miR-185-5p/KIF1B axis, indicating a potential therapeutic target for glioma.


Prothrombin time, activated partial thromboplastin time and dilute Russell's Viper Venom times are not shorter in patients with the prothrombin G20210A mutation, and dilute Russell's Viper Venom time may be longer.
Prothrombin G20210A (PT20210) carriers have increased prothrombin levels and increased risk for venous thrombosis. We hypothesized PT20210 carriers would have decreased PT, aPTT, and dRVVT clotting times. We reviewed 1186 thrombotic risk panels that included PT, aPTT, dRVVT, and PT20210 genotype with potential confounding variables, excluding samples consistent with anticoagulant therapy or lupus anticoagulant presence. We examined relationships of PT20210 with PT, aPTT, and dRVVT correcting for covariates using multivariate regression. We confirmed associations in 1876 separate panel results and a group of homozygotes for PT20210 and used general linear models to determine if associated tests predict PT20210 status. Neither PT, aPTT, nor dRVVT was shorter in PT20210 carriers. Contrary to our hypothesis, PT20210 was significantly associated with higher dRVVT (p=0.001), but not PT or aPTT. dRVVT differences were significant in a replicate sample p=0.035 and an additional sample of PT20210 homozygotes (p=0.02). Of all variables available, only dRVVT predicted PT20210 carrier status (p=0.0008, AUC=0.64). We observed an association between longer dRVVT and the prothrombin G20210A mutation in a retrospective observational study. These findings merit further study in large well-characterized clinical cohorts and laboratory research experiments.


MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia.
The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism. Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML. We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients. Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.


The kleeblattschadel deformity: neurologic outcome with early treatment.
Despite its alarming appearance, the kleeblattschadel anomaly, when it occurs in the absence of a recognizable mental retardation syndrome, is not associated with primary abnormalities of the central nervous system. Early medical and surgical efforts may result in a satisfactory cosmetic and neurologic outcome.


Brazilian Society of Hepatology and Brazilian Society of Infectious Diseases Guidelines for the Diagnosis and Treatment of Hepatitis B.
Chronic hepatitis B is an important health problem that can progress to cirrhosis and complications such as hepatocellular carcinoma. There is approximately 290 million of people with chronic hepatitis B virus (HBV) infection worldwide, however only 10% of patients are currently identified. Most part of Brazil is considered of low prevalence of HBV infection but there are some regions with higher frequency of carriers. Unfortunately, many infected patients are not yet identified nor evaluated for treatment. The Brazilian Society of Infectious Diseases (SBI) and the Brazilian Society of Hepatology worked together to elaborate a guideline for diagnosis and treatment of hepatitis B. The document includes information regarding the population to be tested, diagnostic tools, indications of treatment, therapeutic schemes and also how to handle HBV infection in specific situations (pregnancy, children, immunosuppression, etc). Delta infection is also part of the guideline, since it is an important infection in some parts of the country.


Changes in continuous glucose monitoring metrics and predictors of improvement 12 months after conversion from Freestyle Libre to Freestyle Libre 2.
We sought to assess whether conversion from Freestyle Libre to Freestyle Libre 2 (with low and high glucose alert functions) was associated with improved glucose metrics. A prospective observational study to assess changes in CGM metrics in 672 adults with type 1 diabetes when converting to Freestyle Libre 2. Secondary outcomes included predictors of reduction in time below range (TBR) and increase in time in range (TIR). TBR fell by a median of 1.0% (IQR -2.7 to 0.3, p < 0.001) after 12 months and TIR decreased by 1.0% (-8.7 to 6.0, p = 0.004). TIR did not fall in people using high glucose alerts (p = 0.353). Average duration of low glucose events (<3.9 mmoL/L) fell by 10 min (-46 to 18, p < 0.001). Significant improvements in TIR (p = 0.029) and time above 13.9 mM (p = 0.002) were observed in those using high glucose alerts. Alert threshold settings were not associated with glycaemic response; however, low alert use was independently associated with a fall in TBR of ≥0.5% (HR 1.9 [95% CI 1.2-3.1], p = 0.009) and high alert use was independently associated with a rise in TIR of ≥5% (HR 1.6 [95% CI 1.0-2.5], p = 0.043) at 12 months. Conversion to Freestyle Libre 2 was associated with significant improvements in low glucose metrics. Alert function users were more likely to see improvements across all CGM metrics. Challenges remain in encouraging alert use, helping users set optimal alert thresholds and optimizing response to alerts.


Cross--reactivity of the V3-speciflc antibodies with the human C1q.
It has been previously shown that the sequence similarity between a portion of the envelope glycoprotein 120 (gp120) from the human immunodeficiency virus type-1 (HIV-1) and several types of human collagen and collagen-like molecules exists. That observation led to the suggestion that the antibodies against the third hypervariable region (V3) of HIV-1 gp120 (V3-specific antibodies) might have a role in the autoimmune phenomena observed in HIV-infected persons. In this study we have examined the cross-reactivity of the V3-specific antibodies purified from sera of HIV-infected individuals, sera obtained from the rheumatoid arthritis and systemic lupus crythematosus patients, as well as from the sera of healthy volunteers with the separate chains of a subcomponent of the first component of the human complement system, Clq. Our results show that the V3-specific antibodies are present in the sera of the HIV-infected individuals, patients suffering of the systemic autoimmune diseases as well as in the sera of healthy volunteers. Whereas these antibodies appeared in the HIV+-sera after antigen challenge, those present in the HIV- -sera probably represent the antibodies that are cross-reactive with the antigen. V3-reactive antibodies can be purified by affinity chromatography and they were highly specific for the V3-peptide. Additionally, they showed cross-reactivity with the separate chains of the human Clq as well as with the chicken collagen type VI. Possible physiological implications are discussed.


[Can we rely on Norwegian surgery data? A quality control at central and local hospitals of the procedure codes used in the survey on organization of gastrointestinal cancer surgery].
The nation-wide register of hospital discharges in Norway includes ICD-9 and national procedure codes. Hospitals were asked to check five surgical procedures listed in the register against the primary data sources. 649 discharges were controlled. The response rate was 68%. The results indicate that the quality of the data in the register varies for the different procedures. For procedures with high volume (resection of rectum), the error in the register is 3%. This is the same as reported from other Nordic countries. The proportion of errors in the register was high in hospitals with only one registered procedure code. The quality of data can to some extent be checked on the basis of DRG coding (DRG group 468/477). Quality control of register data is required when the number in DRG 468/477 is high in the nation-wide register or when the number of specific procedures in hospitals is low.


Population pharmacokinetic model to predict steady-state exposure to once-daily cyclosporin microemulsion in renal transplant recipients.
The microemulsion formulation of cyclosporin (CsA-ME) has a less variable absorption profile than the standard formulation (CsA-S), but only limited information is available about once-daily administration of CsA-ME. To develop a population pharmacokinetic model for once-daily CsA-ME that enables the prediction of individual steady-state area under the concentration-time curve (AUC) on the basis of blood concentration measurements and patient covariates. The steady-state pharmacokinetics of once-daily cyclosporin were studied in 60 stable renal transplant recipients before and after conversion from CsA-S to CsA-ME. For each formulation, 7 blood samples were collected from 50 patients (group A) at sparse timepoints over 2 weeks, and 10 blood samples were collected from 10 patients (group B) at fixed timepoints over 24 hours. A 2-compartment population model assuming time-lagged first-order oral absorption was fitted to the data from group A, using nonlinear mixed effects modelling (NONMEM). The data from group B were used to evaluate the predictive performance of the model. Mean [+/- SD; coefficient of variation (%CV)] CsA-S doses of 245mg (+/- 92) resulted in cyclosporin blood concentrations of 214 microg/L (+/- 70) after 12 hours and 108 microg/L (+/- 23) after 24 hours; the mean estimated AUC to 24 hours was 7658 microg x h/L (30%). With mean CsA-ME doses of 206mg (+/- 59), cyclosporin blood concentrations were 212 microg/L (+/- 33) and 132 microg/L (25%) after 12 and 24 hours, respectively, and the mean estimated AUC(24) was 9357 microg x h/L (23%). A strong correlation between 12-hour concentrations and AUC(24) was observed for CsA-ME (r = 0.95, p < 0.001), but not for CsA-S (r = 0.59, nonsignificant); the correlation between 24-hour trough concentrations and AUC(24) was weaker for both formulations (r = 0.64, p < 0.05 and r = 0.37, nonsignificant, respectively). On the basis of the population model derived from group A, the single best timepoint to predict AUC(24) from blood cyclosporin concentration was at 8 hours [AUC(24) (microg x h/L) = 19.6 x cyclosporin concentration at 8 hours (microg/L) + 3035], resulting in a prediction error of 8.3 +/- 6.6% when applied to the measured AUC(24) of group B. Adverse events were observed after conversion in 18 patients; these events generally resolved spontaneously or after dosage reduction, but twice-daily administration was required in some patients. Switching from once-daily CsA-S to CsA-ME results in more consistent and predictable cyclosporin pharmacokinetics. Adjustment of dosage or regimen may be required in some patients.


Characterization of the novel HLA-DPB1*1463:01N allele by sequencing-based typing.
HLA-DPB1*1463:01N differs from HLA-DPB1*02:01:02:04 by one nucleotide substitution in codon 128 in exon 3.


Novel MprA binding motifs in the phoP regulatory region in Mycobacterium tuberculosis.
MprAB and PhoPR are important two-component systems (TCSs) in Mycobacterium tuberculosis, and both regulate EspR, a key regulator of the ESX-1 secretion system. Although previous studies suggest that the response regulator PhoP does not directly regulate mprA, the interplay between MprAB and PhoPR remains unclear. In this study, we found that the response regulator MprA can bind to the phoP promoter. Four repeat motifs, D1-D4, constituting two predicted binding sites, were located in the region protected by MprA in DNA footprinting. D1-D4 lack the reported conserved MprA binding sequences, indicating that MprA can recognize a greater range of target sites. Interestingly, D1-D2 overlap a previously reported PhoP binding site, and mutation of D1-D2 inhibited PhoP binding, whereas the D3-D4 site, but not the D1-D2 site, was required for MprA binding. EMSA assays also suggest that MprA and PhoP compete to bind to the phoP promoter. The results of the transcriptional and western blot assays are consistent with a model in which MprA positively controls the phoP expression, which in turn upregulates the expression of espR. These findings reveal complex regulation of a major mycobacterial TCS by dual TCSs.


Resilience among older adults with multiple sclerosis: Pattern and correlates.
There is an increasing number of older adults with multiple sclerosis (MS) who present with significant challenges associated with aging in conjunction with a chronic, disabling disease. Resilience has been associated with healthy aging in the general population, yet there is limited research on resilience and its correlates among older adults with MS. The current study investigated the difference in resilience between older adults with MS and demographically matched healthy controls. We then examined the associations between resilience and functional, symptomatic, socio-behavioral, and QOL outcomes, along with demographic and clinical characteristics, among only older adults with MS. The sample included 40 older adults with MS and 40 sex and age matched healthy controls who completed measures of resilience and a battery of demographic, clinical, functional, symptomatic, socio-behavioral, and QOL outcomes. There were no differences between older adults with MS and healthy controls regarding overall resilience scores and resilience subscale scores. Resilience was significantly associated with neurological disability, depression, walking performance, self-efficacy, and purpose in life. This study suggests that resilience in older adults with MS was comparable with healthy older adults, and positively associated with walking performance, self-efficacy, and purpose of life, and negatively associated with depression and neurological disability. We believe the time is ripe for developing and delivering interventions among those with lower resilience for improving resilience and associated secondary outcomes.


A systems approach to understanding vaccines.
Researchers are starting to apply the tools of systems biology to better understand human immune responses to vaccination, including HIV vaccine candidates.


Plant growth-promoting rhizobacteria promote plant size inequality.
The uniformity of crop yield is extremely important for consumers and of as much relevance to the grower as overall yield. However, size inequality within a plant population is rarely measured and has never before been considered in relation to the use of beneficial microbes for yield enhancement. For the first time, we show that addition of soil bacteria to calabrese plants significantly increased size inequality. These effects were usually more apparent in above-ground biomass. This was caused by some (but not all) plants growing very large when inoculated with bacteria, while control plants were mostly small. We suggest that the main reason is the incompatibility of the inoculated bacteria with those already present in the rhizosphere. In some cases the inoculum matched the indigenous community, providing a benefit to plant growth, while often it did not and plants remained relatively small. We conclude that analyses of size inequality should be an integral part of experiments using microbial soil amendments. These analyses can help to inform the production of more effective microbial products and to ensure that the integration of beneficial microbes into sustainable production systems does not impair uniformity in yield.


Laparoscopic nephrectomy in children: experience at Srinagarind Hospital, Khon Kaen University.
Laproscopic nephrectomy has become a popular procedure since first being introduced in 1990. Evaluate the feasibility and efficacy of laparoscopic pediatric nephrectomy. The authors reviewed the in-patient medical records at Srinagarind Hospital, Khon Kean University between 2007 and 2011. Laparoscopic nephrectomy was performed on 9 pediatric patients. The demographic data, indications for surgery, route of approach and peri-operative outcomes were analyzed. Ten nephrectomies (6 L; 4 R) were performed on the nine patients (mean age 8.8 years: 7 males; 2 females). One patient underwent a bilateral nephrectomy at a different time. A trans-and retro-peritoneal approach was used on 1 and 9 cases, respectively. The respective mean operative time and hospital stay was 108.8 minutes and 5.8 days. The mean estimated blood loss was 31.8 ml (minimal-100 ml): no blood transfusion was required. Post-operatively, there were no major complications and the mean pain score was 2.3 (0-5). Only one patient was converted to an open nephrectomy and that due to massive adhesion. Laparoscopic pediatric nephrectomy has been a feasible and safe procedure at our institution.


Pathophysiology of canine diabetes.
Diabetes is a fascinating, disease complex. Although much progress has been made in the last three decades to unravel the mysteries behind its multifaceted expressions, much work lies ahead. In dogs diabetes is not identified until late in the disease process. Future research might be directed at identifying early markers of the disease as an aid to improving current modes of treatment.


Aggressive histological features of keratoacanthoma.
Thirty-nine keratoacanthomas from 35 patients have been studied, six of which showed perineural, and one vascular, invasion. Thus far, their aggressive histological behavior has not been paralleled by a similar clinical course. However, continued close follow-up is essential.


Pedometer use in university freshmen: a randomized controlled pilot study.
To describe activity patterns associated with a pedometer intervention in university freshmen and compare the intervention participants to controls for several health outcomes. Forty-six university freshmen were randomized to a group that wore a pedometer across the academic year with a goal of 10,000 steps/day or to a control group. Pedometer counts were highest initially but decreased over the academic year. December presented the fewest counts. There was little difference between groups in fitness or body composition. Consideration of high-risk months and recommended steps/day may be important to effectively use pedometers to influence some health outcomes in university freshmen.


Mangiferin exerts neuroprotective effects against focal cerebral ischemia in mice by regulating NF-κB signaling pathway.
Mangiferin is a natural free radical scavenging antioxidant that induces excitation of the central nervous system. However, the mechanism of neuroprotective effect of mangiferin on focal cerebral ischemia has not been fully investigated. The aim of this study was to investigate the protective effect of mangiferin on focal cerebral ischemia in mice. Middle cerebral artery occlusion (MCAO) was performed to investigate the effect of mangiferin on focal cerebral ischemia. Mice were randomly divided into 5 groups: sham, MCAO, MCAO + 5 mg/kg mangiferin, MCAO + 20 mg/kg mangiferin and MCAO + 5 mg/kg nimodipine. Neurobehavioral scores, brain edema, brain injury scores, relative infarct size and expression of some inflammatory factors in the brain were evaluated. NF-κB pathway was detected by Western blotting and immunofluorescence. The results showed that mangiferin effectively attenuated MCAO-induced brain injury, including improvement of neurological impairment, reduction of brain edema, and reduction of infarct size. Compared with the MCAO group, mangiferin significantly inhibited MCAO-induced neuroinflammation, which can be proved by reduced expression levels of TNF-α, IL-1β, iNOS and COX-2. In addition, we found that phosphorylation of IκBα was inhibited and the expression of NF-κB p65 in the nucleus was reduced after the addition of mangiferin. Our study suggested that mangiferin exerts neuroprotective effects on focal cerebral ischemia in mice by regulating the NF-κB signaling pathway. Mangiferin may be an effective treatment for cerebral ischemia and other neurological disorders.


Measurement of 3-methoxy-4-hydroxyphenylacetic acid (HVA) in plasma by high-performance liquid chromatography with electrochemical detector (HPLC-EC).
A simple and sensitive high-performance liquid chromatography method with electrochemical detector is described for the determination of free 3-methoxy-4-hydroxyphenylacetic acid (HVA) in human plasma. The method does not involve any extraction, is specific and reproducible, and has the potential to measure serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) simultaneously. The plasma concentration of free HVA in eight normal, healthy adult volunteers was 10.9 +/- 4.6 (mean +/- SD). In a preliminary study, in one schizophrenic patient the plasma HVA increased twofold after neuroleptic treatment.


Use of Compartmental Modeling and Datasets for Theoretical Lactating Women to Determine Conditions under Which Vitamin A-Specific Activity in Breast Milk Provides Accurate Estimates of Vitamin A Total Body Stores by Retinol Isotope Dilution.
Vitamin A concentrations in breast milk are related to maternal vitamin A intake and status. Our objective was to identify conditions under which vitamin A specific activity in breast milk (SAm) could be used instead of retinol specific activity in plasma (SAp) to predict vitamin A total body stores (TBS) by retinol isotope dilution (RID). We used 12 previously-studied theoretical lactating women with assigned values for TBS (219-1348 μmol) and retinol kinetic parameters; we assumed subjects ingested a dose of stable isotope-labeled vitamin A. We expanded a 9-compartment steady state tracer model to include a parallel model for tracee (unlabeled retinol) and then adapted that model so vitamin A intake entered the system in 3 meals each day. Using compartmental analysis, we first simulated SAm and SAp after an overnight fast (as in actual RID experiments) and then with vitamin A intake also restricted in sequential meals on the day before sampling for RID. After an overnight fast, SAm at day 21 postdosing was lower than SAp. However, if vitamin A intake was also restricted in 1, 2, or 3 meals before sampling, SAm/SAp (mean ± SD) was 0.92 ± 0.042, 0.96 ± 0.016, or 0.99 ± 0.004, respectively; results for days 14 and 28 were similar. When either SAp or SAm was used to predict TBS by RID on day 21 after 1-d restriction, predictions for all subjects were within 25% of assigned TBS. Results indicate that, for theoretical lactating women with a wide range of vitamin A status, SAm will accurately predict TBS by RID at 2-4 wk postdosing if vitamin A intake is restricted for 1 d before sampling. If confirmed in community settings, results suggest that vitamin A status in lactating women can be determined without collecting blood.


Changes in vascular dynamics of the adult rat testis leading to transient accumulation of seminiferous tubule fluid after administration of a novel 5-hydroxytryptamine (5-HT) agonist.
The aim of the present study was to evaluate the possible mechanisms of testicular toxicity of GR40370X, a follow-up 5-hydroxytryptamine (5-HT) receptor agonist. Administration to adult male rats of a single (toxic) dose of 750 mg/kg GR40370X induced marked distension of seminiferous tubules and an associated increase in testis weight at 12-24 h with a gradual recovery to normal by 96 h. Seminiferous tubule distension was due to expansion of the lumen, which occurred at all stages of the spermatogenic cycle and was accompanied by vacuolation of the cytoplasm of elongating spermatids. Seminiferous tubule distension was preceded/accompanied by distension of the efferent ducts and rete testis with maximal changes evident at 24-48 h. These changes could not be explained by increases in seminiferous tubule fluid or interstitial fluid production, as both were reduced (15-20%), rather than increased, by treatment. Examination of the vasculature after treatment with 750 mg/kg GR40370X revealed significant changes that were maximal at 4 h and thus preceded rete/testicular changes. Veins of the mediastinal venous plexus, which overlies the rete, were constricted and arteriovenous anastomoses in the spermatic cord were shut/constricted, as determined (indirectly) by measurement of the dilution of outflowing testicular venous blood by incoming arterial blood. The latter effect of GR40370X could be blocked by co-administration of minoxidil, a vasodilator. Vascular effects of GR40370X had normalised by 24-48 h. It was also noted that administration of a toxic dose of GR40370X significantly lowered blood levels of LH and testosterone, though these changes were considered to be incidental and not involved in the other changes described above. None of the above changes were induced by a pharmacologically active dose (1 mg/kg) of GR40370X. It is concluded that the mechanism of testicular toxicity induced by 750 mg/kg GR40370X results from primary effects on the vasculature of the testis/neighbouring region, which in turn lead to impaired fluid resorption from the efferent ducts and rete and thence to accumulation of seminiferous tubule fluid in the rete and testis.


Scrotal heating stimulates panting and reduces body temperature similarly in febrile and non-febrile rams (Ovis aries).
It is known that heating the ram scrotum stimulates heat loss resulting in a decrease in body temperature and that during fever core temperature increases, but local scrotal thermoeffectors operate to maintain normal scrotal temperature. We have investigated whether scrotal warming influences core body temperature and the panting effector during fever generation. We measured rectal temperature, intrascrotal temperature, scrotal skin temperature and respiratory frequency in four adult Merino rams following intravascular injection of saline or lipopolysaccharide at an ambient temperature of 18-20 degrees C while scrotal skin temperature was maintained at 33 degrees C or elevated to 41 degrees C. Compared to maintaining normal scrotal temperature, heating the scrotum increased respiratory frequency and reduced rectal temperature by a similar amount following LPS as following saline. Fever was associated with decreased respiratory frequency compared to saline at both 33 and 41 degrees C scrotal temperature, suggesting that the fever was generated mainly by decreasing respiratory heat loss. We conclude that scrotal thermal afferent stimulation resulted in an offset for the set-point of body temperature regulation in both normothermic and febrile rams.


Preference, satisfaction and critical errors with Genuair and Breezhaler inhalers in patients with COPD: a randomised, cross-over, multicentre study.
The specific attributes of inhaler devices can influence patient use, satisfaction and treatment compliance, and may ultimately impact on clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). To assess patient preference, satisfaction and critical inhaler technique errors with Genuair (a multidose inhaler) and Breezhaler (a single-dose inhaler) after 2 weeks of daily use. Patients with COPD and moderate to severe airflow obstruction were randomised in a cross-over, open-label, multicentre study to consecutive once-daily inhalations of placebo via Genuair and Breezhaler, in addition to current COPD medication. The primary end point was the proportion of patients who preferred Genuair versus Breezhaler after 2 weeks (Patient Satisfaction and Preference Questionnaire). Other end points included overall satisfaction and correct use of the inhalers after 2 weeks, and willingness to continue with each device. Of the 128 patients enrolled, 127 were included in the safety population (male n=91; mean age 67.6 years). Of the 110 of the 123 patients in the intent-to-treat population who indicated an inhaler preference, statistically significantly more patients preferred Genuair than Breezhaler (72.7 vs. 27.3%; P<0.001). Mean overall satisfaction scores were also greater for Genuair than for Breezhaler (5.9 vs. 5.3, respectively; P<0.001). After 2 weeks, there was no statistically significant difference in the number of patients who made ⩾1 critical inhaler technique error with Breezhaler than with Genuair (7.3 vs. 3.3%, respectively). Patient overall preference and satisfaction was significantly higher with Genuair compared with Breezhaler. The proportion of patients making critical inhaler technique errors was low with Genuair and Breezhaler.


Gender Differences in Postoperative Pain, Nausea and Vomiting After Elective Laparoscopic Cholecystectomy.
Although reports suggest that pain and postoperative nausea and vomiting (PONV) may be more frequent in women, the evidence is inconsistent. The objective of this study was to investigate whether women are more sensitive to pain and PONV after laparoscopic cholecystectomy (LC). A total of 370 women and 275 men were included in a retrospective cohort study. All underwent LC under standardized general anesthesia. The variables analyzed included clinical and anthropometric parameters. End points were the incidence of nausea, vomiting, pain, and the requirement for additional pain relievers and antiemetics to control these. The women were younger and had lower body weight than the men (p < 0.001). Body mass index was within the normal range for 50% of women and 30% of men (p < 0.001). Pain was more common in women at 1, 6, 12 and 24 h after surgery (p < 0.02). Narcotics in addition to the doses used to lessen pain intensity (p = 0.01) were required in 60 women and 19 men (p < 0.001). PONV was more frequent in women at 1 and 6 h after surgery (p < 0.01). Rescue antiemetics were required in 35 women and 11 men (p = 0.008). Hospital stay was shorter for men (p < 0.001). Four patients in each group developed postoperative complications (p = 0.14). There was no mortality. Early postoperative pain, nausea and vomiting after LC were more common in women, who more frequently required analgesic and antiemetic rescue medication.


Sonographic estimation of fetal weight and Doppler analysis of umbilical artery velocimetry in the prediction of intrauterine growth retardation: a prospective study.
A prospective study was undertaken to examine whether Doppler velocimetry studies of the umbilical artery give a better or an earlier prediction of intrauterine growth retardation (IUGR) than do sonographic estimation of fetal weight. A total of 385 examinations were performed between 30 and 42 weeks of gestation on 168 patients who were at risk for IUGR. Forty-two (25%) of the patients delivered an infant with a birth weight below the tenth percentile. Although sensitivity was lower for the systolic to diastolic ratio (55%) of the umbilical artery than for the sonographic estimation of fetal weight (76%), the umbilical artery studies had a higher specificity (92% versus 80%) and predictive value of a positive test (73% versus 58%) when the last study to delivery interval was within 2 weeks. Furthermore, among 21 IUGR pregnancies with serial studies, the umbilical systolic to diastolic ratio was abnormal at a significantly earlier gestational age than when the sonographic estimate of fetal weight identified growth retardation. These findings indicate that sonographic biometry is a more sensitive technique for identifying IUGR but that the umbilical artery waveforms are a valuable adjunct for improving the diagnostic accuracy for the prenatal detection of IUGR. These data also provide suggestive evidence that umbilical artery velocimetry may be predictive of IUGR at an earlier gestational age than sonographic estimation of fetal weight.


How do aphasic and normal speaking subjects restate a message in response to feedback?
Seven aphasic and seven normal subjects (Ss) viewed and described 25 cartoon drawings. While Ss described individual pictures the experimenter provided one of three types of feedback: explicit feedback, for example, "Can you tell me anything else about it?"; false feedback, for example, asking a question about another picture; or implicit feedback, for example, "I can't find it." five types of responses (recodings) were tallied. These included deletion, expansion, repetition, revision, and "other communicative behaviors." It was found that (1) the normal Ss used significantly more expansion and deletion than the aphasics; (2) there were no significant differences between the groups for repetition, revision, and "other communicative behaviors"; and (3) the Ss' recodings varied depending on the type of feedback presented.


Primary low-grade MALT lymphoma of the gallbladder.
We report a case of primary low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue (low-grade MALT lymphoma) in the gallbladder. A 58-year-old woman suspected of gallbladder carcinoma underwent laparoscopic cholecystectomy. Microscopic examination of the gallbladder demonstrated lymphoid cell infiltration forming lymphoid follicles with hyperplastic secondary follicles. The surrounding monocytoid B cells and centrocyte-like cells selectively infiltrated the crypt epithelium forming lympho-epithelial lesions. Plasma cells were also noted beneath the mucosal epithelium. Bile culture revealed the Gram-negative bacilli Enterococcus faecalis and Morganella morganii. Immunoglobulin heavy chain gene rearrangement was confirmed using polymerase chain reaction (PCR) and oligoclonal lymphoid proliferations was detected. Because autoimmune diseases, or chronic inflammatory disorders, seem to correlate with the occurrence of MALT lymphoma, Gram-negative bacterial infection could also be considered as a prodrome of MALT lymphoma of the gallbladder.


The value of FDG-PET and bone scintigraphy with SPECT in the primary diagnosis and follow-up of patients with chronic osteomyelitis of the mandible.
To appraise the value of FDG-PET and bone scintigraphy using SPECT in the primary diagnosis and follow-up of patients with chronic osteomyelitis of the mandible (COM). In a prospective study the pattern of tracer uptake was investigated using 2 diagnostic methods in 42 patients. Results were compared with histology and radiographs as well as clinical and laboratory parameters. The use of FDG-PET in the primary diagnosis of COM resulted in a sensitivity of 64% and a specificity of 77.7%. The sensitivity of SPECT was 84% and the specificity 33.3%. During the follow-up period of these patients the sensitivity of SPECT increased to 93.7%, while the specificity decreased (6.6%). The sensitivity and specificity of FDG-PET for this follow-up group were 62.5 and 80%, respectively. Because of its high sensitivity, SPECT is vastly superior to other diagnostic methods in initiating treatment. In the follow-up period it might be replaced by FDG-PET, which reflects the disease course better and indicates the time of clinical remission.


Risk communication sources and knowledge of Lassa fever in Nigeria: An impact analysis.
This study examined the predominant risk communication sources for Lassa fever, and explored the correlation between risk communication sources and knowledge of Lassa fever in the most endemic states (Ebonyi, Edo and Ondo) of the disease outbreak in Nigeria, through a mixed-methods approach. Using the multi-stage sampling technique, 72 Focus Group Discussants and 653 survey respondents were selected for the study. Statistical analysis was conducted on the acquired quantitative data, whereas thematic analysis was employed for qualitative analysis. The results suggest that radio, posters and healthcare workers are predominant sources of information about Lassa fever in the endemic states. The majority of the respondents possess adequate knowledge of the Lassa fever vector, transmission routes, risk factors, and preventive measures, but knowledge of asymptomatic patients was generally poor across the selected states. The regression analysis indicates that radio and healthcare workers are the strongest predictor of the knowledge of Lassa fever at (beta = .191, p < .05, Significant. .000) respectively, followed by television and family members/relatives at (beta = .124, p < .05, Significant. .002.) (beta = .110, p < .05, Significant. .007) respectively. The study recommends among others that; more efforts in risk communication should be geared towards the dissemination of the health risk information through radio, healthcare workers, television, and informal communication within the family network to further promote the knowledge of Lassa fever and other epidemics in Nigeria at large.


Experimental study on restricting the robotic end-effector inside a lesion for safe telesurgery.
Using an endoscopic telesurgical robot system (ETSRS), the authors propose a strategy for improving the safety of telesurgery by restricting the movement of an end-effector within a lesion. The strategy is validated by phantom model experiments. The method focused on generation of force feedback and restriction of robotic end-effector movement of ETSRS based on a virtual wall. Collision detection and case classification procedures were used to determine whether the generation of force feedback or restricting the end-effector's movement was continued. The method was implemented in ETSRS and tested using a brain and tofu phantom. Force feedback was well generated proportional to a linear combination of the insertion depth and the velocity of the end-effector of the ETSRS from the surface of the predefined virtual wall. The movement of the end-effector was well limited inside the virtual wall by the method. The virtual wall update was sufficiently fast to check the current surgical situation. The control rate of the entire system was >30 fps so that the method showed acceptable performance in phantom experiments. The results show that the strategy allows for well controlled robotic end-effectors inside a predefined virtual wall by the robot itself and an operator through the signal and force feedback.


Lysosomes and endoplasmic reticulum: targets for improved, selective anticancer therapy.
Most currently used anticancer agents are active against proliferating cells. Apoptosis signaling mechanisms induced by many such agents are impaired in tumor cells, leading to therapy resistance. Lysosomes and the endoplasmic reticulum (ER) hold promise as drug targets and mediators of apoptosis signaling which may be less affected by intrinsic or chemotherapy-induced resistance mechanisms. Tumor cell lysosomes contain increased levels of cathepsins, and the release of these enzymes into the cytosol may result in apoptosis or necrosis, as has been reported for TNF-alpha. It is also reported that tumor transformation leads to increased sensitivity to cathepsin B-dependent apoptosis. Tumor cells often show evidence of constitutive ER stress, possibly due to hypoxia and glucose depletion. Various anticancer drugs, including cisplatin and proteasome inhibitors, have been shown to induce ER stress. Manipulating the ER stress response of tumor cells is an interesting therapeutic strategy. We conclude that organelle damage responses can be used to trigger tumor cell death, and that the response to such damage may be triggered in cells that are resistant to conventional DNA-damaging agents.


Determinants of drug response in a cisplatin-resistant human lung cancer cell line.
To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non-small cell lung cancer cell line (PC-9/CDDP) selected from the wild type (PC-9) for acquired resistance to cisplatin. PC-9/CDDP demonstrated 28-fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (X 6.3), melphalan (X 3.7) and 3-[(4-amino-2-methyl-5-pyrimidinyl)]methyl-1-(2-chloroethyl)-1-nitros our ea (ACNU) (x 3.9). There was no expression of mdr-1 mRNA in either wild-type or resistant cells. The mRNA and protein levels of glutathione S-transferase (GST) pi were similar in the two lines. A GST-mu isozyme was present in equal amounts and the activities of selenium-dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC-9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC-9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.


The Impact of Photobleaching on Microarray Analysis.
DNA-Microarrays have become a potent technology for high-throughput analysis of genetic regulation. However, the wide dynamic range of signal intensities of fluorophore-based microarrays exceeds the dynamic range of a single array scan by far, thus limiting the key benefit of microarray technology: parallelization. The implementation of multi-scan techniques represents a promising approach to overcome these limitations. These techniques are, in turn, limited by the fluorophores' susceptibility to photobleaching when exposed to the scanner's laser light. In this paper the photobleaching characteristics of cyanine-3 and cyanine-5 as part of solid state DNA microarrays are studied. The effects of initial fluorophore intensity as well as laser scanner dependent variables such as the photomultiplier tube's voltage on bleaching and imaging are investigated. The resulting data is used to develop a model capable of simulating the expected degree of signal intensity reduction caused by photobleaching for each fluorophore individually, allowing for the removal of photobleaching-induced, systematic bias in multi-scan procedures. Single-scan applications also benefit as they rely on pre-scans to determine the optimal scanner settings. These findings constitute a step towards standardization of microarray experiments and analysis and may help to increase the lab-to-lab comparability of microarray experiment results.


The Florida sleeve: a new technique for aortic root remodeling with preservation of the aortic valve and sinuses.
Aortic valve salvage remains the procedure of choice for patients with incompetent valves and normal leaflet morphology. Here my colleagues and I describe a new technique for aortic root remodeling with preservation of the aortic valve.


Mechanism of diet-induced uraemia and acidosis in infants.
Five patients aged between 40 and 70 days were admitted to our Clinic with an initial diagnosis of "renal failure", but the high levels of urea nitrogen, metabolic acidosis and oliguria were found to be related to a high renal solute load and to the very high protein and electrolyte content of the diet. By calculating urinary output (V/m'), clearance of osmotically-active substances (COsm), clearance of free water (CH2O), maximum tubular reabsorption of water (TcH2O) and the change in metabolic H+ production, it has been possible to demonstrate that dietary protein and electrolytes were both responsible for the high blood urea nitrogen levels and metabolic acidosis.


Fusarium spp. and storage fungi in suboptimally stored wheat: Mycotoxins and influence on wheat gluten proteins.
When wheat is stored under suboptimal conditions, a further mycotoxin increase of deoxynivalenol (DON), but especially of mycotoxins produced by storage fungi, e.g. ochratoxin A, is possible, lowering wheat quality and food safety. Different storage trials were conducted under suboptimal storage conditions.Fusarium survival during suboptimal storage was monitored by cultural technique and multiplex-PCR and set into relation to DON contents. Furthermore, XANES spectroscopy was applied on a selected storage trial in order to characterize sulfur speciation in low molecular weight (LMW) subunits of glutenin isolated from suboptimally stored wheat samples highly infected withFusarium and from wheat infected withAspergillus andPenicillium. Distinct changes in sulfur speciation were observed in grains infected with storage fungi, especially a significant increase of higher oxidation states (sulfoxide state, sulfonate state).


Erratum to "A prosodic morphophonological analysis of the trilateral perfect passive verbs in Qassimi Arabic" [Heliyon 8(8), (August 2022) Article e10008].
[This corrects the article DOI: 10.1016/j.heliyon.2022.e10008.].


The Association Between Chemotherapy Immediately Before Nivolumab and Outcomes Thereafter.
We investigated whether the efficacy and type of pre-nivolumab chemotherapy influence outcomes in non-small cell lung cancer patients following nivolumab treatment. In this multicenter study, 199 patients treated with nivolumab were retrospectively reviewed. We analyzed the relationships between the clinical response to nivolumab and to chemotherapy administered immediately beforehand. Patients who achieved objective responses to pretreatments showed higher disease control rates with nivolumab than patients who did not (64% vs. 47%, p=0.03), as did those who achieved disease control with pretreatments (62% vs. 35%, p<0.001). Bevacizumab-pretreated patients tended to show better objective response rates with nivolumab (27% vs. 13%, p=0.06); the objective response rate to nivolumab was significantly higher in bevacizumab-pretreated patients who showed clinical responses (42% vs. 9.1%, p=0.02). Achievement of a clinical response to chemotherapy immediately before nivolumab, particularly when combined with bevacizumab, increases the likelihood of disease control post-nivolumab.


[Assesment of RBE of fast neutrons in Ehrlich ascites tumor cells by analysis of mitotic depression (author's transl)].
The depression of mitosis 1 hr following various doses of fast neutrons (6.2 Mev) and gamma rays was studied in an Ehrlich ascites carcinoma of mouse. Doses of 50, 100, 200 and 300 rad of either radiation yielded in the semilogarithmic plot a linear dose dependence of mitosis inhibition. From the regression straight line obtained the Relative Biological Effectiveness was determined, which declined from 2.8 at 50 rad to 1.8 at 300 rad neutron dose. The RBE is given analytically for the dose range investigated in dependence on neutron dose.


Risk of serious COVID-19 outcomes among adults and children with moderate-to-severe asthma: a systematic review and meta-analysis.
The Joint Committee on Vaccination and Immunisation in the United Kingdom requested an evidence synthesis to investigate the relationship between asthma and coronavirus disease 2019 (COVID-19) outcomes. We conducted a systematic review and meta-analysis to summarise evidence on the risk of severe COVID-19 outcomes in people with uncontrolled asthma or markers of asthma severity. High-dose inhaled corticosteroids (ICS) or oral corticosteroids (OCS) were used as markers of asthma severity, following international or national asthma guidelines. Risk of bias was assessed using Joanna Briggs Institute tools. Adjusted point estimates were extracted for random-effects meta-analyses and subgroup analyses. After screening, 12 studies (11 in adults and one in children) met the eligibility criteria. Adults using high-dose ICS or OCS had a pooled adjusted hazard ratio (aHR) of 1.33 (95% CI 1.06-1.67, I2=0%) for hospitalisation and an aHR of 1.22 (95% CI 0.90-1.65, I2=70%) for mortality for COVID-19. We found insufficient evidence for associations between markers on COVID-19 mortality in the subgroup analyses. Adults with severe asthma are at increased risk of COVID-19 hospitalisation compared to nonusers. Our analysis highlighted the dearth of studies in children with asthma investigating serious COVID-19 outcomes.


Endoscopic ultrasonography-guided cholecystogastrostomy using a lumen-apposing metal stent as an alternative to extrahepatic bile duct drainage in pancreatic cancer with duodenal invasion.
Various approaches to biliary drainage, especially endoscopic ultrasonography (EUS)-guided drainage, have become commonly used as an alternative method for biliary decompression for malignant biliary obstruction. Occasionally, however, duodenal obstruction and non-dilated intrahepatic bile duct impede conventional EUS-guided biliary drainage. Herein, we describe a case of cholecystogastrostomy successfully carried out using a newly developed fully covered lumen-apposing self-expandable metallic stent (SEMS). EUS-guided cholecystogastrostomy should be considered an option for biliary decompression. This is a particularly ideal alternative if the patient has duodenal strictures with or without a duodenal metal stent and a non-dilated intrahepatic bile duct, which suggests the impossibility of choledochoduodenostomy and hepaticogastrostomy. Furthermore, the newly developed fully covered lumen-apposing SEMS seems ideal for EUS-guided cholecystoenterostomy.


Highly sensitive and selective cyanide detection via Cu2+ complex ligand exchange.
A new type of fluorescent probe (1) with two triazole groups that are conjugated with a carbazole moiety was synthesized by a Cu(I)-catalyzed alkyne-azide click reaction for the selective and sensitive detection of cyanide via fluorescence enhancement by ligand exchange and metal ion removal.


Indocyanine green fluorescence angiography-guided simultaneous laparoscopic distal gastrectomy and spleen-preserving distal pancreatectomy for conserving the gastrosplenic ligament: A case report.
Indocyanine green (ICG) fluorescence angiography is being increasingly performed intraoperatively to detect restricted blood flow intraoperatively for the prevention of postoperative organ ischemia and anastomotic leakage. This is the first case report of simultaneous laparoscopic distal gastrectomy (LDG) and spleen-preserving distal pancreatectomy (LSPDP) involving ICG angiography use to avoid the remnant stomach ischemia. A 55-year-old man was diagnosed with early cancer of the stomach body and intraductal papillary mucinous neoplasms of the pancreatic tail. We performed simultaneous LDG with D2 dissection and LSPDP to conserve the gastrosplenic ligament and preserve blood supply to the remnant stomach. Intraoperatively, blood flow to the remnant stomach was visualized using ICG fluorescence angiography, after which Roux-en-Y reconstruction was performed. There was no perioperative remnant stomach ischemia. Despite the preserved splenic artery and vein, complete splenic infarction occurs after LSPDP possibly due to thrombus formation during surgical procedures. In this patient, we conserved the gastrosplenic ligament for the short gastric artery, which supplied blood to the remnant stomach; however, remnant stomach ischemia may occur. Therefore, we performed ICG fluorescence angiography during this operation to ensure that sufficient blood supply to the remnant stomach was maintained. Our experience demonstrates that ICG angiography may be useful for the prevention of remnant stomach ischemia.


Development of a practical membrane lung system.
The purpose of this study was to evaluate a compact, single-pump membrane oxygenator system designed for both short-term open-heart procedures and long-term extracorporeal support. Work was directed at developing a compatible, disposable venous reservoir, fabricating a compact mounting board, determining acceptable priming volumes, and establishing safe and effective modes of setup and operation. Ten adult baboons undergoing total cardiopulmonary autotransplantation as part of a separate study were operated on using a 1.5 m2 Kolobow spiral-coil membrane system. Blood gases, oxygen transfer, extracorporeal blood flows, priming volume, and setup times were determined. In addition, 3 infant and 6 adult human subjects undergoing cardiac operations in which spiral-coil membranes of various sizes were used were also similarly studied. The data and experience from these studies suggest that the spiral-coil membrane system utilized is safe and effective in procedures requiring short-term cardiopulmonary bypass.


Ruptured aortic valve cusp: a complication of the Heimlich maneuver.
A case of traumatic rupture of the aortic valve as a complication of the Heimlich maneuver is presented. Conformation was made by comparative echocardiographic studies available from three months before and immediately following the incident. The patient refused surgical intervention and died one month later with severe congestive heart failure despite vigorous medical therapy.


An optimized method for determination of benzene in exhaled air by gas chromatography-mass spectrometry using solid phase microextraction as a sampling technique.
The determination of benzene in exhaled air has contributed for the increase in the use of breath analysis in biological monitoring. This paper describes SPME as a sampling technique for determining benzene in exhaled air by GC-MS. A system was developed to generate a gaseous benzene standard by a permeation method to accomplish the breath analyses. The method presented good resolution, repeatability (the mean of %RSD values for intra-day measurements was 6.3), sensitivity (2.4 and 3.1 ppb for LOD and LOQ, respectively), and linearity of response (R(2)=0.994). After optimizing the conditions, analyses of real samples were performed on two groups (exposed and not exposed to benzene). The results presented an average of 8.2 ppb for the control group and 25.3 ppb for the exposed group.


Mutations I117V and I117M and oseltamivir sensitivity of pandemic (H1N1) 2009 viruses.
Analysis of mutations I117V and I117M in the neuraminidase of influenza A pandemic (H1N1) 2009 viruses showed that I117V confers a mild reduction in oseltamivir sensitivity and has a synergistic effect of further increasing resistance when combined with H275Y. Contrary to recent reports, the I117M mutation does not alter oseltamivir sensitivity.


Unraveling transcriptomics of sorghum grain carotenoids: a step forward for biofortification.
Sorghum (Sorghum bicolor [L.] Moench) is a promising target for pro-vitamin A biofortification as it is a global staple crop, particularly in regions where vitamin A deficiency is prevalent. As with most cereal grains, carotenoid concentrations are low in sorghum, and breeding could be a feasible strategy to increase pro-vitamin A carotenoids to biologically relevant concentrations. However, there are knowledge gaps in the biosynthesis and regulation of sorghum grain carotenoids, which can limit breeding effectiveness. The aim of this research was to gain an understanding of the transcriptional regulation of a priori candidate genes in carotenoid precursor, biosynthesis, and degradation pathways. We used RNA sequencing of grain to compare the transcriptional profile of four sorghum accessions with contrasting carotenoid profiles through grain development. Most a priori candidate genes involved in the precursor MEP, carotenoid biosynthesis, and carotenoid degradation pathways were found to be differentially expressed between sorghum grain developmental stages. There was also differential expression of some of the a priori candidate genes between high and low carotenoid content groups at each developmental time point. Among these, we propose geranyl geranyl pyrophosphate synthase (GGPPS), phytoene synthase (PSY), and phytoene desaturase (PDS) as promising targets for pro-vitamin A carotenoid biofortification efforts in sorghum grain. A deeper understanding of the controls underlying biosynthesis and degradation of sorghum grain carotenoids is needed to advance biofortification efforts. This study provides the first insights into the regulation of sorghum grain carotenoid biosynthesis and degradation, suggesting potential gene targets to prioritize for molecular breeding.


Tetranectin as a Potential Biomarker for Stable Coronary Artery Disease.
This cross-sectional study tested the hypothesis that decreased serum levels of tetranectin (TN), a regulator of the fibrinolysis and proteolytic system, is associated with the presence and severity of CAD. We conducted a systematic serological and immunohistochemical (IHC) analysis to respectively compare the TN levels in serum and artery samples in CAD patients and healthy controls. Our results showed that serum levels of TN were significantly lower in patients with CAD than in healthy controls. Further analysis via trend tests revealed that serum TN levels correlated with the number of diseased arteries. Besides, the multivariate logistic regression model revealed TN as an independent factor associated with the presence of CAD. Additionally, IHC analysis showed that TN expression was significantly higher in atherosclerotic arteries as compared to healthy control tissues. In conclusion, our study suggests that increased serum TN level is associated with the presence and severity of diseased coronary arteries in patients with stable CAD.


Mannosidosis: a study of two patients, presenting clinical heterogeneity.
Two unrelated patients suffering from mannosidosis, aged 9 and 33 years, are reported, presenting two extremes in the phenotypic expression of this lysosomal storage disorder. Clinical, radiological, biochemical and therapeutical aspects of the disease are discussed. Our patients support the concept that mannosidosis is not a homogeneous syndrome but manifests wide clinical heterogeneity.


Accuracy of MR neurography in the diagnosis of brachial plexopathy.
To assess the accuracy of MR neurography (MRN) for the diagnosis for brachial plexopathy. Forty-three 43 consecutive cases or MRN with electrodiagnostic study correlation were reviewed independently by 2 readers. Established diagnostic criteria were employed: increased signal intensity, enlargement, loss of fascicular pattern, perineural edema and enhancement after administration of gadolinium contrast. An additional 37 cases without electrodiagnostic correlation were included in a second portion of the study, which evaluated interobserver variability. The sensitivity of MRN ranged from 41.2% to 70.6%. Specificity was 97.7% to 100%. There was good interobserver agreement, with kappa value of 0.658. Odds ratio for agreement between observers at 3T vs. 1.5T was 1.30. MRN of the brachial plexus showed only moderate sensitivity to brachial neuritis. Interobserver agreement was slightly higher at 3T than at 1.5T. MRN can be helpful in confirming an abnormal brachial plexus, but a normal MRN appearance of the plexus should not negate a clinical diagnosis.


Relationships of hamstring muscle volumes to lateral tibial slope.
Greater posterior-inferior directed slope of the lateral tibial plateau (LTS) has been demonstrated to be a prospective ACL injury risk factor. Trainable measures to overcome a greater LTS need to be identified for optimizing injury prevention protocols. It was hypothesized that Healthy individuals with greater LTS who have not sustained an ACL injury would have a larger lateral hamstring volume. Eleven healthy females (mean +/- standard deviation) (1.63±0.07m, 62.0±8.9kg, 22.6±2.9years) & 10 healthy males (1.80±0.08m, 82.3±12.0kg, 23.2±3.4years) underwent magnetic resonance imaging of the left knee and thigh. LTS, semitendinosus muscle volume, and biceps femoris long head muscle volume were obtained from imaging data. After controlling for potential sex confounds (R2=.00; P=.862), lesser semitendinosus volume and greater biceps femoris-long head volume were indicative of greater LTS (R2∆=.30, P=.008). Healthy individuals with greater LTS have a muscular morphologic profile that includes a larger biceps femoris-long head volume. This may be indicative of a biomechanical strategy that relies more heavily on force generation of the lateral hamstring and is less reliant on force generation of the medial hamstring. Level IV.


Relationship between anaerobic power and jumping of selected male volleyball players of different ages.
The aim of the present study was to evaluate the anaerobic power of elite male volleyball players, using the Wingate Anaerobic Test to examine the relationship between anaerobic power and jumping performance. Athletes (n=56) and Nonathletes (n=53) were divided into three age groups: Adults (18-25 yr.), Juniors (15-16 yr.), and Youth (10-11 yr.). Measurements of height, body mass, vertical jump and Wingate scores indicated higher values for athletes. The specific training effects of anaerobic power were more pronounced at the age of 10-11 years than for Nonathletes. A significant correlation coefficient between peak power and vertical jump was found for Athletes (r=.86) and for the total group (r=.82). These results indicated that vertical jump may predict the maximal anaerobic power and could be used by coaches as a practical and easy-to-apply field screening test for evaluation in volleyball training.


Problematic social networking site use: a brief review of recent research methods and the way forward.
Social networking site (SNS) use is a routine activity for millions of people around the world. Under certain circumstances, an increase in SNS use may lead to problematic social networking site use (PSNSU). Numerous studies have reported associations between PSNSU and various psychosocial variables. The present review briefly examines research methods that have been employed to investigate PSNSU. Cross-sectional studies have been a popular method of investigating PSNSU, but they have significant limitations. Longitudinal and neuroimaging studies may provide important insights, but they are more difficult to conduct and have been less utilised. The field would benefit from a clarification of research priorities, integration of research methods, and studies that include SNS users from various age groups.


Acute antepartum pyelonephritis in pregnancy: a critical analysis of risk factors and outcomes.
To test the incidence and sonographic parameters of pyelonephritis during pregnancy, and to examine risk factors and pregnancy outcomes of women with acute antepartum pyelonephritis. A retrospective population-based study comparing all singleton pregnancies of patients with and without acute antepartum pyelonephritis was performed. Patients lacking prenatal care as well as multiple gestations were excluded from the study. Multiple logistic regression models were used to control for confounders. Out of 219,612 singleton deliveries in 1988-2010, 165 women (0.07%) suffered from acute antepartum pyelonephritis. Abnormal sonographic findings were found in 85.7% of the patients with pyelonephritis. Pyelonephritis was significantly associated with nulliparity (46.1% vs. 24.4%, p<0.001), younger maternal age (26.3 ± 6.0 vs. 28.6 ± 5.8 years, p<0.001), intrauterine growth restriction (IUGR) (6.7% vs. 2.1%, p<0.001), placental abruption (3.6% vs. 0.7%, p<0.001), low 1 min Apgar scores (10.3% vs. 6.0%, p<0.05), urinary tract infection (UTI) (4.2% vs. 0.4%, p<0.001) and preterm delivery (less than 37 weeks gestation; 20.0% vs. 7.8%; p<0.001). Using a multivariable analysis, independent risk factors for acute antepartum pyelonephritis were nulliparity (OR 2.0; 95% C.I 1.4-2.9; p<0.001), UTI (OR 10.3; 95% C.I 4.8-22.1; p<0.001) and younger maternal age (OR 0.96; 95% C.I 0.93-0.99; p=0.009). Using another multivariable analysis, with preterm delivery as the outcome variable, acute antepartum pyelonephritis was found as an independent risk factor for preterm delivery (OR 2.6; 95% C.I 1.7-3.9; p<0.001). Acute antepartum pyelonephritis is associated with adverse perinatal outcomes and specifically is an independent risk factor for preterm delivery.


Mitigation of heavy metal stress in the soil through optimized interaction between plants and microbes.
Agricultural as well as industrial processes, such as mining and textile activities, are just a few examples of anthropogenic activities that have a long-term negative impact on the environment. Each of the aforementioned factors increases the concentration of heavy metals in soil. Heavy metal contamination in soil causes a wide range of environmental issues and is harmful to microbes, plants, and animals. Because of their non-biodegradability and toxic effects, preventing additional metal contamination and remediating the vast majority of contaminated sites around the world is critical. Hence, this review focuses on the effects of metal contamination on soil microbes, as well as plant-microbe interactions. Plant-associated probiotics reduce metal accumulation; the introduction of beneficial microbes is regarded as one of the most promising approaches to improving metal stress tolerance; thus, the study focuses on plant-microbe interactions as well as their actual implications via phytoremediation. Plant-microbe interaction can play an important role in acclimating vegetation (plants) to metalliferous conditions and should thus be studied to improve microbe-aided metal tolerance in plants. Plant-interacted microbes reduce metal accumulation in plant cells and metal bioaccumulation in the soil through a variety of processes. A novel phytobacterial approach, such as genetically modified microbes, is now being used to improve heavy metal cleanup as well as stress tolerance among plants. This review examines our current understanding of such negative consequences of heavy metal stresses, signaling responses, and the role of plant-associated microbiota in heavy metal stress tolerance and interaction.


Factors involved in skin carcinogenesis.
A personal account of skin carcinogenesis is given based on forty years of investigation of normal and pathologic anatomy of the human skin. Symbiosis of acral portions of adnexa and of melanocytes with epidermal keratinocytes is stressed, and perversion of symbiosis to parasitism in tumor formation is discussed. The role of the basement membrane as a combined effort of, and filter between, ectoderm and mesoderm is stressed, and the nature of basal cell epithelioma as the least differentiated member of the tribe of fibroepithelial adnexal tumors is outlined. Experimental data supporting the promoting role of specific mesodermal stroma in basalioma formation and maintenance are presented.


Clinical manifestations, clinical course, and outcomes of immunoglobulin G4-related disease.
Immunoglobulin G4-related disease (IgG4-RD) is an uncommon chronic systemic autoimmune disease, pathologically characterized by lymphoplasma cell and IgG4 plasma cell infiltration with storiform fibrosis. IgG4-RD is a new disease and is not yet widely recognized. The aim of this study was to describe the clinical manifestations and outcomes in Thai patients with IgG4-RD. This multicenter retrospective cohort study included patients aged ≥ 18 years who were diagnosed with IgG4-RD, according to the 2011 comprehensive or consensus diagnostic criteria, between 2000 and 2019 in four academic centers in Thailand. Baseline characteristics, laboratory and pathologic findings, treatments, and outcomes were systematically reviewed. The study included 110 patients (71% male) with a mean age (SD) of 59.6 (13.3) years and median disease duration (interquartile range [IQR]) of 28.8 (14.6-53.5) months. Single organ involvement was observed in 60 patients (54.5%). Most patients (96%) had an IgG4 level of more than 135 mg/dL at presentation. Also, most (92%) were treated with corticosteroid (CS) alone or in combination with immunosuppressive agents. The most commonly used immunosuppressive agents were azathioprine (47%) and methotrexate (11%). Additionally, 20% required surgery, and 6.4% underwent stent insertion. One-quarter (26%), 37%, and 29% were in remission with successfully tapering CS, complete and partial response. Nevertheless, 22% relapsed, with a median time to relapse (IQR) of 22.2 (12.8-41.1) months. IgG4-RD is a chronic systemic autoimmune disease with diverse manifestations, response to treatment, and outcomes. Most patients responded well to treatments but with a notable relapse rate.


Contact with gays and lesbians and same-sex marriage support: The moderating role of social context.
Empirical research on the contact hypothesis has paid inadequate attention to the broader social and normative context in which contact occurs. Using data from the nationally representative Portraits of American Life Study, I test whether individuals' core networks moderate the effect of personal contact with gays and lesbians on same-sex marriage attitudes. OLS regression results demonstrate that, though contact is strongly associated with greater support for same-sex marriage, the effect is attenuated for individuals with a higher proportion of religious conservatives in their core network. This moderating effect holds even after controlling for respondents' religiosity and when the sample is limited to self-identified religious liberals and moderates. Future research on intergroup contact should be attentive to other influences within individuals' social contexts and examine how the outcomes of contact across a variety of social boundaries are moderated by these social influences.


On the feasibility of intraoral maxillo-malar osteotomy.
The maxillo-malar osteotomy is one of the osteotomies developed over the years to correct the deformities of the midface without modifying the nasal projection. After having for many years approached the osteotomy through the classic double access, intraoral and subciliary, we verified the feasibility of this osteotomy via an intraoral route only. For this purpose we modified slightly the classic osteotomy lines, however still including in the mobilized fragment the most prominent and therefore the most aesthetically important portion of the zygoma. At the lower orbital rim the medial osteotomy cut is performed with a fissure bur, the lateral one with an oscillating saw. Both the osteotomies are extended posteriorly in the orbital floor with a fine osteotome. Then, after having performed all other osteotomy cuts, the maxillo-malar complex is down-fractured. The residual thin bone structures which connect the maxillo-malar complex to the cranio-facial skeleton are broken during a careful downfracture, avoiding fracture between the maxilla and zygoma. The complex is advanced and stabilized with intermaxillary fixation, osteosynthesis and bone grafts. A bone graft to the orbital floor is unnecessary.


Intraoperative spinal digital subtraction angiography: indications, technique, safety, and clinical impact.
Cerebral intraoperative DSA (IODSA) is a well-described, routinely performed procedure that allows the effectiveness of cerebrovascular interventions to be evaluated in the operating room. Spinal IODSA, on the other hand, is infrequently obtained and has received less attention. To discuss the indications, technique, safety, and clinical impact of spinal IODSA. Twenty-three patients underwent 45 thoracic and/or lumbar spinal IODSA between 2005 and 2016, either immediately before surgery for lesion localization or after the intervention to evaluate its effectiveness. Indications included 21 vascular malformations and 2 diaphragmatic crus compression syndromes. A long femoral arterial sheath with its hub positioned on the lateral surface of the thigh was used to allow catheter manipulations in the prone position. All targeted intersegmental arteries (ISAs) were successfully catheterized. The course of surgery was changed in 6 instances (26.1%). In 4 cases of epidural or perimedullary arteriovenous fistulae (AVFs), a residual lesion required additional intervention. In one case of epidural AVF, initial IODSA revealed spontaneous resolution of the lesion, preventing unnecessary surgery. Finally, angiography performed in a case of diaphragmatic crus syndrome showed thrombosis of the ISA and non-visualization of the artery of Adamkiewicz. Recanalization was obtained by IA thrombolysis, with excellent clinical outcome. No intraprocedural or postprocedural complication was noted. Spinal IODSA is a safe technique that offers an immediate assessment of the effectiveness of a spinovascular surgical procedure, notably epidural and perimedullary AVFs. Spinal IODSA was technically successful in all cases, influencing the surgical strategy in 6 of 23 patients, including one patient who benefited from intraoperative endovascular therapy.


Comparison of charged cyclodextrin derivatives for the chiral separation of atropisomeric polychlorinated biphenyls by capillary electrophoresis.
Charged cyclodextrin (CD) derivatives were used as chiral selectors in electrokinetic chromatography (EKC) for the chiral separation of highly hydrophobic neutral racemates such as atropisomeric polychlorinated biphenyls (PCBs). beta-CD-phosphated, beta-CD sulfated, succinylated-gamma-CD (Succ-gamma-CD) and succinylated-beta-CD (Succ-beta-CD) were used as anionic CDs. As cationic CD, 6-monodeoxy-6-monoamino-beta-CD (beta-CD-NH(2)) was tested for the first time in order to separate PCBs. From the different CD derivatives employed, the best separations were obtained with the cationic CD derivative. Thus, the use of beta-CD-NH(2 )in phosphate buffer at pH 2.0 containing urea allowed the chiral recognition of eleven PCBs (45, 84, 88, 91, 95, 131, 136, 144, 149, 176, and 197). In this case, the addition of 2 M urea to the buffer solution was crucial to achieve the chiral separation of PCBs. The addition of acetonitrile to 10 mM phosphate buffer (pH 2.0) with 30 mM beta-CD-NH(2) and 2 M urea improved considerably the chiral resolution obtained for PCBs 91, 95, 136, 144, 149, and 197 although an increase in the analysis time was also observed. All the results obtained were compared with those previously obtained with the dual CD system carboxymethyl-gamma-CD/beta-CD.


A Revision Mandibuloplasty: Causes, Indications, Surgical Methods and Treatment Outcomes.
This paper aims to propose a classification system to categorize patients undergoing revision mandibuloplasty according to their dissatisfaction types. This paper also introduces various appropriate revision techniques and evaluates their outcomes. Through this classification system and suggested surgical techniques, surgeons can settle the disappointments experienced by patients after their primary mandibuloplasty, by realizing more natural-looking results. The study subjects consisted of 184 patients who underwent a revision mandibuloplasty from October 2010 to March 2016, conducted by a single surgeon at a single institution. The authors were able to classify the dissatisfaction into two primary types-(1) lack of an overall slender frontal facial contour and (2) unnatural and asymmetrical overall facial appearance due to over- or inaccurate resection of the bone. A self-evaluation of patient's subjective satisfaction based on the scale from 1 to 5, both after the primary operation and after revision surgery, was compared. Dissatisfaction type I accounted for 145 patients (78.8 percent). The number of patients classified into dissatisfaction type II was 39 (21.2 percent). Of the patients categorized into type I, those undergoing revision surgeries due to an under-corrected mandibular tubercle and parasymphysis showed the most remarkable improvement in self-satisfaction score after reoperation-from 2.3 to 4.0. To realize a natural-looking outcome in facial look through mandibular contouring, it is important not only to carefully consider the ratio and shape essential for an optimal slender facial contour, but also to minimize unnecessary resection of the bone. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


A breathing-retraining procedure in treatment of sleep-onset insomnia: theoretical basis and experimental findings.
Increase in CO2 has a sedative effect upon the central nervous system, and the beginning of sleep coincides with modifications in breathing, decrease in ventilation, and in pCO2 increase. In this paper is described a technique of breathing that is useful in producing drowsiness in a very short time. 46 insomniacs were randomly allocated to either a treatment or control condition. In the former, patients were trained in the breathing process. The control group was taught no breathing process. Latencies to sleep for the insomniacs confirmed that the breathing process was useful in producing drowsiness. Theoretical bases are discussed.


Structural and biological function of NYD-SP15 as a new member of cytidine deaminases.
Recent studies were mainly focus on the cytidine deaminase family genes, which contained a lot of members that varied on the function of catalytic deamination in RNA or DNA and were involved in the process of growth maintenance, host immunity, retroviral infection, tumorigenesis, and drug resistance with a feature of C-U deamination. In this study, we identified a new member of cytidine deaminase family, NYD-SP15. Previous work showed that the deduced structure of the protein contained two dCMP_cyt_deam domains, which were involved in zinc ion binding. NYD-SP15 was expressed variably in a wide range of tissues, indicating its worthy biological function and creative significances. Sequence analysis, RT-PCR, western blot, flow cytometry, direct-site mutation and GST pull-down assay were performed to analyze the construction and function of NYD-SP15. The results in our studies showed that NYD-SP15 was closely related to deoxycytidylate deaminase and cytidine deaminase, with authentic cytidine deaminase activity in vivo and vitro as well as homo dimerization effects. NYD-SP15 contained nuclear localization sequence (NLS) and nuclear export-signal (NES) and could dynamically shuttle between the nucleus and cytoplasm. Furthermore, NYD-SP15 gene over-expression reduced the cells growth and blocked G1 to S phase, which implied a potential inhibition effect on cell growth.


Location of [60]fullerene incorporation in lipid membranes.
We confirmed that most C(60) fullerene units are located in the hydrophobic core of the lipid bilayer membrane in water-soluble lipid membrane incorporated C(60) (LMIC(60)) complexes using differential scanning calorimetry (DSC) and (13)C NMR spectra in the presence of radical labels.


Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19?
Severe acute respiratory syndrome coronavirus 2 causes the potentially fatal coronavirus disease 2019 (COVID-19). Already during the outbreak of the severe acute respiratory syndrome coronavirus 1, the use of vitamin C was suggested. Many patients with severe COVID-19 have elevated levels of the mediators interleukin-6 and endothelin-1. These mediators may explain the age dependence of COVID-19 pneumonia, the preponderance of male and obese or hypertensive patients, as well as of persons of color and smokers. There is clear evidence that vitamin C in high doses can reduce these mediators. Vitamin C is cheap and safe. Hence, using a relatively low dose of vitamin C as prophylaxis, and in cases of severe COVID-19, an (intravenous) high-dose regimen may be beneficial. Ongoing clinical trials are expected to provide more definitive evidence.


MAGIC: once upon a time in consent management-a FHIR® tale.
The use of medical data for research purposes requires an informed consent of the patient that is compliant with the EU General Data Protection Regulation. In the context of multi-centre research initiatives and a multitude of clinical and epidemiological studies scalable and automatable measures for digital consent management are required. Modular form, structure, and contents render a patient's consent reusable for varying project settings in order to effectively manage and minimise organisational and technical efforts. Within the DFG-funded project "MAGIC" (Grant Number HO 1937/5-1) the digital consent management service tool gICS was enhanced to comply with the recommendations published in the TMF data protection guideline for medical research. In addition, a structured exchange format for modular consent templates considering established standards and formats in the area of digital informed consent management was designed. Using the new FHIR standard and the HAPI FHIR library, the first version for an exchange format and necessary import-/export-functionalities were successfully implemented. The proposed exchange format is a "work in progress". It represents a starting point for current discussions concerning digital consent management. It also attempts to improve interoperability between different approaches within the wider IHE-/HL7-/FHIR community. Independent of the exchange format, providing the possibility to export, modify and import templates for consents and withdrawals to be reused in similar clinical and epidemiological studies is an essential precondition for the sustainable operation of digital consent management.


Optimizing environmental DNA sampling effort for fish inventories in tropical streams and rivers.
Environmental DNA (eDNA) metabarcoding is a promising tool to estimate aquatic biodiversity. It is based on the capture of DNA from a water sample. The sampled water volume, a crucial aspect for efficient species detection, has been empirically variable (ranging from few centiliters to tens of liters). This results in a high variability of sampling effort across studies, making comparisons difficult and raising uncertainties about the completeness of eDNA inventories. Our aim was to determine the sampling effort (filtered water volume) needed to get optimal inventories of fish assemblages in species-rich tropical streams and rivers using eDNA. Ten DNA replicates were collected in six Guianese sites (3 streams and 3 rivers), resulting in sampling efforts ranging from 17 to 340 liters of water. We show that sampling 34 liters of water detected more than 64% of the expected fish fauna and permitted to distinguish the fauna between sites and between ecosystem types (stream versus rivers). Above 68 liters, the number of detected species per site increased slightly, with a detection rate higher than 71%. Increasing sampling effort up to 340 liters provided little additional information, testifying that filtering 34 to 68 liters is sufficient to inventory most of the fauna in highly diverse tropical aquatic ecosystems.


[Correction of idiopathic juvenile penis deviation with the modified Nesbit operation].
In seven men a congenital penile curvature was corrected using a modified Nesbit operation. All patients obtained an excellent correction of the deformity and satisfactory intercourse. In three cases a small area of hypesthetic skin was observed in the distal parts of the dorsum penis.


In vitro susceptibility of the yeast pathogen cryptococcus to fluconazole and other azoles varies with molecular genotype.
Cryptococcosis is primarily caused by Cryptococcus neoformans and Cryptococcus gattii. These two pathogenic species each divide into four distinct molecular genotypes. In this study, we examined whether genotype influenced susceptibility to antifungal drugs used to treat cryptococcosis using the broth microdilution method described by the Clinical and Laboratory Standards Institute. C. gattii isolates belonging to molecular genotype VGII had significantly higher MIC values for flucytosine and all azole antifungal agents tested, particularly fluconazole, than isolates of other C. gattii genotypes. In an extended analysis of fluconazole susceptibility, VGII isolates from the north and west of Australia required higher drug levels for inhibition than those from Vancouver Island, Canada. Within C. neoformans, genotype VNII had significantly lower geometric mean MICs for fluconazole than genotype VNI. These results indicate that cryptococcal species, molecular genotype, and region of origin may be important when deciding treatment options for cryptococcosis.


Combined effects of interleukin-1β and cyclic stretching on metalloproteinase expression in corneal fibroblasts in vitro.
Corneal tensile strain increases if the cornea becomes thin or if intraocular pressure increases. However, the effects of mechanical stress on extracellular matrix (ECM) remodelling in the corneal repair process and the corneal anomalies are unknown. In this study, the combined effects of interleukin-1β (IL-1β) on matrix metalloproteinases (MMPs) in corneal fibroblasts under cyclic stretching were investigated in vitro. Cultured rabbit corneal fibroblasts were subjected to 5, 10 or 15 % cyclic equibiaxial stretching at 0.1 Hz for 36 h in the presence of IL-1β. Conditioned medium was harvested for the analysis of MMP2 and MMP9 protein production using the gelatin zymography and western blot techniques. Cyclic equibiaxial stretching changed the cell morphology by increasing the contractility of F-actin fibres. IL-1β alone induced the expression of MMP9 and increased the production of MMP2, and 5 % stretching alone decreased the production of MMP2, which indicates that a low stretching magnitude can reduce ECM degradation. In the presence of IL-1β, 5 and 10 % stretching increased the production of MMP2, whereas 15 % stretching increased the production of MMP9. These results indicate that MMP expression is enhanced by cyclic mechanical stimulation in the presence of IL-1β, which is expected to contribute to corneal ECM degradation, leading to the development of post-refractive surgery keratectasia.


Ultrasound detection of submerged dental implants through soft tissue in a porcine model.
Current methods of measuring soft tissue thickness over potential dental implant sites and locating submerged implants may be imprecise or invasive. The purpose of this study was to develop and demonstrate proof of the concept of a customized ultrasound imaging system in locating and measuring the depth of implants submerged beneath soft tissue. A complete ultrasound system, including a customized soft tissue-matched transducer, transceiver, and digital signal processing algorithms, was created for the specific application of detecting dental implants anchored in bone beneath soft tissue. The system was used to locate implants placed in cancellous bone and measure overlying soft tissue depth in a porcine model. Ten measurements were made on each porcine model by manually moving the transducer laterally over the soft tissue surface. Data were analyzed with descriptive statistics. The mean signal-to-noise ratio, SNR (standard deviation), from the bone surfaces, was 19.1 (4.6) dB, and the mean SNR from the implant surfaces was 36.6 (2.2) dB, resulting in a mean difference of 17.5 dB, or x56.2, in average signal power between the bone and implant surfaces. Consequently, implants were easily and accurately (+/-0.2 mm) located beneath at least 5 mm of soft tissue. Likewise, soft tissue depths over bone and implants were accurately measured and were within the corresponding caliper tissue measurement error (+/-0.5 mm). The specialized ultrasound imaging system located and measured the depth of implants placed in bone submerged beneath soft tissue in a porcine model.


Mass culling of minks to protect the COVID-19 vaccines: is it rational?
The Danish Government announced the culling of 17 million minks in rearing after the report of mink-specific mutations of severe acute respiratory syndrome coronavirus 2 in humans. The rationale behind this decision is that these mutations might negatively impact the deployment of anti-coronavirus disease 2019 vaccines. Is it a precautionary attitude or a panic-driven overreaction?


Mutational signatures and mutagenic impacts associated with betel quid chewing in oral squamous cell carcinoma.
Betel quid (BQ) chewing is a prevailing risk for oral squamous cell carcinoma (OSCC) in Southeast Asia. Yet, the detailed mechanisms by which BQ chewing damages the genome are still not fully understood. Through exome sequencing of tumor-normal pairs from 196 male patients with OSCC, including 95 habitual BQ chewers and 101 non-BQ users, we conducted a quantitative survey of mutational signatures and genomic aberrations and explored their association with BQ chewing. We found that BQ-associated elevation in mutation rate was seen in cancers of the tongue, but not in overall OSCC. Additionally, we identified a mutational signature that is enriched in tumors from BQ users. Moreover, the numbers of small insertions and deletions (INDELs) and breakpoints derived from structural variations (SV) were increased, whereas the extent of loss of heterozygosity was decreased in BQ-related OSCC genomes. However, neither the number of base substitutions and microsatellite instability events nor the extent of copy-number alterations differed between BQ-related and -unrelated OSCC. In conclusion, consistent with the proposition that BQ chewing increases OSCC risk as a mutagen, our results unveil a BQ-associated mutational signature and indicate mutagenic impacts of BQ chewing on preferentially eliciting INDELs and SV-related breakpoints in OSCC genomes.