Socioeconomic factors and colorectal cancer incidence, stage and quality of care in Denmark during the COVID-19 pandemic.
Efforts to control the COVID-19 pandemic might reduce accessibility for diagnostics and treatment of colorectal cancer. A universal public healthcare system may modify the availability of healthcare services. The aim of this study was to investigate changes in the quality of care for patients with colorectal cancer during the COVID-19 pandemic. Nationwide data from the Danish Colorectal Cancer database and Statistics Denmark on the number of new diagnoses, disease and health behaviour measures, socioeconomic measures, clinical quality measures and time to adjuvant chemotherapy were retrieved. Measures during the COVID-19 pandemic in 2020 and the different pandemic periods were compared to the pre-pandemic period. In 2020, 4035 patients were diagnosed with colorectal cancer, compared with 4346 in 2019 and 4496 in 2018. During the pandemic, patients were more likely to have UICC stage I disease (25.0% vs 23.4%; PR=1.07(95% confidence interval: 1.00;1.15)), belonging to the highest income quintile (PR=1.06(0.98;1.14), receive surgery with a curative aim (PR=1.02(1.01;1.03)), and to be operated on by a specialist (PR=1.07(1.06;1.08)), and less likely to be 60-69 years of age (PR=0.93(0.86;1.00)), non-western immigrants (PR=0.93(0.86;1.00)), diagnosed by screening (PR=0.79(0.73;0.86)) and receiving an acute operation (PR=0.77(0.66;0.91)). Furthermore, during the pandemic, 11.4% fewer patients waited 28 days or longer for initiation of adjuvant oncological treatment. Based on nationwide data, we observed no major adverse effect on disease measures or clinical quality in a tax funded health care system. However, small changes in the socioeconomic composition of the patient population were observed.


Groundwater arsenic contamination throughout China.
Arsenic-contaminated groundwater used for drinking in China is a health threat that was first recognized in the 1960s. However, because of the sheer size of the country, millions of groundwater wells remain to be tested in order to determine the magnitude of the problem. We developed a statistical risk model that classifies safe and unsafe areas with respect to geogenic arsenic contamination in China, using the threshold of 10 micrograms per liter, the World Health Organization guideline and current Chinese standard for drinking water. We estimate that 19.6 million people are at risk of being affected by the consumption of arsenic-contaminated groundwater. Although the results must be confirmed with additional field measurements, our risk model identifies numerous arsenic-affected areas and highlights the potential magnitude of this health threat in China.


Effects of cocaine and fenfluramine on progressive-ratio performance.
Pigeons obtained food on a progressive-ratio schedule that required 8 additional responses for each successive reinforcement. The number of responses in the final completed ratio of the session was defined as the breaking point. When cocaine was administered (IM, 5 min presession), the breaking point increased and then decreased as a function of increasing doses (0.3-10 mg/kg). In contrast, across the same range of doses of fenfluramine, the breaking point only decreased. At doses of each drug that decreased the breaking point, the high running rate of responding was interrupted by pauses. At doses of cocaine that increased the breaking point, the running rate was also disrupted, but the disruption was characterized by lower, irregular rates rather than pausing. The increases in breaking point observed at 3 mg/kg of cocaine were no longer seen when fenfluramine was administered at the same time.


Reactogenicity and immunogenicity of combined vaccines for bacteraemic diseases caused by Haemophilus influenzae type b, meningococci and pneumococci in 24-month-old children.
To find a wide spectrum vaccine against bacteraemic disease in childhood, we immunized 293 Finnish children at 24 months of age intramuscularly with different combinations of the currently available vaccines, namely Haemophilus influenzae type b polysaccharide-protein conjugate vaccine (PRP-D) mixed with meningococcal and/or pneumococcal capsular polysaccharide vaccines. All the vaccines were immunogenic. The increase in antibody concentration after vaccinations was not affected by the number of polysaccharide antigens. Although no serious reactions were seen, the frequency of both local and fever reactions was greater in groups that received several vaccine antigens. Halving of the vaccine dose decreased the reactogenicity without impairing the immunogenicity.


Ischemic stroke associated with methamphetamine inhalation.
Intracranial hemorrhage and ischemic stroke have been reported to complicate oral or intravenous use of methamphetamine. We report three cases of ischemic stroke following methamphetamine inhalation.


Interferon beta modulates major histocompatibility complex class I (MHC I) and CD3-zeta expression in PC12 cells.
It has been demonstrated that the major histocompatibility complex of class I (MHC I) up regulation by exogenous treatment with interferon beta (IFNbeta) influences the glial reaction and synaptic elimination process. Therefore, the present study aimed to investigate the effects of IFNbeta treatment on the expression of MHC I, CD3-zeta (a subunit of MHC I receptor) and synaptic formation in PC12 cells, an in vitro model for studying the synaptic formation/elimination process. For this purpose, established cultures were subjected to IFNbeta (500 and 1000IU/ml) treatment for 5, 10 and 15 days. The cells were then fixed and processed for immunocytochemistry with antisera against MHC I (OX18), CD3-zeta and synaptophysin. The results were compared with control cultures only treated with basal medium. IFNbeta (500IU/ml) modulated the MHC I expression in PC12 cells, especially after 10 days of treatment. In this sense, IFNbeta induced MHC I as well as CD3-zeta up regulation. It was observed that the highest dose caused culture degeneration. Interestingly, differential regulation of MHC I was paralleled by enhancement in synaptic network remodeling. Altogether, the present data indicate that PC12 cells may be used as an in vitro model for studying MHC I modulation and synaptic plasticity. It also reinforced the role of IFNbeta on the synaptic elimination process.


Increased adipose angiotensinogen gene expression in human obesity.
Adipose angiotensinogen has been suggested as a stimulator of adipose tissue growth and development. Therefore, the association of subcutaneous adipose angiotensinogen gene expression with human obesity was studied. The study group consisted of 17 men, undergoing either gastric banding for obesity or elective laparoscopic cholecystectomy (7 obese, 10 non-obese men; body mass index 22 to 51 kg/m2; age 26 to 68 years). Subcutaneous adipose angiotensinogen mRNA and 18S ribosomal RNA (reference gene) levels were measured using competitive quantitative reverse transcriptase-polymerase chain reaction. Adipose angiotensinogen mRNA expression was about two times increased in obesity. The levels of 18S rRNA did not differ between the two groups. Body weight correlated independently and positively with adipose angiotensinogen mRNA expression after adjusting for differences in age and height. Adipose angiotensinogen gene expression is elevated in obesity in men.


The MALAT1-H19/miR-19b-3p axis can be a fingerprint for diabetic neuropathy.
Diabetic neuropathy (DN) is one of the most common microvascular complications of diabetes that is attributed to impaired immune regulation. In this study, we first examined the expression of long non-coding (lncRNAs) MALAT1 and H19, and their downstream microRNAs (miRNAs) miR-19b-3p, miR-125a-5p, and then assayed the mRNA expression of downstream targets of these miRNAs, including SEMA4C, SEMA4D, PLXNB2, ATG14, and ATG16L1. Peripheral blood samples were obtained from 20 DN patients, 20 diabetic patients without neuropathy (non-DN), and 10 healthy controls (HC). The expression levels of lncRNAs, miRNAs, and target genes were evaluated in whole blood using Real-time PCR. Upregulation of MALAT1, H19, SEMA4C, PLXNB2, and ATG16L1 and downregulation of miR-19b-3p was seen in the DN group compared to the non-DN and HC groups. Non-DN patients had significantly lower expression levels of miR-125a-5p, SEMA4D, ATG14, and ATG16L1 compared to the HC. MALAT1 and H19 had a positive correlation with each other and had a negative correlation with the expression of miR-19b-3p. Expression levels of SEMA4C, SEMA4D, PLXNB2, and ATG16L1 were positively correlated with each other as well as lncRNAs expression. Receiver operating characteristic (ROC) analysis showed Area under the curve (AUC) = 0.9226 for MALAT1, AUC= 0.9248 for H19, and AUC= 0.7683 for miR-19b-3p. The MALAT1-H19/miR-19b-3p axis might be involved in the development of DN and these molecules could be useful biomarkers for DN. Dysregulated expression of SEMA4C, PLXNB2, and ATG16L1, targeted by miR-19b-3p and miR-125a-5p, showed that they probably play a role in the DN development.


No Immunological Interference or Safety Concerns When Adjuvanted Recombinant Zoster Vaccine Is Coadministered With a Coronavirus Disease 2019 mRNA-1273 Booster Vaccine in Adults Aged 50 Years and Older: A Randomized Trial.
There is growing consensus that coronavirus disease 2019 booster vaccines may be coadministered with other age-appropriate vaccines. Adding to the limited available data supporting coadministration, especially with adjuvanted vaccines, could enhance vaccine coverage in adults. In this phase 3, randomized, open-label study, eligible adults aged ≥50 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and a first dose of recombinant zoster vaccine (RZV1) 2 weeks apart (Seq group) or concomitantly (Coad group). The second RZV dose (RZV2) was administered 2 months post-RZV1 in both groups. Primary objectives were noninferiority of anti-glycoprotein E (gE) and anti-spike protein antibody responses in the Coad group compared to the Seq group. Safety and further immunogenicity assessments were secondary objectives. In total, 273 participants were randomized to the Seq group and 272 to the Coad group. Protocol-specified noninferiority criteria were met. The adjusted geometric mean concentration ratio (Seq/Coad) was 1.01 (95% confidence interval [CI], .89-1.13) for anti-gE antibodies 1 month post-RZV2, and 1.09 (95% CI, .90-1.32) for anti-spike antibodies 1 month post-mRNA-1273 booster. No clinically relevant differences were observed in overall frequency, intensity, or duration of adverse events between the 2 study groups. Most solicited adverse events were mild/moderate in intensity, each with median duration ≤2.5 days. Administration site pain and myalgia were the most frequently reported in both groups. Coadministration of mRNA-1273 booster vaccine with RZV in adults aged ≥50 years was immunologically noninferior to sequential administration and had a safety and reactogenicity profile consistent with both vaccines administered sequentially. Clinical Trials Registration. NCT05047770.


Entorhinal-hippocampal connections: a speculative view of their function.
On the basis of neuroanatomical studies, the entorhinal cortex (EC) has long been regarded as a relay station that provides the major source of afferent input to the hippocampus. The perforant path input to the dentate gyrus from layer II has traditionally been regarded as the major pathway by which information is transferred. However, electrophysiological studies are now indicating that other elements of the perforant path that project directly to CA1 and CA3 are more important than thought previously, and that the properties of different neuronal elements in the EC may determine the way in which information is passed on to and processed by the hippocampus. This article summarizes some of the properties of synaptic transmission in the EC and speculates on how frequency-dependent changes in transmission may be involved in the pre- and post-processing of hippocampal information by the EC.


Characteristics of Low Back Pain in Pregnancy, Risk Factors, and Its Effects on Quality of Life.
Low back pain is a common problem experienced during pregnancy, negatively affecting quality of life. The study aimed to determine the prevalence and risk factors of low back pain during pregnancy and its effects on the quality of life. This was a descriptive and cross-sectional study. Its setting was the Kastamonu State Hospital Obstetrics and Gynecology clinics. The study consisted of 400 pregnant women. The sample consisted of 400 pregnant women. Data were collected using an introductory information form, a back pain evaluation form, the Visual Analog Scale (VAS), and the Oswestry Disability Index (ODI). In terms of back pain, 75.3% of the participants experienced back pain during their current pregnancy. The mean VAS score for back pain during their current pregnancy was 4.91±1.88. Low back pain was generally experienced in the third trimester (85.5%) and in the lumbar area (45.5%). Factors associated with low back pain included income status, trimester, gestational weight gain, frequent urinary tract infections, a hunchback posture, having experienced low back pain during previous pregnancies, and a history of low back pain. The mean percentage score on the ODI, which assesses the effect of low back pain on functional status, was 31.87% ± 15.56%, and for the majority of the participants (45.7%), low back pain was found to slightly limit their activities of daily living. The prevalence of low back pain in pregnancy is quite high, and low back pain slightly limits women's activities of daily living.


Analysis and clinical implications of K-ras gene mutations and infection with human papillomavirus types 16 and 18 in primary adenocarcinoma of the uterine cervix.
Experimental models indicate that activated ras genes and HPV oncogenic sequences may cooperate in inducing a completely transformed phenotype in epithelial cells. We searched for K-ras gene mutations and HPV type-16 and -18 sequences in 67 primary adenocarcinomas of the uterine cervix by analyzing DNAs from formalin-fixed, paraffin-embedded tissue samples. Target sequences were amplified by PCR and analyzed by denaturing gradient gel electrophoresis (DGGE) and sequencing for the detection of K-ras gene mutations and by Southern blotting for the detection of HPV infection. We found 16 mutations in 15 cases; 14 were at codon 12 and 2 at codon 13; 11 were base transitions and 5 were transversions. Mutations were more frequent in mucin-secreting than in non-mucinous tumors. HPV oncogenic sequences were detected in 58 cases with no significant difference between K-ras-mutated and wild-type tumors. HPV oncogenic sequences were also more frequent in mucin-secreting than in non-mucinous tumors. Both molecular events were present simultaneously in 13 out of 58 cases, all of which had histologically grade-2 and grade-3 tumors. Clinico-pathological parameters of the disease and the overall survival, however, were independent of K-ras mutations and of HPV-16 and -18 infection, as shown by univariate and multivariate analysis. In contrast, stage of disease, lymph-node metastases, deep infiltration, clear-cell histology and low grade of differentiation were risk factors for tumor-related death.


Vector Doppler imaging of a spinning disc ultrasound Doppler phantom.
Vector Doppler methods are used to obtain angle independent in-plane velocity information. Velocity magnitude as well as direction are reconstructed from regular steered colour flow and from split-aperture Doppler acquisitions. Spatially resolved in-plane velocity was obtained through Doppler colour flow mode and subsequent data triangulation. A depth-invariant constant Doppler angle was achieved by using a depth expanding transmit-receive Doppler aperture. Velocities of up to 50 cm s(-1) and 360 degrees vector velocity directions were measured. This was achieved by creating a spinning solid disc phantom. Such a phantom was built to allow underwater mounting and spinning of a solid disc-shaped ultrasound phantom (maximum velocity of 50 cm s-1). Doppler triangulation was realised by steered Doppler and by a split-aperture approach. Results of both imaging methods are shown. Split-aperture results showed errors of less then 10% for velocity magnitude estimation and less then 2.5 degrees for directional information.


A two-sample Mendelian randomization study of circulating lipids and deep venous thrombosis.
In view of the current debate about the relationship between lipids and deep venous thrombosis (DVT) in clinical studies, a two-sample Mendelian randomization (MR) study was conducted to clarify the effects of five circulating lipids (apolipoprotein A1, apolipoprotein B, low-density lipoprotein, high-density lipoprotein and triglycerides) on DVT from the perspective of genetic inheritance. Five lipids (exposure) were analysed by MR with DVT (outcome) from two different data sources. For the analysis, we used inverse variance weighting and a weighted mode, weighted median, simple mode and MR-Egger regression to analyse the effect of circulating lipids on DVT. In addition, we used the MR-Egger intercept test, Cochran's Q test and "leave-one-out" sensitivity analysis to evaluate horizontal multiplicity, heterogeneity and stability, respectively, in the analysis. In the analysis, the two-sample Mendelian randomization analysis of five common circulating lipids and DVT showed that common circulating lipids had no causal effect on DVT, which is somewhat inconsistent with the findings of many published observational studies. Based on our results, our two-sample MR analysis failed to detect a statistically significant causal relationship between five common circulating lipids and DVT.


Prophylactic treatment of cluster headache with verapamil.
An open study of verapamil in cluster headache is reported. Forty-eight patients participated in the study of whom 33 (= 69%) improved more than 75%. No significant differences in response were observed between episodic and chronic cluster headache.


Tailored extraction and ion mobility-mass spectrometry enables isotopologue analysis of tetrahydrofolate vitamers.
Climate change directs the focus in biotechnology increasingly on one-carbon metabolism for fixation of CO2 and CO2-derived chemicals (e.g. methanol, formate) to reduce our reliance on both fossil and food-competing carbon sources. The tetrahydrofolate pathway is involved in several one-carbon fixation pathways. To study such pathways, stable isotope-labelled tracer analysis performed with mass spectrometry is state of the art. However, no such method is currently available for tetrahydrofolate vitamers. In the present work, we established a fit-for-purpose extraction method for the methylotrophic yeast Komagataella phaffii that allows access to intracellular methyl- and methenyl-tetrahydrofolate (THF) with demonstrated stability over several hours. To determine isotopologue distributions of methyl-THF, LC-QTOFMS provides a selective fragment ion with suitable intensity of at least two isotopologues in all samples, but not for methenyl-THF. However, the addition of ion mobility separation provided a critical selectivity improvement allowing accurate isotopologue distribution analysis of methenyl-THF with LC-IM-TOFMS. Application of these new methods for 13C-tracer experiments revealed a decrease from 83 ± 4 to 64 ± 5% in the M + 0 carbon isotopologue fraction in methyl-THF after 1 h of labelling with formate, and to 54 ± 5% with methanol. The M + 0 carbon isotopologue fraction of methenyl-THF was reduced from 83 ± 2 to 78 ± 1% over the same time when using 13C-methanol labelling. The labelling results of multiple strains evidenced the involvement of the THF pathway in the oxygen-tolerant reductive glycine pathway, the presence of the in vivo reduction of formate to formaldehyde, and the activity of the spontaneous condensation reaction of formaldehyde with THF in K. phaffii.


Reproductive parameters of wild female Rhinopithecus roxellana.
On the basis on 6 years of observation, we estimated the reproductive parameters of a Golden snub-nosed monkey (Rhinopithecus roxellana) group in the Qinling Mountains, China. We observed 88 births in 47 females from 2001 to 2006. Two methods were used to calculate the birthrate. The first method is based on the number of births observed in a year, giving 0.49+/-0.07 (mean+/-SD), and the second method is based on the female-years of observation, giving 0.49+/-0.17 births per female per year in this troop. The mean interbirth interval is 21.88+/-6.01 months (mean+/-SD). The mortality of infant born between 2002 and 2005 was 22.4%. The interbirth intervals of females that had lost an infant before the age of 6 months were significantly shorter than that of females whose infants survived for more than 6 months. A female usually gives birth once every 2 years if the previous offspring survives to a weaning age of 5-6 months, or will give birth in the next year if the previous young dies before reaching an age of 6 months. Births were significantly concentrated during March to May of each year. The mean birth date was on April 14, median was April 12; and the standard deviation was 13.98 days. Birth peak occurs 6-7 months after mating peak. From observations on 15 individuals that gave birth for the first time, we concluded that the wild female Golden snub-nosed monkeys in Qinling Mountains start giving birth at an age of 5 or 6 years. We suggest that the seasonal reproductive pattern is an adaptive response to the availability of seasonal food. Our results are consistent with the hypothesis that these reproductive characteristics are a result of adaptation to the seasonality of mountain climate and food resources.


How clinical rationing works in practice: A case study of morbid obesity surgery.
Difficulties in setting healthcare priorities are encountered throughout the world. There is no agreement on the most appropriate principles or methods for healthcare rationing although there is some consensus that it should be undertaken as systematically and accountably as possible. Although some steps towards achieving accountability have been made at the macro and meso level, at the consultation level rationing remains implicit and poorly understood. Using morbid obesity surgery as a case study, we observed a series of UK National Health Service consultations where rationing was ongoing and conducted in-depth interviews with doctors and patients (2011-2014). A longitudinal approach was taken to research and in total 22 consultations were observed and 78 interviews were undertaken. Sampling was undertaken purposively and theoretically and analyses were undertaken thematically. Clinicians needed to prioritise 55 patients from 450 eligible referrals, but disagreed over the extent to which clinical and financial factors were the driving force behind decision-making. The most prominent rationing technique observed in consultations was rationing by selection, but examples of rationing by delay, by deterrence, and by deflection were also commonplace. Although all clinicians sought to avoid rationing by denial, only six of the 22 patients recruited to the research were known to have been treated at the end of the three-year period. Most clinicians sought to manage rationing implicitly, and only one explained the link between decision-making criteria and financial constraints on care availability. Although existing frameworks for categorising NHS rationing techniques were useful in identifying implicit strategies, in practice these techniques over-lapped substantially and we have proposed a simpler framework for analysing NHS rationing decisions at the consultation level, which includes just three categories - rationing by exclusion, rationing by deterrence, and rationing by delay.


New strategies for inhibition of non-adrenergic prostate smooth muscle contraction by pharmacologic intervention.
Inhibition of prostate smooth muscle contraction by α1 -adrenoceptor antagonists (α1 -blockers) is a first-line medical treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Increased smooth muscle tone in the hyperplastic prostate may drive urethral obstruction, resulting in bladder outlet obstruction and voiding symptoms. However, efficacy of α1 -blockers is limited, as non-adrenergic mediators including endothelin-1 and thromboxane A2 (TXA2 ) increase prostate smooth muscle tension in parallel to α1 -adrenoceptors. This may maintain urethral obstruction despite therapy with α1 -blockers. Consequently, future treatment options with higher efficacy need to target α1 -adrenergic and non-adrenergic contractions simultaneouly. Recently, several compounds were reported to inhibit adrenergic or neurogenic prostate contractions, however, their effects on non-adrenergic contraction are unknown. Here, we examined effects of inhibitors for Rac-GTPase, Src family kinases (SFKs), and p21-activated kinases (PAKs) on non-adrenergic prostate contractions. Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath. Viability of cultured stromal cells was assessed by CCK-8 assay. Inhibition of α1 -adrenergic contractions by Rac inhibitors EHT1864 (100 μM) and NSC23766 (100 μM), and SFK inhibitors AZM475721 (10 μM) and PP2 (10 μM) was confirmed by inhibition of methoxamine-induced contractions. No effects of the PAK inhibitors FRAX486 (30 μM) and IPA3 (300 μM) on α1 -adrenergic contraction were confirmed by absent effects on methoxamine-inuced contractions. EHT1864 caused inhibition of endothelin-1- and U46619-induced contractions. EHT1864 reduced the viability of stromal cells concentration- and time-dependently. EHT1864 attenuated KCl-induced contractions of prostate strips only slightly, so that toxic effects may not account alone for inhibition of agonist-induced contractions. NSC23766 inhibited U46619-induced contractions, but not endothelin-1-induced contractions. AZM475271 had no effects on endothelin-1- or U46619-induced contractions, while PP2 inhibited U46619- but not endothelin-1-induced contractions. FRAX486 caused inhibition of U46619-induced contractions. IPA3 inhibited U46619-, but not endothelin-1-induced contractions. Of all six inhibitors, EHT1864 seems to be most promising from a translational point of view, as it inhibited TXA2 - and endothelin-1-induced besides α1 -adrenergic prostate contractions. This reflects divergent pharmacologic profiles of EHT1864 and NSC23766, although both are Rac-GTPase inhibitors. In vivo, urodynamic effects of EHT1864 and possibly of FRAX486 may exceed those of α1 -blockers.


How the stigma of low literacy can impair patient-professional spoken interactions and affect health: insights from a qualitative investigation.
Low literacy is a significant problem across the developed world. A considerable body of research has reported associations between low literacy and less appropriate access to healthcare services, lower likelihood of self-managing health conditions well, and poorer health outcomes. There is a need to explore the previously neglected perspectives of people with low literacy to help explain how low literacy can lead to poor health, and to consider how to improve the ability of health services to meet their needs. Two stage qualitative study. In-depth individual interviews followed by focus groups to confirm analysis and develop suggestions for service improvements. A purposive sample of 29 adults with English as their first language who had sought help with literacy was recruited from an Adult Learning Centre in the UK. Over and above the well-documented difficulties that people with low literacy can have with the written information and complex explanations and instructions they encounter as they use health services, the stigma of low literacy had significant negative implications for participants' spoken interactions with healthcare professionals.Participants described various difficulties in consultations, some of which had impacted negatively on their broader healthcare experiences and abilities to self-manage health conditions. Some communication difficulties were apparently perpetuated or exacerbated because participants limited their conversational engagement and used a variety of strategies to cover up their low literacy that could send misleading signals to health professionals. Participants' biographical narratives revealed that the ways in which they managed their low literacy in healthcare settings, as in other social contexts, stemmed from highly negative experiences with literacy-related stigma, usually from their schooldays onwards. They also suggest that literacy-related stigma can significantly undermine mental wellbeing by prompting self-exclusion from social participation and generating a persistent anxiety about revealing literacy difficulties. Low-literacy-related stigma can seriously impair people's spoken interactions with health professionals and their potential to benefit from health services. As policies increasingly emphasise the need for patients' participation, services need to simplify the literacy requirements of service use and health professionals need to offer non-judgemental (universal) literacy-sensitive support to promote positive healthcare experiences and outcomes.


In vivo activity of tyrosine hydroxylase in rat adrenal glands following administration of quinpirole and dopamine.
Using adrenal dopamine as indicator we have previously obtained evidence that quinpirole and several other agonists on dopamine D2-like receptors acutely stimulate the synthesis of adrenal catecholamines. In the present study we measured the effect of quinpirole and dopamine on the hydroxylation of tyrosine in the adrenals, using the method of DOPA (3,4-dihydroxyphenylalanine) accumulation following the administration of the inhibitor of aromatic L-amino acid decarboxylase NSD 1015 (3-hydroxybenzylhydrazyne). In view of the large amounts of catecholamines in the adrenal tissue samples, this necessitated a modification of the method for analysing DOPA. Both quinpirole and dopamine significantly enhanced the rate of DOPA accumulation in the adrenals, indicating stimulation of adrenal tyrosine hydroxylase. The effect of dopamine was blocked by domperidone, a dopamine D2 receptor antagonist that penetrates poorly into the central nervous system. Thus the effect of dopamine, which itself penetrates poorly into the central nervous system, was presumably mediated peripherally. Similarly epinine, i.e. the N-methyl derivative of dopamine, appeared to enhance adrenal catecholamine synthesis, as indicated by an elevated adrenal dopamine level. The data support the view that stimulation of peripherally located dopamine D2-like receptors can enhance the rate of adrenal catecholamine synthesis by stimulating the activity of tyrosine hydroxylase.


Protein folding and unfolding by all-atom molecular dynamics simulations.
Computational protein folding can be classified into pathway and sampling approaches. Here, we use the AMBER simulation package as an example to illustrate the protocols for all-atom molecular simulations of protein folding, including system setup, simulation, and analysis. We introduced two traditional pathway approaches: ab inito folding and high-temperature unfolding. The popular replica exchange method was chosen to represent sampling approaches. Our emphasis is placed on the analysis of the simulation trajectories, and some in-depth discussions are provided for commonly encountered problems.


Incidence of alcohol dependence among drunken drivers.
To discriminate 'alcoholics' and 'non-alcoholics', individual Alc-Indices (determined by methanol, acetone, 2-propanol, gamma-GT and CDT-concentrations) were calculated in a collective of 327 alcohol-impaired drivers with regard to the blood alcohol concentration, the time of the event and the age of the drivers. Applying this new defined Alc-Index, 48% of the drivers investigated could be characterised as alcohol dependent. The prevalence of alcoholics among individuals with blood alcohol concentrations (BAC) higher than 1.9per thousand was more than 80%. The diagnostic value of alcohol concentrations for the recognition of 'alcoholics', considering the legal limit in Germany (1.1per thousand) as well as statistically calculated limits, were compared to the Alc-Index.


Monoclonal suppressor T-cell factor displaying V H restriction and fine antigenic specificity.
The production of stable T-cell clones is essential for the study of T-cell-derived, specific immunoregulatory products and of specific T-cell receptors. T-cell clones have been established by radiation leukaemia virus (RadLV)-induced transformation of suppressor T lymphocytes specific for hen egg white lysozyme (HEL). We report here that culture supernatant obtained from these T-cell clones can, when injected into mice, specifically suppress the anti-HEL antibody response. This monoclonal T-cell product suppresses the antibody response induced by HEL and human lysozyme, but not that induced by ring-necked pheasant egg white lysozyme (REL), thus displaying fine antigenic specificity probably restricted to an epitope involving phenylalanine at amino acid residue 3, present in the N-terminal region of HEL and shared by human lysozyme but absent in REL. The suppression induced by this monoclonal T-cell product is restricted by both H-2 and Igh-1 genes whereas anti-HEL antibodies bearing a predominant idiotype are induced in all mice strains tested, irrespective of their H-2 haplotype or Igh-1 allotype.


Leukoencephalopathy and akinetic mutism in a married couple: a probable association with oriental medicine.
Oriental medicines have been associated with severe psychiatric, neurological, and other adverse medical events. These medicines occasionally cause a typical reversible toxic encephalopathy, but most such cases are not recognized because these adverse events are complex and are associated with other systemic signs and symptoms. We describe a married couple with rapid progressive cognitive impairment and akinetic mutism after taking the same oriental medicines on the same day. Brain magnetic resonance images of the couple showed typical leukoencephalopathy in the periventricular white matter and basal ganglia regions, bilaterally. The development of neurobehavioral symptoms and toxic leukoencephalopathy in both patients following the ingestion of oriental medicines is suggestive of a cause-and-effect association, although such a relationship needs to be verified.


Plasma levels of granulocyte elastase during hemodialysis: effects of different dialyzer membranes.
Plasma levels of granulocyte elastase in complex with alpha 1-proteinase inhibitor during hemodialysis were investigated in 15 patients (37.4 +/- 3.2 years) undergoing maintenance hemodialysis (47.0 +/- 12.9 months) with dialyzers made from cellulose hydrate, cuprophan, polymethylmethacrylate, ethylene-vinyl alcohol copolymer, and polyacrylonitrile. Cellulose hydrate membrane caused a maximal increase of the plasma levels of granulocyte elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI: 1,659.0 +/- 256.8 ng/ml). Patients dialyzed with polyacrylonitrile dialyzers failed to exhibit comparable plasma levels of granulocyte elastase (E-alpha 1PI: 237.8 +/- 22.9 ng/ml). During hemodialysis plasma E-alpha 1PI values rose to a peak 643.0 +/- 174.7 ng/ml in patients on polymethylmethacrylate dialyzers, to 557.5 +/- 120.0 ng/ml on cuprophan dialyzers, but to only 381.9 +/- 54.0 ng/ml on ethylene-vinyl alcohol copolymer dialyzers. Plasma lysozyme levels decreased significantly in the presence of polyacrylonitrile and polymethylmethacrylate membranes. We conclude that the degree of PMNs stimulation depends on the nature of the dialyzer membrane material. The following membranes induce a reaction of increasing intensity: polyacrylonitrile, ethylene-vinyl alcohol copolymer, cuprophan, polymethylmethacrylate, and cellulose hydrate.


Enzymatic and morphological properties of primary rat brain astrocyte cultures, and enzyme development in vivo.
The development of (Na+ + K+) ATPase, carbonic anhydrase and HCO3--stimulated ATPase activity was studied in developing rat brain in vivo, and in primary astrocyte cultures from 1--3-day-old rat brain as a function of increasing cell growth. The primary cultures showed an increase in all the above enzyme activities during cell growth, with time courses which were qualitatively similar to their development in vivo. Cell cultures grown separately from the cerebellum plus brain stem regions showed greater carbonic anhydrase activity than cerebral cultures over the entire 4-week growth period, corresponding to development of this activity in these same regions in vivo, HCO3-stimulated ATPase activity was slightly greater in cerebellar cultures and (Na+ + K+) ATPase activity was greater in cerebral cultures up to the second week of growth, resembling development of the same enzyme activities in vivo. C6 glioma and neuroblastoma cells showed no and 10-fold lower carbonic anhydrase activities respectively, compared to the primary astrocyte cultures. Addition of 1 mM N6-2'-O-dibutyryladenosine-3',5'-monophosphate (DBcAMP) in the presence of serum caused marked formation of cellular processes and increased carbonic anhydrase and (Na+ + K+) ATPase activity. Maximum effects were found 2 h after addition of 1 mM DBcAMP and thereafter declined. In the absence of serum such effects persisted for at least 24 h. Electron microscope studies showed large numbers of microtubule (approximately 20 nm diameter) and filamentous structures (less than or equal to 10 nm diameter) in the cytoplasm, which showed changes in distribution in cells treated with DBcAMP. This study suggests that the increase in ATPase and carbonic anhydrase activities in rat brain with increasing age may be in part a reflection of proliferation and development of astroglia cells. Together with the morphological data, it also provides additional evidence that primary cultures derived from neonatal rats may closely resemble developing astroglia in vivo.


Analysis of trihalomethane precursor removal from sub-tropical reservoir waters by a magnetic ion exchange resin using a combined method of chloride concentration variation and surrogate organic molecules.
In small reservoirs in tropical islands in Japan, the disinfection by-product formation potential is high due to elevated concentrations of dissolved organic matter (DOM) and bromide. We employed a combined method of variation of chloride concentrations and the use of DOM surrogates to investigate removal mechanisms of bromide and different fractions of DOM by chloride-based magnetic ion exchange (MIEX®) resin. The DOM in reservoir waters was fractionated by resins based on their hydrophobicity, and characterized by size-exclusion chromatography and fluorescence excitation-emission matrix spectrophotometry. The hydrophobic acid (HPO acid) fraction was found to be the largest contributor of the trihalomethane (THM) precursors, while hydrophilic acid (HPI acid) was the most reactive precursors of all the four THM species. Bromide and DOM with a molecular weight (MW) greater than 1kDa, representing HPO acid (MW 1-3kDa) and HPI acid (MW 1-2kDa), were effectively removed by MIEX® resin; however, DOM with a MW lower than 1kDa, representing HPI non-acid, was only moderately removed. The removal of THM precursors by MIEX® resin was interfered by high chloride concentrations, which was similar to the removal of glutamic acid (HPI acid surrogate) and bromide. However, elevated chloride concentrations had only a minor effect on tannic acid (HPO acid surrogate) removal, indicating that HPO acid fraction was removed by a combination of ion exchange and physical adsorption on MIEX® resin. Our study demonstrated that the combined use of DOM surrogates and elevated chloride concentrations is an effective method to estimate the removal mechanisms of various DOM fractions by MIEX® resin.


Tooth movement during processing of complete dentures and its relation to palatal form.
Tooth movement during processing of acrylic resin complete dentures was investigated in relation to palatal form. Eleven clinical casts were radiographed at four denture-processing stages. Seven points were located across each cast. Radiographs were digitized and the images obtained were processed and analyzed for precise measurement of tooth movement. A palatal form index was developed. With respect to a relationship between tooth movement and palatal form, certain trends were found with varying degree and direction, shedding light on the behavior of base material and the dimensional changes that occurred during processing.


Carbohydrate-based experimental therapeutics for cancer, HIV/AIDS and other diseases.
This review, primarily for general readers, briefly presents experimental approaches to therapeutics of cancer, HIV/AIDS and various other diseases based on advances in glycobiology and glycochemistry. Experimental cancer and HIV/AIDS vaccines are being developed in attempts to overcome weak immunological responses to carbohydrate-rich surface antigens using carriers, adjuvants and novel carbohydrate antigen constructs. Current carbohydrate-based vaccines are used for typhus, pneumonia, meningitis; vaccines for anthrax, malaria and leishmaniasis are under development. The link between O-linked beta-N-acetylglucosamine glycosylation and protein phosphorylation in diseases including diabetes and Alzheimer's disease is also explored. Carbohydrate-associated drugs that are in current use or under development, such as heparan sulfate binders, lectins, acarbose, aminoglycosides, tamiflu and heparin, and technologies using carbohydrate and lectin microarrays that offer improved diagnostic and drug development possibilities, are described. Advances in carbohydrate synthesis, analysis and manipulation through the emerging fields of glycochemistry and glycobiology are providing new approaches to disease therapeutics.


The CD4+ T-cell subset lacking expression of the CD28 costimulatory molecule is expanded and shows a higher activation state in multiple sclerosis.
Multiple sclerosis (MS) is a chronic debilitating disease, in which T-cells are considered to play a pivotal role. CD28 is the quintessential costimulatory molecule on T-cells and its expression declines progressively with repeated stimulations, leading to the generation of CD28(-) T-cells. Our aim was to examine whether CD4(+)CD28(-) T-cells were enriched in MS patients, and characterize the phenotype of this subset in MS patients and healthy controls (HC). All these changes could provide these CD4(+)CD28(-) T-cell characteristics that might be involved in the pathogenesis of MS, turning this T-cell subset into a potential target for future therapeutic strategies.


Identification of GRIN2D as a novel therapeutic target in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a dismal prognosis, and despite significant advances in our understanding of its genetic drivers, like KRAS, TP53, CDKN2A, and SMAD4, effective therapies remain limited. Here, we identified a new therapeutic target GRIN2D and then explored its functions and mechanisms in PDAC progression. We performed a genome-wide RNAi screen in a PDAC xenograft model and identified GRIN2D, which encodes the GluN2D subunit of N-methyl-D-aspartate receptors (NMDARs), as a potential oncogene. Western blot, immunohistochemistry, and analysis on Gene Expression Omnibus were used for detecting the expression of GRIN2D in PDAC. Cellular experiments were conducted for exploring the functions of GRIN2D in vitro while subcutaneous and orthotopic injections were used in in vivo study. To clarify the mechanism, we used RNA sequencing and cellular experiments to identify the related signaling pathway. Cellular assays, RT-qPCR, and western blot helped identify the impacts of the NMDAR antagonist memantine. We demonstrated that GRIN2D was highly expressed in PDAC cells, and further promoted oncogenic functions. Mechanistically, transcriptome profiling identified GRIN2D-regulated genes in PDAC cells. We found that GRIN2D promoted PDAC progression by activating the p38 MAPK signaling pathway and transcription factor CREB, which in turn promoted the expression of HMGA2 and IL20RB. The upregulated GRIN2D could effectively promote tumor growth and liver metastasis in PDAC. We also investigated the therapeutic potential of NMDAR antagonism in PDAC and found that memantine reduced the expression of GRIN2D and inhibited PDAC progression. Our results suggested that NMDA receptor GRIN2D plays important oncogenic roles in PDAC and represents a novel therapeutic target.


Topology-Optimized Micromixer Design with Enhanced Reverse Flow to Increase Mixing Efficiency.
In this work, a serpentine mixing unit model based on topology optimization is proposed to enhance the reverse flow in both horizontal and vertical directions. The increase in reverse flow in both directions can enhance the chaotic advection phenomenon, leading to a rapid increase in the mixing index. The proposed mixing unit model is applied in a T-shaped micromixer to create a new micromixer design, named TOD. Numerical simulations of TOD are performed using Comsol Multiphysics software to analyze the characteristics of the liquid flow, mixing surface, and pressure drop. The simulation results confirm that TOD has an outstanding mixing performance. By widening the surface area of contact and enhancing the chaotic advection phenomenon, TOD shows an excellent mixing performance at both a high and low Reynolds number, making it a promising micromixer design. For Re > 5, the mixing indexes of TOD are all beyond 90%.


Shoulder Long Head Biceps Tendon Pathology Is Associated With Increasing Rotator Cuff Tear Size.
To evaluate the association between rotator cuff tear (RCT) size and long head biceps tendon (LHBT) pathology. We retrospectively enrolled 202 consecutive patients (114 women and 88 men with mean age at surgery of 62.14 years [SD, 7.73]) who underwent arthroscopic rotator cuff repair for different sized full-thickness RCTs. LHBT pathology was evaluated considering the presence of inflammation, section alteration, loss of integrity, dislocation, dynamic instability, and absence. The site of LHBT pathology was evaluated considering 3 portions: (1) the insertional element; (2) the free intra-articular portion; (3) the part that enters the intertubercular groove. Statistics were evluated. The LHBT was absent in 22 cases (10.9%): 2, 4, 15, and 1 patients with small, large, massive, and subscapularis RCTs, respectively. A significant correlation was found between the prevalence of LHBT absence and massive RCTs (P < .001). In 53 patients (26%), there was a healthy LHBT; a healthy LHBT was present in 47%, 20% and 8% of small, large and massive RCTs, respectively. A significant correlation between LHBT inflammation, section alteration, loss of integrity, and RCT severity was found (P < .001, P < .001, and ). The insertional portion was the most involved (57% of cases); RCT severity was significantly associated with the number of involved portions (P < .001). Shoulder LHBT pathology is associated with increasing rotator cuff tear size. Surgeons should be aware that biceps pathology is particularly prevalent in patients with larger RTCs.


The role of completion imaging following carotid artery endarterectomy.
A variety of completion imaging methods can be used during carotid endarterectomy to recognize technical errors or intrinsic abnormalities such as mural thrombus or platelet aggregation, but none of these methods has achieved wide acceptance, and their ability to improve the outcome of the operation remains a matter of controversy. It is unclear if completion imaging is routinely necessary and which abnormalities require re-exploration. Proponents of routine completion imaging argue that identification of these abnormalities will allow their immediate correction and avoid a perioperative stroke. However, much of the evidence in favor of this argument is incidental, and many experienced vascular surgeons who perform carotid endarterectomy do not use any completion imaging technique and report equally good outcomes using a careful surgical protocol. Furthermore, certain postoperative strokes, including intracerebral hemorrhage and hyperperfusion syndrome, are unrelated to the surgical technique and cannot be prevented by completion imaging. This controversial subject is now open to discussion, and our debaters have been given the task to clarify the evidence to justify their preferred option for completion imaging during carotid endarterectomy.


Discoursive Humanity as a Transcendental Basis for Cognitive (Dis)Ability Ethics and Policies.
This article explicates two approaches to the basis of moral worth and status: Eva Kittay's relational view and Jeff McMahan's psychological personhood view. It is argued that these theories alone do not provide adequate support for the conclusions Kittay and McMahan want to draw concerning individuals whose entitlement to fundamental protections can be challenged-infants with severe cognitive disabilities and infants without the support of their families and social environments. The real justification can in each case be found in deeply held convictions regarding entities that must and entities that must not be included in the core community of moral equals. Philosophical discussions about these convictions would be more useful for the advancement of our moral thinking than vain attempts to show that the absolute truth lies on either side of the ongoing debate.


Toxic compounds biodegradation and toxicity of high strength wastewater treated under elevated nitrogen concentration in the activated sludge and membrane bioreactor systems.
This research has assessed the removal efficiencies of toxic compounds in the high strength wastewater (the leachate and agriculture wastewater mixture) using the activated sludge (AS) and membrane bioreactor (MBR) technologies under two carbon to nitrogen (C/N) ratios (C/N 14 and 6) and two toxic compounds concentrations (8-396μg/L and 1000μg/L). In addition, the toxicity evaluations of the AS and MBR effluents to the aquatic environment were undertaken at five effluent dilution ratios (10, 20, 30, 50 and 70% v/v). The findings indicate that the AS treatment performance could be enhanced by the elevation of the nitrogen concentration. Specifically, the C/N 6 environment helps promote the bacterial growth, particularly heterotrophic nitrifying bacteria (HNB) and nitrifying bacteria (NB), which produce the enzymes crucial to the toxic compounds degradation. The improved biodegradation makes the effluents less toxic to the aquatic environment, as evidenced by the lower mortality rates of both experimental fish species raised in the nitrogen-elevated diluted AS effluents. On the other hand, the elevated nitrogen concentration minimally enhances the MBR treatment performance, given the fact that the MBR technology is in itself a biological treatment scheme with very high compounds removal capability. Despite its lower toxic compounds removal efficiency, the AS technology is simple, inexpensive and operationally-friendly, rendering the system more applicable to the treatment operation constrained by the financial, manpower and technological considerations.


A multi-omics signature to predict the prognosis of invasive ductal carcinoma of the breast.
Precisely evaluating the prognosis of invasive ductal carcinoma (IDC) of the breast is challenging as most prognostic signatures use single-omics data based on gene or clinical information. Whole-slide images (WSIs), transcriptome, and clinical data of breast IDC were collected from the Cancer Genome Atlas Database. The cancer-associated fibroblast (CAF) gene sets were downloaded from the Molecular Signatures Database. The WSI feature was extracted by artificial feature engineering. The CAF prognostic genes were determined by the Gene Set Enrichment Analysis, the Wilcoxon test, and univariate Cox regression. The IDC patients were divided into the training and test sets. The prognostic signatures based on WSIs, IDC-CAFs, bi-omics, and tri-omics were constructed using multivariate Cox regression. The samples were divided into low- and high-risk groups according to the median risk score. The Kaplan-Meier survival and receiver operating characteristic curves were applied to validate the prediction performance of the four signatures. In total, 508 IDC patients with complete data were included. The area under the curve (AUC) of single-omics signature based on WSI characteristics and CAFs was 0.765 and 0.775, whereas the AUC of bi-omics was 0.823. The tri-omics signature based on WSIs, CAFs, and lymph node status demonstrated the best predictive value with an AUC of 0.897. The multi-omics signature based on WSIs, CAFs, and clinical characteristics showed excellent prediction ability in breast IDC patients, whose risk factors can also provide a valuable diagnostic reference for the clinical course.


Does a second generation of centrally acting antihypertensive drugs really exist?
The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the rostroventrolateral part of the brainstem: the nucleus reticularis lateralis. After that, it was shown that imidazolines and related substances reduced blood pressure when applied in this area whereas catecholamines were not capable of producing such an effect. These data led us to suggest the existence of receptors specific for imidazoline-like compounds different from the alpha2-adrenoceptors. Soon after, the existence of imidazoline binding sites was reported in the brain and in a variety of peripheral tissues including the human kidney. As expected, these specific binding sites do not bind the catecholamines. The imidazoline binding sites are already subclassified in two groups: the I1-subtype sensitive to clonidine and idazoxan, and the I2-subtype, sensitive to idazoxan and nearly insensitive to clonidine. Functional studies confirmed that the hypotensive effects of clonidine-like drugs involved imidazoline receptors while their most frequent side effects only involved alpha2-adrenoceptors. However, recent functional evidence suggests that a cross talk between imidazoline receptors and alpha2-adrenoceptors is necessary to trigger a hypotensive effect within the ventral brainstem. Rilmenidine and Moxonidine are the leader compounds of a new class of antihypertensive drugs selective for imidazoline receptors. At hypotensive doses, these drugs are devoid of significant sedative effect. Rilmenidine evoked hypotension when injected within the nucleus reticularis lateralis region; it competed for [3H]-clonidine bound to specific imidazoline binding sites in human medullary membrane preparations but proved more selective for cerebral imidazoline receptors than clonidine. It is suggested that this selectivity might explain the low incidence of their side effects. Additional potentially beneficial actions on cardiac arrhythmias or congestive heart failure enlarge the therapeutic interest of imidazoline-related drugs. Recent binding and functional data throw a new light on the optimal pharmacological profile of this second generation of centrally acting antihypertensive drugs.


Bactericidal/permeability-increasing protein in lacrimal gland and in tears of healthy subjects.
To determine the expression of bactericidal/permeability-increasing protein (BPI), a novel antimicrobial molecule, in the main lacrimal gland and its content in tears of young healthy subjects. BPI concentration of tears was measured in 42 healthy volunteers, 13 men and 29 women, with ages ranging from 22 to 30 (mean 24.7+/-2.1) years by a time-resolved fluoroimmunoassay (TR-FIA). Immunohistochemical analysis was made to localize BPI in lacrimal gland and conjunctiva of eight autopsied subjects, two men and six women, with the age range from 44 to 87 (mean 72.3+/-14.9) years. The mean concentration of BPI in tears was 27.8+/-29.5 microg/l, and it decreased with an increase in tear flow rate (P<0.0001). There was no statistically significant difference in BPI content of tears between the genders. BPI was immunohistochemically seen in outer basal epithelial cells of intralobular and excretory ducts, squamous and basal cells of conjunctiva as well as faintly in myoepithelial cell layer of acini. The presence of BPI in the lacrimal gland and in the tear fluid was verified by Western blotting. The results indicate that outer basal epithelial cells of lacrimal gland ducts contain BPI, which occurs in a relatively high concentration in tears. BPI may have a substantial antibacterial role in human tears.


Factors associated with changes in vaginal length and diameter during pelvic radiotherapy for cervical cancer.
This study reports the incidence and factors associated with vaginal stenosis and changes in vaginal dimensions after pelvic radiotherapy for cervical cancer. A descriptive longitudinal study with 139 women with cervical cancer was conducted from January 2013 to November 2015. The outcome variables were vaginal stenosis assessed using the Common Terminology Criteria for Adverse Events (CTCAE v3.0) and changes in vaginal diameter and length after the end of radiotherapy. Independent variables were the characteristics of the neoplasm, clinical and sociodemographic data. Bivariate analysis was carried out using χ 2, Kruskal-Wallis and Mann-Whitney's test. Multiple analysis was carried out using Poisson regression and a generalized linear model. Most women (50.4%) had stage IIIB tumors. According to CTCAE v3.0 scale, 30.2% had no stenosis, 69.1% had grade 1 and 0.7% had grade 2 stenosis after radiotherapy. Regarding changes in vaginal measures, the mean variation in diameter was - 0.6 (± 1.7) mm and the mean variation in length was - 0.6 (± 1.3) cm. In the final statistical model, having tumoral invasion of the vaginal walls (coefficient + 0.73, p < 0.01) and diabetes (coefficient + 1.16; p < 0.01) were associated with lower vaginal stenosis and lower reduction of vaginal dimensions. Advanced clinical stage (coefficient + 1.44; p = 0.02) and receiving brachytherapy/teletherapy (coefficient - 1.17, p < 0.01) were associated with higher reduction of vaginal dimensions. Most women had mild vaginal stenosis with slight reductions in both diameter and length of the vaginal canal. Women with tumoral invasion of the vagina have an increase in vaginal length soon after radiotherapy due to a reduction in tumoral volume.


Visuospatial bootstrapping: long-term memory representations are necessary for implicit binding of verbal and visuospatial working memory.
It has recently been shown that presenting additional visuospatial information alongside to-be-remembered numbers in a digit span task enhances participants' memory for those items. However, the mechanisms behind this visuospatial bootstrapping effect have remained unspecified. In this article, we report evidence that this effect involves an integration of information from verbal and visuospatial temporary memory with long-term-memory (LTM) representations and that the existence of a relevant LTM representation is necessary for bootstrapping to occur.


Effect of repeated transsphenoidal surgery in recurrent or residual pituitary adenomas: A systematic review and meta-analysis.
Recurrent or residual pituitary adenomas previously treated by transsphenoidal surgery are not uncommon. There are no strongly established guidelines to perform treatment of such cases. The objective of this study is to elucidate the effect of transsphenoidal reoperation in residual or recurrent pituitary adenomas. We made a systematic review of the literature to elucidate this effect through electronic search in MEDLINE/PubMed and Cochrane Central database. PRISMA statement was used as a basis for this systematic review and analysis of the risk of bias was made according to the Grading of Recommendations, Assessment, Development and Evaluation recommendations. In this review, fifteen studies were finally pooled analyzed. Although remission rates (RRs) and follow-up periods varied widely, from 149 patients with growth hormone-secreting tumors the mean RR was 44.5%, from 273 patients with adrenocorticotropic hormone-secreting tumors the mean RR was 55.5% and among 173 patients with nonsecreting tumors, RR was 76.1%. There was significant higher RR in nonsecreting tumors. Mean follow-up was 32.1 months. No difference was found between microscopic and endoscopic techniques. A second transsphenoidal surgery is accompanied by a chance of remission in approximately half of cases with secreting tumors. In nonsecreting ones, success is higher.


Carbon Monoxide Exposure in Norwegian Rescue Helicopters.
Exposure to exhaust fumes from combustion engines can lead to carbon monoxide (CO) poisoning. Sea King Rescue helicopter crews are frequently subjected to engine exhaust. This study investigates the extent of CO exposure and potential for intoxication for flight crews during standard operational training procedures. Over a 2-week period, rescue helicopter flight crews were monitored for exposure to exhaust fumes and clinical symptoms of CO intoxication by means of a written survey and measurements of carboxyhemoglobin saturation (SpCO) with a handheld pulse CO oximeter (RAD-57; Masimo, Irvine, CA). Normal ranges for SpCO were defined as ≤ 4%. Sixty-nine completed surveys and 138 SpCO measurements of 37 crewmembers were included in the study. Sixty-four percent (n = 44) experienced subjective exposure to engine exhaust during training. Clinical symptoms were reported in 8.6% (n = 6) and included exhaustion (n = 4), headache (n = 1), and nausea (n = 1). Twenty-nine percent (n = 20) showed postflight SpCO levels outside the normal range (≥ 4%). The maximum postflight SpCO level among all measurements was 7%. Exposure to engine fumes is common, even more so during open cargo door operations. However, clinical symptoms are infrequent and mild. Toxic SpCO levels were not reached in this study, but approximately one third of postflight SpCO levels were outside the normal range.


Necrotizing fasciitis of the thigh due to a secondary aortoduodenal fistula.
Background: Secondary aortoenteric fistula is an iatrogenic complication after aortic reconstructive surgery presenting with gastrointestinal bleeding and/or infectious symptoms. Infrequently, it may manifest with nonspecific and atypical clinical signs. We present a case of necrotizing fasciitis of the thigh complicating secondary aortoduodenal fistula, diagnosed with CT-scan. Case presentation: A 67-year-old man with a history of an open aortic-bifemoral bypass 6 years ago was admitted for a progressively swollen and painful right thigh for the last month. Through laboratory and morphological (CT-scan) investigations, a secondary aortoduodenal fistula associated with necrotizing fasciitis of the right thigh was discovered. After general supportive care and empiric antibiotherapy, the patient underwent a prosthetic explantation, a resection of the perforated bowel with end-to-end anastomosis, and extensive debridement of the necrotic tissue of the thigh. No revascularization has been attempted. The patient died the next day of multiple organ failure. Conclusion: Secondary aortoenteric fistula is rare but with a poor prognosis. Clinical presentation is not always typical. A high index of suspicion is the most important factor for improving outcomes. There is not a consensus about optimal management. Axillo-bifemoral revascularization and subsequent graft removal seem to be the best therapeutic option.


The mechanism for microsporidian parasite suppression of the hindgut bacteria of the migratory locust Locusta migratoria manilensis.
Locusts aggregate into bands of nymphs and swarms of adults that can pose a major threat to crop. Previous studies have shown that infection by the microsporidian parasite Paranosema locustae prevents locust aggregation behavior and we show that gut bacteria, which produce components of locust aggregation pheromones, are substantially reduced in locusts infected with P. locustae. We found that P. locustae could reduce the diversity, abundance and community composition of Locusta migratoria's gut bacteria. The parasite infection was also shown to interrupt the peroxidase activity of locust hindgut. Genome-wide expression analysis showed that the parasite infection suppressed peroxidase mRNA relative expression of locust hindgut, but had no effects on attacin expression and superoxide dismutase at 16 d post-inoculation with 20,000 P. locustae spores. Our findings reveal the mechanisms by which P. locustae impairs bacterial diversity and community structure of Locusta migratoria's gut bacteria.


The phospholipids of rabbit type II alveolar epithelial cells: comparison with lung lavage, lung tissue, alveolar macrophages, and a human alveolar tumor cell line.
The phospholipid composition of type II alveolar epithelial cells from the rabbit was compared with that of alveolar macrophages, lung lavage and lung tissue. In addition, the phospholipid composition of a human alveolar tumor cell line, which is morphologically similar to type II cells, was examined. Phosphatidylcholine accounted for 48% of the total phospholipid in the type II cells, 41% in the tumor cells, and 30% in the macrophages. Phosphatidylcholine was 51% disaturated in the type II cells, 54% in lung lavage, 39% in whole lung, 29% in lavaged lung and macrophages, and 16% in the tumor cells. Palmitic acid was the major fatty acid in phosphatidylcholine from all samples with the exception of the tumor cells in which almost half of the fatty acids were accounted for by oleic acid. The phospholipids of the type II cells were more similar to those of lung lavage, and thus surfactant, than to lung tissue and macrophages. This is consistent with their supposed role in surfactant production. The tumor cells, although morphologically similar to type II cells, were quite different with respect to phospholipid composition.


The formation of all-trans-retinoic acid from all-trans-retinol in hairless mouse skin.
All-trans-retinoic acid formation from topically applied retinol has been demonstrated in the skin of skh/hr1 (hairless) mice. The all-trans-retinoic acid was identified on the basis of its chromatographic properties on HPLC at various pH values, its photoisomerization to reaction products identical to those formed from authentic all-trans-retinoic acid, and its co-chromatography with methyl retinoate after methylation with diazomethane. Topically applied retinol is about 2-fold less potent at inducing epidermal hyperplasia and 7-fold less potent at inhibiting the induction of epidermal ornithine decarboxylase by phorbol esters than all-trans-retinoic acid in this strain of mice. To elucidate the possible role all-trans-retinoic acid formation from retinol may have in these pharmacological activities, the epidermal and dermal all-trans-retinoic acid levels were compared in mice treated topically with retinol or [11-3H]-all-trans-retinoic acid. The levels of all-trans-retinoic acid found after retinol treatment were several orders of magnitude lower than those found after [11-3H]-all-trans-retinoic acid treatment, and they were insufficient to account for the difference in potencies between all-trans-retinoic acid and retinol. Retinol was eliminated from the epidermis at a rate similar to that of all-trans-retinoic acid after topical administration, but the initial tissue levels achieved were lower. These results suggest that the lower potencies of retinol may simply reflect lower tissue uptake.


Suppression of efflux transporters in the intestines of endotoxin-treated rats.
Infection and inflammation suppress the expression and activity of several drug transporters in the liver. In the intestine, P-glycoprotein (PGP/mdr1) and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs. The protein expression and activity of these transporters were examined during inflammation induced by lipopolysaccharide (LPS). The transport of rhodamine123 (Rho123) and 5-carboxyfluorescein (5-CF) was determined in isolated ileal segments from endotoxin-treated or control rats in the presence or absence of inhibitors. The reverse transcription-polymerase chain reaction was used to measure mRNA levels. Compared with the controls, the mRNA levels of mdr1a and mrp2 were significantly decreased by approximately 50% in the ilea of the LPS-treated rats. Corresponding reductions in the basolateral-apical efflux of Rho123 and 5-CF were observed, resulting in significant increases in the apical-basolateral absorption of these compounds. Neither the permeability of fluorescein isothiocyanate labeled dextran 4000 (FD-4), a paracellular marker, nor membrane resistance was altered. These results indicate that endotoxin-induced inflammation reduces the intestinal expression and activity of PGP and MRP2 in rats, which eliciting corresponding changes in the intestinal transport of their substrates. Hence, infection and inflammatory diseases may induce variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters.


Histochemical studies on the long term prostaglandin treatment on adrenal delta5-3beta-hydroxysteroid dehydrogenase and glucose-6-phosphate dehydrogenase activities in rats pretreated with estradiol dipropionate.
Long term Prostaglandin E2 treatment stimulates adrenal weight and steroid output. Indirect studies with histochemical localization of steroidogenic enzymes and hepatocyte glycogen content revealed that in state of adrenal suppression, PGE2 fails to elicit a positive change in steroid output from adrenal cortex, although apparently increases the enzymatic staining reactions. This suggests that the action of Prostaglandin on adrenal steroidogenesis is a pharmacologic one rather than a physiologic response.


Inconsistency in albuminuria predictors in type 2 diabetes: a comparison between neural network and conditional logistic regression.
Albuminuria is a sensitive marker to predict future cardiovascular events in patients with type 2 diabetes mellitus. However, current studies only use conventional regression models to discover predictors of albuminuria. We have used 2 different statistical models to predict albuminuria in type 2 diabetes mellitus: a multilayer perception neural network and a conditional logistic regression. Neural network models were used to predict the level of albuminuria in patients with type 2 diabetes mellitus, which include a matched case-control study for the population. For each case, we randomly selected 1 control matched by age and body mass index (BMI). The input variables were sex, duration of diabetes, systolic and diastolic blood pressure, glomerular filtration rate, high-density lipoprotein, low-density lipoprotein, triglyceride, high-density lipoprotein/triglyceride ratio, cholesterol, fasting blood sugar, and glycated hemoglobin. Age and BMI were included only in the neural network model. This model included 4 hidden layers and 1 bias. Relative error of predictions was 0.38% in the training group, 0.52% in the testing group, and 1.20% in the holdout group. The most robust predictors of albuminuria were high-density lipoprotein (21%), cholesterol (14.4%), and systolic blood pressure (9.7%). Using the conditional logistic regression model, glomerular filtration rate, time of onset to diabetes, and sex were significant indicators in the onset of albuminuria. Using a neural network model, we show that high-density lipoprotein is the most important factor in predicting albuminuria in type 2 diabetes mellitus. Our neural network model complements the current risk factor models to improve the care of patients with diabetes.


Sequence analysis of a monoclonal antibody specific for the preS2 region of hepatitis B surface antigen, and the cloning, expression and characterisation of its single-chain Fv construction.
The nucleotide sequence of the monoclonal antibody F124, specific for the preS2 region of the surface antigen of hepatitis B virus, has been determined and an single-chain Fv fragment (scFv) recombinant construction has been cloned and expressed into the periplasmic region of Escherichia coli. The recombinant antibody fragment contains a (Gly4Ser)3 linker connecting the C-terminus of the heavy chain variable region (V(L)) domain to the N-terminus of the light chain variable region (V(L)) domain. A 23-residue peptide segment, containing a c-myc marker for immunochemical detection of the scFv and hexahistidine tag to facilitate its purification, was added C-terminal to the V(L) domain. The scFv mimics the antibody in binding to the native antigen in the form of recombinant hepatitis B surface antigen (HBsAg) particles as well as to peptide fragments carrying the viral epitope.


Chemical modification of waxy maize starch by esterification with saturated fatty acid chlorides: Synthesis, physicochemical and emulsifying properties.
In the current study, the physicochemical and emulsifying properties of modified waxy maize starch obtained through a new environmentally friendly method of esterification were evaluated. The starch modification was carried out in NaOH solution with different levels of octanoyl, myristoyl, and stearoyl chlorides. Increasing the fatty acid chlorides concentration led to the degree of substitution increment, while reaction efficiency and yield decreased. Based on fourier transform infrared spectroscopy results, the presence of two new bands of carbonyl (1740-1750 cm-1) and carboxyl (1570 cm-1) groups in the ester bond confirmed the successful starch esterification process. The level of 0.1 mL fatty acid chlorides/g of starch demonstrated the highest emulsifying properties. Upon esterification, the crystalline structure of amylopectin was destroyed, indicating no gelatinization features. Therefore, using the fatty acid chlorides in an alkaline condition could be suggested as a feasible way to modify waxy maize starch toward hydrophobicity increment with desirable properties.


Bilateral intra-osseous neurofibromata of the mandible.
A case of bilateral neurofibromata associated with the crowns of impacted third mandibular molars in a patient with known neurofibromatosis is reported.


A Systematic Review of the Psychosocial Impact of Polycystic Ovarian Syndrome Before and After Treatment.
While polycystic ovarian syndrome (PCOS) is one of the most common hormonal endocrine disorders among women of reproductive age, the psychosocial impact of PCOS has not been evaluated across different quality of life (QoL) indicators. We rigorously analyzed available evidence pertaining to the psychosocial burden of PCOS in women of reproductive age and compared validated QoL scores of women with and without PCOS before and after treatment. We searched and considered publications from PubMed, PsychINFO, Embase, and Cochrane Library that evaluated the association between diagnosed PCOS and QoL by standardized and validated questionnaires at baseline and after treatment. Reviewers assessed the risk of bias using established Cochrane and Newcastle-Ottawa Scale guidelines. A total of 33 studies were included in the review: 14 randomized controlled trials and 19 observational studies. The 36-Item Short Form Survey and World Health Organization Quality of Life - BREF questionnaire both revealed that the diagnosis and life experience of PCOS had a disability score that was similar to or surpassed that of heart disease, diabetes mellitus, or breast cancer. QoL scores, associated with mental health issues, infertility, sexual dysfunction, obesity, menstrual disorder, and hirsutism, were lower at the baseline than after treatment in the majority of instruments measuring these variables in women with PCOS. PCOS is associated with significant psychosocial stress and reduced QoL across baseline measures and in comparison, to other diseases. Evidence suggests that treatment with therapy, medications, and lifestyle management decreased psychosocial burdens and alleviated QoL experienced by women with PCOS.


Mass balance modelling of contaminants in river basins: a flexible matrix approach.
A novel and flexible approach is described for simulating the behaviour of chemicals in river basins. A number (n) of river reaches are defined and their connectivity is described by entries in an n x n matrix. Changes in segmentation can be readily accommodated by altering the matrix entries, without the need for model revision. Two models are described. The simpler QMX-R model only considers advection and an overall loss due to the combined processes of volatilization, net transfer to sediment and degradation. The rate constant for the overall loss is derived from fugacity calculations for a single segment system. The more rigorous QMX-F model performs fugacity calculations for each segment and explicitly includes the processes of advection, evaporation, water-sediment exchange and degradation in both water and sediment. In this way chemical exposure in all compartments (including equilibrium concentrations in biota) can be estimated. Both models are designed to serve as intermediate-complexity exposure assessment tools for river basins with relatively low data requirements. By considering the spatially explicit nature of emission sources and the changes in concentration which occur with transport in the channel system, the approach offers significant advantages over simple one-segment simulations while being more readily applicable than more sophisticated, highly segmented, GIS-based models.


Aligning mission to digital health strategy in academic medical centers.
The strategies of academic medical centers arise from core values and missions that aim to provide unmatched clinical care, patient experience, research, education, and training. These missions drive nearly all activities. They should also drive digital health activities - and particularly now given the rapid adoption of digital health, marking one of the great transformations of healthcare; increasing pressures on health systems to provide more cost-effective care; the pandemic-accelerated funding and rise of well-funded new entrants and technology giants that provide more convenient forms of care; and a more favorable regulatory and reimbursement landscape to incorporate digital health approaches. As academic medical centers emerge from a pandemic-related reactionary digital health posture, where pressures to adopt more digital health technologies mount, a broad digital health realignment that leverages the strengths of such centers is required to accomplish their missions.


Effect of annexin-A1 peptide treatment during lung inflammation induced by lipopolysaccharide.
Lung endotoxemia is characterized by neutrophil accumulation, increased vascular permeability and parenchymal injury. This can also affect the endogenous pathways that operate in the host to keep inflammation under control. Here, we demonstrate differential expression of annexin-A1 (AnxA1) protein in mice after the local or intraperitoneal administration of lipopolysaccharide (LPS; 1 mg/kg) in mice and the regulation of the endotoxemic inflammation after the pre-treatment with the AnxA1 peptidomimetic Ac2-26. The intranasal administration of LPS induced the leukocyte migration and cytokine release to the alveolar space, whereas the peritoneal administration of LPS generated a deregulated cellular and cytokine response, with a marked degree of leukocyte adhesion in the microcirculation. The peptide Ac2-26 pre-treatment inhibited the leukocyte migration and the pro-inflammatory cytokine release. Also, it induced the expression of endogenous AnxA1 and the anti-inflammatory cytokine IL-10. In conclusion, our data obtained from endotoxemia induced by local or intraperitoneal LPS administration suggested that the molecular mechanisms induced by AnxA1 peptidomimetic Ac2-26 lead to the regulation of leukocyte activation/migration and cytokine production induced by LPS.


Evaluation of Ia expression in rat ocular tissues following inoculation with interferon-gamma.
It is becoming increasingly clear that IFN-gamma is a potent immunoregulatory protein which influences MHC class II (Ia) antigen expression and cellular functions of B cells, T cells, NK cells and macrophages. During the past 5 yr our laboratory has provided evidence that IFN-gamma modulates class II antigens on retinal cells (retinal pigment epithelial cells, endothelial cells) and is localized within the eye during human inflammatory conditions. In this study we evaluate the direct effect of IFN-gamma on ocular tissue. Lewis rats were inoculated intravitreally or under the retina with either recombinant IFN-gamma (20,000 U) or saline. At 2 hr, 1, 2 and 6 days postinoculation, the eyes were removed and frozen sections were evaluated by immunocytochemical staining with monoclonal anti-Ia antibodies and an irrelevant monoclonal anti-T cell antibody. Saline treated tissue and tissue removed 2 hr after IFN-gamma inoculation showed no significant staining for Ia antigens. However, eyes evaluated 24 hr after IFN-gamma inoculation revealed Ia expression on a variety of ocular cells localized in the conjunctiva and anterior segment, such as conjunctival epithelium, keratocytes, iris epithelium, ciliary epithelium and choroidal cells. In the retina, retinal pigment epithelial (RPE) cells were Ia positive only when IFN-gamma was injected directly under the retina. In conjunction with Ia expression, two striking changes were noted. An iritis was seen and infiltrating cells were detected in the inner retinal layers. Both of these phenomena have been observed in certain inflammatory eye diseases. These studies clearly substantiate the concept that IFN-gamma can regulate class II antigens in the eye and thus may perpetuate immune reactivity in this site.


Prevalence of Neurocognitive Dysfunction and Its Effects on Postoperative Outcomes in Total Joint Arthroplasty.
The prevalence of neurocognitive dysfunction (NCD) and its effects on postoperative outcomes have not been well characterized following total joint arthroplasty (TJA) population. This study aims at better understand this relationship. Patients were evaluated for neurocognitive function using the grooved pegboard test for the dominant (PEG-D) and nondominant hand (PEG-N), and the Rey Auditory Verbal Learning Test (RAVLT). The patient scores for each test was compared to age-controlled normative values in order to identify NCD. Baseline characteristics and postoperative outcomes were then compared amongst the two cohorts. Ninety-nine consecutive patients were prospectively enrolled. Nearly 54% were identified as neurocognitively deficient on at least 1 of the 3 tests (31% by RAVLT, 21% by PEG-D, and 30% by PEG-N). There was a statistically significant prevalence of NCD in patients older than 60 years when compared to normative controls for RAVLT (P < .001). Patients with depression or an American Society of Anesthesiologist score of 3 were 5 times as likely to have NCD, while patients with a body mass index between 20-30 kg/m2 were 5 times less likely to have NCD. Furthermore, patients identified as NCD preoperatively were significantly more likely to be transferred to the intensive care unit (48% vs 14%) and fail physical therapy (64% vs 17%), respectively. NCD is highly prevalent within total joint arthroplasty candidates and may be correlated with higher body mass index, American Society of Anesthesiologist scores, and rates of depression. The condition predisposes patients to suboptimal postoperative outcomes including increased intensive care unit admissions and prolonged rehabilitation.


Thrombophlebitis migrans in ulcerative colitis.
A case of thrombophlebitis migrans in ulcerative colitis in a Maltese housewife is reported. The association of thrombo-embolic disease and ulcerative colitis is reviewed.


Identification of heavy metal leaching patterns in municipal solid waste incineration fly ash based on an explainable machine learning approach.
The leaching risk of heavy metal (HM) in municipal solid waste incineration fly ash (MSWI-FA) leads to a big challenge for FA landfilling. In this work, the HM leaching patterns were identified via 6 highly available indices of FA, in which 160 stabilized FA samples were collected from 4 incineration plants in eastern China and an explainable machine learning approach based on boosting and game analysis was conducted to assess the leaching potentials of 6 HMs (Cr, Cd, Cu, Ni, Pb and Zn). We found that, there remained high exceeding risks of Cd and Pb in stabilized FA. In addition, the S-Cl (soluble chlorine) content was the most influential factor of the leaching behaviors of Cd, Cu, Pb and Zn, more important than pH in regard to Cu, Pb and Zn. We quantified the influence of S-Cl on the HM leaching of Cd, Cu, Pb and Zn, whereby their leaching concentrations would increase by 223.5%, 215.2%, 216.5% and 222.6%, respectively, for every 0.5 mol/L order increase in S-Cl concentration. Finally, a fast determination criterion for the FA landfill was proposed, that is, FA of which S-Cl was less than 0.412 mol/L was acceptable.


Comparison of peritoneal equilibration test with 99mTc-DTPA excretion in the assessment of peritoneal permeability.
Assessment of peritoneal permeability is necessary for successful management of end-stage renal disease (ESRD) patients by continuous ambulatory peritoneal dialysis (CAPD). The objective of this study was to develop an alternative method of assessing the peritoneal permeability and to compare this method with the conventional method, the peritoneal equilibrium test, first described by Twardowski in 1987. Twenty patients undergoing regular CAPD were included in this study. Before starting the peritoneal dialysis, 370 MBq (10 mCi) technetium-99m diethylene triamine penta-acetic acid ((99m)Tc-DTPA) was injected intravenously. A standard dose of the same quantity was kept and used later for calculations. At the end of 4 h, a dialysate fluid sample (1 ml) was collected and the total dialysis effluent fluid volume was measured. Excretion of (99m)Tc-DTPA into the dialysate fluid as a percentage of the injected dose was calculated. Simultaneously, standard peritoneal equilibrium test values were recorded for comparison. Peritoneal excretion of (99m)Tc-DTPA ranged from 8% to 25% of the injected dose, depending on the peritoneal membrane permeability. When the results were compared with the conventional method, a good correlation (r=0.79) was found. This innovative radionuclide technique is a simple and convenient method to assess the peritoneal membrane permeability and can be used as an alternative to the peritoneal equilibrium test, which is very cumbersome and associated with many limitations.


Activity of nsp14 Exonuclease from SARS-CoV-2 towards RNAs with Modified 3'-Termini.
The COVID-19 pandemic has shown the urgent need for new treatments for coronavirus infections. Nucleoside analogs were successfully used to inhibit replication of some viruses through the incorporation into the growing DNA or RNA chain. However, the replicative machinery of coronaviruses contains nsp14, a non-structural protein with a 3'→5'-exonuclease activity that removes misincorporated and modified nucleotides from the 3' end of the growing RNA chain. Here, we studied the efficiency of hydrolysis of RNA containing various modifications in the 3'-terminal region by SARS-CoV-2 nsp14 exonuclease and its complex with the auxiliary protein nsp10. Single-stranded RNA was a preferable substrate compared to double-stranded RNA, which is consistent with the model of transfer of the substrate strand to the exonuclease active site, which was proposed on the basis of structural analysis. Modifications of the phosphodiester bond between the penultimate and last nucleotides had the greatest effect on nsp14 activity.


Endosalpingiosis: More than just an incidental finding at the time of gynecologic surgery?
To describe the clinical characteristics of patients with endosalpingiosis (ES) and examine its association with endometriosis and gynecologic malignancies. We queried the medical record for patients who underwent gynecologic surgery (Gynecologic Surgery Cohort (GSC), n=58,161) from 1998 to 2013 at a single institution for the presence of "endosalpingiosis" (ES). Demographic and clinical characteristics were collected for patients with pathologically confirmed ES (n=838). Within GSC, we compared the frequency of endometriosis and gynecologic malignancies with and without ES. We estimated the expected distribution of ovarian cancer subtypes using cases from the New England Case Control Study (NECC). We used chi-square tests to test for significant differences in frequency distributions and unconditional logistic regression to calculate multivariate odds ratios for the association between ES and ovarian cancer subtypes. We observed concurrent endometriosis (p<0.0001), uterine cancer (p<0.0001), and ovarian cancer (p<0.0001) more frequently in women with ES. Women from the GSC with ES and ovarian cancer were more likely to have serous borderline (OR=10.2, 95% CI=5.1-20.7), clear cell (OR=3.0, 95% CI=1.1-8.0), and invasive mucinous tumors (OR=5.0, 95% CI=1.5-16.6) as compared to ovarian cancer cases from the NECC without ES, after accounting for age, race, menopausal status, parity, tubal ligation, and endometriosis. Women with ES are more likely to also be diagnosed with endometriosis, uterine, and ovarian cancers. Further study is needed to understand these associations so we may appropriately counsel patients with ES diagnosed at time of gynecologic surgery.


[Pain therapy in children following ophthalmic surgery].
Pain following eye surgery is often described as being relatively moderate; however, there are also procedures that lead to a pronounced pain experience. Particularly in pediatric patients, pain therapy is often insufficient due to a lack of knowledge and fear of complications. These individual and organizational deficits lead to unnecessary discomfort for children and parents. Each institution providing surgical treatment must have pain management concepts in its portfolio for the appropriate age groups. This includes a child-oriented setting, age-appropriate information, systematic pain assessment, and pain protocols. Pain management should be planned prior to surgery and individually adapted as it progresses. Children have a right to a perioperative course with low stress and pain.


[Preliminary experiences with superimpoposed high-frequence jet ventilation in intensive care].
The study aimed to evaluate whether superimposed high-frequency jet ventilation (SHFJV) is a useful tool in intensive care medicine to ventilate patients with pulmonary insufficiency. METHODS. SHFJV is the simultaneous application of low- and high-frequency jet ventilation performed using a specially designed ventilator. SHFJV versus conventional mechanical ventilation (CMV) was were applied in three groups of patients. Group 1 (Gr 1) included patients without pulmonary insufficiency; group 2 (Gr 2) patients had moderate and those in group 3 (Gr 3) had severe pulmonary insufficiency. RESULTS. In Gr 1 and Gr 2, SHFJV was associated with a significant decrease in mean airway pressure (mPAW 12.9 vs. 13.3 mm Hg, P < 0.05). In Gr 3 oxygenation was significantly better with SHFJV (mean paO2 140.1 vs. 109.9 mm Hg, P < 0.05; mean FiO2 0.66 vs. 0.86, P < 0.05). Other parameters, such as maximum airway pressure (Pmax) and mean Paw, were significantly lower with SHFJV than CMV (mean Pmax 29.6 vs. 40.1 mm Hg, mean Paw 18 vs. 21.9 mm Hg, P < 0.05). Intrapulmonary shunt fractions showed a significant decrease with SHFJV (24.6 vs. 34.4, P < 0.05). CONCLUSIONS. Significant differences were observed primarily in Gr 3 patients, indicating that patients with severe pulmonary insufficiency may benefit from SHFJV. SHFJV may thus represent an alternative mode of ventilation in critically ill patients.


Menopausal status influences the relationship between serum ghrelin levels and fat mass in healthy women.
To examine the relationships of fasting serum ghrelin levels to bone mass index (BMI) and body fat mass, focusing on the effects of menopausal status and changes in fat distribution in women after menopause. An observational study. Fifty-nine pre-menopausal and 31 post-menopausal healthy Japanese women volunteers were enrolled in the present study. Total and regional body fat mass weight was measured by dual energy x-ray absorptiometry. Serum ghrelin was measured. Relationships of serum ghrelin levels to weight, BMI, total body and regional fat mass weight were separately examined in post-menopausal and pre-menopausal women. Serum ghrelin levels were significantly inversely correlated with weight (r = -0.377, p < 0.05, Pearson's correlation test), right arm fat mass (r = -0.408, p < 0.05), left arm fat mass (r = -0.386, p < 0.05), trunk fat mass (r = -0.361, p < 0.05) and total body fat mass (r = -0.383, p < 0.05) in the post-menopausal women but not in pre-menopausal women. Menopausal status may influence the relationship between serum ghrelin levels and fat mass in healthy women.


Oxidative degradation of ethers promoted by strontium and barium tetraphenylimidodiphosphinates.
The novel M[(OPPh2)2N]2.nTHF (M = Sr (2), Ba (3)) complexes were prepared and characterized. Upon exposure to atmospheric oxygen, 2 and 3 were transformed to the dinuclear species Sr2-[(OPPh2)2N]4.2C3H6O3 (4) and Ba(2)[(OPPh2)2N]4.2C4H8O3 (5), respectively. Compounds 4 and 5 contain coordinated carboxylic acids obtained from the oxidative degradation of DME and THF, respectively, which were used as solvents for crystallization.


[Study of the diagnostic agreement on headaches between neurology and primary care].
Headache as a symptom is a very common disease and one of the main reasons for consultation in primary care. To analyze the characteristics of patients referred from primary care to general neurology whose chief complaint was headache and/or neuralgia and diagnostic agreement. Cross-sectional study of all patients referred from primary care; demographic/clinical variables were collected and diagnostic hypothesis by primary care and general neurology were compared by determining their agreement. 2,514 were referred from primary care patients (588 of them on a preferential basis); in 378 cases the reason for consultation was headache and/or neuralgia (average 42.46 years; 77.8% female). In 139 patients it was established only a semiological diagnostic and other episodic migraine predominated (49.79%), chronic tension headache (18.41%) and trigeminal neuralgia (12.13%). Since general neurology, the most common diagnoses were, respectively, 33.86%, 24.05% and 18.67%. A compatible kappa coefficient of 0.543 (p < 0.05) with a moderate agreement when considering only those patients referred from primary care to a specific diagnosis was obtained. Headaches are a very common reason for consultation in primary care (15%). The diagnostic agreement is moderate in our health sector so it is necessary to design training programs to help outline the criteria for referral to specialists and improve care for our patients.


The loads developed by epicondylar and epitrochlear muscles across the elbow joint. A dynamic simulated model.
The radio-humeral joint has traditionally been believed to support most of the loads transmitted through the elbow. Load transfer through the elbow has been a controversial issue since the publication of the first biomechanical studies on the subject, most of which were based on extrinsic forces acting on the extended joint. The present study analyzes load distribution across the six different compartments in the elbow while the joint is flexed, as well as the intrinsic forces generated in the epicondylar and epitrochlear muscles. Ten cadaveric elbows were positioned at 90° of flexion, forearm in a neutral position and wrist at 0°. Tekscan sensors were used for measuring intraarticular pressures. Forces generated by epitrochlear muscles results in a series of loads that affect mainly the anteromedial facet (40%), followed by the posterolateral facet (34%) of the ulnohumeral joint, with the flexor carpi ulnaris generating the heaviest loads (43% on the anteromedial and 38% on the posterolateral facets). Conversely, the forces generated by the epicondylar muscles, similar in behavior but with an opposite direction, convey heavier loads to the elbow's anterolateral facet (45%), followed by the radiohumeral joint (26%) with the extensor carpi ulnaris generating the heaviest loads (54% on the anterolateral facet and 17% on the radiohumeral joint). Our results indicate that the elbow joint exhibits a characteristic load distribution pattern that depends on the muscles, as intrinsic forces are generated by the epicondylar and epitrochlear muscles. The anterior portion of the ulnohumeral joint is the area bearing the heaviest loads.


A family of Melnick-Needles syndrome: a case report.
Melnick-Needles syndrome (MNS) is an extremely rare osteochondrodysplasia caused by a mutation of FLNA, the gene encoding filamin A. MNS is inherited in an X-linked dominant manner. In this study, we describe three members of the same family with MNS, who exhibited different phenotypic severity despite having an identical FLNA gene mutation. The patient was 16 months old, with a history of delayed physical development, multiple upper respiratory infections and otitis media episodes. She was referred to our orthopedic clinic because of bowed legs and an abnormal plain chest radiograph. Both upper and lower extremities were bowed. Plain X-rays showed thoracolumbar kyphoscoliosis, with anterior and posterior vertebral scalloping, and thin, wavy ribs. Hypoplasia of the pubis and ischium, with bilateral coxa valga, were also noted. Target exome sequencing revealed a heterozygous mutation of FLNA, c.3578 T > C, p.Lys1193Pro, which confirmed the diagnosis of MNS. Her older sister and mother had minimal deformities of the axial and extremity skeleton, but genetic analyses revealed the same FLNA mutation as the patient. The mutation identified in this family has not been previously reported. This report illustrates the potential inherited nature of MNS and the phenotypic variability of clinicoradiologic characteristics. In patients with traits suggestive of MNS, a careful medical and family history should be obtained, and genetic testing should be performed for the patient, as well as all family members.