Differences in the faecal microbiome of non-diarrhoeic clinically healthy dogs and cats associated with Giardia duodenalis infection: impact of hookworms and coccidia.
The protozoan parasite Giardia duodenalis causes a waterborne diarrhoeal disease in animals and humans, yet many Giardia-infected hosts remain asymptomatic. Mixed parasite infections are common in both animals and humans with unknown consequences for Giardia or other parasites. We compared the composition and diversity of bacterial communities from 40 dogs, including free-roaming dogs, and 21 surrendered cats from Australia. The dog cohort included 17 (42.5%) dogs positive for Giardia and 13 (32.5%) dogs positive for dog hookworm (Ancylostoma caninum). The cat samples included eight positive for Giardia and eight positive for Cystoisospora. The V4 region of 16S rRNA was sequenced at an average of 36,383 high quality sequences (>200 bp) per sample using the Ion Torrent PGM platform. In dogs we found significant (P<0.05, AnoSim) difference between the Giardia-positive and -negative groups when evaluating bacterial genera. No such difference was demonstrated between Ancylostoma-positive and -negative dogs. However, there was a modest but not significant separation of the Giardia-negative and -positive dogs (P=0.09, UniFrac) using principal coordinate analysis. Removal of dogs with hookworms further separated Giardia-positive and -negative groupings (P=0.06, UniFrac). In cats, the presence of Giardia was not associated with a significant difference based on bacterial genera (P>0.05, AnoSim). Cystoisospora-positive cats, however, exhibited significantly different profiles from Cystoisospora-negative cats (P=0.02, AnoSim) and UniFrac showed significant separation of Cystoisospora-positive and -negative samples (P<0.01). The results suggest that in clinically heathy dogs and cats, helminths and protozoa are associated with different microbiomes and possibly variable gut microbiota functions. Understanding the association of parasites and microbiomes has important consequences for the administration of antiparasitic drugs in animals and humans.


Super-resolution microscopy enabled by high-efficiency surface-migration emission depletion.
Nonlinear depletion of fluorescence states by stimulated emission constitutes the basis of stimulated emission depletion (STED) microscopy. Despite significant efforts over the past decade, achieving super-resolution at low saturation intensities by STED remains a major technical challenge. By harnessing the surface quenching effect in NaGdF4:Yb/Tm nanocrystals, we report here high-efficiency emission depletion through surface migration. Using a dual-beam, continuous-wave laser manipulation scheme (975-nm excitation and 730-nm de-excitation), we achieved an emission depletion efficiency of over 95% and a low saturation intensity of 18.3 kW cm-2. Emission depletion by surface migration through gadolinium sublattices enables super-resolution imaging with sub-20 nm lateral resolution. Our approach circumvents the fundamental limitation of high-intensity STED microscopy, providing autofluorescence-free, re-excitation-background-free imaging with a saturation intensity over three orders of magnitude lower than conventional fluorophores. We also demonstrated super-resolution imaging of actin filaments in Hela cells labeled with 8-nm nanoparticles. Combined with the highly photostable lanthanide luminescence, surface-migration emission depletion (SMED) could provide a powerful mechanism for low-power, super-resolution imaging or biological tracking as well as super-resolved optical sensing/writing and lithography.


Persistence of nutritional deficiencies after short-term weight recovery in adolescents with anorexia nervosa.
To study nutritional abnormalities in adolescent anorexia nervosa and to establish whether certain abnormalities persist after short-term refeeding. Sixty-one patients (10-19 years old) admitted to a reference unit for eating disorders between 1999 and 2000 with a diagnosis of anorexia nervosa were evaluated at admission and at discharge. A range of biochemical, nutritional, and hormonal parameters were determined. At admission, no protein or lipid deficiencies were found, although many patients presented with hormonal abnormalities and red blood cell folate and zinc deficiencies. Hormonal abnormalities reverted significantly (p <.000) after renutrition. There were decreases in erythrocytes and in levels of hemoglobin (p <.000) and folic acid (p <.05). Red blood cell folate and zinc increased but did not reach normal levels. In a large proportion of adolescent anorexic patients, supplementation of folic acid and zinc is recommended although protein or hormonal replacement does not seem to be necessary.


Mechanisms of retroviral mutation.
Retroviruses, like other RNA viruses, mutate at very high rates (0.05-1 mutations per genome per replication cycle) and exist as complex genetically heterogeneous populations ('quasispecies') that are ever changing. De novo mutations are generated by inherently error-prone steps in the retroviral life cycle that introduce base substitutions, frame shifts, genetic rearrangements and hypermutations.


The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning.
Somatic mutation in neurons is linked to neurologic disease and implicated in cell-type diversification. However, the origin, extent, and patterns of genomic mutation in neurons remain unknown. We established a nuclear transfer method to clonally amplify the genomes of neurons from adult mice for whole-genome sequencing. Comprehensive mutation detection and independent validation revealed that individual neurons harbor ∼100 unique mutations from all classes but lack recurrent rearrangements. Most neurons contain at least one gene-disrupting mutation and rare (0-2) mobile element insertions. The frequency and gene bias of neuronal mutations differ from other lineages, potentially due to novel mechanisms governing postmitotic mutation. Fertile mice were cloned from several neurons, establishing the compatibility of mutated adult neuronal genomes with reprogramming to pluripotency and development.


Effective use of fly ash slurry as fill material.
A lot of effort has been put into increasing coal ash utilization; however, 50% of total amount is disposed of on land and in the sea. Several attempts have been reported recently concerning slurried coal fly ash use for civil engineering materials, such as for structural fill and backfill. The authors have studied this issue for more than 15 years and reported its potential for (1) underwater fills, (2) light weight backfills, and (3) light weight structural fills, through both laboratory tests and construction works. This paper is an overview of the results obtained for slurry, focusing on the following. (1) Coal fly ash reclaimed by slurry placement shows lower compressibility, higher ground density, and higher strength than by the other methods. This higher strength increases stability against liquefaction during earthquake. (2) Higher stability of the fly ash ground formed by slurry placement is caused by higher density and its self-hardening property. (3) Stability of fly ash reclaimed ground can be increased by increasing density and also by strength enhancement by cement addition. (4) Technical data obtained through a man-made island construction project shows the advantages of fly ash slurry in terms of mechanical properties such as higher stability against sliding failure, sufficient ground strength, and also in terms of cost saving. (5) Concentration in leachates from the placed slurry is lower than the Japanese environmental law. (6) In order to enlarge the fly ash slurry application toward a lightweight fill, mixtures of air foam, cement and fly ash were examined. Test results shows sufficient durability of this material against creep failure. This material was then used as lightweight structural fill around a high-rise building, and showed sufficient quality. From the above data, it can be concluded that coal fly ash slurry can be effectively utilized in civil engineering projects.


Genotyping of clinical methicillin-susceptible Staphylococcus aureus isolates in a Dutch teaching hospital.
Methicillin-susceptible Staphylococcus aureus isolates, recovered from 204 patients in our hospital in a 22-month period, were characterized by pulsed-field gel electrophoresis. Among the multiple S. aureus types six clonal lineages dominated, comprising isolates from 158 patients. Despite the limited genetic variation, cross-transmission was made plausible only sporadically.


Prenatal diagnosis of persistent left and absent right superior vena cava.
We report a case of persistent left superior vena cava (LSVC) with absent right superior vena cava (RSVC) diagnosed prenatally. At 27 weeks' gestation, routine fetal ultrasonography showed an abnormal four-chamber view. Fetal echocardiography revealed a markedly enlarged coronary sinus in the four-chamber view. An absent RSVC and a persistent LSVC were demonstrated in the three-vessel view. No additional cardiac malformations were seen before birth. Postnatal imaging confirmed the prenatal diagnosis. The combination of persistent LSVC and absent RSVC without any other cardiac malformations is an extremely rare cardiac anomaly and less commonly detected in utero. Identification of a dilated coronary sinus in the four-chamber view, with atypical features in the three-vessel view, may lead to the antenatal diagnosis of this condition.


Mitochondria as mediators of systemic inflammation and organ cross talk in acute kidney injury.
Acute kidney injury (AKI) is a systemic inflammatory disease that contributes to remote organ failures. Multiple organ failure is the leading cause of death due to AKI, and lack of understanding of the mechanisms involved has precluded the development of novel therapies. Mitochondrial injury in AKI leads to mitochondrial fragmentation and release of damage-associated molecular patterns, which are known to active innate immune pathways and systemic inflammation. This review presents current evidence suggesting that extracellular mitochondrial damage-associated molecular patterns are mediators of remote organ failures during AKI that have the potential to be modifiable.


Crystalline cytoplasmic inclusions in the liver cells of two mongrel dogs.
Crystalline inclusions were found in the cytoplasmic matrix of the liver cells in 2 out of 5 healthy mongrel dogs. The crystals were rectangular, with fine granular structure and free from the surrounding membrane. Their appearance was different from the intramitochondrial crystalline inclusions described in human and dog livers, as well as from those observed in the livers of other species. The significance of this unique finding remains unclear, but it is suggested that these inclusions represent crystalized protein.


The detection and evaluation of human tumor metastases.
Many biochemical indices are purported to have clinical utility in the detection and management of neoplasia. Experience gained during the past decade tends to indicate their having a more important role in the detection and monitoring of metastases than of the primary lesion. From this present review of some of the commoner human tumours, it is concluded that such marker substances are important adjuncts in the management of germ cell and certain endocrine and endocrine-related tumours. The carcinoembryonic antigen (CEA) provides a marker for many gastrointestinal cancers, but there are no presently available substances with clinical usefulness for either breast or lung neoplasms. Alternative approaches to the detection of metastases are also presented. The particular use of antibody probes at an immunohistochemical level has been claimed to be able to detect micrometastastic disease in bone marrow or tumour-related monoclonal antibody probes may have application to other cancers in the future.


Enhancing triethylamine sensing of ZIF-derived ZnO microspheres arising from cobalt doping and defect engineering.
Reasonable doping is beneficial to the generation of defects, which is a feasibility strategy to improve the ZnO sensing performance. Herein, we presented an in situ self-sacrificing template strategy for fabricating Co doped h-ZnO core-shell structures (h-ZnO/ZnCox) with different defect contents, pyrolyzing hierarchical porous ZnO (h-ZnO) sub-microspheres coated by zeolite imidazolate frameworks (h-ZnO/ZIF-ZnCox). The investigations of X-ray photoelectron (XPS), photoluminescence (PL) and Raman spectra indicate that donor defects include zinc interstitial (Zni) and oxygen vacancy (VO) in h-ZnO/ZnCox can be tuned by Co dopant (x = 0-30%). Resultantly, the h-ZnO/ZnCox exhibits a significantly enhanced response and selectivity towards triethylamine (TEA), beyond the undoped h-ZnO, and 15% Co-doped h-ZnO (h-ZnO/ZnCo15%) conducts the maximum responses of 1020 to 50 ppm TEA at 573 K, in the top set for the similar type of sensors. Further, the sensing mechanism of h-ZnO/ZnCox is elaborated, possibly resulting from abundant active oxygen species conversed from more oxygen adsorbed which corresponds to cobalt doping generating rich donor-related defects and additional electrons in h-ZnO/ZnCo15%.


Red blood cell distribution width predicts long-term outcomes in sepsis patients admitted to the intensive care unit.
Although some underpowered studies have proven that increased red blood cell distribution width (RDW) may be associated with short-term prognosis of sepsis, the long-term prognostic value of RDW remains largely unknown. This retrospective observational study was based on the Medical Information Mart for Intensive Care III (MIMIC III), a large critical care database. Baseline RDW and conventional disease severity scores were extracted along with data on 4-year mortality, of adult patients with severe sepsis upon first admission to the intensive care unit (ICU). The prognostic value of RDW was analyzed with Kapan-Meier cure, Cox model, receiver operating characteristic (ROC) curve analysis, net reclassification index (NRI) and integrated discriminatory index (IDI). A total of 4264 subjects were included. The area under ROC curve of RDW for predicting 4-year mortality was 0.64 (95% CI: 0.63-0.66). In multivariable Cox model, increased RDW was independently associated with all-cause mortality, irrespective of anemia. With conventional severity scores as reference, RDW had continuous NRI comprised between 0.18 and 0.20, and IDI comprised between 0.30 and 0.40. RDW values significantly predicts long-term all-cause mortality in critically ill patients with severe sepsis beyond conventional severity scores.


Steroid sulfatase in the human MG-63 preosteoblastic cell line: Antagonistic regulation by glucocorticoids and NFκB.
Steroid sulfatase (STS) converts sulfated steroids into active forms in cells. Preosteoblastic cells possess STS, but its role and regulation in bone are unclear. We examined STS activity and gene expression during differentiation of human MG-63 preosteoblasts. STS activity and gene expression were decreased during differentiation in cells treated with osteogenic supplement containing dexamethasone (DEX). DEX also inhibited STS activity and expression in undifferentiated cells, and the glucocorticoid antagonist RU486 reversed DEX inhibition of STS. These data may have implications for glucocorticoid-induced osteoporosis. The NFκB activators lipopolysaccharide and phorbol myristate acetate increased STS expression in undifferentiated and differentiated MG-63 cells, while the NFκB inhibitor BAY-11-7082 partially blocked these responses. The antagonistic actions of glucocorticoids and NFkB on STS expression are similar to the regulation of inflammatory response proteins. We propose a model of STS regulation whereby inflammation leads to increased STS, resulting in increased estrogen, which modulates the inflammatory response.


Trimetazidine protects cardiomyocytes against hypoxia-induced injury through ameliorates calcium homeostasis.
Intracellular calcium (Ca(2+)i) overload induced by chronic hypoxia alters Ca(2+)i homeostasis, which plays an important role on mediating myocardial injury. We tested the hypothesis that treatment with trimetazidine (TMZ) would improve Ca(2+)i handling in hypoxic myocardial injury. Cardiomyocytes isolated from neonatal Sprague-Dawley rats were exposed to chronic hypoxia (1% O2, 5% CO2, 37 °C). Intracellular calcium concentration ([Ca(2+)]i) was measured with Fura-2/AM. Perfusion of cardiomyocytes with a high concentration of caffeine (10 mM) was carried out to verify the function of the cardiac Na(+)/Ca(2+) exchanger (NCX) and the activity of sarco(endo)-plasmic reticulum Ca(2+)-ATPase (SERCA2a). For TMZ-treated cardiomyocytes exposured in hypoxia, we observed a decrease in mRNA expression of proapoptotic Bax, caspase-3 activation and enhanced expression of anti-apoptotic Bcl-2. The cardiomyocyte hypertrophy were also alleviated in hypoxic cardiomyocyte treated with TMZ. Moreover, we found that TMZ treatment cardiomyocytes enhanced "metabolic shift" from lipid oxidation to glucose oxidation. Compared with hypoxic cardiomyocyte, the diastolic [Ca(2+)]i was decreased, the amplitude of Ca(2+)i oscillations and sarcoplasmic reticulum Ca(2+) load were recovered, the activities of ryanodine receptor 2 (RyR2), NCX and SERCA2a were increased in cardiomyocytes treated with TMZ. TMZ attenuated abnormal changes of RyR2 and SERCA2a genes in hypoxic cardiomyocytes. In addition, cholinergic signaling are involved in hypoxic stress and the cardioprotective effects of TMZ. These results suggest that TMZ ameliorates Ca(2+)i homeostasis through switch of lipid to glucose metabolism, thereby producing the cardioprotective effect and reduction in hypoxic cardiomyocytes damage.


Calcification in high grade gliomas treated with bevacizumab.
Calcification is a rare phenomenon in high grade glioma (HGG). CT scans are sensitive to mineralization but used infrequently for tumor assessment in the MRI era. The presence of calcification can be overlooked on routine MRI. Calcification may reflect chronicity and natural changes in the tumor or its milieu over time and may be accelerated by certain treatments. Calcification may have clinical significance which could signal potential risk for stroke or hemorrhage related to particular therapies; or it may be a positive prognostic factor for treatment response. The true incidence and relevance of calcification in HGG and relation to therapy is unclear. During treatment of HGG patients with bevacizumab (BVZ) we observed significant tumor calcification on brain CT. We performed a retrospective review of HGG patients treated with BVZ to quantitate the incidence of calcification in this group compared to those treated with cytotoxic therapy alone. Sixty-two patients with progressive HGG were treated with BVZ and a cytotoxic agent. Among 19 patients treated for 6+ months, 12 had a CT scan performed. We observed an unexpected phenomenon of calcification in the CT scans of several patients. We were also able to comparatively quantitate the incidence of calcification in a control group of primary glioblastoma (GB) patients not exposed to BVZ therapy. The incidence of calcification in the general GB population is increased with longer survival. The phenomenon is increased with anti-angiogenic therapy for brain tumors. Calcification may have significance as a predictor for treatment response.


Duodenal gossypiboma following complicated cholecystectomy - A rare cause of gastric outlet obstruction.
A surgical sponge, left accidentally inside a patient's body remains an infrequent but serious surgical complication. The retained sponges can lead to significant morbidity and mortality. A 40 year old female patient presented with recurrent pain in epigastric region associated with postprandial vomiting. The patient had underwent a difficult laproscopic conversion to open cholecystectomy 2.5 months ago in another hospital. Physical examination revealed previous surgical scar with tenderness over right hypochondrium. CECT abdomen showed thickening of gastric antropyloric region with possibility of neoplasia. An Upper GI endoscopy showed a large gossypiboma in antral region. With failed endoscopic retrieval, patient underwent an Exploratory Laparotomy with removal of the surgical compress via a duodenotomy and thus the final diagnosis of gossypiboma was made. Gossypiboma or textilomas are infrequent complications of surgery leading to significant morbidity and mortality, medicolegal consequences and lawsuits against the surgeon and hospital. Gossypiboma eroding into duodenum presenting as gastric outlet obstruction, usually diagnosed and retrieved endoscopically but surgical removal is required for failed endoscopic management.


Analysis of 153 gunshot wounds of the liver.
Gunshot wounds of the liver may result in substantial morbidity and death, and optimal management of complex injuries is controversial. One hundred and fifty-three patients with civilian gunshot liver injuries were treated during the 10-year period 1986-1995. Demographic, clinical and operative data were recorded. Factors influencing postoperative complications and death were analysed. One hundred and forty-two patients (93 per cent) had single missile injuries and 11 (7 per cent) had shotgun injuries. Three patients were treated non-operatively and 150 patients underwent operation. In 105 patients (70 per cent) the injuries to the liver were minor and required either no treatment (93) or simple suture of bleeding vessels (12). Forty-five patients (30 per cent) had major injuries which were either packed only (26) or required more complex surgical intervention (19). This included resectional debridement (ten), major venous repair (eight) and hepatotomy (one); eight of these patients required packing combined with the procedure. Associated intra-abdominal injuries occurred in 115 patients (77 per cent). The overall mortality rate was 17 per cent (26 patients). Death was directly attributable to the liver injury in 13 patients (8 per cent), 12 of whom died from uncontrolled bleeding. Complications occurred in 63 (51 per cent) of 124 survivors, and correlated with the type and severity of the liver injury and the number of associated injuries. Most gunshot liver injuries can be managed by simple surgical techniques. In complex injuries control of major haemorrhage is vital and perihepatic packing may be life saving before undertaking definitive repair of the injury under controlled conditions.


Solid state investigation of mefloquine hydrochloride.
Mefloquine hydrochloride was crystallized under different conditions and the products were studied by thermal analysis, IR spectroscopy and X-ray diffraction. It was demonstrated that different conditions of crystallization resulted in different crystal structures. The alpha- and delta-modifications were hydrates, the beta- and gamma-forms were polymorphs, the epsilon-form was an acetone solvate and theta-mefloquine was tetrahydrofuran solvate. During long storage at room temperature, the alpha-, delta- and theta-forms of mefloquine hydrochloride were transformed. By heat treatment of the delta-, epsilon and theta-modifications, a new crystal structure was obtained.


A randomized, controlled trial comparing topical steroid application to wet versus dry skin in children with atopic dermatitis (AD).
Soak and smear (SS), a technique whereby a bath is followed by topical corticosteroid (TCS) application to wet skin, is reported to be a beneficial adjunctive therapy for patients with recalcitrant atopic dermatitis (AD). We evaluated whether SS is of greater benefit than application of TCS to dry skin for the treatment of childhood AD. A randomized, investigator-blinded, controlled study was performed in children with AD. Patients were randomized to apply TCS either via SS (n = 22) or to dry skin (n = 23) for 14 days. The primary outcome was an improvement in the Eczema Area and Severity Index score. Secondary outcomes included assessments of disease burden, pruritus, and sleep; morning cortisol levels; and adverse effects. Patients with AD severity who applied TCS via SS or to dry skin improved 84.8% (95% confidence interval 77.5-92.1) and 81.4% (95% confidence interval 70.3-92.4) by Eczema Area and Severity Index score, respectively. There was no statistical difference between the 2 groups (P value = .85). Small sample size limited the power of our study. We did not find that application of TCS to presoaked skin works better than application to dry skin for the treatment of AD in children.


Severity of Obstructive Sleep Apnea Is Positively Associated With the Presence of Carotid Artery Atheromas.
Hypoxemia and hypertension caused by obstructive sleep apnea (OSA) often result in atherosclerosis of the carotid and coronary vessels and heightened risk of stroke and myocardial infarction (MI). Therefore, this study investigated whether severity of OSA, based on the apnea-hypopnea index (AHI), is associated with the presence of calcified carotid artery (atherosclerotic) plaque (CCAP) seen on panoramic images (PIs). Using a cross-sectional study design, the electronic medical records and PIs of all male patients referred from the sleep medicine service to the dental service from 2010 through 2016 were reviewed. The predictor variable was the patients' OSA intensity level as defined by the American Academy of Sleep Medicine based on the AHI score. The outcome variable was the presence of CCAP on the PI. Other variables of interest, that is, demographic and atherogenic risk factors (age, body mass index, diabetes, hypertension, and hyperlipidemia), were included in a multivariate analysis to assess the association of OSA with CCAP. The study sample consisted of 108 men (mean age, 54.7 ± 13.5 yr). Approximately one third (n = 33; 30.6%) presented with CCAP and this group was significantly older with greater odds of co-diagnosis of diabetes (P < .05). Patients with more "severe" OSA showed significantly greater odds of having CCAP on their PIs compared with those with "milder" OSA (odds ratio = 1.035; 95% confidence interval, 1.008-1.062; P = .010) when adjusted for confounders. There is a significant association between severity of OSA and the presence of CCAP visible on PI. These atherosclerotic plaques are "risk factors" for stroke and "risk indicators" for future MI; therefore, clinicians providing corrective airway surgery for these patients and noting concomitant CCAP on PI should refer these patients for a thorough cerebrovascular and cardiovascular workup.


Relationship between the incidence of type 1 diabetes and enterovirus infections in different European populations: results from the EPIVIR project.
The incidence of type 1 diabetes varies markedly between countries. As enterovirus infections have been linked to type 1 diabetes, we determined whether this variation correlates with the frequency of enterovirus infections in different Caucasian populations in Europe. Enterovirus antibodies were examined in the background population (1-year-old and 10-14-year-old children) in seven countries with either exceptionally high (Finland and Sweden) or low/intermediate incidence of diabetes (Estonia, Germany, Hungary, Lithuania, Russia) using EIA and neutralisation assays. Enterovirus antibodies were less frequent in countries with high diabetes incidence compared to countries with low diabetes incidence (P<0.001). This suggests that enterovirus infections are not particularly common in countries with high diabetes incidence. In contrast, there seems to be an inverse correlation between the incidence of type 1 diabetes and enterovirus infections in the background population, which is in line with the previously proposed polio hypothesis according to which the complications of enterovirus infections become more common in an environment with a decreased rate of infections.


The Impact of a Mobile Support Group on Distress and Physical Activity in Breast Cancer Survivors: Randomized, Parallel-Group, Open-Label, Controlled Trial.
While mobile health apps have demonstrated their potential in revolutionizing health behavior changes, the impact of a mobile community built on these apps on the level of physical activity and mental well-being in cancer survivors remains unexplored. In this randomized controlled trial, we examine the effects of participation in a mobile health community specifically designed for breast cancer survivors on their physical activity levels and mental distress. We performed a single-center, randomized, parallel-group, open-label, controlled trial. This trial enrolled women between 20 and 60 years of age with stage 0 to III breast cancer, an Eastern Cooperative Oncology Group performance status of 0, and the capability of using their own smartphone apps. From January 7, 2019, to April 17, 2020, a total of 2,616 patients were consecutively screened for eligibility after breast cancer surgery. Overall, 202 patients were enrolled in this trial, and 186 patients were randomly assigned (1:1) to either the intervention group (engagement in a mobile peer support community using an app for tracking steps; n=93) or the control group (using the app for step tracking only; n=93) with a block size of 10 without stratification. The mobile app provides a visual interface of daily step counts, while the community function also provides rankings among its members and regular notifications encouraging physical activity. The primary end point was the rate of moderate to severe distress for the 24-week study period, measured through an app-based survey using the Distress Thermometer. The secondary end point was the total weekly steps during the 24-week period. After excluding dropouts, 85 patients in the intervention group and 90 patients in the control group were included in the analysis. Multivariate analyses showed that patients in the intervention group had a significantly lower degree of moderate to severe distress (B=-0.558; odds ratio 0.572; P<.001) and a higher number of total weekly step counts (B=0.125; rate ratio 1.132; P<.001) during the 24-week period. Engagement in a mobile app-based patient community was effective in reducing mental distress and increasing physical activity in breast cancer survivors. ClinicalTrials.gov NCT03783481; https://classic.clinicaltrials.gov/ct2/show/NCT03783481.


Eliminating sternal wound infections: Why every cardiac surgery program needs an I hate infections team.
The majority of studies examining deep sternal wound infection (DSWI) prevention focus on ameliorating 1 variable at a time. There is a paucity of data regarding the synergistic effects of combining clinical and environmental interventions. This article describes an interdisciplinary, multimodal approach to eliminate DSWIs at a large community hospital. We developed a robust, multidisciplinary infection prevention team to evaluate and act in all phases of perioperative care to achieve a cardiac surgery DSWI rate of 0, named: the I hate infections team. The team identified opportunities for improved care and best practices and implemented changes on an ongoing basis. Patient-related interventions consisted of preoperative methicillin-resistant Staphylococcus aureus identification, individualized perioperative antibiotics, antimicrobial dosing strategies, and maintenance of normothermia. Operative-related interventions involved glycemic control, sternal adhesives, medications and hemostasis, rigid sternal fixation for high-risk patients, chlorhexidine gluconate dressings over invasive lines, and use of disposable health care equipment. Environment-related interventions included optimizing operating room ventilation and terminal cleaning, reducing airborne particle counts, and decreasing foot traffic. Together, these interventions reduced the DSWI incidence from 1.6% preintervention to 0% for 12 consecutive months after full bundle implementation. A multidisciplinary team focused on eliminating DSWI identified known risk factors and implemented evidence-based interventions in each phase of care to ameliorate risk. Although the influence of each individual intervention on DSWI remains unknown, use of the bundled infection prevention approach reduced the incidence to 0 for the first 12 months after implementation.


Insights into SARS-CoV-2-associated subacute thyroiditis: from infection to vaccine.
Since the COVID-19 emergence as a global pandemic in March 2020, more than 5 million SARS-CoV-2-related deaths have been globally documented. As the pandemic progressed, it became clear that, although the infection is mainly characterized as a respiratory disease, it also affects other organs and systems, including the thyroid gland. Indeed, emerging evidence suggests that SARS-CoV-2 can act as a trigger for various thyroid disorders, for example, subacute thyroiditis (SAT), Grave's disease, and non-thyroidal illness syndrome. The entry of SARS-CoV-2 into the host cells is mainly mediated by the ACE2-receptor, making organs and systems with high expression of this receptor, such as the thyroid gland, highly vulnerable to COVID-19. Accumulating data propose that SAT may be an underestimated manifestation of COVID-19 infection. Importantly, if SAT remains unrecognized, it may trigger or aggravate potential other complications of the disease, for example, respiratory insufficiency and cardiovascular complications, and thus negatively influence prognosis. Moreover, recent case reports, case series, and systematic reviews highlight SAT as a potential side effect of the vaccination against SARS-CoV-2. The present review aims to raise awareness of SARS-CoV-2-associated- and post-vaccination subacute thyroiditis, to discuss recent evidence regarding its pathophysiology, and to present useful information for this special form of SAT related to daily clinical practice.


Genetic diversity and new therapeutic concepts.
The differences in medicinal drug responses among individuals had been known for quite some time. Some patients exhibit a life-threatening adverse reaction while others fail to show an expected therapeutic effect. Intermediate responses between the above two extreme cases are also known. In fact, it has been recently reported that approximately 100,000 deaths and more than 2 million hospitalizations annually in the United States are due to properly prescribed medications. This interindividual variability could be due in part to genetically determined characteristics of target genes or drug metabolizing enzymes. This has now been substantiated by a variety of studies. We know that "one size fits all" is not correct. Therefore, the application of pharmacogenetic concepts to clinical practice is an excellent goal in the postgenomic era. The successful completion of the human genome project provided necessary molecular tools, such as high-throughput SNP genotyping, HapMap, and microarray, that can be applied to develop proper therapeutic options for individuals. Recently, there have been considerable scientific, corporate, and policy interest in pharmacotherapy. However, identification of causal variations in a target gene is only a starting point, and the progress in this rapidly developing field is slower than expected. One major drawback could be due to the multigene determinant of drug response that requires a genome-wide screening. Additionally, application of pharmacogenetic knowledge into clinical practice requires a high level of accuracy, precision (risk/benefit ratio), and strict regulations. This is because the pharmacogenetic approach raises several ethical, moral, and legal questions. It is also necessary that both health professionals and the general public must be urgently educated. Despite these limitations, translation of pharmacogenomic data into clinical practice would certainly provide better opportunities to increase the safety and efficacy of medicine in the future.


Vitamin D deficiency in the absence of enteropathy in three cases with common variable immunodeficiency.
Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and a defect in antibody production. Herein we describe 3 patients diagnosed with CVID in whom vitamin D deficiency was detected in the absence of enteropathy. Biochemical and immunological analysis, serum osteocalcin, parathyroid hormone, 25-OH vitamin D, 1,25(OH)(2) vitamin D, vitamin A, vitamin E, urinary calcium, and deoxypyridinoline measurements were carried out. Vitamin D receptor (VDR) expression was examined in the peripheral blood mononuclear cells and hair follicles by reverse transcriptase polymerase chain reaction. VDR gene polymorphism was evaluated by high-performance liquid chromatography. None of the patients presented nutrient deficiencies other than vitamin D. Two of them were free of osteomalacia-related symptoms. VDR expression was found to be lower in the peripheral blood mononuclear cells and hair follicles when compared to the control group. Patients with CVID may present asymptomatic vitamin D deficiency. Vitamin D and VDRs play an important role in the innate immune system and modulate Toll-like receptor-related responses. Delay in diagnosis may predispose these patients not only to irreparable bone loss but also to infections, and autoimmune and malignant disorders, thus emphasizing the importance of prompt intervention.


High prevalence of Taenia saginata taeniasis and status of Taenia solium cysticercosis in Bali, Indonesia, 2002-2004.
An epidemiological survey of taeniasis/cysticercosis was carried out in one semi-urban and two urban villages in three districts of Bali, Indonesia in 2002 and 2004. In total, 398 local people from 247 families were diagnosed by anamnesis and clinical examinations, and 60 residents were suspected to be taeniasis carriers. Among 60 suspected carriers, 56 persons expelled a total of 61 taeniid adult worms after praziquantel treatment. From 398 residents, 252 stool samples were available for analysis of taeniid eggs, coproantigens or copro-DNA for identification of taeniid species, and 311 serum samples were available for detection of antibodies against Taenia solium cysticercosis. Taeniasis prevalences were highly variable among three villages (1.1-27.5%), and only one case of cysticercosis due to T. solium infection was detected. All expelled tapeworms were confirmed to be Taenia saginata by mtDNA analysis. There was no Taenia asiatica human case in Bali. Case control analysis of 106 families chosen at random from 179 families in 2004 and another 106 families from non-endemic areas revealed that risk factors of T. saginata taeniasis for families were: level of education (P<0.01); consumption of beef lawar (P<0.01); and the source of lawar (P<0.01).


Understanding autonomous behaviour development: Exploring the developmental contributions of context-tracking and task selection to self-directed cognitive control.
Gaining autonomy is a key aspect of growing up and cognitive control development across childhood. However, little is known about how children engage cognitive control in an autonomous (or self-directed) fashion. Here, we propose that in order to successfully engage self-directed control, children identify, and achieve goals by tracking contextual information and using this information to select relevant tasks. To disentangle the respective contributions of these processes, we manipulated the difficulty of context-tracking via altering the presence or absence of contextual support (Study 1) and the difficulty of task selection by varying task difficulty (a)symmetry (Study 2) in 5-6 and 9-10-year-olds, and adults. Results suggested that, although both processes contribute to successful self-directed engagement of cognitive control, age-related progress mostly relates to context-tracking.


Natural killer cells in human solid tumors.
Natural killer (NK) cells have been studied in human neoplastic diseases in an effort to assess the role of these cells in the control of human neoplasia and to monitor the effects of therapeutic regimens expected to affect this reactivity. NK activity measured against susceptible cell lines is usually somewhat depressed in patients bearing advanced solid tumors, but not at early disease stages. Lymphoid cells associated with solid tumor tissues or effusions have usually low NK cytotoxicity, with considerable differences among histologic types (e.g., nasopharyngeal carcinoma versus other tumors) or at different sites involved by the same tumor (e.g., peritoneal effusions versus solid lesions in ovarian carcinoma). The low levels of NK activity of tumor-associated lymphoid cells are primarily related to a low frequency in the relevant effector cells at the tumor site, although suppression of the in vitro maintenance of cytotoxicity by in situ macrophages and lymphocytes has been described in a few patients. Treatment with immunopharmacologic agents, interferons in particular, has been reported to augment NK activity in cancer patients, but it is unclear how blood NK activity relates to tissue levels of this reactivity. Limited evidence indicates that blood NK levels need not be representative of the activity of tumor associated lymphoid cells. Most studies on NK cells in human neoplasia have dealt with reactivity against susceptible tissue culture lines, but freshly isolated human tumors are generally relatively resistant to these effector cells, particularly when autologous lymphoid cells are used. The resistance of fresh human neoplastic cells to NK activity has not been studied extensively and, together with the poor localization at the tumor site of NK effectors, it represents a major difficulty in envisaging a role for these cells in the control of established human neoplasia.


The location of protein in serum lipoproteins: a fluorescence quenching study.
Quenching of the tryptophan fluorescence of pig serum HDL3 and LDL2 lipoproteins by iodide and succinimide has been used to estimate the accessibility of the fluorophores to the solvent and, by inference, the location of the protein in the macromolecular complexes. At least 80% of the protein is thought to be located at or near the surface in both lipoproteins but its accessibility is hindered especially in LDL2. A difference in surface topography in the two lipoproteins is suggested with the protein in LDL2 more buried in lipid and further away from the charged phospholipid polar groups than in HDL3. A refined treatment of the quenching data has been developed to take account of the heterogeneity of quenching sites found in the lipoproteins.


Sex differences in clinico-pathologic characteristics and long-term survival among 17,192 surgically treated NSCLC patients: Nationwide population-based propensity score-matching study.
More information is needed on gender differences in lung cancer surgery. Thus, we conducted a retrospective study on thoracic treatment of non-small cell lung cancer (NSCLC) patients between 2007 and 2020 in Poland. The aim was to characterize sex differences in survival after complete surgical resection and to compare postoperative complications between Polish men and women. The main aspects that were compared between women and men were as follows: type of surgery and postoperative staging, morbidity and mortality, thoracic surgery complications, comorbidities, and overall survival based on a univariate analysis including propensity score matching (PSM) and a multivariate analysis. Data were collected retrospectively from the Polish Lung Cancer Study Group database. Patients who were surgically treated for NSCLC between 2007 and 2020 (n = 17,192) were included in the study. The univariate analysis showed significantly better survival in women than in men. Women had better 5-year survival compared to men both for adenocarcinoma and squamous cell carcinoma (66% vs. 53%, p < 0.0001 and 65% vs. 51%, p<0.0001%, respectively), for both smokers and non-smokers (65% vs. 52%, p < 0.0001 and 65% vs. 51%, p < 0.0001, respectively), all age groups, and all stages (IA1 to III B). In the PSM analysis, statistically significant differences in favor of women were found for lower lobectomy (67% vs. 50%, p < 0.0001) and upper lobectomy (67% vs. 56%, p < 0.0001). Overall, postoperative complications occurred in 33.1% of patients and were observed more often in men than in women (35.8% vs. 28.6%, p < 0.001). Women with NSCLC who were treated surgically had a better long-term outcome compared to men, with no significant difference in disease severity. In addition to gender, the histological type, comorbidities, and type of surgery and surgical approach are also important.


Temperature--the forgotten vital sign.
To improve the measurement of core body temperature in the resuscitation room. This work was undertaken in the Emergency Department (ED) of a large District General Hospital. The clinical notes for all admissions to the resuscitation suite during a 2 month period were reviewed to establish the frequency of temperature measurement. Following a simple educational program, performance was re-audited using the same methodology. Of the first cohort 13.4% had had their temperature recorded. This improved to 71.6%. The measurement of body temperature in the resuscitation room is important as hypothermia has profound effects on the cardiovascular, pulmonary, neurological and haemostatic systems. Clinical audit highlights poor current performance and enables improvement of practice through simple education.


Visual projections induced into the auditory pathway of ferrets: II. Corticocortical connections of primary auditory cortex.
Although the development of corticocortical projections has been well studied, less is known about the role of sensory inputs in the specification of these connections. As part of an ongoing series of studies in our laboratory, we have examined the role of thalamic input modality in the development of corticocortical connections. These studies involve making unilateral lesions and inducing retinal inputs into the auditory thalamus (MGN) during early development in ferrets, thereby conferring visual responsiveness on primary auditory cortex (AI). In this way we can examine the role of input identity in cortical specification in general, and connectivity patterns specifically. A previous paper (Pallas et al. [1990] J. Comp. Neurol. 298:50-68) described the pattern of thalamocortical and corticothalamic connections of auditory cortex in normal and lesioned animals. This study compares the pattern of auditory corticocortical connections in normal and lesioned animals. We injected neuroanatomical tracers into AI and mapped out the distribution of retrogradely labelled cells in the cortex. We report that the cortical inputs to ferret AI resembled those in cats, and that the pattern of ipsi- and contralateral corticocortical connections of ferret AI with visual input was similar to the normal pattern. Auditory cortex with visual input did not make ectopic connections with visual cortex, but maintained its connections with other auditory cortical areas. These results suggest that the overall corticocortical connections of an area are not influenced by the modality or activity pattern of its inputs. In particular, altering the input activity to a cortical area does not seem to promote the formation of entirely new connections, although small changes in the strength of existing connections are possible (Sur et al. [1990] Trends Neurosci. 13:227-233).


Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment.
New approach methodologies (NAMs) have the potential to become a major component of regulatory risk assessment, however, their actual implementation is challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) was designed to address many of the challenges that exist for the development and implementation of NAMs in modern chemical risk assessment. PARC's proximity to national and European regulatory agencies is envisioned to ensure that all the research and innovation projects that are initiated within PARC agree with actual regulatory needs. One of the main aims of PARC is to develop innovative methodologies that will directly aid chemical hazard identification, risk assessment, and regulation/policy. This will facilitate the development of NAMs for use in risk assessment, as well as the transition from an endpoint-based animal testing strategy to a more mechanistic-based NAMs testing strategy, as foreseen by the Tox21 and the EU Chemical's Strategy for Sustainability. This work falls under work package 5 (WP5) of the PARC initiative. There are three different tasks within WP5, and this paper is a general overview of the five main projects in the Task 5.2 'Innovative Tools and methods for Toxicity Testing,' with a focus on Human Health. This task will bridge essential regulatory data gaps pertaining to the assessment of toxicological prioritized endpoints such as non-genotoxic carcinogenicity, immunotoxicity, endocrine disruption (mainly thyroid), metabolic disruption, and (developmental and adult) neurotoxicity, thereby leveraging OECD's and PARC's AOP frameworks. This is intended to provide regulatory risk assessors and industry stakeholders with relevant, affordable and reliable assessment tools that will ultimately contribute to the application of next-generation risk assessment (NGRA) in Europe and worldwide.


Evaluation of the in vivo function of the Hancock porcine xenograft in the aortic position.
We evaluated the vivo hemodynamic function of the stent-mounted glutaraldehyde-fixed porcine xenograft in 23 patients who had undergone aortic valve replacement from 2 days to 24 months prior to the study. Functional aortic valve orifice areas for the porcine xenograft ranged from 0.58 to 3.0 sq. cm., the average area being 1.36 sq. cm. Six patients had calculated prosthetic valve orifice areas less than 1.0 sq. cm. Valve orifice area did not correlate significantly with valve size or the time interval from surgery to postoperative study. Left ventricular stroke volume showed a significant, positive correlation with calculated xenograft orifice area. Systemic thromboembolism was not encountered. One patient required reoperation for xenograft stenosis caused by dense fibrin deposition on the aortic leaflets. We conclude that use of the stent-mounted glutaraldehyde-fixed porcine xenograft can be associated with significant functional stenosis which may be related to annulus size or inertial properties of the valve. These factors should be taken into consideration when considering use of the stent-mounted glutaraldehyde-fixed porcine xenograft in individual patients.


Hybrid drug delivery system for oropharyngeal, cervical and colorectal cancer - in vitro and in vivo evaluation.
The present investigation was designed with the intention to formulate a versatile 5-fluorouracil(5-FU) matrix tablet surpassing issues associated with current conventional chemotherapeutic drug delivery systems. The novel 5-FU matrix tablet fulfills therapeutic needs by engineering matrix tablets utilizing chitosan-sodium alginate interpolyelectrolyte complex (IPEC). IPEC was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The matrix tablets were formulated utilizing IPEC alone and in combination with chitosan, sodium alginate and sodium deoxycholate as permeation enhancer. Pharmaceutical properties, swelling studies, in vitro dissolution and diffusion studies, mucoadhesive studies and in vivo studies were performed for formulated 5-FU. The selected chitosan-sodium alginate IPEC offers pH independent 5-FU release in comparison to alone or physical mixture of chitosan and sodium alginate. Furthermore, novel matrix tablets demonstrated significantly higher bioadhesive properties with controlled 5-FU release without the initial burst effect and also demonstrated a higher permeation of 5-FU. To conclude, the developed novel 5-FU matrix tablets pave way as an excellent alternative for cancer treatment which could potentially minimize the dose dependent side effects and provide better patient compliance.


Formation of an unprecedented (CuBr)5 cluster and a zeolite-type 2D-coordination polymer: a surprising halide effect.
A unique pentanuclear cluster within a zeolite-type polymer ([Cu5(μ4-Br)(μ3-Br)2(μ2-Br)2](μ2-MeSPr)3)n (1; void space >81%) and a luminescent 1D ([Cu(μ3-I)]4(MeSPr)3)n polymer, 2, are formed when MeSPr reacts with CuBr and CuI.


The effects of fumonisin B1 at the No Observed Adverse Effect Level (NOAEL) and 5-times above on the renal histology and lipidome of rats.
Fumonisin B1 (FB1) mycotoxin was intraperitoneally (IP) administered at the No Observed Adverse Effect Level (NOAEL = 0.2 mg/kg BW/day as IP equivalent, "L") and 5-times above ("H") to male rats, in a controlled ("C"), 5-day study (n = 10/group, total n = 30). BW (bodyweight) of H rats decreased after day 4, kidney weight after 5 days. Renal histology revealed tubular epithelial desquamation, tubular dilatation, nuclear swelling, pale chromatin, cell vacuolation and casual karyopycnosis (H). Lipidomic analysis was performed with liquid chromatography - time-of-flight mass spectrometry (LC-TOF). Renal sphinganine (Sa) concentration increased 500 (L) to 1000-fold (H) and Sa-1-P to over 200 and 350-fold, respectively), with FB1 dose-dependence. Renal triacyclglycerols, diacylglycerols, ceramides and sphingomyelins were depleted, while cholesterol and cholesterol ester concentrations increased. Spearman correlation of free sphingoid bases (Sa, Sa-1-P, sphingosine (So) and So-1-P) was positive with histopathological damage severity, sphingomyelins and ceramides provided negative relationship (-0.78 and -0.8, resp.). Two-way cluster analysis and sparse partial least squares discriminant analysis (sPLS-DA) was used for experimental group classification. Fully effective group separation was achieved for ceramides, sphingomyelins and phosphatidyl-cholines, highlighting molecular species of possible diagnostic value. Lipidomic results highlight possible re-consideration of the NOAEL.


Activation process of the mosquitocidal delta-endotoxin Cry39A produced by Bacillus thuringiensis subsp. aizawai BUN1-14 and binding property to Anopheles stephensi BBMV.
Most delta-endotoxins produced by Bacillus thuringiensis require proteolytic processing in order to become active. The in vitro and in vivo activation processes of Cry39A, a delta-endotoxin that is highly toxic to Anopheles stephensi, were investigated. Cry39A with a molecular mass of 72 kDa was processed in vitro into a 60 kDa fragment by trypsin and gut extract from A. stephensi larvae. N-terminal amino acid sequencing of the 60 kDa fragment revealed that trypsin and the protease(s) in the gut extract cleaved Cry39A between Arg(61) and Gly(62). In contrast, 40 and 25 kDa polypeptides were generated in vivo by intramolecular cleavage of the 60 kDa fragment in A. stephensi larvae. Further, a co-precipitation assay was used to investigate the binding property of the activated Cry39A to A. stephensi BBMV. Cry39A bound to A. stephensi BBMV specifically and did not compete with the Cry4Aa toxin. This indicated that the binding molecule(s) for Cry39A might differ from those for Cry4A. In addition, Cry39A preferentially bound to the Triton X-100-insoluble membrane fraction.


Human cytotoxic T lymphocytes (CTL) against Epstein-Barr virus (EBV) infected cells: EBV specificity and involvement of major histocompatibility complex determinants in the lysis exerted by anti-EBV CTL toward HLA-compatible and allogeneic target cells.
Human peripheral blood lymphocytes (PBL), from anti-Epstein-Barr virus (EBV)-seropositive donors, were stimulated by EBV and were shown to be cytotoxic toward autologous, HLA-compatible, and fully allogeneic EBV-transformed target cells. The lysis was not due to natural killer (NK) cells since the target cells used were resistant to lysis by fresh PBL and by virus-stimulated PBL-depleted of AET-SRBC-rosetting T cells (the latter being still fully cytotoxic on K562 NK-susceptible target cells). Conversely only E-rosette-purified (T) lymphocytes killed EBV-transformed HLA-compatible and allogeneic target cells. Moreover, anti-MHC antibodies inhibited the cytotoxicity exerted by EBV-induced cytotoxic T lymphocytes (CTL) on both autologous and allogeneic target cells. Finally the lysis was EBV specific since PHA blasts were not killed and since only EBV-transformed cells could compete for lysis with the EBV-positive target cells. Efficient competition was achieved by EBV-transformed cells autologous or allogeneic to the targets, even when effector and target cells were fully allogeneic. All together, the data suggest that human anti-EBV CTL may recognize nonpolymorphic HLA determinants on the target cells in association with the virus-induced antigens.


Postoperative bleeding after dental extraction in liver pretransplant patients.
The aim of this prospective observational study was to evaluate the incidence of postoperative bleeding after dental extraction in candidates for liver transplantation and the efficacy of the association of tranexamic acid and absorbable hemostatic sponges. All individuals referred for oral health evaluation requiring extraction were considered in this study. Patients were included in the analysis when the blood examinations showed a platelet count of 30,000/mm(3) or greater and an international normalized ratio (INR) of 3.0 or less. In group 1 local pressure was applied by use of gauze soaked with tranexamic acid, and in group 2 gauze without tranexamic acid was used. Absorbable hemostatic sponges and cross sutures were used as a standard hemostatic measure. In the 23 patients included in this study, 84 simple extractions were performed during 35 dental surgical procedures. The main preoperative blood tests found the following: a mean hematocrit level of 34.54% (SD, 5.84%; range, 21.7%-44.4%), platelet counts from 31,000/mm(3) to 160,000/mm(3), and a mean INR of 1.50 (SD, 0.39; range, 0.98-2.59). Postoperative bleeding occurred during only 1 procedure (2.9%), and local pressure with gauze was effective for achieving hemostasis. No statistically significant difference in the time to hemostasis was found between the 2 groups. This study found a low risk of bleeding for tooth extractions in patients with liver cirrhosis, INRs of 2.50 or less, and platelet counts of 30,000/mm(3) or greater. Blood transfusions were not needed, and in the case of postoperative bleeding, the use of local hemostatic measures was satisfactory.


The West Los Angeles Preterm Birth Prevention Project: II. Cost-effectiveness analysis of high-risk pregnancy interventions.
To examine the cost-effectiveness of the West Los Angeles Preterm Birth Prevention Project. Maternal and neonatal care data were collected on all preterm deliveries (150) and a random sample of term deliveries (140) from high-risk patients at both experimental and control clinic sites. Costs were determined for prenatal care, inpatient preterm labor, delivery and postpartum care, and newborn care. Cost calculations, weighted by the actual proportions of term and preterm births, were confirmed with square-root transformation and trimmed mean (2%) values. When compared to control clinic high-risk patients, experimental clinic high-risk patients had an average cost savings of $2196 for newborn care (P = .02), resulting in a net savings of $1768 per high-risk mother-infant pair. Births before 32 weeks' gestation accounted for the greatest mean cost. Programs of comprehensive prenatal care and patient education may be highly cost-effective for prevention of prematurity.


Toward a Standard Practice to Quantify von Willebrand Factor Degradation During Left Ventricular Assist Device Support.
Continuous-flow left ventricular assist devices (LVADs) cause degradation of von Willebrand factor (VWF) multimers and bleeding. Multiple techniques exist to characterize VWF deficiency. However, a standard methodology has not been established in LVAD patients. Toward this goal, we evaluated 4 methods to quantify VWF multimers. We collected paired blood samples from patients (n = 48) before and after 1 week of LVAD support. After 652 ± 59 days of support, patients were classified as bleeders (≥1 bleeding episode) or nonbleeders. VWF multimers were resolved with electrophoresis and immunoblotting, the gold-standard to evaluate VWF multimers. We evaluated 4 quantification methods. Each method demonstrated significant VWF degradation during LVAD support vs a paired, pre-LVAD sample (method 1, VWF length: 48 of 48 patients, -10% ± 1%, P < .0001; method 2, VWF density: 40 of 48, -34% (interquartile range, -46% to -8%), P < .0001; method 3, pre-LVAD to LVAD ratio: 46 of 48, 17 ± 5: 10 ± 1, P < .0001; method 4, LVAD/pre-LVAD index: 46 of 48, 57% (interquartile range, 50% to 73%), P < .0001). Bleeding occurred in 27 of 48 patients. Method 1 demonstrated significantly fewer VWF multimers in bleeders compared with nonbleeders (-11% ± 1% vs -8% ± 1%; P = .01). Other methods did not demonstrate this potentially important clinical relationship. A standardized methodology is needed to quantify VWF multimer degradation with mechanical circulatory support devices. Novel method 1 successfully quantified the patient-specific change in VWF multimer length during LVAD support and demonstrated a difference in VWF multimers between bleeders and nonbleeders. Adoption of consensus methodology will assist to standardize patient-specific bleeding risk, inform anticoagulation and antiplatelet therapy, and evaluate LVAD hemocompatibility.


Evidence for a morphological sex difference within the medial preoptic area of the rat brain.
The present report demonstrates the existence of a marked sexual difference in the volume of an intensely staining cellular component of the medial preoptic nucleus (MPON) of the rat. Moreover, this sexual dimorphism is shown to be independent of several specific hormonal conditions in the adult, but significantly influenced, perhaps determined, by the perinatal hormone environment. Adult rats were gonadectomized and sacrificed 2 or 5-6 weeks later, or sacrificed after gonadectomy and priming with estradiol benzoate (2 microgram/day x 3) and 500 microgram progesterone, or testosterone propionate (TP, 500 microgram/day x 14), or the ingestion of propylthiouracil (0.15% of the diet) for one month, or following water deprivation for 24 h. These treatments did not affect the sexual dimorphism in the MPON and, in all groups, nuclear volume in the male animals was significantly greater than that of females whether nuclear volume was expressed in absolute terms or relative to brain weight. On the other hand, the volume of the MPON of the adult male castrated neonatally was significantly reduced when compared to that of the male castrated at the time of weaning, i.e. after the period of sexual differentiation of the brain. Consistent with the view that this nuclear region undergoes sexual differentiation is the fact that the volume of the MPON was significantly greater in female rats injected with 1 mg TP on day 4 of life than in oil-treated females. More subtle sex differences in the volume of the suprachiasmatic nucleus were also detected, as were several treatment effects. Although these differences may fall within the error of the analytical procedure, it is possible that hormone- or sex-dependent morphological differences exist elsewhere in the brain. Nevertheless, the gross sexual dimorphism in the MPON clearly demonstrates a possible morphological basis for the sexual differentiation of brain function.


Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate.
Cu/Zn superoxide dismutases (SODs) like the extracellular SOD3 and cytoplasmic SOD1 regulate cell proliferation by generating hydrogen peroxide (H2O2). This pro-oxidant inactivates essential cysteine residues in protein tyrosine phosphatases (PTP) helping receptor tyrosine kinase activation by growth factor signaling, and further promoting downstream MEK/ERK linked cell proliferation. Disulfiram (DSF), currently in clinical cancer trials is activated by copper chelation, being potentially capable of diminishing the copper dependent activation of MEK1/2 and SOD1/SOD3 and promoting reactive oxygen species (ROS) toxicity. However, copper (Cu) overload may occur when co-administered with DSF, resulting in toxicity and mutagenicity against normal tissue, through generation of the hydroxyl radical (•OH) by the Fenton reaction. To investigate: a) whether sub-toxic DSF efficacy can be increased without Cu overload against human melanoma cells with unequal BRAF(V600E) mutant status and Her2-overexpressing SKBR3 breast cancer cells, by increasing H2O2 from exogenous SOD; b) to compare the anti-tumor efficacy of DSF with that of another clinically used copper chelator, tetrathiomolybdate (TTM). a) without copper supplementation, exogenous SOD potentiated sub-toxic DSF toxicity antagonized by sub-toxic TTM or by the anti-oxidant N-acetylcysteine; b) exogenous glucose oxidase, another H2O2 generator resembled exogenous SOD in potentiating sub-toxic DSF. potentiation of sub-lethal DSF toxicity by extracellular H2O2 against the human tumor cell lines investigated, only requires basal Cu and increased ROS production, being unrelated to non-specific or TTM copper chelator sequestration. These findings emphasize the relevance of extracellular H2O2 as a novel mechanism to improve disulfiram anticancer effects minimizing copper toxicity.


Type 2-high asthma is associated with a specific indoor mycobiome and microbiome.
The links between microbial environmental exposures and asthma are well documented, but no study has combined deep sequencing results from pulmonary and indoor microbiomes of patients with asthma with spirometry, clinical, and endotype parameters. The goal of this study was to investigate the links between indoor microbial exposures and pulmonary microbial communities and to document the role of microbial exposures on inflammatory and clinical outcomes of patients with severe asthma (SA). A total of 55 patients with SA from the national Cohort of Bronchial Obstruction and Asthma cohort were enrolled for analyzing their indoor microbial flora through the use of electrostatic dust collectors (EDCs). Among these patients, 22 were able to produce sputum during "stable" or pulmonary "exacerbation" periods and had complete pairs of EDC and sputum samples, both collected and analyzed. We used amplicon targeted metagenomics to compare microbial communities from EDC and sputum samples of patients according to type 2 (T2)-asthma endotypes. Compared with patients with T2-low SA, patients with T2-high SA exhibited an increase in bacterial α-diversity and a decrease in fungal α-diversity of their indoor microbial florae, the latter being significantly correlated with fraction of exhaled nitric oxide levels. The β-diversity of the EDC mycobiome clustered significantly according to T2 endotypes. Moreover, the proportion of fungal taxa in common between the sputum and EDC samples was significantly higher when patients exhibited acute exacerbation. These results illustrated, for the first time, a potential association between the indoor mycobiome and clinical features of patients with SA, which should renew interest in deciphering the interactions between indoor environment, fungi, and host in asthma.


Among 45 variants in 11 genes, HDM2 promoter polymorphisms emerge as new candidate biomarker associated with radiation toxicity.
Due to individual variations in radiosensitivity, biomarkers are needed to tailor radiation treatment to cancer patients. Since single nucleotide polymorphisms (SNPs) are frequent in human, we hypothesized that SNPs in genes that mitigate the radiation response are associated with radiotoxicity, in particular late complications to radiotherapy and could be used as genetic biomarkers for radiation sensitivity. A total of 155 patients with nasopharyngeal cancer were included in the study. Normal tissue fibrosis was scored using RTOG/EORTC grading system. Eleven candidate genes (ATM, XRCC1, XRCC3, XRCC4, XRCC5, PRKDC, LIG4, TP53, HDM2, CDKN1A, TGFB1) were selected for their presumed influence on radiosensitivity. Forty-five SNPs (12 primary and 33 neighboring) were genotyped by direct sequencing of genomic DNA. Patients with severe fibrosis (cases, G3-4, n = 48) were compared to controls (G0-2, n = 107). Results showed statistically significant (P < 0.05) association with radiation complications for six SNPs (ATM G/A rs1801516, HDM2 promoter T/G rs2279744 and T/A rs1196333, XRCC1 G/A rs25487, XRCC5 T/C rs1051677 and TGFB1 C/T rs1800469). We conclude that these six SNPs are candidate genetic biomarkers for radiosensitivity in our patients that have cumulative effects as patients with severe fibrosis harbored significantly higher number of risk alleles than the controls (P < 0.001). Larger cohort, independent replication of these findings and genome-wide association studies are required to confirm these results in order for SNPs to be used as biomarkers to individualize radiotherapy on genetic basis.


Theoretical study of quinolines-I(2) intermolecular interaction and implications on dye-sensitized solar cell performance.
The monomer and intermolecular charge-transfer complexes of 13 different quinoline derivatives with diiodine were studied using ab initio molecular orbital (MO) and density functional theory (DFT) methods. Calculations revealed that the sigma* orbital of iodine interacts with the nitrogen lone pair in the quinoline ring. The open-circuit photovoltage (V(oc)) values of an Ru(II) complex dye-sensitized nanocrystalline TiO(2) solar cell with an I(-)/I(3) (-) redox electrolyte in acetonitrile using quinoline additives were compared to the computational calculations on the intermolecular interaction between quinolines and I(2). The optimized geometries, frequency analyses, Mulliken population analyses, natural bond orbital (NBO) analyses, and interaction energies indicate that the V(oc) value of the solar cell is higher when quinoline complexes more favorably interact with I(2). Therefore, the interaction between the quinoline additives and iodine redox electrolyte is an important factor for controlling dye-sensitized solar cell performance.


Myeloablative therapy and bone marrow transplantation in Jehovah's Witnesses with malignancies: single center experience.
Hematological malignancies in Jehovah's Witnesses are often difficult to cure since these patients deny transfusions. By a retrospective analysis, we report the possibility of treating some tumors, mostly hematological, with either autologous or allogeneic bone marrow transplantation (BMT) without blood support. Eight patients were evaluated, including lymphoma (two patients), acute lymphoblastic (one patient) and myeloblastic (one patient) leukemia, chronic lymphocytic leukemia (one patient), refractory anemia with blasts in transformation (one patient), chronic myeloid leukemia (one patient) and metastatic breast cancer (one patient). All patients experienced a severe cytopenia with no major side effects or life-threatening complications. We had four deaths: three from relapse and progression of the disease (at 5, 8 and 15 months after the stem cell infusion), and one from acute intestinal GVHD (at 2 months after the stem cell infusion). Four patients are in complete clinical remission (at 8, 10, 16 and 26 months after the stem cell infusion), and this was related to the disease outcome. We conclude that autologous and allogeneic BMT are feasible without the support of transfusions. We believe that this should be performed as soon as possible in the course of the disease.


Quantifying diffusion in mucosal systems by pulsed-gradient spin-echo NMR.
Mucus, a thick and slimy secretion produced by submucosal cells, covers many epithelial surfaces in mammalian organs and prevents foreign particles that enter the body from accessing cells. However, the mucus layer also represents a potential barrier to the efficient delivery of nano-sized drug delivery systems (polyplexes, lipoplexes, particles) to the underlying mucosal epithelium. Many studies have considered the ability of nano-sized particles and polymers to diffuse within the mucosal network using a range of different techniques, including multiple-particle tracking (MPT), diffusion chamber studies and fluorescence recovery after photobleaching (FRAP). This review highlights the current understanding of the interaction of the diffusion of nano-sized structures within mucosal networks. Moreover, this article presents an introduction to pulsed-gradient spin-echo NMR (PGSE-NMR), a potential new tool to investigate the mobility of molecular species through mucosal networks and related biological gels.


Four-Dimensional Magnetic Resonance Imaging With 3-Dimensional Radial Sampling and Self-Gating-Based K-Space Sorting: Early Clinical Experience on Pancreatic Cancer Patients.
To apply a novel self-gating k-space sorted 4-dimensional MRI (SG-KS-4D-MRI) method to overcome limitations due to anisotropic resolution and rebinning artifacts and to monitor pancreatic tumor motion. Ten patients were imaged using 4D-CT, cine 2-dimensional MRI (2D-MRI), and the SG-KS-4D-MRI, which is a spoiled gradient recalled echo sequence with 3-dimensional radial-sampling k-space projections and 1-dimensional projection-based self-gating. Tumor volumes were defined on all phases in both 4D-MRI and 4D-CT and then compared. An isotropic resolution of 1.56 mm was achieved in the SG-KS-4D-MRI images, which showed superior soft-tissue contrast to 4D-CT and appeared to be free of stitching artifacts. The tumor motion trajectory cross-correlations (mean ± SD) between SG-KS-4D-MRI and cine 2D-MRI in superior-inferior, anterior-posterior, and medial-lateral directions were 0.93 ± 0.03, 0.83 ± 0.10, and 0.74 ± 0.18, respectively. The tumor motion trajectories cross-correlations between SG-KS-4D-MRI and 4D-CT in superior-inferior, anterior-posterior, and medial-lateral directions were 0.91 ± 0.06, 0.72 ± 0.16, and 0.44 ± 0.24, respectively. The average standard deviation of gross tumor volume calculated from the 10 breathing phases was 0.81 cm(3) and 1.02 cm(3) for SG-KS-4D-MRI and 4D-CT, respectively (P=.012). A novel SG-KS-4D-MRI acquisition method capable of reconstructing rebinning artifact-free, high-resolution 4D-MRI images was used to quantify pancreas tumor motion. The resultant pancreatic tumor motion trajectories agreed well with 2D-cine-MRI and 4D-CT. The pancreatic tumor volumes shown in the different phases for the SG-KS-4D-MRI were statistically significantly more consistent than those in the 4D-CT.


Studies on the sympathetic efferent nerves of brown adipose tissue of lean and obese Zucker rats.
Previous studies have suggested that the sympathetic tone to brown adipose tissue (BAT) is reduced in the genetically obese (fa/fa) rat. The following experiments were designed to examine with electrophysiological techniques the activity of the sympathetic nerve innervating the interscapular BAT. The spontaneous activity of the efferent nerves was reduced in the obese (fa/fa) rat compared with the lean control. The activity of the nerve showed a linear relationship with changes in core temperature in both genotypes. Electrical stimulation of the ventromedial hypothalamus resulted in similar heat increments in BAT temperature for lean and obese, but this was associated with a smaller increase in nerve firing in the obese rat. Intracerebroventricular administration of glucose enhanced the nerve activity, whereas 2-deoxy-D-glucose reduced the nerve activity in both lean and obese rats. These data suggest that the sympathetic tone is suppressed in the genetically obese rat, but the response to temperature and central glucose metabolism is intact.


Gastric carcinogenesis in rats given hypertonic salt at different times before a single dose of N-methyl-N'-nitro-N-nitrosoguanidine.
A 1-ml dose of 4.5 M NaCl was given intragastrically to male Wistar rats at 10 min, 1 h, 4 h, 12 h, 24 h or 48 h before a single intragastric dose of 250 mg/kg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 52 weeks the incidence of forestomach squamous cell carcinoma was 21% in control animals receiving MNNG alone. The cancer incidence in the forestomach varied with the time elapsed between application of NaCl and MNNG, and was significantly increased in animals pretreated with NaCl 4 h (43%), 12 h (54%) and 24 h (41%) before MNNG. These results show that salt has a cocarcinogenic effect on initiation of forestomach carcinogenesis in rats, and that this effect depends on the time interval between pretreatment with NaCl and application of MNNG. Gastric adenocarcinomas occurred more frequently in the antrum (78%) than in the corpus (22%). The incidence of gastric adenocarcinoma in animals pretreated with salt before application of MNNG (11%-22%) was not significantly influenced by the time elapsed between pretreatment with salt and application of MNNG, and did not differ from animals receiving MNNG alone (18%). The lack of a cocarcinogenic effect of NaCl on glandular gastric carcinogenesis might be due to the use of dimethyl/sulfoxide as solvent for MNNG.


Longitudinal changes in sweet preferences in humans.
Preferences for the taste of sucrose were measured in 44 humans when they were 11-15 years of age and again in the same individuals 9-10 years later when they were 19-25 years of age. Preferred level of sweet decreased over the intervening years. This suggests that in humans, as in rats, heightened preferences for sweet observed in the young decline with age.


Chronically unreduced elbow dislocation treated with box-loop ligament reconstruction: The first case series.
Describing our initial experience of performing box-loop ligament reconstruction in patients with chronically unreduced elbow dislocation. Retrospective review. One tertiary referral centre. Six patients treated with box-loop ligament reconstruction from 2015 to 2018 were included in this study. Box-loop ligament reconstruction. Quick disabilities of the arm, shoulder and hand (Q-DASH) and Mayo elbow performance index (MEPI) score. All subjects exhibited substantial increase of range of flexion-extension motion of the affected elbow, from a mean of 24.2° initially to 119.2° postoperatively during the follow-up period (median = 14 months, range 12-31 months). The subjects recorded an average MEPI score of 82.5 points, and average Q-DASH score of 16.2 points. There were no complications that occurred. This is the first case series of patients with chronically unreduced elbow dislocation treated with box-loop ligament reconstruction. Using this technique, all subjects had excellent outcome without any complication. Further studies with larger samples and better methodology are required to investigate the safety and efficacy of such technique.


Room temperature valley polarization via spin selective charge transfer.
The two degenerate valleys in transition metal dichalcogenides can be used to store and process information for quantum information science and technology. A major challenge is maintaining valley polarization at room temperature where phonon-induced intervalley scattering is prominent. Here we demonstrate room temperature valley polarization in heterostructures of monolayer MoS2 and naphthylethylammine based one-dimensional chiral lead halide perovskite. By optically exciting the heterostructures with linearly polarized light close to resonance and measuring the helicity resolved photoluminescence, we obtain a degree of polarization of up to -7% and 8% in MoS2/right-handed (R-(+)-) and left-handed (S-(-)-) 1-(1-naphthyl)ethylammonium lead iodide perovskite, respectively. We attribute this to spin selective charge transfer from MoS2 to the chiral perovskites, where the perovskites act as a spin filter due to their chiral nature. Our study provides a simple, yet robust route to obtain room temperature valley polarization, paving the way for practical valleytronics devices.


Anatomical analysis of inflammation in hand psoriatic arthritis by Dual-Energy CT Iodine Map.
This study aimed to identify the detailed location of inflammatory lesions and its frequency of hand PsA on DECT Iodine Map with referring the cadaveric specimen. Thirty-eight anatomical landmarks were selected as a potential inflammatory sites in the thumb and middle finger. We included 22 symptomatic PsA patients who underwent contrast enhanced DECT of the hand. MR images and macroscopic specimens of thumb and middle finger were prepared from a cadaver. Two musculoskeletal radiologists evaluated DECT with referring the cadaveric images to determine the precise location of inflammatory sites and its frequency. The frequently observed inflammation sites of active PsA patients were either classical or functional entheses, and coincide with the well-known hypothesis that primary inflammatory sites of PsA are enthesis. We have noticed that there was remarkable enhancement around DIP joints (13.6 %-45.5 %). DECT could assess the detailed anatomical sites of the inflammatory lesion in hand psoriatic arthritis, which coincided with enthesis.


Comparison between trans-vaginal and recto-vaginal techniques for transferring embryos in the dromedary camels.
The present study was conducted in two breeding seasons to compare the effect of two non-surgical techniques for embryo deposition intrauterine, trans-vaginal (TV) versus recto-vaginal (RV) techniques, on the pregnancy rate and early pregnancy loss (EPL) in dromedary camels. Embryos were collected from 70 donors and transferred to 210 recipients by TV (n = 256 transfers) or RV technique (n = 186 transfers). Pregnancy diagnosis was conducted on Day 10 after embryo transfer (ET) by using the progesterone-ELISA test and by trans-rectal ultrasonography at Day 60 of gestation. EPL was calculated as the recipients that were diagnosed pregnant on Day 10 post-ET and lost their pregnancy between Days 20-60 of their gestation. Using the RV technique in ET of a single embryo showed higher pregnancy rates at Day 19, especially with the embryos of folded, semi-transparent shapes, or those collected after superovulation with the recovery of >4 embryos per flush. While, the pregnancy rates at 60 days showed increases after ET with the RV technique of single, folded, transparent, and semi-transparent, medium-size embryos and/or those collected after superovulation with any number of the recovered embryos than those transferred by the TV technique. The rate of EPL was increased when the TV technique was used for ET of single, spherical, folded, semi-transparent, medium-sized embryos and those collected without or with the superovulation and recovery of >4 embryos per flush. In conclusion, using the RV technique to deposit the embryos intrauterine improves the pregnancy rate and reduces EPL compared to the TV technique.


Revascularization of the right coronary artery by retrograde perfusion of the mammary artery. An experimental study.
Although the internal mammary artery bypass seems an ideal coronary bypass vessel, it has not usually been possible to use this vessel to bypass distal lesions in the right coronary circulation. In this experiment, the right internal mammary artery was utilized in retrograde fashion to evaluate this anatomically more suitable vessel as a bypass graft to the occluded right coronary artery in the dog. Reversal of acute myocardial ischemia was demonstrated by mapping epicardial ST-segment elevation and measuring surface pH. Preliminary long-term experiments have also demonstrated patency and perfusion of the distal right coronary artery by this method.


Characterization of carbapenem-resistant hypervirulent Acinetobacter baumannii strains isolated from hospitalized patients in the mid-south region of China.
Acinetobacter baumannii has traditionally been considered an opportunistic pathogen with low virulence. In this study, we characterized the carbapenem-resistant hypervirulent A. baumannii (CR-hvAB) stains isolated from our hospital in mid-south region of China. Blood samples collected between January 2017 and May 2019 were used for virulence experiments and biofilm assays of individual carbapenem-resistant A. baumannii (CR-AB) strains, performed using a Galleria mellonella infection model and crystal violet staining method, respectively. CR-AB isolates that induced high mortality in the G. mellonella infection model were subjected to genotyping, susceptibility testing, and clinical data analysis, and the genetic characterization of these isolates was performed by whole-genome sequencing (WGS). Among the 109 CR-AB clinical strains, the survival rate of G. mellonella larvae infected with 7 (6.4%) CR-AB isolates (number of strains with mortality of 0, 10 and 20% was 4, 1, and 2, respectively), was significantly lower than that of A. baumannii ATCC 19606 (100.0%) and the remaining CR-AB isolates (> 80.0%). Consistent with these results, patients infected with these seven isolates had an average 7-day mortality rate of 42.9%, suggesting that the isolates were CR-hvAB. These seven isolates belonged to four sequence types (STs): ST457, ST195, ST369, and ST2088 (a new ST), and mainly ST457 (n = 4). The results of the biofilm study showed that eight strains had powerful biofilm ability (strong [n = 1] and moderate [n = 7] biofilm producers) including these seven CR-hvAB isolates. CR-hvAB isolates that induced a high mortality rate were cloned in our hospital, most of which belonged to ST457; thus, monitoring of these strains, particularly ST457, should be strengthened in the future. Meanwhile, A. baumannii, which was isolated from blood specimens and found to powerful biofilm-forming ability, is a probable hvAB isolate.


[Ageing, medical progress and the growth of healthcare expenditure].
As healthcare expenditure typically rises during a person's lifetime, there are widespread fears that the ageing of the German population together with technical progress in medicine will be a serious threat to future healthcare financing. The relationship between ageing and growth of healthcare expenditure has been intensively studied over the past 15 years both theoretically and empirically. In this article it will be demonstrated that the highest expenditure is not due to age per se but rather to proximity to death. However, even taking this effect into account simulations show that the increase in life expectancy as well as medical progress will contribute to the growth of per capita expenditure in the German healthcare insurance system.


Cardiopulmonary response during incremental shuttle walking test in a hallway versus on treadmill in Phase IV cardiac rehabilitation: a cross-sectional study.
There is widespread use of incremental shuttle walking test (ISWT) to measure functional capacity in cardiac rehabilitation patients. Due to occasional physical space limitations, an incremental shuttle walking test on a treadmill (ISWT-T) was suggested as an alternative. Knowledge about the cardiopulmonary response between the two tests and the factors associated with the distance achieved in Phase IV cardiac rehabilitation is limited. Thus, the study aims to compare the cardiopulmonary response between ISWT and ISWT-T and investigate the factors associated with distance achieved in both tests. Thirteen participants (66.3 ± 7.3 years, 84.6% males) attending phase IV cardiac rehabilitation participated in repeated measures counterbalanced trials. Each participant performed one ISWT and one ISWT-T separated by seven days. Main outcome measures included peak heart rate (HR), systolic and diastolic blood pressure post-test, distance achieved, respiratory frequency, tidal volume (VT), minute ventilation, respiratory exchange ratio, peak oxygen uptake (VO2PEAK), and secondary outcome measures included height, weight, waist circumference (WC) leg length (LL). There were no significant differences in the cardiopulmonary responses between ISWT and ISWT-T except for VO2PEAK (25.4 ± 5.8 vs 23.7 ± 5.1, p = 0.05, respectively). Age and height were significantly correlated with distance achieved during ISWT, and ISWT-T [age (r = - 0.72, vs. r = - 0.73, p ≤ 0.05, respectively)], [height (r = 0.68, vs. r = 0.68, p ≤ 0.05, respectively)]. LL was only correlated with distance achieved on ISWT-T (r = 0.59, p ≤ 0.05). These findings suggest a similar cardiopulmonary response between the two tests, but doing ISWT in the hallway evoked a higher metabolic demand than doing it on a treadmill. Additionally, distance achieved on both tests was related to height and inversely to age.


The progene hypothesis: the nucleoprotein world and how life began.
In this article, I review the results of studies on the origin of life distinct from the popular RNA world hypothesis. The alternate scenario postulates the origin of the first bimolecular genetic system (a polynucleotide gene and a polypeptide processive polymerase) with simultaneous replication and translation and includes the following key features: 1. The bimolecular genetic system emerges not from mononucleotides and monoamino acids, but from progenes, namely, trinucleotides aminoacylated on 3'-end by a non-random amino acid (NpNpNp ~ pX ~ Aa, where N--deoxyribo- or ribonucleoside, p--phosphate, X--a bifunctional agent, for example ribose, Aa--amino acid, ~ macroerge bond). Progenes are used as substrates for simultaneous synthesis of a polynucleotide and a polypeptide. Growth of the system is controlled by the growing polypeptide, and the bimolecular genetic system emerges as an extremely rare event. The first living being (virus-like organism protoviroid, Protoviroidum primum) arises and reproduces in prebiotic liposome-like structures using progenes. A population of protoviroids possessing the genetic system evolves in accordance with the Darwinian principle. Early evolution from protoviroid world to protocell world is shortly described. 2. The progene forming mechanism (NpNp + Np ~ pX ~ Aa) makes it possible to explain the emergence of the prebiotic physicochemical group genetic code, as well as the selection of organic compounds for the future genetic system from the racemic environment. 3. The protoviroid is reproduced on a progene basis via replicative transcription-translation (RTT, the first molecular genetic process) that is similar to its modern counterparts. Nothing is required for the emergence and reproduction of the protoviroid except for progenes and conditions for their formation. 4. The general scheme of early evolution is as follows: prebiotic world → protoviroid (nucleoprotein) world → protocell (DNA-RNA-protein) world → LUCA (Last Universal Common Ancestor) → modern cell world. This scheme exclude the existence of an independent RNA world as predecessor of the cellular world.


Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom.
Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. A total of 193 patients (57% female and 64% Crohn's disease) were included, with a median daily TG dose of 20 mg (range: 20-40 mg), a median treatment duration of 23 months (IQR 10-47) and a median follow-up of 36 months (IQR 22-53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145-1761) and 47 mu/L (IQR 34.5-96). Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.


New satiety hormone nesfatin-1 protects gastric mucosa against stress-induced injury: mechanistic roles of prostaglandins, nitric oxide, sensory nerves and vanilloid receptors.
Nesfatin-1 belongs to a family of anorexigenic peptides, which are responsible for satiety and are identified in the neurons and endocrine cells within the gut. These peptides have been implicated in the control of food intake; however, very little is known concerning its contribution to gastric secretion and gastric mucosal integrity. In this study the effects of nesfatin-1 on gastric secretion and gastric lesions induced in rats by 3.5h of water immersion and restraint stress (WRS) were determined. Exogenous nesfatin-1 (5-40μg/kg i.p.) significantly decreased gastric acid secretion and attenuated gastric lesions induced by WRS, and this was accompanied by a significant rise in plasma NUCB2/nefatin-1 levels, the gastric mucosal blood flow (GBF), luminal NO concentration, generation of PGE2 in the gastric mucosa, an overexpression of mRNA for NUBC2 and cNOS, as well as a suppression of iNOS and proinflammatory cytokine IL-1β and TNF-α mRNAs. Nesfatin-1-induced protection was attenuated by suppression of COX-1 and COX-2 activity, the inhibition of NOS with L-NNA, the deactivation of afferent nerves with neurotoxic doses of capsaicin, and the pretreatment with capsazepine to inhibit vanilloid VR1 receptors. This study shows for the first time that nesfatin-1 exerts a potent protective action in the stomach of rats exposed to WRS and these effects depend upon decrease in gastric secretion, hyperemia mediated by COX-PG and NOS-NO systems, the activation of vagal and sensory nerves and vanilloid receptors.


Genetic deregulation of the PIK3CA oncogene in oral cancer.
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the most commonly deregulated pathways in human cancers. PI3K comprises a catalytic (p110α) and regulatory subunit (p85), and p110α is encoded by the PIK3CA gene. Here, we summarize the known genetic alterations, including amplifications and mutations, of the PIK3CA oncogene in oral cancer. We discuss in detail PIK3CA mutations and their mutual exclusivity with pathway genes in addition to the incidence of PIK3CA mutations in relation to ethnicity. We describe the constitutive activation of PI3K signaling, oncogenicity, and the genetic deregulation of the PIK3CA gene and its association with oral cancer disease stage. We emphasize the importance of therapeutically targeting the genetically deregulated PIK3CA oncogene and its signaling. We also discuss the implications of targeting Akt and/or mTOR, which are the downstream effectors of PI3K that may possibly pave the way for molecular therapeutic targets for PIK3CA-driven oral carcinogenesis. Furthermore, this critical review provides a complete picture of the PIK3CA oncogene and its deregulation in oral cancer, which may facilitate early diagnosis and improve prognosis through personalized molecular targeted therapy in oral cancer.


Depression among pregnant women and associated factors in Hawassa city, Ethiopia: an institution-based cross-sectional study.
Depression is the most prevalent psychiatric disorder during pregnancy. It is not only common and chronic among women throughout the world but also principal source of disability in pregnant women. The scarce information and limited attention to the problem might aggravate the consequence of the problem and can limit the intervention to be taken. The objective of the study was to assess the prevalence and factors associated with depression among pregnant women in public health institutions, Hawassa, Ethiopia. Institution based cross sectional study was conducted in May to July 2017. Pregnant women were selected by using systematic sampling technique. Data were collected through face-to-face interviews on socio-demographic, obstetric, psychosocial characteristics and depressive symptoms. Edinburgh Postnatal Depression Scale (EPDS) and Oslo Social Support Scale (OSS-3) were used to asses' depressive symptoms and social support respectively. Descriptive and logistic regression analyses were carried out. The mean age of the respondents was 23.82 ± (SD = 6.65) years. The prevalence of antenatal depression was 21.5%. When we adjusted for the effect of potential confounding variables, being in age group of 20-30 years [AOR = 5.85 (95% CI: (3.70, 10.14)], current pregnancy complication [AOR = 4.98 (95% CI: (3.01, 10.37)], unplanned pregnancy [AOR = 7.12, (95% CI: (3.12, 9.63)], categories of stressors (LTE) Health risk [AOR = 1.76, (95% CI: (1.01, 3.22)], previous history of depression [AOR = 2.76 (95% CI: (1.94, 6.75)], history of abortion [AOR = 1.52, (95% CI:1.04, 5.09)], history of still birth [AOR = 1.18, (95% CI: 1.08, 2.91)], poor social support [AOR = 2.14, (95% CI: 1.49, 3.11)] and poor baby father support [AOR = 3.21 (95% CI:1.93, 6.71)] were significantly associated with antenatal depression. For early detection and appropriate intervention, antenatal clinics should develop screening tools for depression during the routine antenatal care.