Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group.
Vinorelbine, a semisynthetic vinca alkaloid, represents a well-tolerated treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC). We explored the quality of life (QoL) of such patients in a multicenter randomized trial that compared vinorelbine treatment with supportive care alone. Eligible patients were 70 years of age or older, had stage IV or IIIB NSCLC that was ineligible for radiotherapy, and had a performance status of 0-2 (a status of fully active to a status of capable of all self-care but unable to work). Vinorelbine was given intravenously on days 1 and 8 of a 21-day treatment cycle, for a total of six cycles. QoL was evaluated with European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-LC13, and the QoL data were analyzed by fitting a linear mixed model for each QoL scale. Survival curves were plotted and were compared with the Mantel-Haenszel test. Relative hazards of death and 95% confidence intervals (CIs) were estimated by the Cox model. Investigators, blinded to the results, stopped the trial early because of a low enrollment rate. (From April 1996 to November 1997, 191 of the 350 targeted patients were randomly assigned.) Data from 161 patients have been analyzed. Vinorelbine-treated patients scored better than control patients on QoL functioning scales, and they reported fewer lung cancer-related symptoms but reported worse toxicity-related symptoms. There was a statistically significant (two-sided P = .03) survival advantage for patients receiving vinorelbine; median survival increased from 21 to 28 weeks in the vinorelbine-treated group. The relative hazard of death for vinorelbine-treated patients was 0.65 (95% CI = 0.45-0.93). Vinorelbine improves survival of elderly patients with advanced NSCLC and possibly improves overall QoL.


Recent advances following anterior cruciate ligament reconstruction: rehabilitation perspectives : Critical reviews in rehabilitation medicine.
Injuries to the anterior cruciate ligament are common. Surgical reconstruction is more prevalent than ever. This review article discusses treatment of the patient following surgical reconstruction of the anterior cruciate ligament. Various phases of rehabilitation are discussed with emphasis on early return of passive motion, early weight bearing, bracing, kinetic chain exercises, neuromuscular electrical stimulation and accelerated rehabilitation. Although evidence exists for the treatment of the surgically reconstructed cruciate ligament, more is needed to better define specific timeframes for advancement. Evidence exists that many of these young individuals are not fully returning to unlimited high level activities. This review article presents some of the latest evidence regarding anterior cruciate ligament rehabilitation in an attempt to help the busy clinician understand and relate basic and clinical research to rehabilitation of a patient following reconstruction.


Influence of breed on the clinical and hemato-biochemical parameters in sheep experimentally infected with Leptospira sp.
Early diagnosis of leptospirosis may aid in a favorable prognosis in infected animals, but there are few reports of clinical and hematochemical changes in the ovine species, nor whether the breed exerts any influence on the response to infection. Thus, the objective of the present study was to evaluate the clinical, biochemical and hematological alterations in Santa Inês and crossbred ewes challenged with Leptospira interrogans serogroup Pomona serovar Kennewicki. Twenty-four sheep were used in this experiment, 12 crossbred (group A) and 12 Santa Inês (group B). In each group, sheep were conjunctivally and intraperitoneally challenged. During 60 days post-infection the ewes were evaluated for the presentation of clinical signs and the blood was collected for hemogram and serum biochemistry. Concentration of urea and creatinine; serum aspartate aminotransferase activity (AST); gamma-glutamyltransferase (GGT); total protein and albumin; total bilirubin, direct and indirect were analyzed. The urine of these sheep was collected for urinalysis. Only two Santa Inês sheep showed blood in the urine. Clinical signs implicated in Leptospira sp. infection were not identified. Some sheep had anemia, especially crossbred. However, anemia may be attributed to the more effective cellular response that has been identified in crossbred animals. Only one animal presented leukocytosis with neutrophilia, while 11 presented atypical leukopenia, especially those of the Santa Inês breed. There was a decrease in total protein and albumin, as well as the increase in gammaglutamyltranspeptidase (GGT), especially in Santa Inês sheep. The level of aspartate aminotransferase (AST) remained within the normal range for the species. A significant increase (p < 0.05) in conjugated bilirubin levels in challenged animals was detected. Only one sheep intraperitoneally challenged presented a high level of urea in the blood, but the creatinine level remained within the normal range. The intraperitoneal route was responsible for more significant changes (p < 0.05) in the hemogram and biochemistry when compared to the conjunctival route. The results indicate that crossbred sheep have a more efficient cellular response than Santa Inês sheep, which may confer a greater resistance to infection. Clinical signs are not good parameters to follow the development of leptospirosis in crossbred and Santa Inês breed. Hematological and biochemical analyzes were useful in the detection of anemia and possible liver changes caused by leptospirosis. The intraperitoneal route was able to cause more conclusive alterations of the analyzed parameters, however, it is possible that the alterations caused by the conjunctival route reproduce in a more faithful way what happens in a natural situation of infection.


A novel molecular imprinted QCM sensor based on MoS2NPs-MWCNT nanocomposite for zearalenone determination.
Zearalenone (ZEN) is a mycotoxin that has a carcinogenic effect and is often found at a high rate in frequently consumed foods. In this study, a characteristic molecular imprinted quartz crystal microbalance (QCM) sensor based on molybdenum disulfide nanoparticle (MoS2NPs)-multiwalled carbon nanotube (MWCNT) nanocomposite (MoS2NPs-MWCNTs) is presented for selective determination of ZEA in rice samples. Firstly, molybdenum disulfide nanoparticle (MoS2NP)-multiwalled carbon nanotube nanocomposites were characterized by using microscopic, spectroscopic, and electrochemical techniques. Then, ZEA-imprinted QCM chip was prepared in the presence of methacryloylamidoglutamicacid (MAGA) as monomer, N,N'-azobisisobutyronitrile (AIBN) as initiator, and ZEA as target molecule by using UV polymerization. The sensor revealed a linearity toward ZEA in the range 1.0-10.0 ng L-1 with a detection limit (LOD) of 0.30 ng L-1. The high repeatability, reusability, selectivity, and stability of the developed sensor enable reliable ZEA detection in rice samples.


The prevalence and temporal trends of food allergy among preschool children in Northern Thailand between 2010 and 2019.
Although recent studies suggest that the prevalence of food allergy (FA) has not changed, the data from developing countries are limited. This study aimed to investigate time trends in the prevalence of FA among preschool children in 2010 and 2019 in Northern Thailand. Two cross-sectional studies were performed, 9 years apart (2010 and 2019), using the same methods, in children aged 3-7 years living in Chiang Mai, Thailand. Parent-reporting questionnaire surveys were conducted. Families with children reporting FA were invited to undergo further investigations with skin prick testing, serum specific IgE, and oral food challenge (OFC). The prevalence of parent-reported FA, food sensitization, and OFC-confirmed FA were compared between the 2 periods. A total of 1013 out of 1146 questionnaires (452/546 in 2010 and 561/600 in 2019) were returned. The response rate was 88.4%. The prevalence of parent-reported food allergy in 2019 was significantly lower than that in 2010 (5.5% vs 9.3%; p = 0.02). However, there was no significant change in the prevalence of OFC-confirmed FA (0.9% vs 1.1%; p = 0.75). Three leading causative foods of parent-reported FA were cow's milk, shrimp, and eggs. Shrimp was still the most common OFC-confirmed food allergen. Atopic dermatitis was the most significantly parent reported factor associated with FA. The overall prevalence of FA among preschool children in Northern Thailand had not increased during the past decade. There was no significant difference in the prevalence of OFC-confirmed FA between 2010 and 2019.


A new probability mapping method to describe the development of atherosclerotic lesions in cholesterol-fed rabbits.
A new probability mapping method was developed to quantify the size and location of lesions near aortic orifices. The precise location of any part of the lesion could be compared between rabbits. Colour photographs of lesions were projected onto a digitizing tablet, and coded as lesion or non-lesion. Next the orifices were warped onto a standard orifice, and then the lesion mapped to maintain the original length and angular location of the lesion from the edge of the orifice. This method, unlike the previously used polar mapping method, excludes neither absent lesions nor ones which surround more than one orifice. In contrast to other probability mapping methods it warps the orifice rather than the artery wall containing the lesion, and so is easier to use for correlation with histological studies. The eventual aim is to use the probability maps as a tool to estimate the age of various positions of the lesion and to identify areas for histological sampling. The method was used to describe the distribution of lesions in 21 rabbits fed a diet with cholesterol levels declining from 0.5% during the first week, to 0.25% during the next two weeks, to 0.125% for weeks 3-10, to 0.1% for weeks 11-24. This feeding protocol produces fatty lesions which are transformed into fibro-fatty and fibrous lesions with time.


3-O-methyl-D-glucose and beta-alanine: rapid axoplasmic transport of metabolically inert low molecular weight substances.
The dynamics of the axoplasmic transport of free beta-alanine and 3-O-methyl-D-glucose were quantitatively characterized in vivo in the pike olfactory nerve following intranasal application of the tritiated substances. Both compounds were found to be taken up by the epithelium but not metabolized to a significant extent. Axoplasmic transport showed the same dynamics as rapid transport of protein and free leucine in this nerve. No synthesis or transport of carnosine was detectable. The results are in agreement with the view that rapid axoplasmic transport is capable of conveying free, low molecular weight molecules in a non-specific manner.


A short dasatinib and quercetin treatment is sufficient to reinstate potent adult neuroregenesis in the aged killifish.
The young African turquoise killifish has a high regenerative capacity, but loses it with advancing age, adopting several aspects of the limited form of mammalian regeneration. We deployed a proteomic strategy to identify pathways that underpin the loss of regenerative power caused by aging. Cellular senescence stood out as a potential brake on successful neurorepair. We applied the senolytic cocktail Dasatinib and Quercetin (D + Q) to test clearance of chronic senescent cells from the aged killifish central nervous system (CNS) as well as rebooting the neurogenic output. Our results show that the entire aged killifish telencephalon holds a very high senescent cell burden, including the parenchyma and the neurogenic niches, which could be diminished by a short-term, late-onset D + Q treatment. Reactive proliferation of non-glial progenitors increased substantially and lead to restorative neurogenesis after traumatic brain injury. Our results provide a cellular mechanism for age-related regeneration resilience and a proof-of-concept of a potential therapy to revive the neurogenic potential in an already aged or diseased CNS.


Prognostic potential of automated Ki67 evaluation in breast cancer: different hot spot definitions versus true global score.
The proliferation-associated biomarker Ki67 has potential utility in breast cancer, including aiding decisions based on prognosis, but has unacceptable inter- and intralaboratory variability. The aim of this study was to compare the prognostic potential for Ki67 hot spot scoring and global scoring using different digital image analysis (DIA) platforms. An ER+/HER2- breast cancer cohort (n = 139) with whole slide images of sequential sections stained for hematoxylin-eosin, pancytokeratin and Ki67, was analyzed using two DIA platforms. For hot spot analysis virtual dual staining was applied, aligning pancytokeratin and Ki67 images and 22 hot spot algorithms with different features were designed. For global Ki67 scoring an automated QuPath algorithm was applied on Ki67-stained whole slide images. Clinicopathological data included overall survival (OS) and recurrence-free survival (RFS) along with PAM50 molecular subtypes. We show significant variations in Ki67 hot spot scoring depending on number of included tumor cells, hot spot size, shape and location. The higher the number of scored tumor cells, the higher the reproducibility of Ki67 proliferation values. Hot spot scoring had greater prognostic potential for RFS in high versus low Ki67 subgroups (hazard ratio (HR) 6.88, CI 2.07-22.87, p = 0.002), compared to global scoring (HR 3.13, CI 1.41-6.96, p = 0.005). Regarding OS, global scoring (HR 7.46, CI 2.46-22.58, p < 0.001) was slightly better than hot spot scoring (HR 6.93, CI 1.61-29.91, p = 0.009). In adjusted multivariate analysis, only global scoring was an independent prognostic marker for both RFS and OS. In addition, global Ki67-based surrogate subtypes reached higher concordance with PAM50 molecular subtype for luminal A and B tumors (66.3% concordance rate, κ = 0.345), than using hot spot scoring (55.8% concordance rate, κ = 0.250). We conclude that the automated global Ki67 scoring is feasible and shows clinical validity, which, however, needs to be confirmed in a larger cohort before clinical implementation.


Hypothermia therapy: neurological and cardiac benefits.
Due to its protective effect on the brain and the myocardium, hypothermia therapy (HT) has been extensively studied in cardiac arrest patients with coma as well as in patients presenting with acute myocardial infarction (MI). In the setting of cardiac arrest, randomized studies have shown that HT decreases mortality and improves neurological outcomes. Subsequent guidelines have therefore recommended cooling (32°C to 34°C) for 12 to 24 h in unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest due to ventricular fibrillation. Observational studies have also confirmed the feasibility of this therapy in clinical practice and support its early application in patients with nonventricular fibrillation cardiac arrest and in post-resuscitation circulatory shock. In patients with acute MI, available clinical evidence does not yet support HT as the standard of care, because no study to date has shown a clear net benefit in such a cohort. After a brief review of the mechanisms of action for HT, we provide a review of the clinical evidence, cooling techniques, and potential adverse effects associated with HT in the setting of post-cardiac arrest patient and acute MI.


The effect of combined deendothelialization and hypercholesterolemia on some arterial lysosomal and glycolytic enzymes and lactate in rabbits.
In eight New Zealand white male rabbits the abdominal aorta and one iliofemoral artery was balloon deendothelialized (group A). After 2 weeks they were kept for 6 weeks on a high cholesterol diet together with eight unoperated rabbits (group B). Eight more rabbits were kept on a commercial diet only (group C). The degree of atherosclerosis was much higher in the deendothelialized Group A vessels than in the uninjured group B vessels. The activity of lactate dehydrogenase and of the rate-limiting glycolytic pyruvate kinase was significantly increased and the activity of lipoamide dehydrogenase decreased in the group A aortas. In the iliofemoral arteries a similar but statistically insignificant tendency was detected. There was no significant difference, however, in aortic lactate between the three groups. Thus, local hypoxia did not significantly contribute to the high degree of atherosclerosis in the group A animals in spite of the enzyme activity differences. Previous experience of the authors, using arterial microcathode pO2 measurements, indicates that following deendothelialization an adaptive proliferation of nutrient vessels and increased arterial oxygenation takes place. The average activity of the lysosomal N-acetyl-beta-glucosaminidase was five times and that of beta-glucuronidase, seven times higher in the Group A than Group B aortas; in the iliofemoral arteries the differences were even larger. The huge elevation of these hydrolases, which are involved in glycosaminoglycan catabolism, provides indirect indication that accumulation of glycosaminoglycans and possibly their ability to form complexes with apoB-containing lipoproteins played a major role in the much increased degree of atherosclerotic lesions in the Group A rabbits.


The 1.8 A structure of the complex between chymostatin and Streptomyces griseus protease A. A model for serine protease catalytic tetrahedral intermediates.
The naturally occurring serine protease inhibitor, chymostatin, forms a hemiacetal adduct with the catalytic Ser195 residue of Streptomyces griseus protease A. Restrained parameter least-squares refinement of this complex to 1.8 A resolution has produced an R index of 0 X 123 for the 11,755 observed reflections. The refined distance of the carbonyl carbon atom of the aldehyde to O gamma of Ser195 is 1 X 62 A. Both the R and S configurations of the hemiacetal occur in equal populations, with the end result resembling the expected configuration for a covalent tetrahedral product intermediate of a true substrate. This study strengthens the concept that serine proteases stabilize a covalent, tetrahedrally co-ordinated species and elaborates those features of the enzyme responsible for this effect. We propose that a major driving force for the hydrolysis of peptide bonds by serine proteases is the non-planar distortion of the scissile bond by the enzyme, which thereby lowers the activation energy barrier to hydrolysis by eliminating the resonance stabilization energy of the peptide bond.


The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebo-controlled trial.
We recently showed that testosterone therapy worsens sleep-disordered breathing at 6-7 weeks, but not after 18 weeks, in men with obstructive sleep apnea. Changes in ventilatory chemoreflexes may be responsible. The effect of testosterone on ventilatory chemoreflexes in men with obstructive sleep apnea has not been systematically studied before. Twenty-one obese men with obstructive sleep apnea, a subgroup of our recent report, were randomised in an 18-week, randomised, double-blind, placebo-controlled, parallel group trial to three intramuscular injections (0, 6, 12 weeks) of either 1000 mg testosterone undecanoate (n = 10) or placebo (n = 11). Awake ventilatory chemoreflex testing was performed before (week 0), during (week 6) and at the end of treatment (week 18) to determine the ventilatory carbon dioxide recruitment threshold and chemosensitivity. Sleep and breathing was assessed by overnight polysomnography at 0, 7 and 18 weeks. Serum hormones levels were measured at every visit. A significant increase in blood testosterone levels (5.65 nmol L(-1) , 0.51-10.8 nmol L(-1) , P = 0.03) and lean muscle mass (2.36 kg, 0.8-3.9 kg, P = 0.007) between the two groups was observed as expected. No significant differences were seen in ventilatory chemoreflexes between the two groups at 6 weeks or at 18 weeks. However, positive correlations were observed between changes in serum testosterone and hyperoxic ventilatory recruitment threshold (r = 0.55, P = 0.03), and between changes in hyperoxic ventilatory recruitment threshold and time spent with oxygen saturations during sleep <90% (r = 0.57, P = 0.03) at 6-7 weeks, but not at 18 weeks. Time-dependent alterations in ventilatory recruitment threshold may therefore mediate the time-dependent changes in sleep breathing observed with testosterone.


Overexpression of rice WRKY89 enhances ultraviolet B tolerance and disease resistance in rice plants.
WRKY proteins are a large family of transcriptional regulators involved in a variety of biological processes in plants. Here we report functional characterization of a rice WRKY gene, OsWRKY89. RNA gel blot analysis indicated that OsWRKY89 was strongly induced by treatments of methyl jasmonate and UV-B radiation. The transient expression analysis of the OsWRKY89-eGFP reporter in onion epidermal cells revealed that OsWRKY89 was targeted to nuclei. Transcriptional activity assays of OsWRKY89 and its mutants fused with a GAL4 DNA binding domain indicated that the 67 C-terminal amino acids were required for the transcriptional activation and that the leucine zipper region at the N-terminus enhanced its transcriptional activity. Overexpression of OsWRKY89 led to growth retardation at the early stage and reduction of internode length. Scanning electron microscopy revealed an increase in wax deposition on leaf surfaces of the OsWRKY89 overexpression lines and a decrease in wax loading in the RNAi-mediated OsWRKY89 suppression lines. Moreover, extractable and cell-wall-bound phenolic compounds were decreased in the overexpressor lines, but its SA levels were increased. Lignin staining showed an increase in lignification in culms of the overexpressor lines. Interestingly, overexpression of the OsWRKY89 gene enhanced resistance to the rice blast fungus and white-backed planthopper as well as tolerance to UV-B irradiation. These results suggest that OsWRKY89 plays an important role in response to biotic and abiotic stresses.


Transplantation of epidermis of scar tissue on acellular dermal matrix.
This study enrolled 22 participants with hypertrophic scarring after burn who received treatment with co-transplantation of acellular dermal matrix and epidermis of either normal skin or scar tissue. Scar thickness was evaluated with high frequency ultrasonography and the distribution of keratinocyte stem cells was detected by immunostaining. The results showed p63-positive keratinocyte stem cells throughout the epidermis of scar tissue. However, if co-transplanted on acellular dermal matrix, this effectively inhibited scar formation and pruritus, providing an alternative method to treat hypertrophic scarring.


Interclinician and intraclinician variability in the mechanics of the pivot shift test for posterolateral rotatory instability (PLRI) of the elbow.
Posterolateral rotatory instability (PLRI) of the elbow results from injury to the lateral collateral ligament complex from trauma or iatrogenic injury. The lateral pivot-shift test (PST) is standard for diagnosing PLRI, but its subjectivity affects diagnosis and makes it difficult to train young surgeons. A well-controlled investigation has not been done to quantify interclinician and intraclinician variability in PST mechanics in the intact and unstable elbow. The authors predict that there exist differences in PST mechanics between clinicians. Five unpaired elbow specimens underwent PST intact and after sequential sectioning of lateral stabilizing ligaments. Multiple PST trials were performed on each specimen by 3 clinicians (1 expert, 2 in-training) while 3-dimensional motion and loads were recorded. Intraclinician and interclinician variability were analyzed. Mean supination torque, valgus torque, and axial force were 3.6 ± 1.9 Nm, 5.6 ± 3.1 Nm, and -8.3 ± 15.7 N, respectively. Mean radial head displacement was 13.7 ± 4.6 mm. There were no significant differences in these measures after sequential ligament sectioning. One surgeon (in-training 2) applied significantly greater axial compressive forces across the elbow joint (5-9 N difference). Variability of axial force (380% ± 473%) was greater than that of supination torque (20% ± 11%), valgus torque (14% ± 4%), and radial head displacement (8% ± 6%; P < .05 for analysis of variance). The clinicians performed the PST consistently and with comparable loads, with the exception of axial compressive force across the radiohumeral joint, which varied across clinicians by 1 to 2 pounds (5-9 N). This study suggests that the PST is a mechanically reproducible clinical examination, despite differing levels of training in performing the maneuver. With the exception of axial force, PST mechanics are highly repeatable for a given surgeon applying the test on a single specimen.


Life history of Macrocheles muscaedomesticae (Parasitiformes: Macrochelidae): new insights on life history and evidence of facultative parasitism on Drosophila.
Macrocheles muscaedomesticae is a cosmopolitan macrochelid mite whose populations have likely diverged considering the many locations they inhabit, but most of the work published on this mite species has been on the basis of their association with the house fly, Musca domestica. Here, we studied several aspects of the biology of M. muscaedomesticae associated with drosophilid flies collected in Alberta, Canada. We assessed the degree of divergence of our populations from others, compared their life history to other published populations and experimentally tested whether M. muscaedomesticae feeds on Drosophila hydei hosts by comparing the body mass of mites that attached to hosts to those that did not. There was no strong phylogenetic differentiation among any of the M. muscaedomesticae specimens, suggesting multiple recent introductions of this species to Canada. Compared to other populations, our mites exhibited lower fecundity, which may have been a result of the temperature or nematode-only diet in which they were maintained. Finally, mites that attached to hosts for 4 h weighed significantly more than those that did not. Without direct evidence for host tissue transfer to the mites, it is difficult to determine whether the mites are indeed feeding on their hosts while attached. However, the existing evidence for the costs fly hosts endure at the expense of these mites makes this relationship antagonistic.


Exercise training improves hypertension-induced autonomic dysfunction without influencing properties of peripheral cardiac vagus nerve.
We examined the vagal transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained Spontaneously Hypertensive Rats (SHR). To this end, male SHR and Wystar-Kyoto (WKY) rats with 48-50weeks of age-old were divided into 4 groups: sedentary (SHRS, n=12) and trained (SHRT, n=14) hypertensive rats, sedentary (WKYS, n=13) and trained (WKYT, n=13) normotensive rats. The trained groups were submitted to swimming protocol for 9weeks. Blood pressure (BP), HR, HR variability (HRV), BP variability (BPV), baroreflex sensitivity and cardiac tonus were recorded in baseline conditions. Following, electric stimulation of peripheral vagus nerve was performed in anesthetized conditions. Resting bradycardia was observed in SHRT and WKYT when compared to their respective sedentary groups (p<0.001). The BP was lower in SHRT than in SHRS (p<0.001). The SHRT and WKYT rats showed higher baroreflex-mediated tachycardia values when compared to their respective sedentary counterparts (p<0.001). Baroreflex bradycardic response in SHRT was higher than in SHRS (p<0.005). The SHRT and WKYT rats showed a decreased sympathetic activity in comparison to their respective sedentary groups (p<0.05). The cardiac vagal tonus was higher in SHRT than in SHRS (p<0.05). Regarding the dynamic transducer properties of peripheral vagus nerve to the heart no difference was observed among the groups. In conclusion, our results demonstrate that exercise training decreased BP in SHR and improved cardiovascular autonomic balance to the heart without changes in transduction properties of peripheral cardiac vagus nerve.


A Traditional Chinese Medicine Xiao-Ai-Tong Suppresses Pain through Modulation of Cytokines and Prevents Adverse Reactions of Morphine Treatment in Bone Cancer Pain Patients.
Treating cancer pain continues to possess a major challenge. Here, we report that a traditional Chinese medicine Xiao-Ai-Tong (XAT) can effectively suppress pain and adverse reactions following morphine treatment in patients with bone cancer pain. Visual Analogue Scale (VAS) and Quality of Life Questionnaire (EORTC QLQ-C30) were used for patient's self-evaluation of pain intensity and evaluating changes of adverse reactions including constipation, nausea, fatigue, and anorexia, respectively, before and after treatment prescriptions. The clinical trials showed that repetitive oral administration of XAT (200 mL, bid, for 7 consecutive days) alone greatly reduced cancer pain. Repetitive treatment with a combination of XAT and morphine (20 mg and 30 mg, resp.) produced significant synergistic analgesic effects. Meanwhile, XAT greatly reduced the adverse reactions associated with cancer and/or morphine treatment. In addition, XAT treatment significantly reduced the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and increased the endogenous anti-inflammatory cytokine interleukin-10 in blood. These findings demonstrate that XAT can effectively reduce bone cancer pain probably mediated by the cytokine mechanisms, facilitate analgesic effect of morphine, and prevent or reduce the associated adverse reactions, supporting a use of XAT, alone or with morphine, in treating bone cancer pain in clinic.


Protection of human erythrocyte using Crinum asiaticum extract and lycorine from oxidative damage induced by 2-amidinopropane.
The intention of this investigation was to evaluate the free radical scavenging activity and erythrocyte protective activity of ethanolic extract of Crinum asiaticum (L) and lycorine. The ethanolic extract of C. asiaticum (L) and lycorine were found to have different levels of antioxidant properties in the test models. Both ethanolic extract of C. asiaticum (L) (0.5-2.5 mg/ml) and lycorine (0.010 mg-0.050 mg/ml) increases the percentage of lipid peroxidation inhibition (26.25 ± 0.23% and 19.25 ± 0.23%) and enhances the free radical scavenging activity (20.92 ± 0.22% and 20.52 ± 0.22%), scavenging of hydrogen peroxide (25.67 ± 0.17% and 23.07 ± 0.3%) superoxide anion scavenging activity (27.69 ± 0.16% and 16.09 ± 0.7%) at concentration of 2.5 and 0.050 mg of C. asiaticum (L) and lycorine, respectively. But compared with tocopherol (P < 0.05) less activity was observed by C. asiaticum (L) and lycorine. The ethanolic extract of C. asiaticum (L) and lycorine were normalized to reduce the level of glutathione and also to sustain the status of protein in erythrocytes during the peroxyl radical [2,2-azobis (2-amidinopropane) dihydrochloride (AAPH)] induced oxidative damage in ex vivo model. The present results of the investigations demonstrated that protective nature of the C. asiaticum (L) and lycorine will be considered as a significant natural antioxidant source.


Intensity of adaptations to heat stress in poultry farms: A behavioural analysis of farmers in Ondo state, Nigeria.
The detrimental consequences of heat stress due to high ambient temperatures, particularly in the poultry industry, have led to the invention of several adaptation strategies. However, there is still limited information on the intensity of adaptations and the likely behavioural factors that influence farmers' decisions. Thus, understanding the practical adaptation behaviours of poultry farmers would improve our knowledge of the fundamental mechanisms for developing effective interventions. To fill this void, using a count data model, the study empirically examines the farmers' behavioural factors and the intensity of heat stress adaptation strategies' adoption among poultry farmers in Ondo State, Nigeria. The data were drawn from a survey of 150 poultry farmers using a multistage sampling procedure. The empirical results show that the majority of the farmers perceived an increase in temperature, frequently experienced heat stress, and believed that heat stress is induced by climate change. An average of six adaptation strategies were simultaneously adopted to mitigate heat stress in the area. The results of the count regression model reveal that farm-level factors such as permanent water sources, the quantity of feed, and bird stock density exert a significant effect on the intensity of adaptations. Climate-related factors such as access to climate information, training participation, perceived increases in temperature, attitudes toward climate change, and motives for adoption have a significant behavioural effect on the intensity of adaptations. Likewise, variables such as poultry farming experience, educational status, and access to credit are accounted for as socioeconomic behavioural factors that influence the intensity of adopting heat stress adaptation strategies in the area. This concludes that behavioural factors are crucial in addressing heat stress adaptations and assisting in improving environmental management, which would form a key variable in the policy interventions.


Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion.
Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacological or RNA interference-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRC(Y416)). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared with either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.


Oligopeptide cyclophilin inhibitors: a reassessment.
Potent cyclophilin A (CypA) inhibitors such as non-immunosuppressive cyclosporin A (CsA) derivatives have been already used in clinical trials in patients with viral infections. CypA is a peptidyl prolyl cis/trans isomerase (PPIase) that catalyzes slow prolyl bond cis/trans interconversions of the backbone of substrate peptides and proteins. In this study we investigate whether the notoriously low affinity inhibitory interaction of linear proline-containing peptides with the active site of CypA can be increased through a combination of a high cis/trans ratio and a negatively charged C-terminus as has been recently reported for Trp-Gly-Pro. Surprisingly, isothermal titration calorimetry did not reveal formation of an inhibitory CypA/Trp-Gly-Pro complex previously described within a complex stability range similar to CsA, a nanomolar CypA inhibitor. Moreover, despite of cis content of 41% at pH 7.5 Trp-Gly-Pro cannot inhibit CypA-catalyzed standard substrate isomerization up to high micromolar concentrations. However, in the context of the CsA framework a net charge of -7 clustered at the amino acid side chain of position 1 resulted in slightly improved CypA inhibition.


Anti-drug antibodies to LMB-100 are enhanced by mAbs targeting OX40 and CTLA4 but not by mAbs targeting PD1 or PDL-1.
LMB-100 is a recombinant immunotoxin being developed for cancer treatment that is composed of a Fab that binds to mesothelin and a portion of Pseudomonas exotoxin A. LMB-100 is in clinical trials for the treatment of mesothelioma and pancreatic cancer. To determine if check point modulating antibodies enhance the formation of anti-drug antibodies (ADA) against LMB-100, we treated mice with LMB-100 and four different immune modulating monoclonal antibodies that have different mechanisms of action; anti-CTLA4, anti-OX40, anti-PD-1 and anti-PDL-1. We found that anti-PD-1 and anti PDL-1 do not increase the formation of ADA, but anti-CTLA-4 and anti-OX-40 do increase the onset of ADA. These results indicate that combining anti-CTLA-4 and anti-OX-40 with antibodies and other protein-based therapeutics may enhance ADA formation in humans.


Function of agricultural waste montmorillonite-biochars for sorptive removal of 17β-estradiol.
Agricultural wastes of cow manure and wheat straw were used to prepare montmorillonite (Mt)-biochars (CMt and WMt) for sorptive removal of 17β-estradiol (E2) from aqueous solution. The E2 adsorption performance of the two Mt-biochars was investigated using systematic adsorption kinetics and isotherms. The results exhibited that the maximum E2 adsorption amount of CMt was 41.02 mg/g, while it was 62.89 mg/g for WMt. Meanwhile, intraparticle diffusion model demonstrated that intraparticle diffusion was not the only rate-limiting step, both film diffusion and intraparticle diffusion were involved in the diffusion process. Higher pH levels (>10) decreased the adsorption capacities of Mt-biochars for E2. However, the ionic strength and the background electrolytes did not significantly affect adsorption process. Moreover, the two Mt-biochars both exhibited excellent regeneration and reusability. These results provided a potential solution to the recycling of agricultural wastes and the problem of estrogen contaminant.


Cochlear Implantation for Rudimentary Otocysts: Two Case Reports.
Rudimentary otocyst (RO) is characterized by an otic capsule without an internal auditory canal, which is considered a contraindication to cochlear implantation (CI). In this study, we were the first to report two patients with ROs who underwent CI. Two patients (18 months old and 2 years old) presenting with bilateral congenital hearing loss were diagnosed with ROs. CI was performed. The transmastoid slotted labyrinthotomy approach was used with customized MED-EL electrode arrays. Categorical auditory performance, infant-toddler meaningful auditory integration of sound, the speech intelligibility rating, and meaningful use of speech scale. Both children could understand common phrases and had intelligible, connected speech 2 years after CI. With proper indication, surgical approach and postoperative training, a child with an RO may benefit from CI.


Observational Study of Third-Trimester Vitamin D3 Supplementation and Implications for Mothers and Neonates at Term.
To determine 25-hydroxyvitamin D (25OHD) levels in pregnant women at 28 weeks and supplement based on these levels and check maternal and neonatal levels after delivery at term. This is a prospective observational study wherein pregnant women aged 18-35 years received cholecalciferol from 28 weeks till delivery at term. Women with 25OHD levels ≥ 75 nmol/L received 12.5 μg/day, those with levels 50-74.9 nmol/L received 100 μg/day and those with levels ≤ 49.9 nmol/L received 1500 μg/week. Of 555, 532 women (95.8%) completed the study. Of 532, 77 (14.5%) women had 25OHD ≥ 75 nmol/L at 28 weeks; 34/77 (44.15%) became deficient at term, and the mean 25OHD reduced from 99 ± 29.9 to 77 ± 30.4 nmol/L (p < 0.0001). One hundred and seventy-one women had 25OHD 50-74.9 nmol/L at 28 weeks; in 99 (57.89%), levels normalised at term, and mean 25OHD increased from 60.5 ± 7.5 to 78.2 ± 21.9 nmol/L (p < 0.0001). Two hundred and nineteen women had 25OHD 25-49.9 nmol/L at 28 weeks; in 135 (61.64%), levels normalised at term, and mean 25OHD increased from 36.6 ± 7.5 to 83.3 ± 32.7 nmol/L (p < 0.0001). Sixty-five women had 25OHD < 25 nmol/L at 28 weeks; In 39 (60.94%), levels normalised at term, and the mean 25OHD increased from 17.9 ± 5 to 80.6 ± 34.1 nmol/L (p < 0.0001). Seven neonates (1.3%) had cord blood ionised calcium values < 1 mmol/L, and all these had 25OHD < 50 nmol/L (mean 22.2 ± 2.5 nmol/L). Standard 12.5 μg/day supplementation in women with normal 25OHD levels at 28 weeks leads to deficiency in 44% women by term. Cholecalciferol in doses of 100 μg/day and 1500 μg/week leads to a significant increase in 25OHD levels in vitamin D-deficient pregnant women though nearly 40% may still have deficient levels at term along with their newborns. Only 1.3% of newborns had hypocalcaemia.


Follicle-stimulating hormone receptors expression in ovine corpora lutea during luteal phase: effect of nutritional plane and follicle-stimulating hormone treatment.
Corpus luteum (CL), a transient endocrine gland critical for reproductive cyclicity and pregnancy maintenance, is controlled by numerous regulatory factors. Although LH is widely recognized as the major regulator, other factors may also affect luteal functions. It has been demonstrated that FSH receptors (FSHR) are expressed not only in ovarian follicles but also in other tissues within the reproductive tract, including the CL. To evaluate FSHR expression in nontreated (nonsuperovulated; experiment 1) or FSH-treated (superovulated; experiment 2) sheep fed a control (C; maintenance), excess (O; 2 × C), or restricted (U; 0.6 × C) diet, CL were collected at the early, mid and/or late luteal phases (n = 5-7 per group). Protein and messenger RNA (mRNA) expression of FSHR were detected in the CL from all groups using immunohistochemistry followed by image analysis and quantitative RT-PCR, respectively. Follicle-stimulating hormone receptor was immunolocalized to steroidogenic small and large and nonsteroidogenic luteal cells. In both experiments, FSHR protein expression was not affected by stage of luteal development or diet. In experiment 1, expression of mRNA for all FSHR variants was greater (P <0.02 to 0.0003) at the late phase than mid or early luteal phase, and in experiment 2, it was greater (P < 0.001) at the mid than early luteal phase. Plane of nutrition did not affect FSHR mRNA expression. Comparison of FSH-treated with nontreated ewes demonstrated that FSH increased FSHR protein expression by 1.5- to 2-fold (P < 0.0001) in all groups, and mRNA expression by 7- to 30-fold (P < 0.001) for (1) FSHR-1 in all groups except U at the early luteal phase, (2) FSHR-2 in C, O, and U at the mid-phase, but not early luteal phase, and (3) FSHR-3 in U at the mid-luteal phase. Our data demonstrate that (1) FSHRs are expressed in ovine CL at several stages of luteal development, (2) FSHR protein expression does not change during the luteal phase and is not affected by diet, (3) FSHR mRNA expression not only depends on the stage of the estrous cycle but also not affected by diet in nonsuperovulated or superovulated ewes, and (4) in vivo FSH treatment enhanced FSHR protein and/or mRNA expression in the CL depending on diet and phase of the estrous cycle. Presence of FSHR in the CL indicates a regulatory role of FSH in luteal function in sheep. As very little is known about the possible role of FSH and FSHR in luteal functions, further studies should be undertaken to elucidate the endocrine, molecular, and cellular mechanisms of FSH effects on the CL.


Treatment outcomes of intracranial germinoma: a retrospective analysis of 170 patients from a single institution.
To perform a retrospective analysis of patients with intracranial germinoma treated in our department to evaluate treatment outcomes and determine optimal treatment strategies. We reviewed the treatment outcomes of 170 patients with intracranial germinoma who were treated in our department from January 1996 to January 2017. The median patient age was 15 years old. Among the patients, 56 (33%) were pathologically diagnosed, and 114 (67%) were diagnosed clinically. Various radiation fields and doses were used. Cerebrospinal fluid (CSF) and serum beta-human chorionic gonadotropin (β-HCG) levels were examined before treatment in 114 patients. Endocrinological evaluation was performed in 141 patients before and after treatment. A total of 38 patients received chemotherapy prior to radiotherapy (RT). The median follow-up time was 64.5 months (range 4-260.5 months). The 5- and 10-year overall survival (OS) rates were 94.5% and 91.3%, respectively. The relapse-free survival (RFS) rates at 5- and 10-years were 91.9% and 78.1%, respectively. Relapses occurred in 18 patients within 6 months-10 years. The spinal cord metastasis rate was 3.4% in patients with a localized lesion who did not receive spinal cord irradiation and 16.7% in patients with bifocal disease who were treated using whole ventricular irradiation (WVI) or whole brain radiotherapy (WBRT). Treatment failure did not occur in patients receiving chemoradiotherapy or in patients receiving three-dimensional conformal radiation therapy (3D-CRT)/intensity-modulated radiation therapy (IMRT). The RFS rate did not have a statistically significant correlation with the CSF/serum β-HCG level. After RT, 19.1% of the patients developed newly impaired pituitary function and required hormone replacement therapy. WVI or WBRT+ primary boost (PB) is a sufficient irradiation field for localized intracranial germinoma, while patients with bifocal disease should undergo craniospinal irradiation (CSI), especially when treated with RT alone. CSF β-HCG is not a prognostic marker for intracranial germinomas. The treatment results of chemotherapy followed by reduced-dose RT are comparable to those of RT alone. IMRT is recommended for intracranial germinoma to improve the target volume accuracy and decrease the complications of RT.


Monitoring vegetation sensitivity to drought events in China.
The frequency and severity of drought events have increased over the decades under the influence of global warming. Continued drought increases the risk of vegetation degradation. Many studies have investigated the responses of vegetation to drought but rarely from the perspective of drought events. Moreover, the spatial distributions of vegetation sensitivity to drought events are not well understood in China. Thus, the spatiotemporal patterns of drought events were quantified based on the run theory at different time-scales in this study. The relative importance of drought characteristics for vegetation anomalies during drought events were calculated by using the BRT model. Then, the sensitivity of vegetation anomalies and vegetation phenology was quantified by dividing standardized anomalies of vegetation parameters (NDVI and phenological metrics) and SPEI during drought events for different regions in China. The results show that Southern Xinjiang and Southeast China experienced relatively higher values of drought severity, especially at the 3-month and 6-month scales. Most arid areas experienced more drought events but of low severity, while some humid zones underwent few drought events but of high severity. Notable negative NDVI anomalies appeared in the Northeast China and Southwest China, while positive NDVI anomalies were observed in Southeast China and Northern central region. Drought interval, intensity and severity contributed approximately 80 % of the model's explained vegetation variance in most regions. The sensitivity of vegetation anomalies to drought events (VASD) varied regionally in China. The Qinghai-Tibet Plateau and Northeast China tended to exhibit higher sensitivity to drought events. Vegetation in these regions with high sensitivity faced a high risk of degradation and could function as warning signals of vegetation degradation. Drought events at high timescales had a greater impact on vegetation sensitivity in dry zones, while they had a smaller impact on humid areas. With the increase in drought degree of climate zones and the decrease in vegetation coverage, VASD showed a gradual increase. Furthermore, a strong negative correlation between VASD and the aridity index (AI) was observed in all vegetation types. The change in VASD for sparse vegetation was the largest with the change in AI. For vegetation phenology, drought events in most regions delayed the end of the growing season and extended the length of growing season, especially for sparse vegetation. The start of the growing season was advanced in most humid areas, while being delayed in most dry areas during drought events. Knowledge of vegetation sensitivity to drought events will be beneficial to provide decision-making references for the prevention and control of vegetation degradation, especially in the ecological fragile regions.


Edge-to-Edge Technique Used as a Bailout for Suboptimal Mitral Repair: Long-term Results.
For cases of initial suboptimal mitral valve repair, the edge-to-edge (EE) technique has been used as a bailout procedure. However the long-term durability of those rescued mitral valves is currently unknown. With this study we aim to evaluate the long-term clinical and echocardiographic results of the EE technique used to rescue patients with initial suboptimal conventional mitral valve repair. A retrospective review of our institutional database was done to query for patients who had undergone mitral valve repair with the EE technique used as a bailout procedure. The cumulative incidence function using death as a competing event was used to estimate cardiac death and redo for mitral valve replacement. To describe the time course of mitral regurgitation, we performed a longitudinal analysis using generalized estimating equations with random intercept for correlated data. Eighty-one patients were selected. The median follow-up was 9.1 years (interquartile range, 6.7-12.1; maximum, 22.6 years). At 15 years the estimated Kaplan-Meier overall survival was 63.2% ± 8.69% (95% confidence interval, 43.76-77.46) and the predicted rate of moderate to severe mitral regurgitation recurrence was 16.67%. At 15 years the cumulative incidence function for redo for mitral valve replacement with death as a competing event was 2.5% (95% confidence interval, 0.48-7.84). No case of more than mild mitral stenosis was detected. The EE technique can be effectively used as a bailout procedure in patients with suboptimal conventional mitral valve repair with satisfactory long-term results.


Alanine: glyoxylate aminotransferase 1 is present in the peroxisomes of guinea pig kidney.
The subcellular distribution of alanine: glyoxylate aminotransferase 1 in guinea pig and rabbit kidneys was examined by centrifugation in a sucrose density gradient. The enzyme was located in the peroxisomes of guinea pig kidney and cross-reactive with the antibody against rat liver alanine: glyoxylate aminotransferase 1. This is the first report on the presence of the enzyme in the peroxisomes of mammalian kidney. The enzyme was found to be located in the mitochondria but not in the peroxisomes in rabbit kidney.


6-OHDA mediated neurotoxicity in SH-SY5Y cellular model of Parkinson disease suppressed by pretreatment with hesperidin through activating L-type calcium channels.
Parkinson's disease (PD) is a neurological condition with selective progressive degeneration of dopaminergic neurons. Routine therapies are symptomatic and palliative. Although, hesperidin (Hsd) is known for its neuroprotective effects, its exact cellular mechanism is still a mystery. Considering the important role of calcium (Ca2+) in cellular mechanisms of neurodegenerative diseases, the present study aimed to investigate the possible effects of Hsd on Ca2+ channels in cellular model of PD and the possible association between the selective vulnerability of neurons in cellular models of PD and expression of the physiological phenotype that changes Ca2+ homeostasis. SH-SY5Y cell line was used in this study; cell damage was induced by 150 µM 6-OHDA and the cells' viability was examined using MTT assay. Intracellular calcium, reactive oxygen species (ROS) and mitochondrial membrane potential were determined by the fluorescence spectrophotometry method. The expressions of calcium channel receptors were determined by gel electrophoresis and immunoblotting. Loss of cell viability and mitochondrial membrane potential were confirmed in 6-OHDA treated cells. In addition, intracellular ROS and calcium levels, calcium channel receptors significantly increased in 6-OHDA-treated cells. Incubation of SH-SY5Y cells with hesperidin showed a protective effect, reduced the biochemical markers of cell damage/death, and balanced calcium hemostasis. Based on our findings, it seems that hesperidin could suppress the progression of the cellular model of PD via acting on intracellular calcium homeostasis. Further studies are needed to confirm the potential benefits of preventive and therapeutic effects of stabilizing cellular calcium homeostasis in neurodegenerative disease.


Associations of BMI with all-cause mortality in normoglycemia, impaired fasting glucose and type 2 diabetes mellitus among an elderly Chinese population: a cohort study.
To explore the associations of body mass index (BMI) and mortality among people with normal fasting glucose (NFG), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM) in an elderly Chinese population. METHODS: A retrospective cohort study was conducted that included 59,874 elderly people who were aged 60 and older at baseline. Data for the study came from a health check-up program in China between 2011 and 2019. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazard models of BMI categories by glycemic status. During the median of 5.96 years of follow-up, 7928 participants died (6457/49057 with NFG, 712/5898 with IFG and 759/4919 with T2DM). In adjusted Cox models, risk of mortality showed a decreasing trend with BMI < 18.5 kg/m2, 24 ≤ BMI < 28 kg/m2, and BMI ≥ 28 kg/m2 compared to 18.5 ≤ BMI < 24 kg/m2: HR (95% CI): 1.33 (1.18 to 1.49), 0.88 (0.83 to 0.93), and 0.90 (0.82 to 0.98), respectively, for NFG; 0.89 (0.55 to 1.46), 0.84 (0.71 to 0.99), and 0.88 (0.70 to 1.11), respectively, for IFG; and 1.42 (0.88 to 2.29), 0.75 (0.64 to 0.89), and 0.76 (0.62 to 0.93), respectively, for T2DM. There were curvilinear-shaped associations between BMI and mortality in the NFG and T2DM groups (P overall < 0.001 and P overall < 0.001, respectively; P nonlinearity < 0.001 and P nonlinearity = 0.027, respectively) and no significantly association between BMI and all-cause mortality was observed in the IFG group (P overall = 0.170). High BMI compared to normal BMI was associated with decreased mortality, especially in the old populations with NFG and T2DM. Future studies are needed to explain the obesity paradox in elderly patients with T2DM.


Olfactory training with essential oils for patients with post-COVID-19 smell dysfunction: A case series.
It is estimated that up to one third of COVID-19 patients can develop long-lasting smell dysfunction. Viral infections, especially COVID-19, can cause anosmia through different pathomechanisms, and different strategies have been proposed for effectively managing post-COVID-19 olfactory dysfunction in clinical practice, with olfactory training being recommended as a first-line treatment option. This report describes a non-consecutive series of clinical cases. After COVID-19, eight cases (5 females, 3 males) of adult patients with long-lasting (3+ months) post-viral smell dysfunction followed a 30-day olfactory training protocol with a set of plant-derived essential oils. At baseline and at the end of the treatment, the patients were administered the Assessment of Self-reported Olfactory Functioning (ASOF) questionnaire, an inventory used to measure olfactory dysfunction and health-related quality of life. For any of the outcomes assessed with the ASOF scale, a significant improvement from baseline was reported, even though mean value ameliorations were more pronounced for olfactory function per se (Subjective Olfactory Capability: from 3.6 to 5.6 out of 10; Self-Reported capability of Perceiving specific odors: from 1.8 to 3.0 out of 5), rather than for health-related quality of life (Olfactory-Related Quality of life: from 2.9 to 3.9 out of 6). It was observed that patients with long-lasting COVID-19-related smell dysfunction improved after a 30-day olfactory training protocol. Further controlled clinical studies would be useful to better investigate the role of olfactory training in patients with postviral smell dysfunction.


A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour-specific p53 overexpression through E1A-dependent p21 and MDM2 suppression.
Oncolytic viruses engineered to replicate in tumour cells but not in normal cells could be used as tumour-specific vectors carrying the therapeutic genes. We previously developed a telomerase-specific oncolytic adenovirus, OBP-301, that causes cell death in human cancer cells with telomerase activities. Here, we further modified OBP-301 to express the wild-type p53 tumour suppressor gene (OBP-702), and investigated whether OBP-702 induces stronger antitumour activity than OBP-301. The antitumour effect of OBP-702 was compared to that of OBP-301 on OBP-301-sensitive (H358 and H460) and OBP-301-resistant (T.Tn and HSC4) human cancer cells. OBP-702 suppressed the viability of both OBP-301-sensitive and OBP-301-resistant cancer cells more efficiently than OBP-301. OBP-702 caused increased apoptosis compared to OBP-301 or a replication-deficient adenovirus expressing the p53 gene (Ad-p53) in H358 and T.Tn cells. Adenovirus E1A-mediated p21 and MDM2 downregulation was involved in the apoptosis caused by OBP-702. Moreover, OBP-702 significantly suppressed tumour growth in subcutaneous tumour xenograft models compared to monotherapy with OBP-301 or Ad-p53. Our data demonstrated that OBP-702 infection expressed adenovirus E1A and then inhibited p21 and MDM2 expression, which in turn efficiently induced apoptotic cell death. This novel apoptotic mechanism suggests that the p53-expressing OBP-702 is a promising antitumour reagent for human cancer and could improve the clinical outcome.


How to make a red flower: the combinatorial effect of pigments.
Red flowers have evolved repeatedly across angiosperms and are frequently examined in an ecological context. However, less is known about the biochemical basis of red colouration in different taxa. In this study, we examine the spectral properties, anthocyanin composition and carotenoid expression of red flowers in the tomato family, Solanaceae, which have evolved independently multiple times across the group. Our study demonstrates that Solanaceae typically make red flowers either by the sole production of red anthocyanins or, more commonly, by the dual production of purple or blue anthocyanins and orange carotenoids. In using carotenoids to modify the effect of purple and/or blue anthocyanins, these Solanaceae species have converged on the same floral hue as those solely producing red anthocyanins, even when considering the visual system of pollinators. The use of blue anthocyanins in red flowers appears to differ from other groups, and suggests that the genetic changes underlying evolutionary shifts to red flowers may not be as predictable as previously suggested.


Chronotropic and dromotropic components of cardiac reflexes in rabbits.
The relationships between dromotropic and chronotropic components of five reflexes were studied in rabbits: intravenous and intraarterial blood injections, occlusion of the carotid arteries, Aschner maneuver, and stimulation of depressors. All these stimuli reduced heart rate (except carotid artery occlusion, which induced approximately equal number of tachi- and bradycardic responses). The former three stimuli also reduced atrioventricular (AV) conduction velocity, the changes in these two parameters were proportional. Changes in heart rate induced by Aschner maneuver were more pronounced than changes in AV conduction. Stimulation of depressor induced co-directed shifts in these parameters during the first seconds, but then AV conduction increased, while heart rate remained decreased; bradycardia and AV acceleration persisted for long time after termination of stimulation. Our findings attest to independent regulation of heart rate and AV conduction velocity and to the absence of a strict relationship between these two parameters.


Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin.
Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions. The effects of rifampin on the pharmacokinetics of tamoxifen (study I) and toremifene (study II) were examined in 2 randomized, placebo-controlled crossover studies. Ten (study I) or 9 (study II) healthy male volunteers took either 600 mg rifampin or placebo orally once a day for 5 days. On the sixth day, 80 mg tamoxifen or 120 mg toremifene was administered orally. Blood samples were collected up to 336 hours after drug administration. Rifampin reduced the area under the plasma concentration-time curve (AUC) of tamoxifen by 86% (P < .001), peak plasma concentration (Cmax) by 55% (P < .001), and elimination half-life (t1/2) by 44% (P < .001). The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin. During the rifampin phase, the AUC of N-demethyltamoxifen was 38% (P < .001) and the AUC of N-demethyltoremifene was 20% (P < .01) of that during the placebo phase. Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.


Sensitive and long-term monitoring of intracellular microRNAs using a non-integrating cytoplasmic RNA vector.
MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression at the post-transcriptional level. Different types of cells express unique sets of miRNAs that can be exploited as potential molecular markers to identify specific cell types. Among the variety of miRNA detection methods, a fluorescence-based imaging system that utilises a fluorescent-reporter gene regulated by a target miRNA offers a major advantage for long-term tracking of the miRNA in living cells. In this study, we developed a novel fluorescence-based miRNA-monitoring system using a non-integrating cytoplasmic RNA vector based on a replication-defective and persistent Sendai virus (SeVdp). Because SeVdp vectors robustly and stably express transgenes, this system enabled sensitive monitoring of miRNAs by fluorescence microscopy. By applying this system for cellular reprogramming, we found that miR-124, but not miR-9, was significantly upregulated during direct neuronal conversion. Additionally, we were able to isolate integration-free human induced pluripotent stem cells by long-term tracking of let-7 expression. Notably, this system was easily expandable to allow detection of multiple miRNAs separately and simultaneously. Our findings provide insight into a powerful tool for evaluating miRNA expression during the cellular reprogramming process and for isolating reprogrammed cells potentially useful for medical applications.


Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors.
Inhibitor of growth 4 (ING4) has deserved attention as a tumor suppressor gene in many malignant tumors. In our study, we investigated ING4 immunoexpression in gastrointestinal stromal tumors (GISTs) and its prognostic value. The expression of ING4 and Ki67 was investigated in 41 samples of various risk gastrointestinal stromal tumors by immunohistochemical technique. The associations of ING4 expression and clinicopathological parameters, and prognosis of the patients, were analyzed by multivariate Cox regression analysis. ING4 expression showed a decreased trend from lower-risk to high-risk gastrointestinal stromal tumors, and an opposite trend for Ki67 expression. In lower-risk tumors, it was found the expression level of ING4 was 78.95 % ± 27.90 % and that of Ki67 was 4.42 % ± 3.75 %. However, in high-risk tumors, the expression level of ING4 was 9.23 % ± 7.66 % and that of Ki67 was 18.50 % ± 9.09 %. There was a strongly negative correlation between the expression levels of ING4 and Ki67. A significant difference was observed in the expression of ING4 between invasion and non-invasion (p < 0.001). The expression of ING4 was markedly correlated with tumor size (p < 0.001), mitotic index (p < 0.001), tumor necrosis (p = 0.021), invasion (p < 0.001), recurrence and metastasis (p = 0.021), and mortality (p < 0.001). The low expression level of ING4 protein was correlated with high-risk GISTs. ING4 might be involved in the progression of GISTs and inhibit its invasion. ING4 might be one of the prognostic indicators in GISTs.


[Carcinoma of the appendix. Presentation of one clinical case and review of the literature (author's transl)].
After presenting one case of carcinoma of the appendix of their own observation, the authors discuss several aspects of the anatomopathology, clinical course, and diagnosis of tumors of the appendix. From a review of existing literature it emerges that no case of carcinoma of the appendix was ever diagnosed preoperatively. The authors evaluate the difficulties inherent in such diagnosis and recommend some means of investigation that are currently applied to other organs.


To analyse a trace or not? Evaluating the decision-making process in the criminal investigation.
In order to broaden our knowledge and understanding of the decision steps in the criminal investigation process, we started by evaluating the decision to analyse a trace and the factors involved in this decision step. This decision step is embedded in the complete criminal investigation process, involving multiple decision and triaging steps. Considering robbery cases occurring in a geographic region during a 2-year-period, we have studied the factors influencing the decision to submit biological traces, directly sampled on the scene of the robbery or on collected objects, for analysis. The factors were categorised into five knowledge dimensions: strategic, immediate, physical, criminal and utility and decision tree analysis was carried out. Factors in each category played a role in the decision to analyse a biological trace. Interestingly, factors involving information available prior to the analysis are of importance, such as the fact that a positive result (a profile suitable for comparison) is already available in the case, or that a suspect has been identified through traditional police work before analysis. One factor that was taken into account, but was not significant, is the matrix of the trace. Hence, the decision to analyse a trace is not influenced by this variable. The decision to analyse a trace first is very complex and many of the tested variables were taken into account. The decisions are often made on a case-by-case basis.


Impact of COVID-19 upon changes in emergency room visits with chest pain of possible cardiac origin.
A decrease in Emergency Department (ED) visits for cardiac conditions has recently been reported from the US and Western Europe due to the COVID-19 pandemic. The data are still scant, and the correlation between cardiac symptoms and confirmed diagnoses are not available. There are no reports on changes in ED volumes at a national level, or from countries in the Asia-Middle Eastern region. We report data from national referral centers for tertiary care and cardiac care centers in Qatar, which see > 80% of cardiac emergencies in the country. We analyzed 102,033 ED visits in the COVID-19-era (March-April 2020 and 2019) and determined the proportion presenting for cardiac symptoms and their confirmed diagnoses. We observed a 16-37% decline in ED volumes overall, with a 25-50% decline in patients presenting with cardiac symptoms in March and April 2020 compared with March and April 2019. Among those presenting with cardiac symptoms, we observed a 24-43% decline in cardiac diagnoses in March and April 2020 compared with March and April 2019.


Long-term outcomes and social independence level after arterial switch operation.
Various issues regarding the long-term survivors of arterial switch operation (ASO) have been clarified according to the improvement of surgical mortality. We reviewed the long-term results and social independence level after ASO. Two hundred and four (204) patients who had undergone ASO more than 15 years ago were studied retrospectively. ASO was performed as a primary operation (group I, n=99) or as a secondary operation (group II, n=105). Lecompte procedure was performed in 197 patients, modified Aubert procedure in 5, and original Jatene procedure in 2. There were 11 late deaths. Kaplan-Meier survival rate (not including operative deaths) was 94.9% at 10 years and 94.9% at 15 years in group I, and 96.9% at 10 years and 94.4% at 15 years in group II. Forty-eight reoperations were performed (aortic valve replacement in 6, aortic valvoplasty in 2, Konno procedure in 1, double valve replacement in 1, right ventricular outflow tract reconstruction in 35). The reoperation-free rate including late death was 82.2% at 10 years and 75.7% at 15 years in group I, and 88.2% at 10 years and 78.1% at 15 years in group II. One hundred and seventy-eight patients were classified as NYHA class I and 7 patients as class II. All the patients except those with mental disorder (1) or neurodevelopmental impairment (3) were attending school or working. There was no significant difference in left ventricular function between group I and II, both showing values within the normal range. The long-term (>15 years) outcome of ASO survivors was satisfactory. Most patients showed excellent cardiac function and were socially independent.


Bioinformatics analysis of miRNAs in the neuroblastoma 11q-deleted region reveals a role of miR-548l in both 11q-deleted and MYCN amplified tumour cells.
Neuroblastoma is a childhood tumour that is responsible for approximately 15% of all childhood cancer deaths. Neuroblastoma tumours with amplification of the oncogene MYCN are aggressive, however, another aggressive subgroup without MYCN amplification also exists; rather, they have a deleted region at chromosome arm 11q. Twenty-six miRNAs are located within the breakpoint region of chromosome 11q and have been checked for a possible involvement in development of neuroblastoma due to the genomic alteration. Target genes of these miRNAs are involved in pathways associated with cancer, including proliferation, apoptosis and DNA repair. We could show that miR-548l found within the 11q region is downregulated in neuroblastoma cell lines with 11q deletion or MYCN amplification. In addition, we showed that the restoration of miR-548l level in a neuroblastoma cell line led to a decreased proliferation of these cells as well as a decrease in the percentage of cells in the S phase. We also found that miR-548l overexpression suppressed cell viability and promoted apoptosis, while miR-548l knockdown promoted cell viability and inhibited apoptosis in neuroblastoma cells. Our results indicate that 11q-deleted neuroblastoma and MYCN amplified neuroblastoma coalesce by downregulating miR-548l.


Magnetic resonance imaging of abnormal shoulder pain following influenza vaccination.
The influenza vaccine is increasingly available to the general public and mandated by many employers in the United States. The prevalence of post-vaccination complications is likely on the rise. Complications are well known to general clinicians, but are under-reported in the imaging literature. We present four cases of post-vaccination shoulder pain with magnetic resonance imaging (MRI) findings. An intrasubstance fluid-like signal in deep muscular and/or tendinous structures was the most common finding on MRI of these four cases. Focal bone marrow signal within the humeral head and inflammatory changes in the subacromial/subdeltoid bursa were also observed. The most likely reason for a humeral intraosseous edema-like signal was presumed injection of vaccine substance directly into osseous structures that might lead to focal osteitis. In the published literature, there is little emphasis on the imaging of local injection site complications accompanying influenza vaccination. We intended to increase familiarity of MRI findings in the setting of prolonged or severe clinical symptoms following influenza vaccination through the imaging findings of these four cases.


Clinical evaluation of nares-vocal cord distance and its correlation with various external body parameters.
The optimal visualisation of vocal cords during fibreoptic intubation may be utilised for the nares-vocal cord distance (NVD) estimation. The present study was conducted to measure NVD and to correlate with various external body parameters. This study was conducted on 50 males and 50 females. We measured NVD and analysed its relationship with height, nares to tragus of ear distance (NED), nares to angle of mandible distance (NMD), sternal length (SL), thyro-mental distance (TMD), sterno-mental distance (SMD) and arm span (AS). The mean NVD of the males was 18.5 ± 1.5 cm, and that of the females was 15.9 ± 1.1 cm. The relationship between the NVD and body height (males P = 0.001, r = 0.463, females P = 0.000, r = 0.555), SL (males P = 0.000, r = 0.463, females P < 0.000, r = 0.801) or AS (males P = 0.000, r = 0.561, females P = 0.000, r = 0.499) showed a significant correlation but NED, NMD, TMD, SMD did not. After combining male and female groups, (n = 100), the correlation of NVD with external body parameters is as follows SL (r = 0.887), height (r = 0.791), AS (r = 0.769), weight (r = 0.531), SMD (r = 0.466), NED (r = 0.459), NMD (r = 0.391), TMD (r = 0.379). The relationship of NVD to external body parameters had strong correlation in all parameters in the combined group; whereas when gender was taken into consideration NVD correlated significantly only with SL, height and AS.


[Hyperuricemia and disorders in content of amino acids-purine precursors in patients with autoimmune diseases and gout].
Patients with system lupus erythematosus, rheumatic arthritis, chronic active hepatitis and gout were found to have considerable hyperuricemia and be decreased in aminoacides content, which are the predecessors of purine. Hyperactivity of xanthineoxidase and POL content were also revealed. The close correlation relation of purine indices of such patients has been observed. The obtained data allow applying methods of correction of immunity system and purine metabolism to these patients by introducing in a complex therapy inhibitors of xanthineoxidase.


Changing occupational structures and residential segregation in New York, London and Tokyo.
Based on data from the 1980s, Sassen's influential book 'The Global City' interrogated how changes in the occupational structure affect socio-economic residential segregation in global cities. Here, using data for New York City, London and Tokyo, we reframe and answer this question for recent decades. Our analysis shows an increase in the share of high-income occupations, accompanied by a fall in low-income occupations in all three cities, providing strong evidence for a consistent trend of professionalization of the workforce. Segregation was highest in New York and lowest in Tokyo. In New York and London, individuals in high-income occupations are concentrating in the city centre, while low-income occupations are pushed to urban peripheries. Professionalization of the workforce is accompanied by reduced levels of segregation by income, and two ongoing megatrends in urban change: gentrification of inner-city neighbourhoods and suburbanization of poverty, with larger changes in the social geography than in levels of segregation.


First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis.
Adequate platelet reactivity is required for maintaining hemostasis. However, excessive platelet reactivity can also lead to the formation of occlusive thrombi. Platelet 12(S)-lipoxygenase (12-LOX), an oxygenase highly expressed in the platelet, has been demonstrated to regulate platelet function and thrombosis ex vivo, supporting a key role for 12-LOX in the regulation of in vivo thrombosis. However, the ability to pharmacologically target 12-LOX in vivo has not been established to date. Here, we studied the effect of the first highly selective 12-LOX inhibitor, ML355, on in vivo thrombosis and hemostasis. ML355 dose-dependently inhibited human platelet aggregation and 12-LOX oxylipin production, as confirmed by mass spectrometry. Interestingly, the antiplatelet effects of ML355 were reversed after exposure to high concentrations of thrombin in vitro. Ex vivo flow chamber assays confirmed that human platelet adhesion and thrombus formation at arterial shear over collagen were attenuated in whole blood treated with ML355 comparable to aspirin. Oral administration of ML355 in mice showed reasonable plasma drug levels by pharmacokinetic assessment. ML355 treatment impaired thrombus growth and vessel occlusion in FeCl3-induced mesenteric and laser-induced cremaster arteriole thrombosis models in mice. Importantly, hemostatic plug formation and bleeding after treatment with ML355 was minimal in mice in response to laser ablation on the saphenous vein or in a cremaster microvasculature laser-induced rupture model. Our data strongly support 12-LOX as a key determinant of platelet reactivity in vivo, and inhibition of platelet 12-LOX with ML355 may represent a new class of antiplatelet therapy.


Long-term immunogenicity, efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients.
The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq® ) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A. Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study. Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%-88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0-0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0-1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported. No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.


[Reproducibility study of the "400 Points assessment", a measurement of the hand's functional ability].
Evaluate the inter-rater and test-retest reproducibility of the "400 Points assessment", a measurement of the functional ability of the hand. The scale included four tests: function of the hand, prehension strengths, handling and displacement of things, and function with both hands. Thirty patients with hand injuries were participated. The inter-rate agreements were examinated between three occupational therapists. The First rater was an experienced user of this instrument (observer 1), the second one was a novice user (observer 2), the last rater is a student who had never used it before (observer 3). Subjects were tested twice by the same raters independently, with 30 minutes intervals between tests. Statistical analysis was done by calculating average differences and intraclass correlation coefficient. (i) The difference between the three raters agreements was small for the two measurements, except for function with both hands in the second period. Every intraclass correlation coefficient was higher than 0.95. (ii) Difference between the two measurements was small for every observer. These differences are not significant except for function with both hands. Intraclass correlation coefficients are all higher than 0.82 even than 0.90 for the total score. The difference between the two periods for the overall test is small, from 5% to 10% for seven patients and from 10 to 15% for two patients. Differences at two times had the same agreement for the three observers. "400 Points assessment" is reproducible (inter-rater and test-retest reproductibility). The test "function with both hands" requires more experience of the assessment.


The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance.
Chemotherapy in cancer patients is still not satisfactory because of drug resistance. The main mechanism of drug resistance results from the ability of cancer cells to actively expel therapeutic agents via transport proteins of the ABC family. ABCB1 and ABCG2 are the two main proteins responsible for drug resistance in cancers. Recent investigations indicate that aldehyde dehydrogenase (ALDH) can also be involved in drug resistance. Expression of the ABC transporters and ALDH enzymes is observed in normal stem cells, cancer stem cells and drug resistant cancers. Current chemotherapy regimens remove the bulk of the tumour but are usually not effective against cancer stem cells (CSCs) expressing ALDH. As a result, the number of ALDH positive drug resistant CSCs increases after chemotherapy. This indicates that therapies targeting drug resistant CSCs should be developed. A number of therapies targeting CSCs are currently under investigation. These therapies include differentiation therapy using different retinoic acids (RA) as simple agents or in combination with DNA methyltransferase inhibitors (DNMTi) and/or histone deacetylase inhibitors (HDACi). Therapies that target cancer stem cell signaling pathways are also under investigation. A number of natural compounds are effective against cancer stem cells and lead to decreasing numbers of ALDH positive cells and downregulation of the ABC proteins. Combinations of differentiation therapies or therapies targeting CSC signaling pathways with classical cytostatics seem promising. This review discusses the role of ALDH and ABC proteins in the development of drug resistance in cancer and current therapies designed to target CSCs.


Monosomy 7 and multipotential stem cell transformation.
Monosomy 7 was the sole karyotypic abnormality seen in a case of biphenotypic leukaemia involving both the myeloid and lymphoid lineages and in a case of de novo ALL undergoing a phenotypic shift to acute myeloid leukaemia at relapse. These observations suggest that monosomy 7 can be associated with transformation of a common lymphoid-myeloid progenitor cell.


MiR-497-3p induces Premature ovarian failure by targeting KLF4 to inactivate Klotho/PI3K/AKT/mTOR signaling pathway.
Premature ovarian failure (POF), as a gynecological endocrine disease, features the manifestation of irregular menstruation, amenorrhea, infertility and perimenopausal syndrome. MicroRNAs (miRNAs) have been reported to modulate POF. However, the specific regulatory mechanism of miR-497-3p in POF remain unclear. Quantitative reverse transcription-PCR (RT-qPCR) and western blot were implemented to analyze RNA and protein levels, respectively. Comet assay was performed for the detection of DNA damage. Flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed to measure apoptosis of CTX-induced KGN cell (POF cell model). Bioinformatics was utilized to screen out the downstream mRNAs potentially regulated by miR-497-3p. Chromatin immunoprecipitation (ChIP) assay, luciferase reporter assay and RNA pulldown assays were performed to demonstrate the interaction between miR-497-3p and Kruppel-like factor 4 (KLF4) or between KLF4 and Klotho (KL). Rescue assays were performed to verify the involvement of Klotho in miR-497-3p-mediated functions of POF cell model. MiR-497-3p was upregulated in CTX-treated KGN cells. Knockdown of miR-497-3p could reverse the promoting effects of CTX on DNA damage and cell apoptosis. MiR-497-3p negatively regulated Klotho expression by directly targeting the transcription activator KLF4. KLF4 activated Klotho transcription. MiR-497-3p inactivated PI3K/AKT/mTOR signaling pathway through KLF4/Klotho axis. Klotho knockdown reversed the effects of MiR-497-3p on the functions of POF cell model. MiR-497-3p promotes DNA damage and apoptosis in CTX-treated KGN cells by targeting KLF4 to downregulate Klotho and inactivate the PI3K/AKT/mTOR signaling pathway. This study unveils novel mechanisms associated with cell functional changes in POF and may enrich therapeutic strategy for POF.


Vitamin D deficiency among apparently healthy children and children with common medical illnesses in Sub-Saharan Africa: A systematic review and meta-analysis.
Studies show that 25 (OH) D status appears to have beneficial influence on the incidence and severity of some types of infections. However, studies with vitamin D supplementation on young children produced conflicting results. This study was conducted to assess and compare the pooled prevalence of vitamin D deficiency among healthy and sick children in sub-Saharan Africa. A systematic review of PubMed, CINAHL, Web of science, global health and Google scholar electronic databases was conducted. Both published and unpublished observational studies conducted among under-five children in the year 2010-2020 were included. STATA Version 14 was used for analysis. Heterogeneity of studies was assessed using I2 test. A random-effects model was used to estimate the pooled prevalence among both healthy and sick children. A total of 1212 articles were retrieved from data bases, of which 10 papers were included. The pooled prevalence of vitamin D deficiency among healthy children was 50.06% with mean serum vitamin D level of 41.06 nm/L. The pooled prevalence among the sick children was 39.36% with 66.96 nm/L of mean concentration. The pooled prevalence among healthy children was significantly higher compared to those who have common medical illnesses and the pooled mean concentration among the sick was also much higher than the mean concentration among healthy children. The pooled prevalence among both groups of population was significantly high and a concerning public health problem. The prevalence among healthy children was much higher as compared to sick children.


In vitro and in vivo therapeutic antileishmanial potential of ellagic acid against Leishmania donovani in murine model.
Parasite of genus Leishmania viz. L. donovani and L. infantum cause visceral leishmaniasis (VL) or Kala-azar, systemic disease with significant enlargement of the liver and spleen, weight loss, anemia, fever and immunosuppression. The silent expansion of vectors, reservoir hosts and resistant strains is also of great concern in VL control. Considering all these issues, the present study focused on in vitro and in vivo antileishmanial screening of ellagic acid (EA) against L. donovani. The in vitro study was performed against the protozoan parasite L. donovani and a 50% inhibitory concentration was calculated. The DNA arrest in the sub-G0/G1 phase of the cell cycle was studied. In vivo studies included the assessment of parasite burden and immunomodulation in response to treatment of ellagic acid in BALB/c mice. The levels of Th1 and Th2 cytokines and isotype antibodies were assessed in different groups of mice. EA showed in vitro parasiticidal activity with IC50 18.55 µg/mL and thwarted cell-cycle progression at the sub-G0/G1 phase. Administration of ellagic acid to the BALB/c mice reported diminution of splenic and hepatic parasite burden coupled with an expansion of CD4+ and CD8+ T lymphocytes. EA further potentiated a protective immune response with augmentation of Th1 type immune response evidenced by elevation of serum IgG2a levels and DTH response. EA was reported to be safe and non-toxic to the THP-1 cell line as well as to the liver and kidneys of mice. These findings endorse the therapeutic potential of EA with significant immunomodulation and can serve as a promising agent against this debilitating parasitic disease.


Choice of surgical approach influences the combined anteversion needed for a stable and impingement-free total hip arthroplasty.
Accurate component positioning is the key for successful outcome after total hip arthroplasty (THA). Positioning acetabular and femoral components in a safe zone of 25°-50° on the basis of combined anteversion (CA) has shown to reduce instability and impingement. This safe zone was described for THAs performed through the posterior approach and has not been validated for other surgical approaches. Seventy patients who underwent unilateral uncemented THA were included in the study; 35 patients-using posterior approach and the remaining 35-using trans-gluteal approach. All patients included had a stable and impingement-free THA at a mean follow-up of 39.2 ± 9.5 months. CT scan was performed to assess component positioning by calculating CA. The values were compared between the two groups to study possible differences. CA in the trans-gluteal group was significantly lower (32° ± 3.7° vs 38.4° ± 4.6°, P < .001) compared to posterior group. The difference in CA was due to the differences in acetabular anteversion, which was significantly low in the trans-gluteal group than the posterior group (22.1° ± 3.6° vs 27.8° ± 4.2°, P < .001). The mean femoral anteversion was similar in both groups. All trans-gluteal hips fell within the safe zone of 20°-40°, and all posterior hips fell within the safe zone of 25°-50°. A safe zone of 25°-50° is valid for THAs performed from the posterior approach but not universally applicable. For trans-gluteal approach, a safe zone of 20°-40° is better to provide a stable and impingement-free THA. CA varies with the surgical approach. THAs performed through the trans-gluteal approach can be stable and impingement-free with lesser CA compared to THAs performed through the posterior approach.


Post-exposure administration of edaravone attenuates noise-induced hearing loss.
We investigated the effects of the antioxidant edaravone against acoustic trauma in guinea pigs. Edaravone (1.722 x 10(-2) M) was infused into the right ear by an osmotic pump, and the left ear was untreated for control. Animals received edaravone 9 h before (-9 h group, n = 7) and 9 h (+9 h group, n = 8), 21 h (+21 h group, n = 7) and 33 h (+33 h group, n = 4) after 3-h exposure to 130-dB noise. Seven days after noise exposure, we examined the shift in auditory brainstem response thresholds and histopathologic characteristics of the sensory epithelia. The smallest shift in auditory brainstem response threshold and smallest proportion of missing outer hair cells were observed in the +9 h group. This result was supported by immunohistochemical analysis of 4-hydroxy-2-nonenal. Our data suggest that edaravone may be clinically effective in the treatment of acoustic trauma, especially if given within 21 h of noise exposure.


Increased psychomotor retardation and tension as short-term neuropsychiatric adverse events of immune checkpoint inhibitors: A prospective cohort study.
Patients undergoing cancer treatment as well as cancer survivors commonly describe behavioral alterations. As a matter of fact, neuropsychiatric adverse events (NPAEs) have been extensively described with older immunotherapies, especially with interferon alfa. However, there are little data investigating the NPAEs of immune checkpoint inhibitors (ICIs). Therefore, the aim of this study is to evaluate the safety profile of ICI in terms of NPAEs. This is a prospective, interventional, self-controlled study. Participants receiving ICIs as unique therapy, between February and December 2019, were evaluated at the beginning of their treatment protocol, at 1 month and finally at 3 months. During the three evaluations, disease and patients' characteristics were assessed, as well as NPAEs using the Brief Psychiatric Rating Scale (BPRS) questionnaire, the psychological stress due to cancer's burden using the Herth hope index, and the performance status (PS) using the Eastern Cooperative Oncology Group (ECOG) score. Forty-four patients were enrolled, of whom 24 patients completed their three evaluation visits. No changes in BPRS total score were found throughout the study period. However, two subscores of the BPRS, "motor retardation" (P = 0.008) and "tension" or "nervousness" (P = 0.002), increased starting the 1st month of treatment. Moreover, age (r = 0.426, P = 0.038) and the baseline PS (P = 0.027) were the main risk factors of such manifestations. This study suggests that ICI could be responsible for motor retardation and increased tension starting the 1st month of treatment, with higher ECOG score and older age being the main risk factors.


Hospitals with and without neurosurgery: a comparative study evaluating the outcome of patients with traumatic brain injury.
We leveraged the data of the international CREACTIVE consortium to investigate whether the outcome of traumatic brain injury (TBI) patients admitted to intensive care units (ICU) in hospitals without on-site neurosurgical capabilities (no-NSH) would differ had the same patients been admitted to ICUs in hospitals with neurosurgical capabilities (NSH). The CREACTIVE observational study enrolled more than 8000 patients from 83 ICUs. Adult TBI patients admitted to no-NSH ICUs within 48 h of trauma were propensity-score matched 1:3 with patients admitted to NSH ICUs. The primary outcome was the 6-month extended Glasgow Outcome Scale (GOS-E), while secondary outcomes were ICU and hospital mortality. A total of 232 patients, less than 5% of the eligible cohort, were admitted to no-NSH ICUs. Each of them was matched to 3 NSH patients, leading to a study sample of 928 TBI patients where the no-NSH and NSH groups were well-balanced with respect to all of the variables included into the propensity score. Patients admitted to no-NSH ICUs experienced significantly higher ICU and in-hospital mortality. Compared to the matched NSH ICU admissions, their 6-month GOS-E scores showed a significantly higher prevalence of upper good recovery for cases with mild TBI and low expected mortality risk at admission, along with a progressively higher incidence of poor outcomes with increased TBI severity and mortality risk. In our study, centralization of TBI patients significantly impacted short- and long-term outcomes. For TBI patients admitted to no-NSH centers, our results suggest that the least critically ill can effectively be managed in centers without neurosurgical capabilities. Conversely, the most complex patients would benefit from being treated in high-volume, neuro-oriented ICUs.


Osteopontin can decrease the expression of Col-II and COMP in cartilage cells in vitro.
To observe the effect of osteopontin (OPN) on the expression of collagen type II (Col-II) and oligomeric matrix protein COMP in cartilage cells of knee osteoarthritis, and explore the mechanism of OPN in the knee osteoarthritis. Cartilage cells were isolated from fetal rabbit, they were divided into 3 groups: A (control); B (0.5 μM OPN) and C (1 μM OPN). The expression levels of Col-2 and COMP were detected by RT-PCR and Western blotting methods. MMP-13 was detected using ELISA. The proliferation was determined by MTT method. Compared with the group, the expression levels of Col-2 and COMP in cartilage cells decreased in the intervention group with dose dependent (P<0.05). The expression of MMP-13 in culture supernatant and the proliferation increased in the intervention group (P<0.05). OPN can down-regulate the expression levels of Col-2 and COMP in cartilage cells and up-regulate the expression of MMP-13 in culture supernatant and promote the proliferation of cells, which could accelerate the pathological process of cartilage cells.