Expression of androgen-responsive properties in human skin fibroblast strains of genital and nongenital origin.
Specific 5alpha-dihydrotestosterone (DHT) binding capacity (Bmax) has been determined for human skin fibroblast strains from non-genital areas of males and females (N = 8), as well as prepuce and labium majus (N = 9). Genital strains had a mean three times that of non-genital ones (32 vs. 11 fmol/mg cell protein). There were no sex differences. Variation among strains was not simply correlated with donor age; that within strains was unrelated to in vitro age. The lowest values for genital strains overlapped the nongenital ones; those of the nongenital strains approached the limit of detectability. These results parallel those for delta4-3-ketosteroid 5alpha-reductase activity. Thus, serially cultured genital and nongenital skin fibroblasts express their relative differentiative ancestry as androgen target cells. This expression may affect the diagnosis of androgen insensitivity and certain inborn errors of metabolism; its variability is discussed in terms of clonal heterogeneity.


Pilot Study Using Telemedicine Video Consultation for Vascular Patients' Care During the COVID-19 Period.
The aim of this pilot study was to evaluate the effectiveness and patients satisfaction of using telemedicine virtual communications to provide remote health care to vascular patients during the coronavirus disease 2019 (COVID-19) period in China. Video calls using WeChat software (Tencent, Shenzhen, China) between patients and vascular surgeons were conducted in a period when there were restrictions and limitations for people' travels in China. At the end of each video call, a short questionnaire was used to evaluate the patient satisfaction level. During the COVID-19 period from 19 February to March 16, 2020, a sample of 114 from 165 (69%) patients was reached after one phone call attempt. One hundred forty-two telemedicine remote communications were made between the two vascular surgeons and 114 patients. The mean age of this cohort of patients were 60 ± 15.2 (range 25 to 90) years old, and 74 (65%) were men. Twenty-five patients (22%) were outside of our province when they received the video call. The mean duration of the video call was 11.0 ± 8.9 minutes. All of the patients thought telemedicine was a good substitute for coming to hospital, and 95% (108/114) of them preferred to have remote telemedicine rather than postpone the appointment. All the patients agreed with the advantages of telemedicine including no infection risks, no need to travel, and no need to wait for long time. All the patients were "satisfied" or "highly satisfied" with the video call and they would like to use telemedicine for follow-up in the future. Telemedicine virtual communications was effective to provide remote health care with a high patient satisfaction during the COVID-19 period. Telemedicine offers support to vulnerable vascular patients without the need for travel and face-to-face hospital consultation, and so avoided transmission and infection.


Bioaccumulation of organochlorine pesticides in Antarctic krill (Euphausia superba): Profile, influencing factors, and mechanisms.
Accumulation of organochlorine pesticides (OCPs) in Antarctic krill (Euphausia superba), a keystone species in the Southern Ocean, is potentially harmful to the Antarctic ecosystem and human health. In the current study, we collected E. superba specimens (including muscle and carapace tissues) from Bransfield Strait in northern Antarctic Peninsula and South Georgia to analyze the profile, influencing factors and mechanisms of OCPs bioaccumulation in them. Results indicated that the biological traits (δ13C, δ15N and lipid contents) of krill were significantly affected by habitat. There may exist growth dilution of OCPs in Antarctic krill and no fresh OCPs input in Antarctica, except for endosulfan I. Based on lipid-normalized concentrations, no significant differences were observed between the two regions at most sampling sites. However, OCP levels showed tissue and sex dependence. Boosted regression trees (BRTs) and partial least squares structural equation models (PLS-SEMs) were built to better investigate the main factors affecting the bioaccumulation of OCPs. Lipid content, negatively correlated with OCP levels, was the main factor. In vitro silicon modeling indicated that CYP3A4 metabolism capacity in krill contributed to the OCP residues except for endosulfan I. The results of this study expand current knowledge of OCPs in Antarctic marine biota, as well as their influencing factors and potential mechanisms.


Protective role of citric acid against oxidative stress induced by heavy metals in Caenorhabditis elegans.
The adverse effects of heavy metals, such as cadmium, zinc, and copper, occur due to the generation of reactive oxygen species (ROS). The use of Caenorhabditis elegans for the purposes of conservation and biomonitoring is of great interest. In the present study, ROS, malondialdehyde (MDA), and citric acid levels and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in a model organism were tested to study toxicity. C. elegans was exposed to three different concentrations of cadmium (CdCl2, 5, 10, 50 μM), zinc (ZnSO4, 10, 100, 500 μM), and copper (CuSO4, 10, 100, 500 μM) for 3 days. ROS levels increased by 1.3- to 2.1-fold with increasing metal concentrations. The MDA content increased by approximately 7-, 5-, 2-fold after exposure to high concentrations of cadmium, zinc, and copper, respectively. Furthermore, the citric acid content increased by approximately 3-fold in the cadmium (Cd, 5 μM), zinc (Zn, 10 μM), and copper (Cu, 100 μM) treatment groups compared to that in untreated C. elegans. Therefore, citric acid may play an important role in heavy metal detoxification. Excess citric acid also slightly increased the LC50 by 1.3- to 2.0-fold, basic movements by 1.0- to 1.5-fold, decreased the ROS content by 2.4- to 2.1-fold, the MDA content by 4- to 2-fold, the SOD activity by 9- to 3-fold, the GPx activity by 4.0- to 3.0-fold, and the mRNA expression levels of GPxs by 3.2- to 1.8-fold after metals treatment. And it is most significantly in the alleviation of citric acid to cadmium. This study not only provides information to further understand the effects of heavy metal exposure on ROS, MDA, GPx, SOD, and citric acid in worms but also indicates that supplemental citric acid can protect animals from heavy metal stress and has broad application prospects in decreasing oxidative damage caused by heavy metals.


Dragon Training and Changing Culture: A Review of DreamWorks' How to Train Your Dragon.
DreamWorks' How to Train Your Dragon is an animated coming-of-age story in which the hero uses behavioral techniques to befriend and then to train an adversary. This movie provides an example of the successful dissemination of behavioral principles and technologies to the general population. Although it does not represent best practices in every instance, the movie may be an indication of a broader social acceptance of behavioral approaches to conflict resolution.


Mental health response to the COVID-19 pandemic in Kenya: a review.
The COVID-19 pandemic has exerted considerable impact on public mental health globally. With the pandemic rapidly rising in sub-Saharan Africa including Kenya, there is need to provide evidence to guide the mental health response in the region. The objective of this review is (1) to describe the mental health response to the COVID-19 pandemic in Kenya, guided by the Mental Health Preparedness and Action Framework (2) to offer context specific recommendations for improvement of the mental health response in Kenya. Such information could be useful in decision-making in Kenya as well as in the greater sub-Saharan Africa region. This narrative review is based on information obtained from official government documents released from 13th March 2020, the beginning of the pandemic in Kenya, up to 31st July 2020. The COVID-19 response in Kenya has no formal mental health response plan. There is an unmet need for psychological first aid in the community. While guidelines for the management of mental health conditions during the COVID-19 pandemic have been prepared, implementation remains a major challenge due to a poorly resourced mental health system. There is no mental health surveillance system in place limiting ability to design evidence-based interventions. We propose four key strategies for strengthening the mental health response in order to mitigate the harmful impact of COVID-19 on public mental health in Kenya: (1) preparation of a formal mental health response plan specific to the COVID-19 pandemic with allocation of funding for the response (2) training of community health workers and community health volunteers on psychological first aid to enable access to support for those in need during the pandemic (3) scaling up of mobile health to increase access to care (4) conducting systematic and continuous text message surveys on the mental health impact of the COVID-19 pandemic in order to inform decision-making.


Relationships between euglobulin clot lysis time and the plasma levels of tissue plasminogen activator and plasminogen activator inhibitor 1.
The relationships between tissue plasminogen activator (tPA), its fast acting inhibitor (PAI-1) and euglobulin clot lysis time (ELT) were investigated with healthy volunteers' plasma. Turbidimetric clot lysis assay by the microtiter plate reader was utilized for ELT with a slight modification. Both tPA and PAI-1 showed the significant correlation with ELT. tPA had a significantly positive, not negative, correlation with ELT (R = 0.387, p less than 0.001). Higher correlation coefficients (R = 0.580, p less than 0.001 and R = 0.599, p less than 0.001) were obtained between ELT and total PAI-1 or free PAI-1 than tPA or tPA-PAI-1 complex (R = 0.427, p less than 0.001). The positive correlation was also obtained between tPA and PAI-1. These data suggest that PAI-1 is a highly important factor for ELT, especially, the amounts of free PAI-1 being the key factor to determine the ELT, which can represent the potential activity of the fibrinolytic system.


Evaluation of Cerebellar Function and Integrity of Adult Rats After Long-Term Exposure to Aluminum at Equivalent Urban Region Consumption Concentrations.
High amounts of aluminum (Al) are found in soil and water. It is highly bioavailable, which makes it an important agent of environmental imbalance. Moreover, Al is considered a neurotoxic agent that is associated with several neurodegenerative diseases. Thus, this study investigated the effects of long-term Al chloride (AlCl3) exposure on motor behavior, oxidative biochemistry, and cerebellar tissue parameters. For this, adult Wistar rats were divided into three groups: Al-D1 (8.3 mg kg-1 day-1), Al-D2 (5.2 mg kg-1 day-1), and control (distilled water); all groups were orally exposed for 60 days by intragastric gavage. After the exposure period, animals performed the open field, elevated plus maze, rotarod, and beam walking tests. Then, the blood and cerebellum were collected to evaluate Al levels and biochemical and morphological analyses, respectively. Our results demonstrate that animals exposed to Al doses presented a higher Al level in the blood. In the spontaneous locomotor activity, Al exposure groups had traveled a lower total distance when compared with the control group. There was no statistically significant difference (p > 0.05) between exposed and control groups when anxiogenic profile, forced locomotion, fine motor coordination/balance, pro-oxidative parameter, and density Purkinje cells were compared. Thus, aluminum exposure in equivalent doses to human consumption in urban regions did not promote significant changes in the cerebellum or motor parameters.


Behavioral mimicry of eating in mice.
Nonconscious behavioral mimicry is prevalent in humans and highly social animals who imitate the behaviors of others without awareness. Previous studies indicated people tended to match their amount of eating to that of their eating companions due to behavioral mimicry, however whether such phenomena were existed in rodents is still unknown. Developing a behavioral paradigm would be helpful to better understand the molecular and circuit mechanisms underlying behavioral mimicry. In this study, we examined behavioral mimicry of eating in C57BL/6J mice which had strong sociality and were widely used as animal model in researches. We set up an eating monitoring platform, and this platform could record the data of mice eating behavior in real time. We further examined the behavioral mimicry of eating in mice, and found that the mice observing eating behavior of food-restricted mice would consume more food than control mice, and visual cue with eating behavior was sufficient to increased food consumption in mice. Our study indicated behavioral mimicry of eating was existed in mice and provided a mouse model for future studies on the mechanism of behavioral mimicry of eating.


Ascending multisynaptic pathways from the trigeminal ganglion to the anterior cingulate cortex.
By means of retrograde transneuronal transport of rabies virus, ascending multisynaptic pathways from the trigeminal ganglion (TG) to the anterior cingulate cortex (ACC) were identified in the rat. After rabies injection into an electrophysiologically defined trigeminal projection region of the ACC, transsynaptic labeling of second-order neurons via the medial thalamus (including the parafascicular nucleus) was located in the spinal trigeminal nucleus pars caudalis. Third-order neuron labeling occurred in the TG. Most of these TG neurons were medium- or large-sized cells giving rise to myelinated Aδ or Aβ afferent fibers, respectively. By contrast, TG neurons labeled transsynaptically from the orofacial region of the primary somatosensory cortex contained many small cells associated with unmyelinated C afferent fibers. Furthermore, the TG neurons retrogradely labeled with fluorogold injected into the mental nerve were smaller in their sizes compared to those labeled with rabies. Our extracellular unit recordings revealed that a majority of ACC neurons responded to trigeminal nerve stimulation with latencies of shorter than 20ms. Thus, somatosensory information conveyed to the ACC by multisynaptic ascending pathways derived predominantly from myelinated primary afferents (i.e., the medial nociceptive system) and may be used to subserve affective-motivational aspects of pain. Lack of overlap with the lateral nociceptive system is notable and suggests that the medial and lateral nociceptive systems perform separate and non-overlapping functions.


Attenuation of stress-induced gastrointestinal motility disorder by gentiopicroside, from Gentiana macrophylla Pall.
The current study was designed to explore the mechanism of the prokinetic activity of Gentiopicroside (Ge), from Gentiana macrophylla Pall which is widely used to strengthen gastric motility in clinic. Gastrointestinal motility disorder rats were induced by stress stimulation and the rats were treated with Ge. The functions of gastric emptying and intestinal propelling were measured after blood was obtained to assay the levels of plasmatic motilin (MTL), vasoactive intestinal peptide (VIP), somatostatin (SST), gastrin (GAS), neurotensin (NT) and substance of P (SP). The expressions of MTL receptor (MTLR), VIP receptor 2 (VIPR2) and SST receptor 2 (SSTR2) were measured also. In addition, an isolated guinea pig ileum was applied to evaluate the influences of Ge on M-R, H1-R, 5-HT4-R and D-R in vitro. Ge increased gastric emptying and intestinal propelling obviously. It also decreased the level of SST and increased GAS in plasma significantly. Moreover, it promoted the expressions of MTLR in gastric antrum, duodenum, jejunum and ileum, and restrained the expression of VIPR2 in duodenum. Piboserod and loratadine had no obvious restrain to Ge' exciting ileum effect and Ge also didn't affect dopamine paralyzing ileum. However, Ge failed to improve the hypofunction of guinea pigs ileums pre-treated with atropine sulfate. The mechanisms of Ge' prokinetic effect were associated with modulating the levels of SST and GAS in plasma, raising the expressions of MTLR in gastric antrum, duodenum, ileum and jejunum, reducing the expression of VIPR2 in duodenum and activating M-R.


Organization and interrelationship of neuropeptides in the central amygdaloid nucleus of the rat.
The organization and interactions of neuropeptides in the central nucleus of the amygdala (Ce) were studied using single and double label immunocytochemical techniques. Immunocytochemical localization of substance P (SP), neurotensin (NT), met-enkephalin (m-ENK), somatostatin (SS) and vasoactive intestinal polypeptide (VIP) revealed all of these peptides within discrete regions of the Ce. The regions differed from the classical medial and lateral anatomical divisions reported for the Ce. Instead, three easily recognizable neuropeptidergic subdivisions were evident: a medial zone, a central zone and a lateral capsular zone. Two types of interrelationships between peptides were noted. The first involved a peptidergic fiber in apposition to a peptidergic perikarya. The most prevalent peptidergic interaction of this type occurred between SP and NT. The second interrelationship involved two different peptidergic fibers in apposition to an immunonegative cell. Two interactions of this type were commonly observed. The first involved NT and m-ENK fibers simultaneously apposed to an unstained cell. The second involved SP and m-ENK fibers adjacent to the same immunonegative cell. The interactions between peptidergic systems may suggest a role of these substances in the regulation of autonomic functions in the Ce.


Induction of cytotoxic T lymphocyte activity by immunization with recombinant Semliki Forest virus: indications for cross-priming.
For the rational design of vaccines capable of inducing CD8+ T cell responses knowledge of the identity of the antigen-presenting cell (APC) and the mechanism of antigen presentation is very important. Here, we address these issues for alphavirus-based immunization, in particular immunization with recombinant Semliki Forest virus (rSFV). Studies with dendritic cells (DCs) from various origins revealed that rSFV has a very limited capacity to transfect this cell type in vitro. To further investigate in vivo whether rSFV transfects professional antigen-presenting cells directly or whether the antigens reach APCs via a mechanism of cross-priming we compared the immunological effects of three different SFV-constructs encoding the influenza nucleoprotein (NP). These constructs differ in the amount of NP produced per cell or in the stability of the NP, respectively. Induction of cytotoxic T lymphocytes (CTLs) appeared to benefit from a large amount of stable antigen. In contrast, rapid antigen degradation, and thus availability of antigenic peptides in the transfected cell, was found to be disadvantageous. Based on these in vitro and in vivo results, we hypothesize that antigen presentation after SFV-based immunization proceeds via a mechanism in which APCs are not transfected directly but acquire antigen from other transfected cells and present it to CTLs in a process of cross-priming.


Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms.
Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, which is often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder. Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y, a neuropeptide partially coexpressed in SST-IR neurons. Total numbers (Nt) of IR neurons were measured. Time of death was used to test associations with circadian rhythms. SST-IR neurons were decreased in the lateral amygdala nucleus in BD (Nt, p = .003) and SZ (Nt, p = .02). In normal control subjects, Nt of SST-IR neurons varied according to time of death. This pattern was altered in BD subjects, characterized by decreases of SST-IR neurons selectively in subjects with time of death corresponding to the day (6:00 am to 5:59 pm). Numbers of neuropeptide Y-IR neurons were not affected. Decreased SST-IR neurons in the amygdala of patients with SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these individuals. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.


Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer.
To evaluate the efficacy and safety of combined gemcitabine and S-1 as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer. This study included patients who had been diagnosed with unresectable, locally advanced or metastatic adenocarcinoma arising from the pancreas, which was histologically or cytologically confirmed and involved at least 1 unidimensionally measurable lesion. The regimen consisted of intravenous 1,000 mg/m(2) gemcitabine on day 1 and 8 combined with oral S-1 on days 1-14 every 21 days. The dosage of S-1 was based on the body surface area (BSA) as follows: 40 mg bid (total 80 mg/day) for a BSA of <1.25, 50 mg bid (total 100 mg/day) for a BSA of ≥1.25 but <1.5, and 60 mg bid (total 120 mg/day) for a BSA of ≥1.5. Treatment consisted of at least 2 courses unless rapid disease progression was noted. The primary end points were the response and disease control rates, and the secondary end points were toxicity and survival. Thirty-seven patients were enrolled between August 2005 and December 2010. The median number of chemotherapy cycles was 4 (range 1-28 cycles). Response to treatment could be evaluated in 31 patients. None of the patients showed complete response, but 5 achieved partial response. The response rate was thus 13.5 % [95 % confidence interval (CI) 2.7-24.3 %] in the intent-to-treat population. Sixteen patients (43.2 %; 95 % CI 27-59.5 %) showed stable disease, and the overall disease control rate was 56.8 % (95 % CI 40.6-72.9 %). For all 37 patients, the median progression-free survival was 4.6 months (95 % CI 1.8-7.6 month), and the median overall survival was 9.4 month (95 % CI 5.8-12.6 month). Chemotherapy-related grade 3/4 hematological toxicities were neutropenia (36.1 %), leucopenia (22.2 %), and anemia (13.9 %). The non-hematological toxicities were generally mild. Combination chemotherapy with gemcitabine and S-1 was effective, convenient, and safe in patients with advanced pancreatic cancer.


Covered self-expanding metal stents for the management of common bile duct stones.
Little medical literature exists for the use of fully covered self-expanding metal stents (CSEMSs) in the management of retained common bile duct (CBD) stones. Our aim was to assess the safety and efficacy of CSEMSs for the indication of retained "difficult" CBD stones. This retrospective cases series included 44 patients (30 women; median age, 69 years [range, 24-88]) who underwent CSEMS insertion for the indication of retained "difficult" CBD stones in 2 tertiary referral centers. Patients underwent temporary placement of CSEMSs after incomplete stone clearance at ERCP. Follow-up ERCP was arranged for stent removal and subsequent attempt at duct clearance. Procedure-related adverse events were also recorded. Successful biliary drainage was achieved in all cases after CSEMS placement. Forty-two stents were removed with successful duct clearance achieved in 36 cases (82%) after a median in-stent duration of 8 weeks. There were 10 cases (22.7%) of stent migration, all noted incidentally during follow-up. One patient died of nonbiliary causes before attempted removal. This is the largest published retrospective case series for use of CSEMSs for management of retained CBD stone disease to date. We have shown high success rates for this indication. A well-designed, multicenter, randomized controlled trial might address the uncertainty of cost-to-benefit ratio and appropriate duration for CSEMSs to be left in situ. Specific stent modification for this indication, including wider distal flare and retrieval purse string loop, may also be useful.


The effect in vitro of 2'-deoxycytidine on the metabolism and cytotoxicity of 2',3'-dideoxycytidine.
We examined in vitro the effect of high, but clinically achievable and non-toxic, concentrations of 2'-deoxycytidine (dCyd) (greater than or equal to 100 mumols/l on the metabolism and cytotoxicity of 2',3'-dideoxycytidine (DDC) in normal human bone marrow mononuclear cells (BMMCs) and a cultured T-lymphocyte (HUT-102) cell line. Colony formation in semi-solid medium by bone marrow progenitor cells (CFU-GM and CFU-GEMM) was significantly protected by dCyd against the cytotoxic effects of high doses of DDC. In contrast, in HIV-infected HUT-102 cells, anti-HIV effect of DDC (10 mumols/l) was preserved in the presence of 100 mumols/l dCyd but partially reversed by higher levels of dCyd. dCyd reduced the generation of DDC triphosphate (DDC-TP) relative to dCyd triphosphate (dCTP) pools to a significantly greater extent in BMMCs versus HUT-102 cells. This might explain dCyd-mediated abrogation of DDC cytotoxicity against marrow progenitor cells with relative preservation of its anti-HIV-1 activity in HUT-102 cells.


Changes in the compositions of the null cell compartment with murine autoimmunity.
The subpopulations that comprise the null cell compartment were examined sequentially in various strains of autoimmune-prone mice. Different patterns emerged that were consistent within strains but differed from strain to strain. Abnormalities appear earlier in life in short-lived mice, such as male BXSB and MRL/l mice, than in relatively long-lived strains, such as female BXSB and NZB mice. The accumulation of T cells in MRL/l mice was accompanied by null cell changes that contrasted with those that developed in AKR/J mice after their spleens were infiltrated with leukemic T cells. It would seem that lymphocyte perturbations with murine autoimmunity also involve their precursor cells and that these precursor cell changes vary in different strains, perhaps in relation to different genetic factors.


Difference in resistance of subunits A and B of Vibrio cholerae toxin (choleragen) to treatment with pronase.
Disc electrophoresis in sodium dodecyl sulphate, performed on choleragen after incubation with pronase, only showed the band corresponding to the B subunit, while the A subunit was lost. When examined in immunodiffusion, the digested choleragen was still able to precipitate with specific antibodies. On the other hand, toxicity was considerably reduced.


Sex differences in global metabolomic profiles of COVID-19 patients.
Coronavirus disease (COVID-19), caused by SARS-CoV-2, leads to symptoms ranging from asymptomatic disease to death. Although males are more susceptible to severe symptoms and higher mortality due to COVID-19, patient sex has rarely been examined. Sex-associated metabolic changes may implicate novel biomarkers and therapeutic targets to treat COVID-19. Here, using serum samples, we performed global metabolomic analyses of uninfected and SARS-CoV-2-positive male and female patients with severe COVID-19. Key metabolic pathways that demonstrated robust sex differences in COVID-19 groups, but not in controls, involved lipid metabolism, pentose pathway, bile acid metabolism, and microbiome-related metabolism of aromatic amino acids, including tryptophan and tyrosine. Unsupervised statistical analysis showed a profound sexual dimorphism in correlations between patient-specific clinical parameters and their global metabolic profiles. Identification of sex-specific metabolic changes in severe COVID-19 patients is an important knowledge source for researchers striving for development of potential sex-associated biomarkers and druggable targets for COVID-19 patients.


The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome.
Trisomy 21 (Down Syndrome, DS) is the most common chromosomal anomaly. Although DS is mostly perceived as affecting cognitive abilities and cardiac health, individuals with DS also exhibit dysregulated immune functions. Levels of pro-inflammatory cytokines are increased, but intrinsic alterations of innate immunity are understudied in DS. Furthermore, elevated Reactive Oxygen Species (ROS) are well documented in individuals with DS, further exacerbating inflammatory processes. Chronic inflammation and oxidative stress are often precursors of subsequent tissue destruction and pathologies, which affect a majority of persons with DS. Together with ROS, the second messenger ion Ca2+ plays a central role in immune regulation. TRPM2 (Transient Receptor Potential Melastatin 2) is a Ca2+-permeable ion channel that is activated under conditions of oxidative stress. The Trpm2 gene is located on human Chromosome 21 (Hsa21). TRPM2 is strongly represented in innate immune cells, and numerous studies have documented its role in modulating inflammation. We have previously found that as a result of suboptimal cytokine production, TRPM2-/- mice are highly susceptible to the bacterial pathogen Listeria monocytogenes (Lm). We therefore used Lm infection to trigger and characterize immune responsiveness in the DS mouse model Dp10(yey), and to investigate the potential contribution of TRPM2. In comparison to wildtype (WT), Dp10(yey) mice show an increased resistance against Lm infection and higher IFNγ serum concentrations. Using a gene elimination approach, we show that these effects correlate with Trpm2 gene copy number, supporting the notion that Trpm2 might promote hyperinflammation in DS.


Remote Imaging Capture with Widefield Swept-Source OCT Angiography During the COVID-19 Pandemic.
The COVID-19 pandemic has had a widespread impact on the health sector worldwide, both in the clinical and research subsector. This has necessitated for the invention of protocols compliant with social distancing policies to efficiently tackle the current needs. Our aim is to describe a novel remote imaging technique, which helped us continue our research with widefield swept-source optical coherence tomography angiography (WF SS-OCTA). As a part of this cross-sectional observational study from August 2020 to September 2020 at Massachusetts Eye and Ear (MEE), we used our institute approved remote desktop, outside of MEE, to gain full access to the on-site WF SS-OCTA device in the imaging room for the purpose of remote imaging. With only the patient being in the imaging room, effective communication was established via video conferencing on an encrypted tablet computer device for the entire procedure. We imaged four patients with various retinal pathologies, aged 32-69 years. All images obtained were of high quality and signal strength (median score 9/10 for both) and all patients reported a highly satisfactory, comfortable, and safe experience amidst the COVID-19 pandemic. This novel method is better for remote imaging compared to the previously described techniques as it is time and cost effective, requires limited resources without compromising the image quality or patient satisfaction and adheres to the various guidelines for infection control, most importantly social distancing. As a paradigm shift, this can also be employed in future for setups with limited staff like busy emergency departments or a rural setup with limited access or difficult commute, in the "new-normal" era.


Noise effects in an electronic model of a single neuron.
We consider a simple electronic circuit model of a single neuron. The neuron is assumed to be driven by an external signal comprising constant (dc) and random components. In addition, the nonlinearity parameter in the circuit is assumed to fluctuate, thereby giving rise to critical behavior including the onset of hysteresis phenomena even for system parameter values that would not otherwise support such behavior. This "noise-induced critical behavior" is analysed, in the long time limit, through a study of the probability density function describing the neural response.


A novel electrochemical sensor based on magneto Au nanoparticles/carbon paste electrode for voltammetric determination of acetaminophen in real samples.
An electrochemical magneto Au nanoparticles/carbon paste electrodes (MAuNP/CPE) which is used for the determination of acetaminophen (AC) in real samples was developed. Initially, Au nanoparticles were immobilized at the surface of Fe3O4 (AuNPs@Fe3O4), which was used as a sorbent for capturing AC molecules. After adding AuNPs@Fe3O4 to the AC solution and stirring for 20 min, the AuNPs@Fe3O4 was gathered on the magneto electrode based on its magnetic field. The AC molecules which became adsorbed at AuNPs@Fe3O4 were analyzed by differential pulse voltammetry (DPV). For characterization and investigation of the performance of AuNPs@Fe3O4 and MAuNPs/CPE, various methods, including scanning electron microscopy, X-ray diffraction, UV-Vis spectroscopy, electrochemical impedance spectroscopy, cyclic voltammetry and DPV were used. Under the optimized conditions, the anodic peak current was linear to the concentration of AC in the range of 0.1 to 70.0μmol L(-1) with the detection limit of 4.5×10(-2)μmol L(-1). This method was also successfully used to detect the concentration of AC in pharmaceutical formulations and human serum samples. In addition, the proposed magneto sensor exhibited good reproducibility, long-term stability and fast current response.


[Application areas of artificial intelligence in the context of One Health with a focus on antimicrobial resistance].
Societal health is facing a number of new challenges, largely driven by ongoing climate change, demographic ageing, and globalization. The One Health approach links human, animal, and environmental sectors with the goal of achieving a holistic understanding of health in general. To implement this approach, diverse and heterogeneous data streams and types must be combined and analyzed. To this end, artificial intelligence (AI) techniques offer new opportunities for cross-sectoral assessment of current and future health threats. Using the example of antimicrobial resistance as a global threat in the One Health context, we demonstrate potential applications and challenges of AI techniques.This article provides an overview of different applications of AI techniques in the context of One Health and highlights their challenges. Using the spread of antimicrobial resistance (AMR), an increasing global threat, as an example, existing and future AI-based approaches to AMR containment and prevention are described. These range from novel drug development and personalized therapy, to targeted monitoring of antibiotic use in livestock and agriculture, to comprehensive environmental surveillance.


Gait biomechanics following lower extremity trauma: Amputation vs. reconstruction.
Surgical advances have substantially improved outcomes for individuals sustaining traumatic lower extremity injury. Injuries once requiring lower limb amputation are now routinely managed with limb reconstruction surgery. However, comparisons of functional outcomes between the procedures are inconclusive. To compare gait biomechanics after lower limb reconstruction and transtibial amputation. Twenty-four individuals with unilateral lower limb reconstruction wearing a custom ankle-foot orthosis (Intrepid Dynamic Exoskeletal Orthosis), 24 with unilateral, transtibial amputation, and 24 able-bodied control subjects underwent gait analysis at a standardized Froude speed based on leg length. Lower extremity joint angles, moments, and powers, and ground reaction forces were analyzed on the affected limb of patients and right limb of able-bodied individuals. ANOVA with Tukeys post-hoc tests determined differences among groups and post-hoc paired t-tests with Bonferroni-Holm corrections determined differences between limbs. The ankle, knee, and hip exhibited significant kinematic differences between amputated, reconstructed and able-bodied limbs. The reconstruction group exhibited less ankle power and range of motion while the amputee group exhibited lower knee flexor and extensor moments and power generation. Gait deficiencies were more pronounced at the ankle following limb reconstruction with orthosis use and at the knee following transtibial amputation with prosthesis use. Although both groups in the cohorts tested can replicate many key aspects of normative gait mechanics, some deficiencies still persist. These results add to the growing body of literature comparing amputation and limb reconstruction and provide information to inform the patient on functional expectations should either procedure be considered.


Reoperation for post-hepatectomy hemorrhage: increased risk of mortality.
Reoperation for post-hepatectomy hemorrhage (PHH) represents an important complication in patients undergoing liver resection. Yet, few studies have reported its presentation and patient outcomes of this event. Among the 2,086 patients who underwent elective hepatectomy from 2000 to 2009 in our HPB unit, the perioperative data of 12 (0.6 %) patients who underwent re-laparotomy for PHH were retrospectively analyzed. The diagnosis of PHH was established in all cases by the presence of blood in the drain. The mean interval time between the end of liver resection and the diagnosis of bleeding and reoperation were 17 h (1-43) and 38 h (1-93), respectively. The causes of bleeding were the hepatic vein branch (n = 4), liver cut surface (n = 3), and a hepatic artery branch (n = 2). In three cases, no bleeding spot was identified. Postoperative death occurred in 3 patients (25 %) between 15 and 18 days after re-laparotomy. These 3 patients were all cirrhotic; 2 underwent early re-laparotomy (≤6 h) and 1 underwent re-laparotomy 24 h after the first recognition of active bleeding. Reoperation for PHH remains an important morbid event after liver resection. Death in patients with this complication is considerably high. It is diagnosed mainly on the aspect of the abdominal drain, justifying its use in risky patients.


Relationship between infant and child mortality and fertility--an enquiry into goan women.
This paper has an attempt to demonstrate the influence of childhood mortality on fertility behaviour of women in Goa. The replacement effect of child mortality has been examined by comparing fertility behaviour of those who have and who have not experienced a child loss. The insurance effect has been studied through fertility differentials of those who perceived that the level of mortality has decreased in the region with the women who left it to be the otherwise. It shows that the net effect of child mortality could be substantial. Women with personal experience of child loss and having pessimistic opinion about the level of mortality, produced, on an average, about two children more than similar women who never experienced a child loss and were optimistic about the level. The tendency to replace a dead child was found to cut across the level of literacy and religious background of women. The insurance effect on the other hand, was predominant among illiterate women.


Postoperative alveolar-arterial oxygen tension difference: its relation to the operative incision in obese patients.
Forty-eight markedly obese patients for elective jejunoileal bypass were studied during spontaneous ventilation preoperatively and then postoperatively after 2 to 4 hours and on each of days 1 to 5 to determine the effect of the operative incision (midline versus transverse) on the alveolar-arterial oxygen tension difference (A-aDO2). Compared with control (Pre-op.) A-aDO2, there was a significant increase in A-aDO2 in all patients, beginning in the postanesthetic recovery area and continuing through postoperative (P.O.) day 4. Comparing the mean increase in A-aDO2 (P.O.-Pre-op.) between the two incision groups, patients with a midline incision had a significantly greater (p smaller than 0.001) increase in A-aDO2 on control (Pre-op.) value by day 5. The authors conclude that in markedly obese subjects, the midline incision can be expected to result in both more profound and more prolonged reduction in arterial oxygenation postoperatively.


A comparison of the psychological effects of robot motion in physical and virtual environments.
A mixed-methods approach was used to assess the fidelity of virtual environments as ergonomic assessment tools for human-robot interaction. Participants performed a visual search task in the physical environment while a nearby collaborative robot repeatedly extended its arm toward them. This scenario was reconstructed in two virtual environments with different levels of graphical detail. Measures of presence, task performance, workload, and anxiety were taken to determine the effect of robot motion in all three environments. Task performance decreased in response to robot motion in the physical environment, while workload and anxiety increased. This simple effect of motion was consistent across environments for measures of task performance and anxiety. However, people performed faster overall in virtual reality, and the effect of motion on workload was greatly reduced in virtual reality. Results in the virtual environments suggest that people were distracted by the sound of the robot, and that presence was affected by manipulations of immersion and coherence.


Effects of 4-aminopyridine on neuromuscular transmission.
4-Aminopyridine (4-AP) powerfully increases transmitter release from motor nerve terminals of rat and frog skeletal muscle in response to single nerve impulses. The drug also enhances transmitter release during repetitive nerve activity but, at D-tubocurarine-blocked endplates, only the first impulses cause increased transmitter release at stimulation frequencies at or above 50 Hz. At magnesium- and botulinum-poisoned endplates, 4-AP potentiates transmitter release at every stimulus during tetanic nerve stimulation and restores neuromuscular transmission. Spontaneous transmitter release in the rat is not affected by the drug, but at some frog endplates miniature endplate potential (mepp) frequency increases. The drug has no post-synaptic action, as evidenced by its lack of effect on amplitude or time course of mepps. Decreasing the temperature from 37 to 15 degrees C does not abolish the effect of 4-AP on neuromuscular transmission. In the presence of 4-AP, single nerve impulses produce repetitive spontaneous activity in the nerve terminal of the frog nerve-muscle preparation. Experiments on the mode of action of 4-AP suggest that the drug increases transmitter release by enhancing the influx of calcium ions during depolarization of the nerve terminal.


Localization and synthesis of type III collagen and fibronectin in human reparative dentine. Immunoperoxidase and immunogold staining.
The injury of dental pulp tissue, following caries, is accompanied by the deposit of a typical hard scar tissue known as reparative dentine which should be regarded as the mineralization of a new organic matrix. Highly purified antibodies were used in combination with immunoperoxidase or immunogold technique at the ultrastructural level to reveal the distribution and synthesis of types I and III collagen and fibronectin elaborated by typical matrix-forming cells in the new tissue. Specific immunoperoxidase labelling, on demineralized teeth, clearly demonstrated that type I collagen represents the main type of collagen (88%). It is associated with bundles of fine striated fibrils of type III collagen and in close vicinity with fibronectin and constituted, at least, the new organic matrix of reparative dentine. Immunogold staining gave precise localization mainly over Golgi apparatus for the 3 components, thus suggesting that the cells concerned should not be considered as new odontoblasts but rather as pulpal cells in the process of differentiation participating in the formation of new dentine. Moreover, these events are very similar to those observed during wound healing in other tissues.


Type I protein kinase C isozyme in the visual-information-processing pathway of monkey brain.
Previously using PKC isozyme-specific antibodies for immunoblot analysis, we demonstrated the heterogeneous distribution of PKC isozymes in various regions of monkey and rat brains and that type I PKC was most abundant in cerebellum, hippocampus, amygdala, and cerebral cortex (Huang et al.: J Biol Chem 262:15714-15720, 1987). Using these antibodies, we have also demonstrated that type I, II, and III PKC are products of PKC genes gamma, beta, and alpha, respectively (Huang et al.: Biochem Biophys Res Commun 149:946-952, 1987). By immunocytochemical analysis, type I PKC-specific antibody showed strong reactivity in various types of neuron in hippocampal formation, amygdala, cerebellum, and neocortex. In hippocampal formation, granule cells of dentate gyrus and pyramidal cells of hippocampus were heavily stained. By immunoblot analysis, relative levels of PKC isozymes in several areas of monkey cerebral cortex involved in the visual information processing and storage were determined. Both type II and III PKCs appeared to be evenly distributed and at moderate levels, type I PKC formed a gradient of increasing concentration rostral along the cerebral cortex of occipital to temporal and then to the limbic areas. Neurobehavioral studies have demonstrated that the neocortical and limbic areas of the anterior and medial temporal regions participate more directly than the striate, prestriate, and posterior temporal regions in the storage of visual representations and that both hippocampus and amygdala are important in the memory formation. As type I PKC is present at high levels in hippocampus, amygdala, and anterior temporal lobe, we predict that the type I protein kinase C may participate in the plastic changes important for mnemonic function.


MHC class II+ cells in the gills of Atlantic salmon (Salmo salar L.) affected by amoebic gill disease.
Amoebic gill disease (AGD) is characterised by the association of Neoparamoeba sp. with hyperplastic gill tissue of affected fishes, however, the identity and role of host cells associated with AGD lesions are not known. Here, we investigated cells with an immunological role that were associated with AGD lesions by locating cellular MHC class II beta chain. A tank housing Atlantic salmon (Salmo salar) was inoculated with Neoparamoeba sp., and MHC class II beta chain expression in the gills was qualitatively assessed by immunohistochemistry. In AGD-naïve control fish, MHC class II+ cells were detected basolateral to the interlamellar epithelium as well as upon the interlamellar and secondary epithelium. In the gills of AGD affected fish MHC class II+ cells were observed in both affected and unaffected tissue. Within AGD lesions, numerous MHC class II+ cells were present and these cells exhibited variable levels of expression suggesting that like mammals, MHC class II expression is highly regulated. The presence of MHC class II+ cells within gill lesions is indicative of immune cell trafficking and these cells could contribute in an antigen presentation capacity to the development of an antibody response in fish chronically affected by AGD.


Molecular characterization and serodiagnostic evaluation of the Echinococcus ortleppi recombinant glutaredoxin 1 protein for cystic echinococcosis in buffalo (Bubalus bubalis).
Cystic echinococcosis (CE), caused by the metacestode of Echinococcus granulosus sensu lato (s.l.), adversely affects the physiology of the vital organs in which they grow. Condemnation of meat causes substantial economic loss to the livestock industry. Conventionally the infection is detected by necropsy as serological diagnosis of the infection in livestock is ambiguous. Identification of specific diagnostic antigens would be a substitute for the cyst fluid antigens which lack adequate diagnostic sensitivity and specificity. BLAST analysis supported by the negligible pairwise nucleotide distance of the 389 nt COX1, 489 nt NAD1, and 425 nt ITS1 with the related sequences of E. ortleppi ascertained the association of E. ortleppi with CE in buffaloes. Given the extensive distribution of glutaredoxin 1 in every developmental stage of Echinococcus granulosus s.l that makes it an ideal serodiagnostic antigen for CE, we expressed the 14 kDa E. ortleppi glutaredoxin 1 (rEoGrx1) protein in E. coli BL21 (DE3) and tested a total of 225 sera samples, including 126 sera samples from the necropsy-positive buffalo, by the rEoGrx1 IgG-ELISA. The ELISA could detect a total of 82/126 sera samples as positive. The diagnostic sensitivity and specificity of the rEoGrx1 IgG-ELISA were 65.1 % and 51.5 %, respectively. The protein showed serological cross-reaction against Fasciola gigantica, Toxoplasma gondii, and Sarcocystis sp. The in silico bioinformatics analysis of the E. ortleppi, F. gigantica, and T. gondii glutaredoxin sequences revealed fully conserved amino acids at positions 11 and 21, the substitution of conserved amino acids at positions 14 and 6, and semi-conserved substitutions at positions 3 and 4, respectively. The findings partly explain the molecular basis of the serological cross-reactivity of the protein.


Inhibition of fructose-1,6-biphosphatase by the photoaffinity AMP analog, 8-azidoadenosine 5'-monophosphate.
Inhibition studies with the photoreactive AMP analog, 8-azidoadenosine 5'-monophosphate (8-azido-AMP), demonstrate that this compound is, like AMP, an allosteric inhibitor of pig kidney and muscle fructose-1,6-biphosphateses. Photolysis of a mixture of purified pig kidney fructose-1,6-biphosphate and 8-azido-[14C]AMP results in the loss of enzyme activity and the reagent is incorporated to the protein. The incorporation of reagent linearly correlates with the loss of enzyme activity. Extrapolation to zero activity correlates with the incorporation of 3.7 mol of reagent/mol of enzyme (i.e. 0.9 per subunit). Thus, 8-azido-AMP appears to be a photoaffinity label for the allosteric AMP binding site of fructose-1,6-biphosphatase.


Selection of Type I and Type II methanotrophic proteobacteria in a fluidized bed reactor under non-sterile conditions.
Type II methanotrophs produce polyhydroxybutyrate (PHB), while Type I methanotrophs do not. A laboratory-scale fluidized bed reactor was initially inoculated with a Type II Methylocystis-like dominated culture. At elevated levels of dissolved oxygen (DO, 9 mg/L), pH of 6.2-6.5 with nitrate as the N-source, a Methylobacter-like Type I methanotroph became dominant within the biofilms which did not produce PHB. A shift to biofilms capable of PHB production was achieved by re-inoculating with Type II Methylosinus culture, providing dissolved N(2) as the N-source, and maintaining a low influent DO (2.0mg/L). The resulting biofilms contained both Types I and II methanotrophs. Batch tests indicated that biofilm samples grown with N(2) became dominated by Type II methanotrophs and produced PHB. Enrichments with nitrate or ammonium were dominated by Type I methanotrophs without PHB production capability. The key selection factors favoring Type II were N(2) as N-source and low DO.


Elimination of inhibitory synapses is a major component of adult ocular dominance plasticity.
During development, cortical plasticity is associated with the rearrangement of excitatory connections. While these connections become more stable with age, plasticity can still be induced in the adult cortex. Here we provide evidence that structural plasticity of inhibitory synapses onto pyramidal neurons is a major component of plasticity in the adult neocortex. In vivo two-photon imaging was used to monitor the formation and elimination of fluorescently labeled inhibitory structures on pyramidal neurons. We find that ocular dominance plasticity in the adult visual cortex is associated with rapid inhibitory synapse loss, especially of those present on dendritic spines. This occurs not only with monocular deprivation but also with subsequent restoration of binocular vision. We propose that in the adult visual cortex the experience-induced loss of inhibition may effectively strengthen specific visual inputs with limited need for rearranging the excitatory circuitry.


Immunocytochemical demonstration of a novel system of neuroendocrine peptidergic neurons in the pond snail Lymnaea stagnalis, with antisera to the teleostean hormone hypocalcin and mammalian parathyroid hormone.
Immunocytochemical staining with antisera raised against trout hypocalcin, the hypocalcemic hormone of the Stannius corpuscles and against bovine parathyroid hormone (bPTH1-84), revealed a new system of neuroendocrine neurons in the pond snail Lymnaea stagnalis. The neurons are located in small groups or single cells in the visceral, parietal, and pedal ganglia of the central nervous system. The axons of these cells are running to the periphery of the pleuroparietal, visceroparietal, and pleuropedal connections, the dorsopedal commissure, and to several nerves originating in the visceral, parietal, and pedal ganglia. The axons are ending with characteristic axonal distensions in the periphery of these connectives, commissure, and nerves. These regions probably act as neurohaemal areas. The affinity of this neuroendocrine system for both the anti-hypocalcin and anti-PTH sera is another indication for a special relationship between hypocalcin and PTH, which possess some immunological resemblance and similar biological activities, although no similarity in primary structure.


Visual acuity loss in patients with Stargardt's macular dystrophy.
Ninety-five patients with Stargardt's macular dystrophy were appraised for visual loss with age by both life-table analyses and cross-sectional procedures. The probability of maintaining a visual acuity of 20/40 or better in at least one eye was 52% by age 19, 32% by age 29, and 22% by age 39. In the population studied, once a patient's visual acuity dropped below 20/40, it tended to decrease rapidly and stabilize at 20/200. Fluorescein angiograms obtained on 64 of the 95 patients showed a "dark choroid" in 55 (85.9%). This finding, therefore was present in the majority of the patients, although its absence does not rule out Stargardt's macular dystrophy.


When it is too much: Identifying butamben excess on the surface of pharmaceutical preformulation samples by Raman mapping.
Butamben is a topical local anesthetic which formulation in lipid-based drug delivery systems (DDS) is challenging due to its affinity for hydrophilic excipients. This means that a medium polarity excipient is preferred for the development of a stable nanostructured lipid carrier (NLC) formulation. In turn, in NLC, the type and number of excipients will determine the active pharmaceutical ingredient (API) solubility and the maximum drug upload. To solve this dilemma and get the best formulation, a throughout screening study to evaluate API solubilization in different excipients was carried out. Subsequently, excipients with different solubilization capacities were selected for microscopic evaluation by Raman mapping, and in turn analysis of the distributional homogeneity index (DHI) and standard deviation of the histograms allowed solving the posed question. Design of experiments (DoE) was employed to understand better the interactions between the excipients; linear and higher-order models were obtained with R2 above of 0.8824. Even though DHI is a good parameter to be used as response, an API concentration higher than 30% (w/w) provided a homogeneous surface in case of good miscibility and, in this case, this parameter needs to be employed with an inspection and/or evaluation of other parameters. A curve of concentration vs. mean scores of images proved to be an alternative to identify the saturation/limit of linear range.


Monoclonal antibodies for characterization of rabies virus isolated from non-hematophagous bats in Brazil.
In Brazil, various isolates of rabies virus (RABV) show antigenic profiles distinct from those established by the reduced panel of eight monoclonal antibodies (MAbs) determined by the Centers for Disease Control and Prevention (CDC), utilized for the antigenic characterization of RABV in the Americas. The objective of this study was to produce MAbs from RABV isolates from insectivorous bats with an antigenic profile incompatible with the pre-established one. An isolate of RABV from the species Eptesicus furinalis that showed an antigenic profile incompatible with the panel utilized was selected. Hybridomas were produced utilizing the popliteal lymph nodes of mice immunized with ribonucleoproteins purified from the isolate. Two MAbs-producing clones were obtained, BR/IP1-3A7 and BR/IP2-4E10. Fifty-seven isolates of RABV from different species of animals and different regions of Brazil were analyzed utilizing the MAbs obtained. In the analysis of 23 RABV isolates from non-hematophagous bats, the MAbs cross-reacted with ten isolates, of which four were of the species Nyctinomops laticaudatus, one of the species Eptesicus furinalis, and five of the genus Artibeus. Of the nine isolates of non-hematophagous isolates that displayed an incompatible profile analyzed, characteristic of insectivorous bats, BR/IP1-3A7 reacted with five (55.55%) and BR/IP2-4E10 with four (44.44%). The MAbs obtained were able to recognize epitopes common between the three genera, Artibeus, Eptesicus, and Nyctinomops, thereby allowing the antigenic characterization of RABV isolates in Brazil.


Muscle strength and tibolone: a randomised, double-blind, placebo-controlled trial.
To investigate the effects of tibolone, a tissue-specific compound with a mixed (estrogenic, progestogenic and androgenic) hormonal profile, on skeletal muscle strength in a group of healthy postmenopausal women. Randomised, parallel group, double-blind, placebo-controlled, single-centre trial conducted between August 1997 and July 1999. Eighty-five healthy women, between one and 15 years postmenopausal, (mean [SD] age, 54.2 [4.7] years) recruited from local paper advertisements. Participants were randomly assigned to 2.5 mg tibolone or to identically appearing placebo pills daily for 12 months, taken orally in the morning. Both maximal handgrip strength, representing upper body strength, and maximal quadriceps strength, representing lower body strength, were measured isometrically. Treatment effect estimates (between group differences) in handgrip strength and isometric knee extension at last visit. Tibolone significantly (P = 0.04) increased handgrip strength compared with placebo (difference 0.99 kg, [95% CI 0.1-1.9]). No significant treatment effect (P = 0.61) was observed in isometric knee extension strength. Isometric strength adjusted for body mass index resulted in a trend favouring tibolone (P = 0.06). Individual trend analysis showed a significant difference in rate of change throughout the year (6.8% [95% CI 2.1-10.7]) favouring tibolone. Administration of tibolone increased handgrip strength in postmenopausal women compared with placebo. A trend indicating a positive effect in isometric knee extension strength adjusted for body mass index was observed. Tibolone seems to mitigate the menopause-related decline in muscle strength.


Postnatal development in intermittent hypoxia enhances resistance to myocardial ischemia/reperfusion in male rats.
To assess the tolerance of rats that developed from birth in intermittent hypoxia (IH) to myocardial ischemia and reperfusion, we set up a reproducible model in our laboratory. IH rats were raised 60 days from birth in a hypobaric chamber at 5000 m for 6 h daily, while controls were in continuous normoxic conditions. At 60 days after birth, the antioxidant capacity of the heart was determined; arterial and venous partial pressures of oxygen were measured at sea level and 5000 m altitude. In addition, isolated hearts of each group were perfused in Langendorff mode and submitted to 30 min global ischemia followed by 30 min reperfusion to compare functional recovery and lactate dehydrogenase release. For the IH rats, recovery of left ventricular developed pressure (DP), the maximum of the positive or negative first derivative of left ventricular pressure with respect to time (+/-LV d P/d t), end-diastolic pressure (EDP), and pressure-rate product (PRP) were all superior ( P<0.05) to those of control rats. The myocardial antioxidant capacity was also significantly increased in the left ventricle of IH rats. Further, at 5000 m altitude the arterio-venous oxygen gradient ( Pa-vO(2)) was significantly ( P<0.01) higher in the IH rats than in the controls. These data indicate that IH from birth enhances the tolerance of the heart to ischemia/reperfusion, elevates the myocardial antioxidant capacity, and increases oxygen extraction.


Belief in numbers: When and why women disbelieve tailored breast cancer risk statistics.
To examine when and why women disbelieve tailored information about their risk of developing breast cancer. 690 women participated in an online program to learn about medications that can reduce the risk of breast cancer. The program presented tailored information about each woman's personal breast cancer risk. Half of women were told how their risk numbers were calculated, whereas the rest were not. Later, they were asked whether they believed that the program was personalized, and whether they believed their risk numbers. If a woman did not believe her risk numbers, she was asked to explain why. Beliefs that the program was personalized were enhanced by explaining the risk calculation methods in more detail. Nonetheless, nearly 20% of women did not believe their personalized risk numbers. The most common reason for rejecting the risk estimate was a belief that it did not fully account for personal and family history. The benefits of tailored risk statistics may be attenuated by a tendency for people to be skeptical that these risk estimates apply to them personally. Decision aids may provide risk information that is not accepted by patients, but addressing the patients' personal circumstances may lead to greater acceptance.


In vivo absorption and phosphorylation of pyridoxine . HCl in rat jejunum.
The absorption and phosphorylation of 3H-pyridoxine . HCl were studied in vivo in isolated loops of rat jejunum. Uptake was rapid and linear over the concentration range of 0.2-1 mM; tissue content of absorbed vitamin was saturable and consisted primarily of phosphorylated forms of vitamin B6. Phosphorylation was saturable with a Km of 11.6 micronM and a Vmax of 1.65 nmol/5 min/g wet tissue. Inhibition of phosphorylation changed neither the t 1/2 of 3H-pyridoxine . HCl disappearance from the lumen nor the calculated uptake after either 5-min or 30-min absorption periods. Inhibition of phosphorylation, however, significantly decreased the t 1/2 for transmural absorption and significantly increased the calculated transmural absorption after a 5-min absorption period. These studies indicate that (a) pyridoxine absorption, over the concentration range tested, is nonsaturable and consistent with passive diffusion; (b) jejunal phosphorylation of pyridoxine occurs in vivo, is saturable, and results in saturation of tissue content of the absorbed vitamin; and (c) phosphorylation has no significant effect on the uptake of pyridoxine but significantly delays the transmural absorption of a finite amount of the vitamin.


A new method for measuring the yield stress in thin layers of sedimenting blood.
A new method is presented to describe the low shear rate behavior of blood. We observed the response of a thin layer of sedimenting blood to a graded shear stress in a wedge-shaped chamber. The method allows quantitation of the degree of phase separation between red cells and plasma, and extracts the yield stress of the cell phase as a function of hematocrit. Our studies showed that the behavior of normal human blood underwent a transition from a solid-like gel to a Casson fluid. This transition began at the Casson predicted yield stress. The viscoelastic properties of blood were examined at shear stresses below the yield stress. The measured Young's elastic moduli were in good agreement with published data. The yield stress of blood showed a linear dependence on hematocrit up to 60%, and increased more rapidly at higher hematocrit.


Posterior pericardial ascending-to-descending aortic bypass through median sternotomy.
Adult patients with complex forms of descending aortic disease remain a surgical challenge and have a high risk of postoperative mortality and morbidity. Surgical management may be complicated when there is an associated cardiac defect, necessitating repair, or a hostile anatomy exists. We present our experience with extra-anatomic bypass through posterior pericardial route at the same stage with intracardiac/ascending aortic aneurysm repair. Patients that underwent one-stage surgery with posterior pericardial bypass between ascending and descending aorta during 2003-2007 were reviewed. Data from early and mid-term follow-up, including mortality, perioperative blood loss, graft-related complications, patency, and persistent hypertension, were noted. Six male patients with a mean age of 20.8 +/- 0.7 years were operated for coarctation of the aorta associated with additional pathologies (three cases of ascending aortic aneurysm-one with associated aortic valve insufficiency, one case of isolated aortic valve regurgitation, two cases of mitral valve regurgitation). No early or mid-term mortality was observed during follow-up of a mean of 21.6 +/- 10.0 months. No late graft-related complications or reoperations were observed with patent grafts. Systolic blood pressure decreased after surgery by an average of 43 mmHg. Coarctation of the aorta with concomitant cardiac lesions can be repaired simultaneously through sternotomy and posterior pericardial approach, when patients present in adulthood, to minimize morbidity and mortality.


Ex vivo detection of tumoral lymph nodes of colorectal origin with fluorescence imaging after intraoperative intravenous injection of indocyanine green.
The aim of this study was to investigate the potential role of indocyanine green (ICG) fluorescence imaging after intraoperative intravenous (IV) injection for the "ex vivo" detection of metastatic lymph nodes (mLNs) of colorectal cancer origin. Fresh-fixed LNs in cassettes and/or paraffin-embedded LNs of patients included in a study that evaluated the role of ICG in the detection of peritoneal metastases of colorectal origin (Protocol NCT-01995591) were further explored with a dedicated near-infrared camera system for their fluorescence. An IV injection of ICG was delivered intraoperatively at 0.25 mg/kg. Signal to background ratios (SBRs) were calculated. LNs on operative specimens were evaluated for 12 patients (5 males, 7 females). A total of 182 LNs were analyzed. The mean LN number per patient was 15.2 (median: 15.5; range 3-22). SBRs of mLNs were significantly more fluorescent than benign LNs, 1.41 versus 1.04 arbitrary units (P < 0.0002). On univariate analysis, fluorescence was statistically correlated with LN surface area (>20 mm(2) ) (P < 0.0004). Ex vivo ICG fluorescence imaging after intraoperative IV injection represents a potential method for detecting invaded LN's of colorectal cancer origin on operative specimens. Further clinical studies are needed to better define optimal techniques. J. Surg. Oncol. 2016;114:348-353. © 2016 Wiley Periodicals, Inc.


Corrigendum: Health benefits of probiotics in sport and exercise-Non-existent or a matter of heterogeneity? A systematic review.
[This corrects the article DOI: 10.3389/fnut.2022.804046.].


Extraction of a strongly focusing He+ beam from three-stage concave electrodes for alpha particle measurement system in ITER.
A strongly focusing He(+) ion beam source equipped with concave multi-aperture electrodes was developed for production of He(-) through a charge exchange cell. The beam was extracted at a voltage less than 20 kV from 301 apertures distributed in an area of 100 mm φ, and focused at 750 mm distance. The beam current and the beam size of 2 A and 20 mm in diameter, respectively, were achieved with an arc power less than 10 kW. The optimum perveance was obtained at 0.02 A∕kV(1.5) at the beam energy less than 20 keV which is suitable for the conversion to He(-) in an alkali vapor cell.


Frailty assessment and impact of frailty on outcomes after transcatheter aortic valve replacement.
Certain frail patients fail to achieve adequate functional or mortality benefit despite successful transcatheter aortic valve replacement (TAVR). Therefore, frailty assessment methods are becoming an important tool to identify and intervene on this high-risk patient subset for improving clinical outcomes. Areas covered: The authors provide an overview of frailty and frailty assessment tools being used in clinical practice and discuss the impact of frailty on the cardiac patients, particularly among the TAVR population. Expert commentary: Available evidence suggests that frailty assessment is critical for identifying patients at high risk of morbidity and mortality after TAVR procedures. However, there is lack of consensus for the best methodology to determine frailty and its optimal management in TAVR populations. Although, physical exercise is a commonly employed intervention to reduce frailty, a greater attention towards improving nutrition may convey more benefit than either intervention alone. Ongoing studies are investigating the benefits of a multicomponent approach to improve clinical outcomes in frail patients undergoing TAVR.


Responsiveness of Inhaled Epoprostenol in Respiratory Failure due to COVID-19.
Inhaled pulmonary vasodilators are used as adjunctive therapies for the treatment of refractory hypoxemia. Available evidence suggest they improve oxygenation in a subset of patients without changing long-term trajectory. Given the differences in respiratory failure due to COVID-19 and "traditional" ARDS, we sought to identify their physiologic impact. This is a retrospective observational study of patients mechanically ventilated for COVID-19, from the ICUs of 2 tertiary care centers, who received inhaled epoprostenol (iEpo) for the management of hypoxemia. The primary outcome is change in PaO2/FiO2. Additionally, we measured several patient level features to predict iEpo responsiveness (or lack thereof). Eighty patients with laboratory confirmed SARS-CoV2 received iEpo while mechanically ventilated and had PaO2/FiO2 measured before and after. The median PaO2/FiO2 prior to receiving iEpo was 92 mmHg and interquartile range (74 - 122). The median change in PaO2/FiO2 was 9 mmHg (-9 - 37) corresponding to a 10% improvement (-8 - 41). Fifty-percent (40 / 80) met our a priori definition of a clinically significant improvement in PaO2/FiO2 (increase in 10% from the baseline value). Prone position and lower PaO2/FiO2 when iEpo was started predicted a more robust response, which held after multivariate adjustment. For proned individuals, improvement in PaO2/FiO2 was 14 mmHg (-6 to 45) vs. 3 mmHg (-11 - 20), p = 0.04 for supine individuals; for those with severe ARDS (PaO2/FiO2 < 100, n = 49) the median improvement was 16 mmHg (-2 - 46). Fifty percent of patients have a clinically significant improvement in PaO2/FiO2 after the initiation of iEpo. This suggests it is worth trying as a rescue therapy; although generally the benefit was modest with a wide variability. Those who were prone and had lower PaO2/FiO2 were more likely to respond.


Anthropometric, Biochemical, and Food Consumption Parameters are Associated with Venous Leg Ulcer Area and Duration.
To describe the dietary habits and anthropometric and biochemical parameters of patients with active venous leg ulcers and to verify the association of these variables with wound duration and area. A cross-sectional study conducted with 33 participants diagnosed with venous leg ulcers in outpatient care. Socioeconomic data, anthropometric parameters, biochemical parameters, food consumption, and wound characteristics were analyzed by an interprofessional team. Participants were an average of 58 ± 13 years, 57.6% women, 84.8% overweight, and had a median wound duration of 10 months (range, 1-192 months) and an average wound area of 5 cm (range, 0.22-61.1 cm). Diets were typically hypocaloric and hypoproteic, with a low amount of vitamin A and magnesium. Wound duration was negatively associated with polyunsaturated fat intake (P = .032), whereas wound area was significantly associated with lipid intake (P = .002) and C-reactive protein (P = .040). Patients with active venous leg ulcers were overweight (leading to systemic inflammation) and had low consumption of calories, protein, and micronutrients that could support cicatrization. Wound area was associated with a high-fat diet, whereas wound duration was negatively associated with polyunsaturated fat intake.


High rates of inapparent dengue in older adults in Singapore.
Although the dengue iceberg phenomenon is well known, there is a paucity of data on inapparent dengue. Results from a seroepidemiological study conducted during a dengue epidemic in 2007 in Singapore showed a seroprevalence of 65.9% and an inapparent dengue rate of 78%. Older adults (> 45 years old) had significantly higher rates of inapparent dengue infections (P < 0.05).


Study on metabonomics of Chinese herbal medicine in the treatment of type 2 diabetes mellitus complicated with community-acquired pneumonia.
Community-acquired pneumonia (CAP) is the main acute complication of type 2 diabetes mellitus (T2DM) and the main cause of hospitalization for infectious diseases. Unfortunately, in the treatment of type 2 diabetes mellitus complicated with community-acquired pneumonia (T2DM-CAP), modern medicine is still faced with enormous challenges because of insulin resistance and drug-resistant bacteria. In recent decades, clinical and experimental evidence shows that Chinese herbal medicine (CHM) has a certain beneficial effect on diabetes and pneumonia. Therefore, this trial aims to assess the efficacy and safety of CHM plus western medicines for the treatment of T2DM-CAP. We propose a double-blind, placebo-controlled, randomized superiority trial.A total of 92 participants with T2DM-CAP will be randomly allocated at a 1:1 ratio to either the experimental group, which will receive modified Ban-Xia-Xie-Xin-Decotion and basic treatment, or the control group, which will receive basic treatment only. The study duration will be 14 days. The primary outcome will be the total clinical effective rate. The secondary outcomes are traditional Chinese medicine symptom score scale, pneumonia severity index, usage time of antibiotic, time required for blood sugar to reach the required level, frequency of hypoglycemia, and chest CT. Liquid chromatograph-mass spectrometry method will be used to explore the blood metabolism profiles of the subjects, to explore the pathogenesis of T2DM-CAP and the mechanism of CHM on T2DM-CAP. Adverse events will also be evaluated. This trial will provide evidence of the effectiveness and safety of traditional CHM in treating patients with T2DM-CAP. ChiCTR2000035204.


Dietary Salt Intake and Gastric Cancer Risk: A Systematic Review and Meta-Analysis.
The results of prospective cohort studies regarding the role of salt intake and subsequent gastric cancer risk are inconsistent. Thus, we performed a systematic review and meta-analysis to summarize the strength of the association of salt intake with gastric cancer morbidity and mortality. PubMed, EmBase, and Cochrane Library were systematically searched to identify eligible studies published throughout September 2021. The effect estimates with 95% confidence intervals (CIs) for gastric cancer morbidity or mortality in each study were applied to calculate the pooled results; these analyses were performed using the random-effects model. Twenty-six prospective cohort studies involving 4,956,350 individuals were selected; these studies reported 19,301 cases of gastric cancer and 2,871 cases of gastric cancer-associated mortality. High (RR: 1.25; 95%CI: 1.10-1.41; P = 0.001) or moderate (RR: 1.20; 95%CI: 1.04-1.38; P = 0.012) salt intake was associated with a greater risk of gastric cancer. High pickled food intake was associated with an increased gastric cancer risk (RR: 1.28; 95%CI: 1.05-1.57; P = 0.017), while moderate pickled foods intake had no significant effect on gastric cancer risk (RR: 1.10; 95%CI: 0.88-1.37; P = 0.390). Neither high (RR: 1.14; 95%CI: 0.95-1.36; P = 0.161) nor moderate (RR: 1.10; 95%CI: 0.87-1.40; P = 0.436) salted fish intake were associated with gastric cancer risk. A high intake of processed meat was significantly associated with a higher risk of gastric cancer (RR: 1.24; 95%CI: 1.03-1.49; P = 0.023), while moderate processed meat intake had no significant effect on the gastric cancer risk (RR: 1.01; 95%CI: 0.92-1.11; P = 0.844). High (RR: 1.04; 95%CI: 0.90-1.19; P = 0.626) and moderate (RR: 1.02; 95%CI: 0.94-1.11; P = 0.594) miso-soup intake had no effects on the gastric cancer risk. High intakes of salt, pickled food, and processed meat are associated with significantly increased risks of gastric cancer; these increased risks are also seen when participants consumed moderate amounts of salt.


Methionine Uptake and Required Radiation Dose to Control Glioblastoma.
The purpose of this study was to retrospectively assess the feasibility of radiation therapy planning for glioblastoma multiforme (GBM) based on the use of methionine (MET) positron emission tomography (PET), and the correlation among MET uptake, radiation dose, and tumor control. Twenty-two patients with GBM who underwent MET-PET prior to radiation therapy were enrolled. MET uptake in 30 regions of interest (ROIs) from 22 GBMs, biologically effective doses (BEDs) for the ROIs and their ratios (MET uptake:BED) were compared in terms of whether the ROIs were controlled for >12 months. MET uptake was significantly correlated with tumor control (odds ratio [OR], 10.0; P = .005); however, there was a higher level of correlation between MET uptake:BED ratio and tumor control (OR, 40.0; P < .0001). These data indicated that the required BEDs for controlling the ROIs could be predicted in terms of MET uptake; BED could be calculated as [34.0 × MET uptake] Gy from the optimal threshold of the MET uptake:BED ratio for tumor control. Target delineation based on MET-PET was demonstrated to be feasible for radiation therapy treatment planning. MET-PET could not only provide precise visualization of infiltrating tumor cells but also predict the required radiation doses to control target regions.


Effects of hyaluronan-fortified surfactant in ventilated premature piglets with respiratory distress.
We hypothesized that enriching surfactant with hyaluronan would restore lung function when tested in a premature animal model. Newborn piglets (85% gestation, term 112-114 days) were delivered by cesarean section, subjected to mechanical ventilation (tidal volume 6- 8 ml/kg) and randomly assigned to treatment with 50 or 100 mg/kg Curosurf (C50 and C100), 50 or 100 mg/kg Curosurf mixed with 2.5% HA (w/w, CH50 and CH100). A ventilated and not treated group (Cont) and a not treated and not ventilated group (Non) were included as controls. Six hours after treatment the lungs were removed and biochemical, biophysical, cytological and histological analyses were carried out. The CH100, CH50, C100 and C50 groups had variable but significantly improved alveolar phospholipid content, minimal surface tension, alveolar aeration and wet/dry lung weight ratios, but little histological evidence of lung injury. CH100, CH50 and C100 groups had the best effects in terms of oxygenation, lung compliance and histology and evidence of decreased inflammation (IL-8 and TNF-alpha mRNA expression). We conclude that HA added to 50 mg/kg Curosurf or use of 100 mg/kg Curosurf with or without HA provides the best effects in terms of lung function and reduction of inflammation.


The Zika virus: Lurking behind the COVID-19 pandemic?
The sudden and extensive outbreak of coronavirus (SARS-CoV-2) has overshadowed another developing viral threat: the Zika flavivirus. Of particular concern is that pregnant women can pass Zika virus to the foetus, and there is a strong implication of an association between Zika virus infection and foetal microcephaly. Currently, there is no vaccine, and there is no cure. Published literature and Internet sources were searched for information related to Zika virus, its transmission, its clinical presentation and sequalae, prevention and implications (practice and regulatory) for healthcare providers. The identified English sources were reviewed, assessed and synthesized. Emphasis was placed on providing an overview of the problem, and identification of unmet needs and future directions. Zika virus poses a major challenge for healthcare providers, particularly in areas unaccustomed to it, since it is transmitted to humans by the vector Aedes aegypti mosquito. The outbreak impacts every healthcare provider, because every provider is required to report cases of Zika infection to their state or local health agencies--whether the infection is confirmed or merely suspected. Since the virus has become a worldwide crisis, healthcare providers will need to work across national boundaries and medical disciplines in order to educate patients about Zika symptoms and the mosquito vector. Until further information is known, infected patients (male and female) are being advised to avoid conceiving a child. Until a vaccine is developed or effective treatment for Zika virus is discovered, healthcare providers must be AVP (aware, vigilant and proactive) in order to lessen the spread and impact of the implicated devastating birth defects (microcephaly) and other neurological disorders (eg Guillain-Barré Syndrome) of this infection. Unfortunately, many knowledge gaps exist. There is an urgent need for a reliable, inexpensive diagnostic test, an effective treatment and an approved and readily available vaccine.


Anterior blepharitis is associated with elevated plectin levels consistent with a pronounced intracellular response.
Anterior blepharitis is a frequent ocular condition which may result in severe ocular surface disease. In this study, advanced proteome analysis was performed to elucidate biological mechanisms underlying anterior blepharitis. All patients underwent full ophthalmological examination including Ocular Surface Disease Index score (OSDI). Measurement of non-invasive break-up time (NBUT), Oxford score, and meibography were performed. Tear film samples from treatment naïve patients with anterior blepharitis (n = 15) and age-matched controls (n = 11) were collected with Schirmer filtration paper. The samples were analyzed with label-free quantification nano liquid chromatography - tandem mass spectrometry (LFQ nLC-MS/MS). Significantly regulated proteins were identified with a permutation-based calculation with a false discovery rate at 0.05. Among the 927 proteins detected, a total of 162 proteins were significantly changed. Regulated proteins were involved in cytoplasmic translation, positive regulation of B cell activation, complement activation and phagocytosis. High levels of plakin proteins, a group of proteins involved in cytoskeleton organization, were observed in anterior blepharitis, including plectin, desmoplakin, envoplakin, epiplakin, periplakin, and vimentin. The upregulation of plectin was confirmed with single reaction monitoring. Patients with anterior blepharitis had lower levels of immunoglobulin chains, VEGF coregulated chemokine 1 (CXCL17), and platelet-derived growth factor C. Anterior blepharitis was associated with a high level of plectin indicating a pronounced intracellular response with cytoskeletal reorganization. Our data suggest a lack of immunoglobulin chains and CXCL17 in anterior blepharitis with potential alterations in the ocular surface immune response.


Changes in the amount of lung and airway phosphatidylcholine in 0.5-12.5-day-old rabbits.
Newborn rabbits delivered spontaneously at term and cared for by the mothers were studied from 0.5 to 12.5 days of age. Curves are constructed to describe the changes in weight, lung and alveolar wash phosphatidylcholine and saturated phosphatidylcholine, and lung protein. The curves are complex and non-linear. However. expressing the increases in lung and alveolar wash phosphatidylcholine and saturated phosphatidylcholine pool sizes relative to animals weight results in a decreasing linear relationship from 0.5 to 12.5 days of age. By 12.5 days the ratios of lung phosphatidylcholine and saturated phosphatidylcholine to weight approximate the ratios measured for adult rabbits. The ratios of saturated to total phosphatidylcholine in the alveolar washes and lungs remained invarient throughout the study period.


Survival and radioclinical evaluation of the Optimys™ short stem at more than 6years' mean follow-up: A retrospective study of 108 cases.
The short stems developed in recent years offer an interesting alternative to standard long stems. The Optimys™ short stem has been widely studied, but not according to the National Institute for Health and Care Excellence (NICE) criteria. We therefore conducted a retrospective study of Optimys™ at a minimum 5years' follow-up, to assess: (1) survival on NICE criteria, (2) complications, (3) functional results, and (4) subsidence, restoration of offset and bone remodeling. Optimys™ shows survival comparable to that of other non-cemented standard and short stems, with a<0.5% per year revision rate or<2.5% at 5years on NICE criteria. A single-center retrospective study included 108 Optimys™ stems at a mean 76.5months' follow-up (range: 60-112months). Clinical [Harris, Oxford-12 and forgotten hip (French version: SHO-12) scores] and radiologic data were collected pre- and postoperatively. Analysis focused on implant survival, complications, functional results and radiological results (restoration of offset, bone remodeling, subsidence and osseointegration) and risk factors for stem migration. At a mean 76.5months' follow-up (range: 60-112months), Optimys™ survival was 97.7% (95% CI: 0.945-1). Oxford and Harris scores improved significantly: respectively, 16.1 vs. 44.7 [Δ=28.598; 95% CI: 27.410-29.785 (p<0.001)] and 45.3 vs. 95 [Δ=49.662; 95% CI: 47.442-51.882 (p<0.001)]. Mean forgotten hip score (SHO-12) at last follow-up was 82.7±19.6 (range: 35.4-100.0). There was 1 case of aseptic revision at 11months for femoral osseointegration defect. Mean subsidence was 1.64mm (range: 0-20.63mm); no predisposing factors could be identified. Femoral offset increased by a mean 2.41±4.53mm (range: -10.10 to 14.70mm). The present study reports good survival for the Optimys™ stem, which meets NICE criteria. Radiologic and clinical results were encouraging, with a low rate of subsidence, comparable to other series, but with increased femoral offset. IV; retrospective cohort study.


Steps to translate preconditioning from basic research to the clinic.
Efforts to treat cardiovascular and cerebrovascular diseases often focus on the mitigation of ischemia-reperfusion (I/R) injury. Many treatments or "preconditioners" are known to provide substantial protection against the I/R injury when administered prior to the event. Brief periods of ischemia itself have been validated as a means to achieve neuroprotection in many experimental disease settings, in multiple organ systems, and in multiple species suggesting a common pathway leading to tolerance. In addition, pharmacological agents that act as potent preconditioners have been described. Experimental induction of neuroprotection using these various preconditioning paradigms has provided a unique window into the brain's endogenous protective mechanisms. Moreover, preconditioning agents themselves hold significant promise as clinical-stage therapies for prevention of I/R injury. The aim of this article is to explore several key steps involved in the preclinical validation of preconditioning agents prior to the conduct of clinical studies in humans. Drug development is difficult, expensive and relies on multi-factorial analysis of data from diverse disciplines. Importantly, there is no single path for the preclinical development of a novel therapeutic and no proven strategy to ensure success in clinical translation. Rather, the conduct of a diverse array of robust preclinical studies reduces the risk of clinical failure by varying degrees depending upon the relevance of preclinical models and drug pharmacology to humans. A strong sense of urgency and high tolerance of failure are often required to achieve success in the development of novel treatment paradigms for complex human conditions.


[Juvenile chronic arthritis. Double-blind study of the efficacy and tolerance of D-penicillamine].
Seventy-four children with juvenile chronic arthritis were admitted to a 6-month multicentric double blind comparative study of the efficiency of D-Penicillamine or placebo. The results evaluated in 55 patients who completed the study, indicated an improvement in the total number of stiff joints and in the total index of severity measuring joint pain and inflammation. A significant reduction of the concurrent use of non steroidal antiinflammatory drugs was also observed. The tolerance was good except in two patients. Some children in the placebo group exhibited a definite improvement.


Abscisic Acid-Induced Autophagy Selectively via MAPK/JNK Signalling Pathway in Glioblastoma.
As a widely known plant hormone, Abscisic acid plays an important role in the progress of planting cell and their stress response. Recently, we reported that ABA might play an anti-cancer role in glioma tissues. In the present study, the molecular mechanism of ABA anti-cancer was further explored in glioblastoma cells. By measuring LC3 puncta formation and conversion in glioblastoma cells, inhibiting the autophagic pathway, targeting the essential autophagic modulator beclin 1 with RNA interference, and analysing cellular morphology via transmission electron microscopy, we found that ABA-treated glioblastoma cells exhibited the features of autophagy. Specifically, ABA-induced autophagy in glioblastoma cells was mediated by the MAPK/JNK signalling pathway rather than the PI3K/AKT/mTOR axis. Moreover, the inhibition or knockdown of JNK specifically blocked ABA-induced autophagic cell death. ABA-induced autophagy was further confirmed in tumour-bearing mice and was accompanied by the inhibition of glioma growth in vivo. This report is the first to describe autophagy induced by ABA and mediated by the MAPK/JNK pathway in human cancer cells and tumour-bearing mice. These results may shed some light in new therapeutic strategies of glioma.


Elevated red cell adenosine deaminase activity: a marker of disordered erythropoiesis in Diamond-Blackfan anaemia and other haematologic diseases.
Red-cell adenosine deaminase (ADA) activity in children with Diamond-Blackfan anaemia is significantly increased (1.91 +/- 0.90 U/g Hb) compared to that seen in transient erythroblastopenia of childhood (0.80 +/- 0.16 U/g Hb) or normal individuals (0.61 +/- 0.13 U/g). These data thus further support that measurement of this purine metabolic enzyme is useful in diagnosing the cause of pure RBC aplasia in children. Of interest, however, elevated RBC-ADA activity also is seen in some children with acute leukaemia and other haematologic disorders. In children with acute lymphoblastic leukaemia (ALL), the increase in RBC-ADA activity is proportional to the degree of anaemia. However, the elevated RBC-ADA activity in this leukaemic population is not related to the fetal haemoglobin concentration. These data suggest increased RBC-ADA activity may be a non-specific manifestation of abnormal erythroid stem cell function, an alteration distinct from that seen with reactivation of fetal erythropoiesis. However, since almost all patients with Diamond-Blackfan anaemia manifest elevated RBC-ADA activity, this chemical alteration yet may reflect the specific erythroid differentiation lesion in this disorder.


[GNU Pattern: open source pattern hunter for biological sequences based on SPLASH algorithm].
To construct a high performance open source software engine based on IBM SPLASH algorithm for later research on pattern discovery. Gpat, which is based on SPLASH algorithm, was developed by using open source software. GNU Pattern (Gpat) software was developped, which efficiently implemented the core part of SPLASH algorithm. Full source code of Gpat was also available for other researchers to modify the program under the GNU license. Gpat is a successful implementation of SPLASH algorithm and can be used as a basic framework for later research on pattern recognition in biological sequences.


The identification of a robust leucine dehydrogenase from a directed soil metagenome for efficient synthesis of L-2-aminobutyric acid.
L-2-aminobutyric acid (L-2-ABA) is a chiral precursor for the synthesis of anti-epileptic drug levetiracetam and anti-tuberculosis drug ethambutol. Asymmetric synthesis of L-2-ABA by leucine dehydrogenases has been widely developed. However, the limitations of natural enzymes, such as poor stability, low catalytic efficiency, and inhibition of high-concentration substrates, limit large-scale applications. Herein, by directed screening of a metagenomic library from unnatural amino acid-enriched environments, a robust leucine dehydrogenase, TvLeuDH, was identified, which exhibited high substrate tolerance and excellent enzymatic activity towards 2-oxobutyric acid. In addition, TvLeuDH has strong affinity for NADH. Subsequently, a three-enzyme co-expression system containing L-threonine deaminase, TvLeuDH, and glucose dehydrogenase was established. By optimizing reaction conditions, 1.5 M L-threonine could be converted to L-2-ABA with a 99% molar conversion rate and a space-time yield of 51.5 g·L-1 ·h-1 . In this process, no external coenzyme was added. The robustness of TvLeuDH allowed the reaction to be performed without the addition of extra salt as the buffer, demonstrating the simplest reaction system currently reported. These unique properties for the efficient and environmentally friendly production of chiral amino acids make TvLeuDH a particularly promising candidate for industrial applications, which reveals the great potential of directed metagenomics for industrial biotechnology.


The relationship between plasma concentrations of ionized calcium and magnesium with cardiac energetics and systemic oxygen transport in neonates after the Norwood procedure.
We sought to determine the relationship between plasma calcium and magnesium concentrations with postoperative systemic hemodynamics and oxygen transport in neonates after the Norwood procedure. Postoperative systemic oxygen consumption was continuously measured using respiratory mass spectrometry for 72 hours in 17 neonates. Arterial, superior vena caval and pulmonary venous blood gases and pressures, plasma calcium, and lactate levels were measured at 2- to 4-hour intervals to calculate cardiac output, rate pressure product, cardiac power output, systemic oxygen delivery, and oxygen extraction ratio. Plasma magnesium levels were measured at 2- to 8-hour intervals. Plasma calcium levels decreased in the first 8 hours from 1.08±0.13 mmol/L to 0.98±0.08 mmol/L, followed by an increase to 1.10±0.26 mmol/L at 72 hours (P<.0001). Mg2þ change was significantly related to time after logarithmic transformation, rapidly decreasing from 1.62±0.25 mg/L to 0.90±0.15 mg/L in the first 40 hours and further decreasing slowly thereafter to 0.64±0.13 mg/L at 72 hours (P<.0001). Plasma magnesium levels had a significant positive correlation with cardiac output (P=.008) and cardiac power output (P=.01), and a negative correlation with heart rate (P=.05). Plasma magnesium levels correlated positively with systemic oxygen delivery and negatively with systemic oxygen consumption (P=.08 for both), resulting in significant negative correlations with oxygen extraction ratio (P=.04) and lactate levels (P=.05). For a given cardiac power output, plasma magnesium showed a significantly negative correlation with rate pressure product (P=.01). Plasma calcium levels showed the opposite trend, which was statistically insignificant except for lactate (P=.007). Plasma magnesium may exert favorable effects on myocardial energetics and systemic oxygen transport in neonates after the Norwood procedure, whereas plasma calcium may be harmful. Maintaining a relatively high level of plasma magnesium and a low level of plasma calcium may improve myocardial work efficiency and the balance of systemic and myocardial oxygen transport.


What if the hand piece spring disassembles during robotic radical prostatectomy?
Robot-assisted laparoscopic radical prostatectomy (RALRP) is successfully being performed for treating prostate cancer (PCa). However, instrumentation failure associated with robotic procedures represents a unique new problem. We report the successful completion of RALRP in spite of a disassembled hand piece spring during the procedure. A PubMed/Medline search was made concerning robotic malfunction and robot-assisted laparoscopic radical prostatectomy to discuss our experience. We performed RALRP in a 60-year-old male patient with localized PCa. During the procedure, the spring of the hand piece disassembled, and we were not able to reassemble it. We completed the procedure successfully however without fixing the disassembled hand piece spring. We were able to grasp tissue and needles when we brought our fingers together. The only movement we needed to do was to move fingers apart to release tissue or needles caught by robotic instrument. Although malfunction risk related to the da Vinci Surgical System seems to be very low, it might still occur. Sometimes, simple maneuvers may compensate for the failed function as occurred in our case. However, patients should be informed before the operation about the possibility of converting their procedure to laparoscopic or open due to robotic malfunction.