Enhanced chemotherapeutic efficacy of docetaxel in human lung cancer cell line via GLUT1 inhibitor.
The dose-dependent adverse effects of anticancer agents need new methods with lesser toxicity. The objective of the current research was to evaluate the efficacy of GLUT1 inhibitor, as an inhibitor of glucose consumption in cancer cells, in augmenting the efficiency of docetaxel with respect to cytotoxicity and apoptosis. Cell cytotoxicity was assessed by using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Annexin V/PI double staining was employed to evaluate apoptosis percentage. Quantitative real-time polymerase chain reaction (RT-PCR) analysis was accomplished to detect the expression of genes involved in the apoptosis pathway. The IC50 values for docetaxel and BAY-876 were 3.7 ± 0.81 and 34.1 ± 3.4 nM, respectively. The severity of synergistic mutual effects of these agents on each other was calculated by synergy finder application. It showed that the percentage of apoptotic cells following co-administration of docetaxel and BAY-876 increased to 48.1 ± 2.8%. In comparison without GLUT1 co-administration, the combined therapy decreased significantly the transcriptome levels of the Bcl-2 and Ki-67 and a remarkable increase in the level of the Bax as proapoptotic protein(p < 0.05). Co-treatment of BAY-876 and docetaxel depicted a synergistic effect which was calculated using the synergy finder highest single agent (HSA) method (HSA synergy score: 28.055). These findings recommend that the combination of GLUT-1 inhibitor and docetaxel can be considered as a promising therapeutic approach for the treatment of patients with lung cancer.


A Survey of Patient Response to Office Surgery
Over 3 years, 407 women (mean age 32 yrs, range 20-57 yrs) were selected to be interviewed before, immediately after, and 8 weeks and 6 months after surgery performed in the office. All patients had undergone both in-hospital and outpatient gynecologic procedures at least once in the past. A questionnaire elicited information on 10 common emotional responses to office surgery: surrender of control, depersonalization, helplessness, anxiety, fear of pain, fear of loss of identity, emotional lability, regression or dependency, feeling of illness, and grief. Of 407 patients, 382 completed the study to the 6-month interview. Office surgery resulted in overall decreases in all 10 categories compared with hospital-based surgery. Women's feelings concerning confidentiality, decreased paperwork, and a familiar environment were significant. Office surgery was clearly well accepted compared with the hospital, and 90% of women said they would choose this setting again if offered. Further study with control groups will be performed to evaluate these initial findings for statistical significance.


Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials.
This study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for ≥10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for light-touch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO(2) laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm(2)) and large (20 mm(2)) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd ≤-2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors.


Partial purification and characterization of an aldohexose 1-P phosphatase from pig skeletal muscle.
An enzyme with a molecular weight of 54,000 which possesses phosphatase activity acting on glucose 1-P, galactose 1-P and mannose 1-P has been partially purified and characterized from pig skeletal muscle. The enzyme is free of phosphoglucomutase and galactokinase activities, and it possesses a neutral optimum pH. Pi acts as an inhibitor; glucose, galactose and mannose do not produce any effect. Divalent cations are required for activity, Mg2+ being the most effective activator. Micromolar levels of fluoride and millimolar levels of chloride act as inhibitors; however, vanadate does not produce any effect. The enzyme may have an important role when galactose accumulates in tissues; for example, in galactosemic patients and in young animals ingesting high-galactose diets.


The Value of Reciprocal Electrocardiographic Leads.
In a woman with chest pain, <0.1 mV ST-segment elevation in lead III, and virtually no ST elevation in leads II and aVF, striking ST-segment depression in lead aVL, the reciprocal lead to lead III, confirmed the diagnosis of acute inferior myocardial infarction.


Improving competencies and skills across clinical contexts of care: a qualitative study on Malawian nurses' experiences in an institutional health and training programme.
To explore what competencies and skills Malawian nurses gained after participating in an institutional health and training programme in Norway and how they viewed these competencies applicable upon return to Malawi. Furthermore, to examine facilitators and challenges experienced on the exchange programme and opportunities and obstacles to make the competencies usable in own local hospital context. Qualitative study with an explorative design. Fourteen interviews and one focus group discussion were conducted at Queen Elizabeth Central Hospital, Blantyre, Malawi, from August to September 2018. Competencies gained in Norway included clinical skills, teamwork, coordination and strengthened professionalism. The main finding was that the exchange programme was a transformative experience. Upon return to Malawi, the competencies gained on the exchange were helpful. However, the return was characterized by mixed emotions due to the considerable difference between the two clinical settings.


GSTA4 Governs Melanoma Immune Resistance and Metastasis.
Considering the importance of GSTA4 in controlling IFNγ responsiveness and the metastatic potential of other melanoma cells, our results highlight a novel mechanism whereby cancer cells escape from host immunity and gain metastatic ability by acquiring resistance to oxidative stress responses through the upregulation of GSTA4.


Information flow in the rat thalamo-cortical system: spontaneous vs. stimulus-evoked activities.
The interaction between the thalamus and sensory cortex plays critical roles in sensory processing. Previous studies have revealed pathway-specific synaptic properties of thalamo-cortical connections. However, few studies to date have investigated how each pathway routes moment-to-moment information. Here, we simultaneously recorded neural activity in the auditory thalamus (or ventral division of the medial geniculate body; MGv) and primary auditory cortex (A1) with a laminar resolution in anesthetized rats. Transfer entropy (TE) was used as an information theoretic measure to operationalize "information flow". Our analyses confirmed that communication between the thalamus and cortex was strengthened during presentation of auditory stimuli. In the resting state, thalamo-cortical communications almost disappeared, whereas intracortical communications were strengthened. The predominant source of information was the MGv at the onset of stimulus presentation and layer 5 during spontaneous activity. In turn, MGv was the major recipient of information from layer 6. TE suggested that a small but significant population of MGv-to-A1 pairs was "information-bearing," whereas A1-to-MGv pairs typically exhibiting small effects played modulatory roles. These results highlight the capability of TE analyses to unlock novel avenues for bridging the gap between well-established anatomical knowledge of canonical microcircuits and physiological correlates via the concept of dynamic information flow.


The immune response is initiated by dendritic cells via interaction with microorganisms and interleukin-2 production.
The immune system of vertebrate animals is characterized by the capacity to respond to disturbances. This function requires 2 different approaches. First, the immune system responds in a few hours to infectious agents (innate immunity) by recognizing molecular patterns typical of microorganisms (but absent in self-tissues). Second, it mounts a late response that differentiates among different microbes, giving rise to memory (adaptive immunity). In this context, dendritic cells (DCs) play a central role, becoming efficient stimulators of both innate and adaptive responses after microbial activation. Recent data generated by global transcriptional profiling of DCs after bacterial encounter are discussed, as are the unique DC functional plasticity and the central role of DC-derived interleukin-2 in priming early and late immune responses.


The photochemical reaction cycle and photoinduced proton transfer of sensory rhodopsin II (Phoborhodopsin) from Halobacterium salinarum.
Sensory rhodopsin II (HsSRII, also called phoborhodopsin) is a negative phototaxis receptor of Halobacterium salinarum, a bacterium that avoids blue-green light. In this study, we expressed the protein in Escherichia coli cells, and reconstituted the purified protein with phosphatidylcholine. The reconstituted HsSRII was stable. We examined the photocycle by flash-photolysis spectroscopy in the time range of milliseconds to seconds, and measured proton uptake/release using a transparent indium-tin oxide electrode. The pKa of the counterion of the Schiff base, Asp(73), was 3.0. Below pH 3, the depleted band was observed on flash illumination, but the positive band in the difference spectra was not found. Above pH 3, the basic photocycle was HsSRII (490) --> M (350) --> O (520) --> Y (490) --> HsSRII, where the numbers in parentheses are the maximum wavelengths. The decay rate of O-intermediate and Y-intermediate were pH-independent, whereas the M-intermediate decay was pH-dependent. For 3 < pH < 4.5, the M-decay was one phase, and the rate decreased with an increase in pH. For 4.5 < pH < 6.5, the decay was one phase with pH-independent rates, and azide markedly accelerated the M-decay. These findings suggest the existence of a protonated amino acid residue (X-H) that may serve as a proton relay to reprotonate the Schiff base. Above pH 6.5, the M-decay showed two phases. The fast M-decay was pH-independent and originated from the molecule having a protonated X-H, and the slow M-decay originated from the molecule having a deprotonated X, in which the proton came directly from the outside. The analysis yielded a value of 7.5 for the pKa of X-H. The proton uptake and release occurred during M-decay and O-decay, respectively.


Tumour-necrosis factor from the rabbit. III. Relationship to interferons.
Tumour-necrosis factor (TNF) is growth-inhibitory or cytotoxic to certain tumour cell lines, and is present in the serum of rabbits injected i.v. with BCG and endotoxin 2 weeks apart (TNF serum). TNF serum also has interferon activity, and as TNF and interferons have a number of properties in common their relationship has been investigated further. TNF was assayed by cytotoxicity in vitro against L cells and interferon by a CPE-inhibition assay with Semliki Forest virus.TNF appears not to be an interferon, on the following bases:1. TNF activity could be separated from the Type I interferon of TNF serum by passage through a Cibacron blue-agarose column or by sequential salt precipitation, ion-exchange chromatography and gel filtration.2. Preparations of Type I interferon induced by poly I, poly C or virus lacked TNF activity.3. Though it was not possible to compare TNF with rabbit Type II interferon (as methods used to induce Type II interferon in other species were unsuccessful in the rabbit) rabbit TNF has a number of properties which distinguish it from the Type II interferons of other species.4. Rabbit TNF inhibited the growth of a human melanoma cell line, and also had effects on certain mouse and rabbit cell lines, whereas the anti-cellular effects of interferons are reported to be species-specific.


Charged PVDF multilayer nanofiber filter in filtering simulated airborne novel coronavirus (COVID-19) using ambient nano-aerosols.
The novel coronavirus (COVID-19), average size 100 nm, can be aerosolized by cough, sneeze, speech and breath of infected persons. The airborne carrier for the COVID-19 can be tiny droplets and particulates from infected person, fine suspended mists (humidity) in air, or ambient aerosols in air. To-date, unfortunately there are no test standards for nano-aerosols (≤100 nm). A goal in our study is to develop air filters (e.g. respirator, facemask, ventilator, medical breathing filter/system) with 90% capture on 100-nm airborne COVID-19 with pressure drop of less than 30 Pa (3.1 mm water). There are two challenges. First, this airborne bio-nanoaerosol (combined virus and carrier) is amorphous unlike cubic NaCl crystals. Second, unlike standard laboratory tests on NaCl and test oil (DOP) droplets, these polydispersed aerosols all challenge the filter simultaneously and they are of different sizes and can interact among themselves complicating the filtration process. For the first time, we have studied these two effects using ambient aerosols (simulating the bio-nanoaerosols of coronavirus plus carrier of different shapes and sizes) to challenge electrostatically charged multilayer/multimodule nanofiber filters. This problem is fundamentally complicated due to mechanical and electrostatic interactions among aerosols of different sizes with induced charges of different magnitudes. The test filters were arranged in 2, 4, and 6 multiple-modules stack-up with each module having 0.765 g/m2 of charged PVDF nanofibers (mean diameter 525 ± 191 nm). This configuration minimized electrical interference among neighboring charged nanofibers and reduced flow resistance in the filter. For ambient aerosol size>80 nm (applicable to the smallest COVID-19), the electrostatic effect contributes 100-180% more efficiency to the existing mechanical efficiency (due to diffusion and interception) depending on the number of modules in the filter. By stacking-up modules to increase fiber basis weight in the filter, a 6-layer charged nanofiber filter achieved 88%, 88% and 96% filtration efficiency for, respectively, 55-nm, 100-nm and 300-nm ambient aerosol. This is very close to attaining our set goal of 90%-efficiency on the 100-nm ambient aerosol. The pressure drop for the 6-layer nanofiber filter was only 26 Pa (2.65 mm water column) which was below our limit of 30 Pa (3.1 mm water). For the test multi-module filters, a high 'quality factor' (efficiency-to-pressure-drop ratio) of about 0.1 to 0.13 Pa-1 can be consistently maintained, which was far better than conventional filters. Using the same PVDF 6-layer charged nanofiber filter, laboratory tests results using monodispersed NaCl aerosols of 50, 100, and 300 nm yielded filtration efficiency, respectively, 92%, 94% and 98% (qualified for 'N98 standard') with same pressure drop of 26 Pa. The 2-6% discrepancy in efficiency for the NaCl aerosols was primarily attributed to the absence of interaction among aerosols of different sizes using monodispersed NaCl aerosols in the laboratory. This discrepancy can be further reduced with increasing number of modules in the filter and for larger 300-nm aerosol. The 6-layer charged nanofiber filter was qualified as a 'N98 respirator' (98% capture efficiency for 300-nm NaCl aerosols) but with pressure drop of only 2.65-mm water which was 1/10 below conventional N95 with 25-mm (exhaling) to 35-mm (inhaling) water column! The 6-layer charged PVDF nanofiber filter provides good personal protection against airborne COVID-19 virus and nano-aerosols from pollution based on the N98 standard, yet it is at least 10X more breathable than a conventional N95 respirator.


Acquired Demyelinating Syndromes.
Acquired demyelinating syndromes (ADS) are a heterogenous group of inflammatory demyelinating conditions that include presentations of optic neuritis, transverse myelitis, and acute demyelinating encephalomyelitis. They can be monophasic or can develop into relapsing episodes of the initial demyelinating event or evolve to include other types of demyelination. Significant progress has been made in differentiating subtypes of ADS that differ in their tendency to relapse and in which anti-inflammatory therapies are effective. Differentiating between these subtypes is important for the optimal management of these patients. Clinical features, labs (especially autoantibodies), and MRI findings can help to differentiate between the different ADS.


The role of liver and kidney on the pharmacokinetics of a recombinant amino terminal fragment of bactericidal/permeability-increasing protein in rats.
The pharmacokinetics of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein that binds to and neutralizes endotoxin, was investigated. rBPI23 was administered to rats at doses 0.01-10 mg/kg and plasma rBPI23 levels were measured by ELISA. rBPI23 was also administered to bilaterally nephrectomized rats. In addition, rBPI23 was administered intra-hepatically via the pyloric vein to determine the first-pass effect by the liver. rBPI23 concentrations were also simultaneously measured in the right atrium and aorta to determine the removal of rBPI23 by the lungs. The concentration-time profile of rBPI23 was described by a 3-compartmental model with parallel first order and Michaelis-Menten (saturable) elimination. The clearance of rBPI23 was not altered by bilateral nephrectomy. Clearance of intra-hepatically administered rBPI23 was 4.5 fold lower than intra-femorally administered rBPI23. The concentration difference of rBPI23 between aortic and right atrial blood was no greater than 11%. Clearance of rBPI23 in rats could be reduced up to 10 fold by co-administration of heparin. Uptake by liver of intra-hepatically administered rBPI23 was prevented by co-administration of heparin. rBPI23 is not significantly cleared by the kidneys, and no more than 11% of the rBPI23 was removed by the lungs with each pass. The liver could remove 78% of the rBPI23 from the hepatic circulation. Studies with heparin suggest rBPI23 is cleared by binding to heparan sulfate sites in the liver.


Diverging prognostic impacts of hypoxic markers according to NSCLC histology.
We aimed to explore the prognostic impact of the hypoxia induced factors (HIFαs) 1-2 and the metabolic HIF-regulated glucose transporter GLUT1, lactate dehydrogenase 5 (LDH5) and carbonic anhydrase IX (CAIX) in non-small cell lung cancer (NSCLC). Tumor and stroma tissue samples from 335 unselected patients with stage I-IIIA NSCLC were obtained and tissue microarrays constructed. Immunohistochemistry was used to evaluate expression. For squamous cell carcinoma patients, high tumor cell expression of HIF1α and low stromal cell expression of HIF1α and HIF2α correlated significantly with a poor disease-specific survival (DSS) in both univariate (tumor HIF1α, P=0.001; stromal HIF1α, P=0.009; stromal HIF2α, P=0.005) and multivariate analyses (tumor HIF1α, HR=3.3, P=0.001; stromal HIF1α, HR=2.1, P=0.008; stromal HIF2α, HR 2.3, P=0.005). Among adenocarcinoma patients high tumor expression of GLUT1 and low stromal expression of LDH5 correlated significantly with a poor DSS in both univariate (GLUT1, P=0.01; LDH5, P=0.03) and multivariate analyses (GLUT1, HR=1.9, P=0.046; LDH5, HR=2.3, P=0.03). These markers show highly diverging prognostic impacts between histological subgroups and between tumor and stromal compartments in NSCLC.


Role of SNPs located in the exon 9 of ATAPA1 gene on goose egg production.
The meat and egg of goose is one of the main components of human food supply. The improvement of goose egg production is particularly important for the increasing human population. However, limited information is available about the effective molecular markers and mechanisms of egg production in goose. In this study, we jointly utilized the data of genome resequencing in different egg production Sichuan white goose and transcriptome at different follicle development stages to identified the molecular markers and mechanisms of egg production. The coefficient of variation of individual egg production in Sichuan white goose population is 0.42 to 0.49. Fifty individuals with the highest (laying 365 days egg number, LEN365 = 79-145) and 50 individuals with the lowest (LEN365 = 8-48) egg production were divided into high and low egg production groups. Based on whole-genome sequencing data of the selected samples, 36 SNPs (annotation novel.12.470, CELF2, ATP1A1, KCNJ6, RAB4A, UST, REV3L, DHX15, CAVN2, SLC5A9, Cldn5, MRPS23, and Tspan2) associated with the LEN365 were identified, involving multiple pathways such as metabolism and endocrinology. Notably, 5 SNPs located in the exon9 of ATP1A1 were identified by GWAS analysis. The association analysis with LEN365 showed the phenotypic variance explained of this haplotype consisting of 5 SNPs is 20.51%. Through transcriptome data analysis, we found the expression of ATP1A1 in the granular layers was increased in the stage of small yellow follicle to large yellow follicle (LYF) and LYF to F5, while decreased in F2 to F1. For the first time, we report the haplotype region formed by 5 SNPS on exon9 of ATP1A1 is associated with egg production in goose and involved in follicle selection and maturation processes.


Cutaneous sequelae in neonatal lupus: A retrospective cohort study.
Cutaneous eruptions in neonatal lupus erythematosus (NLE) are thought to be self-resolving. Limited literature suggests cutaneous changes may persist. To characterize cutaneous residua in NLE and identify predictors for their development. A retrospective cohort study of patients with cutaneous NLE born between January 1980 and May 2017 was performed. Primary outcome was the proportion of patients with cutaneous residua. Secondary outcomes included associations/predictors of sequelae. At the last follow-up, at a mean age of 4 years (range, 0.5-18.7 years), 34% of 106 patients had cutaneous sequelae, 13% had telangiectasia, 17% had dyspigmentation, and 9% had atrophic scarring. Scarring at the last follow-up was significantly associated with the presence of skin lesions at birth (P < .001). This study was limited by the retrospective design, short follow-up duration in a subset of patients, and small sample size. Cutaneous NLE can exhibit long-term cutaneous residua. These findings underlie the importance of accurate diagnosis, long-term monitoring, and appropriate counseling.


Toward electronic health recording: evaluation of electronic patient reported outcome measures (e-PROMs) system for remote monitoring of early systemic lupus patients.
The study aimed to assess the value of evaluation of electronic patient reported outcome measures (e-PROMs) in the assessment and management of SLE disease activity flares, its association with adherence to therapy as well as organ damage. A randomized, controlled crossover study was carried out over a 24-month duration. One hundred forty-seven SLE patients meeting the revised American College of Rheumatology (ACR) criteria were enrolled. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was used to assess disease activity, whereas organ damage was scored using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index. In the first 12 months, the patients were assessed every 3 months. At 12 months, the patients were randomized into a cohort of 73 patients who continued their care in the same style and 74 patients who completed an online e-PROMs questionnaire on monthly basis for another 12-month period. The data captured were then retrospectively analyzed at the end of the 24-month study period. At the end of the first year of the study, the mean SLEDAI and SDI scores were 8.72 (6.1) and 1.9 (2.2). At the end of the second year, the mean SLEDAI and SDI scores in the e-PROMs cohort were 3.1 (2.6) and 1.2 (1.3), whereas in the control group, the scores were 7.63 (6.7) and 1.8 (2.3), respectively (p < 0.01). Adjusting for possible confounding variables, the number of flares, regardless of their severity, was associated with damage accrual (OR 2.03, 95% CI 1.34 to 2.83, p < 0.001). Adherence to therapy was significantly (p < 0.1) higher in the e-PROMs group. e-PROMs was equivalent to PROMs paper format and has a potential disease-modifying effect as it facilitated close monitoring of disease activity with an option of management escalation whenever indicated.


Dystrophic neurites are associated with early stage extracellular neurofibrillary tangles in the parkinsonism-dementia complex of Guam.
We found tangle-associated neuritic clusters (TANCs), previously reported as being present in Alzheimer's disease (AD), to be common in early and mild cases of the parkinsonism-dementia complex of Guam (PDC, bodig disease). These entities were observed around extracellular neurofibrillary tangles (eNFTs), apparently as a transient phenomenon. They were not observed around normal neurons, or neurons with intracellular neurofibrillary tangles (iNFTs). They were also not observed around late stage eNFTs. The TANCs contained both type 1 (elongated) and type 2 (globular) dystrophic neurites, as well as small, granular structures. The type 1 dystrophic neurites in TANCs were immunostained by antibodies to neuroskeletal proteins, while type 2 dystrophic neurites were immunostained by antibodies to amyloid precursor protein (APP). The eNFTs surrounded by TANCs were almost all immunopositive for amyloid P, while only some were immunopositive for C4d, and only a minority had beta-amyloid protein (A beta) associated with them. We hypothesize that the eNFTs are a source of complement activation which results in destruction of surrounding neurites. We further hypothesize that the degenerating neurites are a source of A beta which forms long-term deposits around eNFTs.


Conceptualizing Professionalism in Dietetics: An Australasian Qualitative Study.
Professionalism is a vital aspect of health care and multidisciplinary teamwork. Although there is substantive professionalism literature in medicine and an expanding health care professions literature, there is a significant gap in understanding professionalism in dietetics. There are very few research papers in the dietetics literature on this issue compared with other health professions. Given the multidisciplinary nature of health care, it is important to understand what professionalism means within each profession to develop shared understandings across health care teams. The study aim was to explore how dietetics professionalism is conceptualized by dietetic practitioners/preceptors, faculty, and new graduates. A constructionist exploratory qualitative interview study was conducted. One hundred participants (dietetics graduates, faculty, and practitioners/preceptors), associated with 17 universities across Australia and New Zealand and from diverse geographical and work settings, participated in 27 group and 24 individual interviews from March 2018 to June 2019. Thematic framework analysis was used to examine participants' understandings of professionalism. Twenty-three dimensions of dietetics professionalism were identified, with the most common being communication and including four novel dimensions of professionalism (generational, emotion management, cultural capability, and advocacy) not previously described in other professions. Professionalism as emotion management and generational adds new insights to the professionalism literature, expanding understandings of this vital aspect of health care. Although high levels of consistency in professionalism understandings existed across the three stakeholder groups, some interesting differences were found. The profession of dietetics shares similarities with other professions in the ways professionalism is conceptualized. Using these dimensions of professionalism as a framework for teaching and learning about professionalism will help in clarifying expectations and expand shared understandings about professionalism for dietitians, other health professions, and across multidisciplinary teams.


Viral kinetic modeling: state of the art.
Viral kinetic (VK) modeling has led to increased understanding of the within host dynamics of viral infections and the effects of therapy. Here we review recent developments in the modeling of viral infection kinetics with emphasis on two infectious diseases: hepatitis C and influenza. We review how VK modeling has evolved from simple models of viral infections treated with a drug or drug cocktail with an assumed constant effectiveness to models that incorporate drug pharmacokinetics and pharmacodynamics, as well as phenomenological models that simply assume drugs have time varying-effectiveness. We also discuss multiscale models that include intracellular events in viral replication, models of drug-resistance, models that include innate and adaptive immune responses and models that incorporate cell-to-cell spread of infection. Overall, VK modeling has provided new insights into the understanding of the disease progression and the modes of action of several drugs. We expect that VK modeling will be increasingly used in the coming years to optimize drug regimens in order to improve therapeutic outcomes and treatment tolerability for infectious diseases.


[What indicators of primary care activity are offered in the Spanish National Health System? Comparison between regionals governments health departments].
The identification and evaluation of specific health care activity indicators of primary care and family medicine of the regional health ministries is proposed, analyzing their experiences. A descriptive observational study of healthcare information on institutional websites and its availability, accessibility, and quality, offered between 2015-2020 has been developed. A sample of 19 websites has been compiled. The information is freely accessible, aggregated at the regional/area level, updated (2018) and in "pdf" format. Only Catalonia and Valencia discern by sex and age. Most used indicators: assigned cards (health coverage), attendance and healthcare pressure. Average indicators per community: 6. The current experiences in indicators and activity data of primary care and family medicine at the level of the Spanish National Health System are shown. Catalonia and Madrid have stood out in offering quality of care and health outcomes. The constructive debate focuses on offering a coordinated proposal of information on quality and health outcomes, accessible, relevant, understandable, and updated, learning from current best practices.


Optimal nitrogen fertilizer, which determines straw properties, and pyrolysis temperatures produce desired-biochars that can be used as a soil amendment.
This study investigated the straw harvested after nitrogen (N) fertilizer application levels (0, 75, 150 and 225 kg N hm-2). The N fertilizer increased straw yield by 115.4-190.6%. In addition to N fertility, the pyrolysis temperatures (300, 500 and 700 °C) induced significant changes of the straw-derived biochar samples. The yield reduced from 41.4 wt% to 23.2 wt%, the residence time increased from 272 yr to 2194 yr, and the residual coefficient of organic C (Fperm) increased from 0.65 to 0.93 for the biochar samples as the temperature rising. The parameters of C sequestration were mainly affected by pyrolysis temperature. The N + P2O5+K2O content (5.6-8.8%) of the biochar samples was more in the 500 °C treatment. The characteristics of nutrient supply were affected by both the N fertility and pyrolysis temperature. The N fertilizer rate of 150 kg N hm-2 in the soil for wheat straw, together with the 500 °C treatment induces the best nutrient donor and C sequestration after biochar incorporation into the soil.


Evolution of DNA structure: direction, mechanism, rate.
On the basis of the results of an analysis of frequencies of pyrimidine oligonucleotides, the degree of pyrimidine clustering of DNA in species from different taxa has been determined. A tendency for an increase in the index of clustering of DNA was revealed in the sequence: invertebrates, fishes, amphibians, reptiles, birds, mammals. A mechanism is postulated, according to which the increase in the degree of clustering of DNA d-ring the evolution may be associated with the accumulation of mutations, Purine equalibrium Pyrimidine transversions, resulting in a selective enrichment of one of the chains of DNA with pyrimidines and the other- with purines, i.e. in an increase in the degree of purine-pyrimidine imbalance (asymmetry) of DNA complementary chains. This mechanism of DNA evolution is supported by the presence of positive correlation between the degree of clustering and the degree of the chain asymmetry of natural DNAs, as well as the character of the amino acid substitutions in cytochromes c in different species. The progressive evolution of different groups of organisms on the whole may have been accompanied by an acceleration of the rates of evolution of the DNA structure. On the basis of the amino acid sequence of cytochromes c in different species the degree of clustering and the degree of the chain asymmetry of the corresponding structural genes of DNA was found to have a general tendency towards an increase in the following order: invertebrates, fishes, amphibians, reptiles, birds, mammals. Thus, evolution of cytochrome c cistron is a vector process based on a selection of mutations which, on the one hand, are neurtral to protein, and, on the other hand, result in the sense chain of DNA being enriched with pyrimidines and the nonsense one (and the corresponding mRNA)- with purines. Hence, it is the polynucleotide template rather than protein, that must have been the "object of selection". The frequency of substitutions in cytochromes c cistron for vertebrates is 1.56x13(-9) per nucleotide per year. It is believed that the evolutionary modification of the DNA structure may be associated with an increase in the interference resistance of the translation, i.e. with selection for codons of highest readout stability.


Preoperative frailty risk in deep brain stimulation patients: Risk analysis index predicts Clavien-Dindo IV complications.
Deep brain stimulation (DBS) improves patients' quality of life in multiple movement disorders and chronic neurodegenerative diseases. There are no published studies assessing frailty's impact on DBS outcomes. We evaluated frailty's impacts on DBS outcomes, comparing discriminative thresholds of the risk analysis index (RAI) to modified frailty index-5 (mFI-5) for predicting Clavien-Dindo complications (CDIV). Patients who underwent DBS between 2015 and 2019 in the ACS-NSQIP registry were included. We employed receiver operating characteristic (ROC) curve to examine the discriminative thresholds of RAI and mFI-5 and multivariable analyses for postoperative outcomes. Our primary outcome was CDIV, and secondary outcomes were discharge to higher-level care facility, unplanned reoperation within 30 days, in any hospital, for any procedure related to the index procedure, and extended length of stay. A total of 3795 patients were included. In the ROC analysis for CDIV, RAI showed superior discriminative threshold (C-statistic = 0.70, 95% CI 0.61-0.80, <0.001) than mFI-5 (C-statistic = 0.60, 95% CI 0.49-0.70, P = 0.08). On multivariable analyses, frailty stratified by RAI, had independent associations with CDIV, i.e., pre-frail 2-fold increase OR 2.04 (95% CI: 1.94-2.14) p < 0.001, and frail 39% increase OR 1.39 (95% CI: 1.27-1.53), p < 0.001. Frailty was an independent risk-factor for CDIV. The RAI had superior discriminative thresholds than mFI-5 in predicting CDIV after DBS. Our ability to identify frail patients prior to DBS presents a novel clinical opportunity for quality improvement strategies to target this specific patient population. RAI may be a useful primary frailty screening modality for potential DBS candidates.


Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit human immunodeficiency virus replication. 2. Effect of heteroaromatic linkers on the activity of bicyclams.
A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.


Self-inactivating helper virus for the production of high-capacity adenoviral vectors.
Standard methods for producing high-capacity adenoviral vectors (HC-Ads) are based on co-infection with a helper adenovirus (HV). To avoid HV encapsidation, its packaging signal (Ψ) is flanked by recognition sequences for recombinases expressed in the producing cells. However, accumulation of HV and low yield of HC-Ad are frequently observed, due in part to insufficient recombinase expression. We describe here a novel HV (AdTetCre) in which Ψ is flanked by loxP sites that can be excised by a chimeric MerCreMer recombinase encoded in the same viral genome. Efficient modulation of cleavage was obtained by simultaneous control of MerCreMer expression using a tet-on inducible system, and translocation to the nucleus by 4-hydroxytamoxifen (TAM). Encapsidation of AdTetCre was strongly inhibited by TAM plus doxycicline. Using AdTetCre and 293Cre4 cells for the production of HC-Ads, we found that cellular and virus-encoded recombinases cooperate to minimize HV contamination. The method was highly reproducible and allowed the routine production of different HC-Ads in a medium-scale laboratory setting in adherent cells, with titers >10¹⁰ infectious units and <0.1% HV contamination. The residual HVs lacked Ψ and were highly attenuated. We conclude that self-inactivating HVs based on virally encoded recombinases are promising tools for the production of HC-Ads.


2013 ACC/AHA cholesterol treatment guideline: Paradigm shifts in managing atherosclerotic cardiovascular disease risk.
The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults represents a major shift from prior cholesterol management guidelines. The new guidelines include data from individual randomized trials as well as the most comprehensive meta-analyses, and introduce several major paradigm shifts, which include: aiming for ASCVD risk reduction as opposed to targeting LDL-C levels, advocating for the use of evidence-based doses of statins as first line therapy, and utilizing a new risk calculator and risk cut point to guide initiation of statin therapy. These major changes have created controversy and confusion among the medical community, with some clinicians hesitant to embrace the shift. We review the evidence that forms the basis for these major changes, compare them to other major lipid guidelines, and recommend an integrated approach to managing dyslipidemia to decrease atherosclerotic cardiovascular disease risk.


Profiles of liver function abnormalities in elderly patients with Coronavirus Disease 2019.
The profiles of liver function abnormalities in COVID-19 patients need to be clarified. In this retrospective study, consecutive COVID-19 patients over 60 years old in Renmin Hospital of Wuhan University from January 1 to February 6 were included. Data of demographics, clinical characteristics, comorbidities, laboratory tests, medications and outcomes were collected and analysed. Sequential alterations of serum alanine aminotransferase (ALT) were monitored. A total of 330 patients were included and classified into two groups with normal (n = 234) or elevated ALT (n = 96). There were fewer females (40.6% vs 54.7%, P = .020) and more critical cases (30.2% vs 19.2%, P = .026) in patients with elevated ALT compared with the normal group. Higher levels of bacterial infection indices (eg, white blood cell count, neutrophil count, C-reactive protein and procalcitonin) were observed in the elevated group. Spearman correlation showed that both ALT and AST levels were positively correlated with those indices of bacterial infection. No obvious effects of medications on ALT abnormalities were found. In patients with elevated ALT, most ALT elevations were mild and transient. 59.4% of the patients had ALT concentrations of 41-100 U/L, while only a few patients (5.2%) had high serum ALT concentrations above 300 U/L. ALT elevations occurred at 13 (10-17) days and recovered at 28 (18-35) days from disease onset. For most patients, the elevation of serum ALT levels occurred at 6-20 days after disease onset and reached their peak values within a similar time frame. The recovery of serum ALT levels to normal frequently occurred at 16-20 days or 31-35 days after disease onset. Liver function abnormalities were observed in 29.1% of elderly people COVID-19 patients, which were slightly and transient in most cases. Liver function abnormalities in COVID-19 may be correlated with bacterial infection.


Synthesis and assembly of an adjuvanted Porphyromonas gingivalis fimbrial antigen fusion protein in plants.
The gram-negative anaerobic oral bacterium Porphyromonas gingivalis initiates periodontal disease by binding to saliva-coated oral surfaces. To assess whether edible plants can synthesize biologically active P. gingivalis fimbrial antigen, for application as an oral vaccine, a cDNA fragment encoding the C-terminal binding portion of P. gingivalis fimbrial protein (FimA), was cloned into a plant expression vector immediately downstream of a cDNA fragment encoding the cholera toxin B subunit (CTB). The chimeric plasmid was transferred into potato (Solanum tuberosum) cells and the ctb-fimA cDNA fragment detected in transformed leaf genomic DNA by PCR amplification methods. A novel protein band of 21 kDa was detected in transformed potato tuber extracts by immunoblot analysis. Oligomeric CTB-FimA (266-337) fusion protein was identified in the extracts through the binding of anti-CTX and anti-native fimbriae antibodies. The pentameric structure of CTB-FimA fusion protein was confirmed by ELISA measurements of GM1 ganglioside receptor binding. Quantification of the CTB-FimA fusion protein by ELISA indicated that the chimeric protein made up about 0.33% of total soluble tuber protein. The biosynthesis of immunologically detectable CTB-FimA fusion proteins and the assembly of fusion protein monomers into biologically active pentamers in transformed potato tuber tissues demonstrate the feasibility of synthesizing adjuvanted fimbrial protein in edible plants for development of adjuvanted mucosal vaccines against P. gingivalis generated periodontal disease.


Localization of intercellular adhesion molecule-1 in middle ear cholesteatoma.
Intercellular adhesion molecule-1 (ICAM-1) may have a role in acquired cholesteatoma, which is usually associated with an inflammatory reaction occurring in the middle ear cavity. The presence of ICAM-1 in human cholesteatomas was demonstrated by an immunoblotting assay using a specific monoclonal anti-ICAM-1 antibody after protein extraction. Distribution of ICAM-1 in the cholesteatoma tissues was then studied by avidin-biotin-peroxidase complex staining. ICAM-1 appeared to be localized on keratinocytes in all layers of the epithelium and on Langerhans cells in both the epithelium and granulation tissue of cholesteatoma. ICAM-1 was not found in the epidermis of normal external ear canal skin, normal tympanic membrane or normal facial skin, but significant staining was seen on keratinocytes of hair follicles and glands in the facial skin. The present study is the first to demonstrate ICAM-1 in cholesteatoma and suggests that it may have an important role in the clinical development of cholesteatoma, including migration, adhesion and proliferation of lymphocytes, Langerhans cells and keratinocytes.


Effects of polystyrene microplastic on uptake and toxicity of copper and cadmium in hydroponic wheat seedlings (Triticum aestivum L.).
Microplastics are widespread in freshwater environments, their biological effects and combined effects of other pollutants have attracted extensive attention. In this study, we investigated the adsorption properties of heavy metals onto polystyrene (PS) microplastics as well as the bioavailability and toxicity of microplastics and heavy metals by hydroponic wheat seedlings experiment. Results showed that PS microplastics (0.5 µm, 100 mg/L) had no significant effect on wheat seedlings growth, photosynthesis, and reactive oxygen species (ROS) content. However, PS microplastics could adsorb copper and cadmium, with a predominantly chemisorption. The accumulation of copper and cadmium in wheat seedlings reduced in the presence of PS microplastics, which meant the toxic effect by heavy metals might be mitigated. Compared with single heavy metals treatments, the combination of PS microplastics and heavy metals increased chlorophyll content, enhanced photosynthesis and reduced the accumulation of ROS. These findings suggest that PS microplastics (0.5 µm, 100 mg/L) have a mitigating effect on the bioavailability and toxicity of copper and cadmium.


Identification of a TRIM32 from Penaeus monodon is involved in autophagy and innate immunity during white spot syndrome virus infection.
Many tripartite motif (TRIM) family proteins played an important role in regulating innate immune and autophagy pathway and were important for host defenses against viral pathogens. However, the role of TRIM proteins in autophagy and innate immunity during virus infection was seldom studied in crustaceans. In this study, a novel TRIM32 homolog was identified from Penaeus monodon (named PmTRIM32). PmTRIM32 was significantly upregulated by rapamycin stimulation and WSSV infection. RNA interference experiments showed that PmTRIM32 could restrict WSSV replication and lead P. monodon more resistance to WSSV challenge. Autophagy could be induced by WSSV or rapamycin challenge and has been proved to play a positive role in restricting WSSV replication in P. monodon. The autophagy activity induced by WSSV or rapamycin challenge could be obviously inhibited by silence of PmTRIM32 in P. monodon. Further studies revealed that PmTRIM32 positively regulated the expression of nuclear transcription factor (NF-κB) and it mediated antimicrobial peptides. Moreover, Pull-down and in vitro ubiquitination assay demonstrated that PmTRIM32 could interact with WSSV envelope protein and target it for ubiquitination in vitro. Collectively, this study demonstrated that PmTRIM32 restricted WSSV replication and was involved in positively regulating autophagy and NF-κB pathway during WSSV infection in P. monodon.


Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand.
Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in T(H)2 priming and polarization. We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection. Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12. OX40L was expressed mainly on CD11c(+)MHC class II (MHCII)(+)CD11b(+) DCs but not CD103(+) DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection. In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and T(H)2 polarization, accounting for the enhanced response on reinfection.


Rates of pregnancy among levonorgestrel and copper intrauterine emergency contraception initiators: Implications for backup contraception recommendations.
This study assessed the timing, frequency, use of backup method and 1-month pregnancy rates among individuals who had an intrauterine device (IUD) placed as emergency contraception and reported intercourse within 7 days post-placement. In this secondary analysis of a randomized control trial of IUDs for emergency contraception, 518 individuals reporting unprotected intercourse in the preceding 5 days had a 52 mg levonorgestrel intrauterine system (IUS) or 380 mm2 copper IUD placed outside the first week of their menstrual cycle. All participants were advised to use backup contraception for 7 days. We assessed pregnancy status 1 month after placement by urine testing or, when not available, by survey responses and electronic health record review. Participants reported whether their first sexual activity after device placement occurred within 7 days of their placement, the frequency of intercourse and whether they used backup contraception. Rapid return to sexual activity was common and use of backup contraception was rare, regardless of type of IUD placed. Of participants who resumed penile-vaginal intercourse in the first month, most (286/446, 64.1%) participants reported intercourse within 7 days of IUD placement; only 16.4% (74/446) used condoms or withdrawal. No pregnancies occurred among users of the levonorgestrel IUS who reported intercourse within 7 days of placement (0/138, 0.0%, 95% CI 0.0%, 2.6%) nor among users of the 380mm2 copper IUD (0/148, 0.0%, 95% CI 0.0%, 2.5%). Pregnancy rates are low after placement of an IUD for emergency contraception, even among the many who resume intercourse within days following IUD placement without use of backup contraception. Clinical guidelines should facilitate access to contraception, including elimination of unnecessary recommendations for backup contraception or abstinence in the 7 days following 52 mg levonorgestrel intrauterine system.


Impact on Child Psychiatry.
The American pediatric mental health system is in crisis; the COVID-19 pandemic highlighted and exacerbated existing gaps. All youth were affected by the pandemic, an impact medicated by mental illness, the closing of schools, reduced access to mental health services, loss and bereavement, and financial and emotional stress on families. The pandemic's fallout is likely to be felt for years to come as today's youth move through successive developmental stages. Improvements in health care systems for youth, innovations in how care is delivered, and ongoing community support for recovery and resilience are needed moving forward.


Human embryonic stem cells and macroporous calcium phosphate construct for bone regeneration in cranial defects in rats.
Human embryonic stem cells (hESCs) are an exciting cell source as they offer an unlimited supply of cells that can differentiate into all cell types for regenerative medicine applications. To date, there has been no report on hESCs with calcium phosphate cement (CPC) scaffolds for bone regeneration in vivo. The objectives of this study were to: (i) investigate hESCs for bone regeneration in vivo in critical-sized cranial defects in rats; and (ii) determine the effects of cell seeding and platelets in macroporous CPC on new bone and blood vessel formation. hESCs were cultured to yield mesenchymal stem cells (MSCs), which underwent osteogenic differentiation. Four groups were tested in rats: (i) CPC control without cells; (ii) CPC with hESC-derived MSCs (CPC+hESC-MSC); (iii) CPC with hESC-MSCs and 30% human platelet concentrate (hPC) (CPC+hESC-MSC+30% hPC); and (iv) CPC+hESC-MSC+50% hPC. In vitro, MSCs were derived from embryoid bodies of hESCs. Cells on CPC were differentiated into the osteogenic lineage, with highly elevated alkaline phosphatase and osteocalcin expressions, as well as mineralization. At 12weeks in vivo, the groups with hESC-MSCs and hPC had three times as much new bone as, and twice the blood vessel density of, the CPC control. The new bone in the defects contained osteocytes and blood vessels, and the new bone front was lined with osteoblasts. The group with 30% hPC and hESC-MSCs had a blood vessel density that was 49% greater than the hESC-MSC group without hPC, likely due to the various growth factors in the platelets enhancing both new bone and blood vessel formation. In conclusion, hESCs are promising for bone tissue engineering, and hPC can enhance new bone and blood vessel formation. Macroporous CPC with hESC-MSCs and hPC may be useful for bone regeneration in craniofacial and orthopedic applications.


Spinal collision lesions.
Collision lesions are rare neoplasms often described in the hepatobiliary system, genitourinary system and adrenal glands. Vertebral haemangiomas (VH) are the most common lesions involving the vertebral bodies. VHs are usually asymptomatic and considered as "Do not touch" lesions. Rarely they can be symptomatic. Imaging findings of typical and atypical haemangiomas, variant forms of haemangioma such as aggressive haemangiomas are well known. Collision lesions involving VHs are extremely rare. This article presents a series of cases with collision lesions of the vertebral body involving VHs. This Case series demonstrates the various collision lesions in spinal haemangioma.


X-ray diffraction studies of cross-bridges weakly bound to actin in relaxed skinned fibers of rabbit psoas muscle.
X-ray diffraction patterns were obtained from skinned rabbit psoas muscle under relaxing and rigor conditions over a wide range of ionic strengths (50-170 mM) and temperatures (1 degree C-30 degrees C). For the first time, an intensification of the first actin-based layer line is observed in the relaxed muscle. The intensification, which increases with decreasing ionic strength at various temperatures, including 30 degrees C, parallels the formation of weakly attached cross-bridges in the relaxed muscle. However, the overall intensities of the actin-based layer lines are low. Furthermore, the level of diffuse scattering, presumably a measure of disorder among the cross-bridges, is little affected by changing ionic strength at a given temperature. The results suggest that the intensification of the first actin layer line is most likely due to the cross-bridges weakly bound to actin, and that the orientations of the weakly attached cross-bridges are hardly distinguishable from the detached cross-bridges. This suggests that the orientations of the weakly attached cross-bridges are not precisely defined with respect to the actin helix, i.e., nonstereospecific. Intensities of the myosin-based layer lines are only marginally affected by changing ionic strength, but markedly by temperature. The results could be explained if in a relaxed muscle the cross-bridges are distributed between a helically ordered and a disordered population with respect to myosin filament structure. Within the disordered population, some are weakly attached to actin and others are detached. The fraction of cross-bridges in the helically ordered assembly is primarily a function of temperature, while the distribution between the weakly attached and the detached within the disordered population is mainly affected by ionic strength. Some other notable features in the diffraction patterns include a approximately 1% decrease in the pitch of the myosin helix as the temperature is raised from 4 degrees C to 20 degrees C.


Glutathione peroxidase activities during selenium depletion of adult female rats and during selenium repletion of their offspring.
The main purpose of the present investigation was to produce young rats with severe selenium deficiency, but with no clinical signs of this deficiency, and to examine their liver and red blood cell (RBC) glutathione peroxidase activities during selenium repletion. To achieve this goal, female breeders were fed a selenium-deficient diet beginning 2 weeks before mating. The liver glutathione peroxidase activity of the dams was significantly lower than the activity of comparable nonpregnant females after 5 and 10 weeks of selenium depletion. This difference arose exclusively during the period of pregnancy. In contrast, the RBC glutathione peroxidase activity was significantly increased during this period. Only traces of liver enzyme activity were found in the offspring, and the RBC enzyme activity was only 2% of that of the selenium-repleted controls. Body weight was retarded in the male offspring. However, no severe signs of clinical selenium deficiency were observed. The glutathione peroxidase activity in the liver and RBCs of the offspring was determined after 0, 2, 4, 7, 14, and approximately 40 days of selenium repletion. The liver enzyme activity increased faster in females than in males, while the opposite was found for the RBCs. After 14 days of selenium repletion, the glutathione peroxidase activity of the liver was essentially restored, and the RBC enzyme activity was about half that of the control values. This type of rat may prove useful in studies in which young selenium-deficient rats are preferable, as well as in studies of selenium functions that might not be directly related to the role of selenium in glutathione peroxidase.


Disposition of enantiomers of sulpiride in humans and rats.
Pharmacokinetics of sulpiride enantiomers after intravenous administration of (+/-)-, (+)-, and (-)-sulpiride was examined in humans and rats. Pharmacokinetics profiles were similar in (+)- and (-)-enantiomers after intravenous administration of (+/-)-sulpiride. Metabolic inversion at a chiral centre was not observed after intravenous administration of each enantiomer in rats.


Arterial haemodynamics on ventricular hypertrophy in rats with simulated aortic stiffness.
Aortic stiffness (AS) exerts significant impact on the cardiovascular risks. We developed a new model to produce AS. The purposes were to evaluate the haemodynamic consequence and to correlate the haemodynamic parameters with the extent of ventricular hypertrophy (VH). We applied silicon gel for embedding of the abdominal and/or thoracic aorta. After 1-4 weeks of AS, the left ventricular weight (LVW), LVW to body weight (BW) ratio (LVW/BW), and the morphological changes in cardiomyotes were quantified for VH. We determined the aortic pressure (AP), stroke volume, cardiac output, total peripheral resistance (TPR), characteristic impedance (Zc), pulse wave reflection (P(b)) and pulse wave velocity (PWV). Aortic embedding (AE) increased LVW, LVW/BW, systolic and pulse pressure (PP), Zc, P(b) and PWV accompanied by decreases in diastolic pressure and arterial compliance. The magnitude of these haemodynamic and cardiac changes were in an order of combined, thoracic and abdominal AE. Correlation analysis revealed that the VH was well correlated with pulsatile haemodynamics such as Zc, PP, P(b) and PWV, while less with steady components (Mean AP and TPR). Our results indicate that pulsatile haemodynamic parameters are significantly elevated after AS. The alterations in pulsatile haemodynamics are the major causes leading to VH.


Targeted VEGFA therapy in regulating early acute kidney injury and late fibrosis.
Damage to peritubular capillaries is a key process that contributes to acute kidney injury (AKI) progression. Vascular endothelial growth factor A (VEGFA) plays a critical role in maintaining the renal microvasculature. However, the physiological role of VEGFA in various AKI durations remains unclear. A severe unilateral ischemia‒reperfusion injury model was established to provide an overview of VEGFA expression and the peritubular microvascular density from acute to chronic injury in mouse kidneys. Therapeutic strategies involving early VEGFA supplementation protecting against acute injury and late anti-VEGFA treatment for fibrosis alleviation were analyzed. A proteomic analysis was conducted to determine the potential mechanism of renal fibrosis alleviation by anti-VEGFA. The results showed that two peaks of extraglomerular VEGFA expression were observed during AKI progression: one occurred at the early phase of AKI, and the other occurred during the transition to chronic kidney disease (CKD). Capillary rarefaction progressed despite the high expression of VEGFA at the CKD stage, and VEGFA was associated with interstitial fibrosis. Early VEGFA supplementation protected against renal injury by preserving microvessel structures and counteracting secondary tubular hypoxic insults, whereas late anti-VEGFA treatment attenuated renal fibrosis progression. The proteomic analysis highlighted an array of biological processes related to fibrosis alleviation by anti-VEGFA, which included regulation of supramolecular fiber organization, cell-matrix adhesion, fibroblast migration, and vasculogenesis. These findings establish the landscape of VEGFA expression and its dual roles during AKI progression, which provides the possibility for the orderly regulation of VEGFA to alleviate early acute injury and late fibrosis.


Organizing the synaptic junctions.
Synaptic adhesion molecules (SAMs) are essential for driving the formation, maturation, and plasticity of synaptic connections for neural networks. MAM domain-containing glycosylphosphatidylinositol anchors (MDGAs) are a type of SAM that regulates the formation of trans-synaptic bridges, which are critical for neurotransmission and synaptic differentiation. In a recent issue of the JBC, Lee et al. uncovered that MDGA1 can control protein-protein interactions and synaptic cleft activity by adopting different global 3D conformations. This novel molecular mechanism may be applicable to other SAMs that regulate protein-protein interactions and nanoscale organization in the synaptic cleft.


Unsupervised pharmacophore modeling combined with QSAR analyses revealed novel low micromolar SIRT2 inhibitors.
Situin 2 (SIRT2) enzyme is a histone deacetylase that has important role in neuronal development. SIRT2 is clinically validated target for neurodegenerative diseases and some cancers. In this study, exhaustive unsupervised pharmacophore modeling was combined with quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent SIRT2 inhibitors using 146 known SIRT2 ligands. A computational workflow that combines genetic function algorithm with k-nearest neighbor or multiple linear regression was implemented to build self-consistent and predictive QSAR models based on combinations of pharmacophores and physicochemical descriptors. Successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve profiles. Optimal QSAR models and their associated pharmacophore hypotheses were experimentally validated by identification and in vitro evaluation of several new promising SIRT2 inhibitory leads retrieved from the National Cancer Institute structural database. The most potent hit illustrated IC50 value of 5.4μM. The chemical structures of active hits were validated by proton nuclear magnetic resonance and mass spectroscopy.


[Changes in the relation between therapist and group in the phases of intended dynamic group psychotherapy].
The progress of a group under intended dynamic direction was recorded over a period of 65 hours on the basis of interaction frequencies and directions as well as interaction contents and styles. It could be demonstrated that by means of this relatively simple or global approach an adequate and sufficiently sensitive picture of the therapist/patient activities and their phase-specific change could be reflected. On the basis of an example of a cohesive group, the change in significance of the therapist postulated in our conception and the interaction process between group, therapist and patient could be confirmed. The data obtained for the individual hours have been condensed for a demonstration of the phase-typical course.


[Aortic valve sparing in 120 patients with aortic root aneurysms].
Several aortic valve sparing techniques have been described for the treatment of aortic root aneurysms. We report our experience using the reimplantation technique in 120 patients. Between March 2004 and October 2010, 120 patients with aortic root aneurysms underwent David operations. Of these, 51 were diagnosed with Marfan syndrome. Mean patient age was 31 ± 12 years. The mean diameter of the sinuses of Valsalva was 51 ± 5 mm and moderate/severe aortic regurgitation was present in 16% of these patients. In the other 69 patients mean age was 56 ± 14 years, the mean diameter of the sinuses of Valsalva was 53 ± 7 mm and moderate/severe aortic regurgitation was present in 66%. A bicuspid aortic valve was presented in 14 cases. Hospital mortality was 1.7%. Mean follow-up was 37 ± 21 months; 94% of the patients survived and 96% had an aortic regurgitation below grade II during 5 years of follow-up. One patient required re-operation because of severe aortic regurgitation. No endocarditis or thromboembolic complications have been documented, and 96% of the patients did not receive any anticoagulation therapy. Short- and mid-term results with the reimplantation technique for aortic root aneurysms are excellent. This technique prevents the need for chronic anticoagulation treatment as well as the complications arising from mechanical prostheses, and it should be the treatment of choice for young patients.


Liver functional volumetry for portal vein embolization using a newly developed 99mTc-galactosyl human serum albumin scintigraphy SPECT-computed tomography fusion system.
We developed a new combined (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy single-photon emission computed tomography (SPECT)/CT system to evaluate the changes in functional liver volume with portal vein embolization (PVE). We performed a prospective analysis of 25 patients treated with right PVE, and evaluated their functional liver volume perioperatively with a (99m)Tc-GSA scintigraphy SPECT-CT fusion system. The percentage of the non-tumorous remnant liver volume (%LV) and the percentage of functional remnant liver volume (%FLV) were estimated by using the following calculations: (future remnant volume - tumor volume)/(total liver volume - tumor volume) and functional future remnant liver volume/functional total liver volume, respectively. Before PVE, the correlation was strongly significant between %LV and %FLV of the non-embolized liver, and the data were nearly equal (the regression coefficient was 1.005, P < 0.0001). In contrast, after PVE, there was a significant correlation between %LV and %FLV (P < 0.0001), but the regression coefficient was 1.192. The % LV increased significantly, from 38.1 to 52.0%, and the increment was 13.9% (P < 0.0005). The %FLV was also increased significantly, from 36.6 to 58.0%, and the increment was 21.4% (P < 0.0001). The increment was 7.5% greater for the %FLV compared to that of the %LV (P < 0.001). The (99m)Tc-GSA scintigraphy SPECT-CT fusion system can estimate the correct functional liver volume and is useful in comparison with conventional CT volumetry.


An efficient synthesis of coumestrol and coumestans by iodocyclization and Pd-catalyzed intramolecular lactonization.
[reaction: see text] The iodocyclization of acetoxy-containing 2-(1-alkynyl)anisoles and subsequent direct palladium-catalyzed carbonylation/lactonization provide an efficient route to naturally occurring coumestan and coumestrol, and their related analogues.


Mechanisms and outcomes of catheter ablation for biatrial tachycardia in adults with congenital heart disease.
Biatrial tachycardia (BiAT) is a rare form of macroreentry not previously characterized in adults with congenital heart disease (ACHD). The purpose of this study was to determine the prevalence, mechanisms, and outcomes of catheter ablation for BiAT in ACHD. All ACHD undergoing catheter ablation for macroreentrant atrial tachycardia over a 10-year period were evaluated for evidence of BiAT. Patients were categorized as prior Senning, Fontan, or other biventricular operation. A novel biatrial global activation histogram (GAH) analysis was used to demonstrate the presence of interatrial connections (IACs). Among 263 ACHD, BiAT was identified at 11 procedures in 10 patients (4.2%; median age 35 years; 30% male). The congenital category was Fontan in 6, Senning in 3, and biventricular in 2. Diagnosis of BiAT was associated with ablation era and mapping technology (P <.001) and could be confirmed with a novel GAH mapping approach for normally septated atrial connections. Catheter ablation targeted an IAC in 5 cases (Bjork Fontan and biventricular operations), a posterior isthmus in 3 (Senning operation), and the cavotricuspid isthmus or equivalent in 3 (lateral tunnel [LT] Fontan). Recurrence was isolated to ablation to sites at the expected location of the Bachmann bundle, and durable success could be achieved after repeat ablation. BiAT occurs in approximately 4% of ACHD but is likely underrecognized. BiAT could be targeted at an IAC for normally septated atria and at a conventional critical isthmus after Senning and LT Fontan operations.


Non-discriminating flash pyrolysis and thermochemolysis of heavily contaminated sediments from the Hamilton Harbor (Canada).
Analytical pyrolysis of sediments contaminated with pollutants of medium to high molecular weights (up to approximately 500 Da) is very challenging when using conventional pyrolysis systems due to discrimination of high molecular weight analytes. In the framework of this contribution, non-discriminating pyrolysis and thermochemolysis using rapid heating in a Silcosteel capillary were applied to study organic pollutants in heavily contaminated sediments taken from the Hamilton Harbor. The novel pyrolysis approach, requiring very small amounts of sample, turned out to be very useful as a rapid screening method, e.g. for risk assessment studies, proving superior to commonly used solvent extraction. Main pollutants in the sediments under study included aromatic hydrocarbons, chiefly originating from coal tar and petroleum. Polycyclic aromatic hydrocarbons (PAHs) beyond six-rings, including coronene and truxene, could be detected. Sequential tetramethyl ammonium hydroxide-induced thermochemolysis performed at 500 and 750 degrees C enabled the differentiation between organic pollutants sorbed onto the sediment matrix on the one hand, and structural moieties of the condensed polymeric humic sediment matrix along with bound residues on the other hand. Thermochemolysis at 500 degrees C removed sorbates quantitatively, leaving only bare polymeric humic matrix. Significant PAH source indicators provided evidence that the lipidic fraction sorbed onto the sediments originated from PAHs formed chiefly in coal combustion processes. The polymeric humic organic matter network of the less polluted sediment was mainly of petrogenic origin, whereas black carbon, kerogen, etc. contributed to the organic carbon of the heavily polluted sediment. Thermochemolysis at 500 degrees C was also used to study fatty acid profiles of the sediments. The fatty acid methyl ester patterns obtained for the two sites under study differed significantly, with strong indications that microbial attenuation of the pollutants at the heavily polluted site 2 was strongly suppressed.


Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario.
Mitochondrial outer membrane permeabilization (MOMP) is considered the 'point of no return' as this event is responsible for engaging the apoptotic cascade in numerous cell death pathways. MOMP is directly governed by a subset of the BCL-2 family of proapoptotic proteins, which induce disruptions in the outer mitochondrial membrane (OMM) and subsequent release of death-promoting proteins like cytochrome c. The proposal here is centered on our hypothesis that MOMP is dictated by an interaction between the cytosol and the OMM, and although proteins of the OMM may be important in the process, the 'decision' to undergo apoptosis originates within the cytosol with no participation (in terms of yes, no and when) by mitochondria.


Simultaneous determination of iron and aluminium by differential kinetic spectrophotometric method and chemometrics.
A differential kinetic spectrophotometric method was researched and developed for the simultaneous determination of iron and aluminium in food samples. It was based on the direct reaction kinetics and spectrophotometry of these two metal ions with Chrome Azurol S (CAS) in ethylenediamine-hydrochloric acid buffer (pH 6.3). The results were interpreted with the use of chemometrics. The kinetic runs and the visible spectra of the complex formation reaction were studied between 540 and 750 nm every 30 s over a total period of 285 s. A set of synthetic metal mixture samples was used to build calibrations models. These were based on the spectral and kinetic two-way data matrices, which were processed separately by the radial basis function-artificial neural network (global RBF-ANN) method. The prediction performance of these models was poorer than that from the combined kinetic-spectral three-way array, which was similarly processed by the same method (% relative prediction error (RPE(T))=5.6). These results demonstrate that improved predictions can be obtained from the data array, which has more information, and that appropriate chemometrics methods can enhance analytical performance of simple techniques such as spectrophotometry. Other chemometrics models were then applied: N-way partial least squares (NPLS), parallel factor analysis (PARAFAC), back propagation-artificial neural network (BP-ANN), single radial basis function-artificial neural network (RBF-ANN), and principal component neural network (PC-RBF-ANN). There was no substantial difference between the methods with the overall %RPE(T) range being 5.0-5.8. These two values corresponded to the NPLS and BP-ANN models, respectively. The proposed method was applied for the determination of iron and aluminium in some commercial food samples with satisfactory results.


Isolated pleural effusion as a presentation of high cardiac output heart failure in a hemodialysis patient.
Congestive heart failure is a well-recognized complication of hemodialysis arteriovenous fistula. Symptoms of dyspnea are usually associated with signs of congestive heart failure including pulmonary edema, pleural effusions, lower extremity edema, and liver enlargement, to name a few. We present a case of a gentleman with end-stage renal disease on chronic hemodialysis, which developed acute bilateral transudative pleural effusions in the absence of other signs of systemic venous congestion, associated with pulmonary venous congestion. We also discuss the pathogenesis and role of hemodialysis in management of this patient.


Endogenous production of leukotriene D4 mediates autocrine survival and proliferation via CysLT1 receptor signalling in intestinal epithelial cells.
The cysteinyl leukotriene1 (CysLT1) receptor (CysLT1R) enhances survival and proliferation of intestinal cells via distinct pathways. Here, we have demonstrated that there is significant endogenous production of CysLTs from both non-tumour- and tumour-derived intestinal epithelial cells. Treatment of two non-tumour cell lines, Int 407 and IEC-6, with CysLT1R antagonists led to shrinkage and detachment of cells, confirmed as apoptotic cell death, and a dose-dependent reduction in proliferation. However, in the tumour intestinal cell lines Caco-2, SW480, HCT-116 and HT-29, treatment with CysLT1R antagonists significantly reduced proliferation, but had no effect on apoptosis. A unique characteristic of intestinal cancer cells is the presence of nuclear CysLT1Rs, which are inaccessible to receptor antagonists. In these cells, inhibition of the endogenous production of CysLTs indirectly, by 5-lipoxygenase inhibition, impaired CysLT1R signalling throughout the cell, and resulted in apoptosis of the tumour cells. These data reveal the existence of constitutive CysLT1R signalling that mediates both survival and proliferation in intestinal cells. Importantly, we propose that tumour-derived intestinal cells are resistant to CysLT1R antagonist-induced apoptosis, a phenomena that could be explained by nuclear CysLT1R signalling.


TLR2- and TLR3-activated microglia induce different levels of neuronal network dysfunction in a context-dependent manner.
Recognition of pathogen- or damage-associated molecular patterns (PAMPs, DAMPs) by innate Toll-like receptors (TLRs) is central to the activation of microglia (brain macrophages) in many CNS diseases. Notably, TLR-mediated microglial activation is complex and modulated by additional exogenous and endogenous immunological signals. The impact of different microglial reactive phenotypes on electrical activity and neurotransmission is widely unknown, however. We explored the effects of TLR ligands on microglia and neuronal network function in rat organotypic hippocampal slice cultures (in situ), i.e., postnatal cortical tissue lacking adaptive immunity. Single exposure of slice cultures to TLR2 or TLR3 ligands [PGN, poly(I:C)] for 2-3 days induced moderate microglial activation featuring IL-6 and TNF-α release and only mild alterations of fast neuronal gamma band oscillations (30-70 Hz) that are fundamental to higher cognitive functions, such as perception, memory and behavior. Paired exposure to TLR3/TLR2 or TLR3/TLR4 ligands (LPS) induced nitric oxide (NO) release, enhanced TNF-α release, and associated with advanced network dysfunction, including slowing to the beta frequency band (12-30 Hz) and neural bursts (hyperexcitability). Paired exposure to a TLR ligand and the leukocyte cytokine IFN-γ enhanced NO release and associated with severe network dysfunction, albeit sensitive parvalbumin- and somatostatin-positive inhibitory interneurons were preserved. Notably, the neuronal disturbance was prevented by either microglial depletion or pharmacological inhibition of oxidant-producing enzymes, inducible NO synthase (iNOS) and NADPH oxidase. In conclusion, TLR-activated microglia can induce different levels of neuronal network dysfunction, in which severe dysfunction is mainly caused by reactive oxygen and nitrogen species rather than proinflammatory cytokines. Our findings provide a mechanistic insight into microglial activation and functional neuronal network impairment, with relevance to neuroinflammation and neurodegeneration observed in, e.g., meningoencephalitis, multiple sclerosis and Alzheimer's disease.


Functional similarities in the mechanical design of the aorta in lower vertebrates and mammals.
The mechanical properties of the aorta from the toad Bufo marinus, the lizard Gekko gecko and the garter snake Thamnophis radix were compared to those of the rat, by inflation of vessel segments in vitro. The arteries of the lower vertebrates, like those of mammals, were compliant, highly resilient, and non-linearly elastic. The elastic modulus of the artery wall was similar in the lower vertebrates and mammals, at their respective mean physiological pressures. We conclude that the aorta in each of these animals is suitably designed to function effectively as an elastic pulse smoothing component in the circulation; differences in the pressure wave transmission characteristics of lower vertebrates and mammals do not result from dissimilarities in arterial elastic properties, but from substantial differences in heart rate of these two groups.


Anatomic variations in underdeveloped right ventricle related to tricuspid atresia and stenosis.
In the anatomy of 416 hearts, the seat of tricuspid stenosis or atresia is examined, with special reference to Fontan-like surgical procedures. A classification is offered which includes cases with and without regular or inverted transposition, and with decreased or increased pulmonary flow. The size and thickness of the right atrium, the size and architecture of the right ventricle, the size of the pulmonary tree, the types of atrial and ventricular septal defects, the condition of the mitral valve, and the size and thickness of the left atrium and left ventricle are analyzed. In addition the various intracardiac and extracardiac abnormalities are enumerated. Reference is also made to the tendency of the aorta and pulmonary trunk to override the septum, in some cases producing double-outlet left ventricle. It is considered that many cases of tricuspid valve atresia and stenosis with or without transposition may be amenable to Fontan-like procedures in the proper age group. All the above anatomic considerations have a bearing on the suitability and type of operative tricuspid bypass procedures, and they may influence the prognosis of surgical therapy.


Estimating the cost of status epilepticus admissions in the United States of America using ICD-10 codes.
Estimate the cost of status epilepticus (SE) admissions in the USA using claim databases based on ICD-10 codes. Descriptive retrospective study using national estimates for the year 2016 from the KID's Inpatient Database (KID) for pediatric patients and from the National Inpatient Sample (NIS) for adults. These databases are comprehensive collections of all-payer, encounter-level hospital care data in the United States of America. From a population of 6,106,405 pediatric admissions there were 580 admissions related to SE. From a population of 29,274,158 adult admissions there were 1,405 admissions related to SE. The median (p25-p75) cost of pediatric admissions related to SE was $8,749 ($4,875-$19,067) in 2016 USA dollars [$9,295 ($5,180-$20,258) in inflation-adjusted 2019 USA dollars], and for adult admissions related to SE it was $14,678 ($7,203-$28,388) in 2016 USA dollars [$15,595 ($7,653-$30,161) in inflation-adjusted 2019 USA dollars]. Transforming to 2019 USA dollars, the values from the current study are consistent with prior estimates in the literature from the KID and NIS databases with a progressive increase, except for the cost of super-refractory SE in children that has increased disproportionately. This study estimates that the cost of admissions related to SE in the USA is approximately $9,000 in children and $15,000 in adults and shows that the cost estimates have not markedly changed with the advent of ICD-10.


Novel splice variants of amphiphysin I are expressed in retina.
Using RT-PCR-based cDNA cloning, we identified novel splice variants of amphiphysin I, termed amph Ir, that are expressed specifically in retina. In comparison with the prototype amphiphysin I, amph Ir contained two novel insertions (inserts A and B) and one deletion. Insert A is only 9 bp in length but appears to be a determinant for the retina-specific expression. In contrast, insert B is a large domain of 1740 bp and two shorter transcripts with 3'-truncated insert B were also expressed. All the insert sequences were present as unidentified exons in the amphiphysin I gene on human chromosome 7. Western blot analysis of various rat tissues with anti-insert B antibody confirmed the presence and tissue specificity of the variant proteins.


The Association of Vision, Hearing, and Dual-Sensory Loss with Walking Speed and Incident Slow Walking: Longitudinal and Time to Event Analyses in the Health and Retirement Study.
With the aging of the population, vision (VL), hearing (HL), and dual-sensory (DSL, concurrent VL and HL) loss will likely constitute important public health challenges. Walking speed is an indicator of functional status and is associated with mortality. Using the Health and Retirement Study, a nationally representative U.S. cohort, we analyzed the longitudinal relationship between sensory loss and walking speed. In multivariable mixed effects linear models, baseline walking speed was slower by 0.05 m/s (95% confidence interval [CI] = 0.04-0.07) for VL, 0.02 (95% CI = 0.003-0.03) for HL, and 0.07 (95% CI = 0.05-0.08) for DSL compared with those without sensory loss. Similar annual declines in walking speeds occurred in all groups. In time-to-event analyses, the risk of incident slow walking speed (walking speed < 0.6 m/s) was 43% (95% CI = 25-65%), 29% (95% CI = 13-48%), and 35% (95% CI = 13-61%) higher among those with VL, HL, and DSL respectively, relative to those without sensory loss. The risk of incident very slow walking speed (walking speed < 0.4 m/s) was significantly higher among those with HL and DSL relative to those without sensory loss, and significantly higher among those with DSL relative to those with VL or HL alone. Addressing sensory loss and teaching compensatory strategies may help mitigate the effect of sensory loss on walking speed.


D-dimer increase after percutaneous transluminal angioplasty and clinical recurrence after primary revascularization in acute myocardial infarction? A pilot study.
It has been reported that the increase of plasminogen activator inhibitor-1 activity immediately after elective coronary angioplasty is related to subsequent clinical recurrence in patients with chronic coronary artery disease. The aims of our study were to evaluate the behavior of plasminogen activator inhibitor-1 and D-Dimer after revascularization in acute myocardial infarction patients treated with angioplasty and stenting and if this behavior is predictive of subsequent clinical recurrence. D-Dimer and plasminogen activator inhibitor-1 activity were evaluated in two groups of patients. Group 1 consisted of 54 consecutive patients undergoing primary angioplasty for acute myocardial infarction and Group 2 consisted of 48 patients undergoing elective angioplasty. Patients underwent control coronary angiography only in the case of clinical recurrence and/or positivity of provocative tests. D-Dimer and plasminogen activator inhibitor-1 baseline levels were significantly higher in group 1 than in group 2 (P<0.0005 and P<0.05, respectively). The percentage of group 1 patients with a post-procedural increase in D-Dimer was significantly higher among those with subsequent clinical recurrence with restenosis (61%) than among those with no recurrence (25%, P<0.05). No difference was observed in group 2. The percentage of group 2 patients in whom no decrease of plasminogen activator inhibitor-1 was observed after angioplasty was significantly higher (83%) among those with subsequent recurrence than among those with no recurrence (38%, P<0.05). This pattern was not observed in group 1. In conclusion, the role of early changes in plasminogen activator inhibitor-1 in predicting clinical recurrence after primary angioplasty in acute myocardial infarction patients is less clear than that observed after elective angioplasty. A significant role seems to be played by a more-marked clotting activation with increased fibrin formation.


Colony formation in the absence of added growth factors by peripheral blood T-cell colony-forming cells of patients with T-cell malignancies.
Clonogenic cells from peripheral blood of 13/16 patients with T-cell malignancies generated colonies in methylcellulose in absence of added growth factors or mitogenic stimulation. Spontaneous colonies were also obtained from purified cell fractions (E-OKT3- and/or E+ cells) in 73% and 57% of the patients, respectively. No spontaneous colony growth was observed with mononuclear cells of patients with solid tumors, non-T-cell leukemias or normal subjects. Colonies consisted of acid-phosphatase-positive, myeloperoxidase-and PAS-negative lymphoblasts bearing T-cell surface markers. Although the phenotype of pooled colony cells from either unfractionated mononuclear cells or E-OKT3- -derived colonies varied from patient to patient, the colonies, like fresh leukemic cells, were mostly composed of relatively immature cells as assessed by the high proportion (greater than 40%) of OKT6+ and OKT10+ cells and the low proportion (less than 40%) of OKT3+ and/or E+ cells. Cytogenetic analysis of colony cells revealed either normal metaphases or chromosome anomalies similar to those observed in fresh leukemic cells. Moreover, cells from primary colonies exhibited a capacity for self-renewal in the absence of added growth factors.


Tat-biliverdin reductase A inhibits inflammatory response by regulation of MAPK and NF-κB pathways in Raw 264.7 cells and edema mouse model.
Reactive oxygen species (ROS) accumulation induces oxidative stress and cell damage, which then activates several signaling pathways and triggers inflammatory response. Biliverdin is a natural product of heme metabolism which is converted to bilirubin by the enzyme biliverdin reductase A (BLVRA) which also plays a role in antioxidant activity via the ROS scavenging activity of bilirubin. In this study, we examined the anti-inflammatory and anti-apoptotic effects of Tat-BLVRA protein on lipopolysaccharide (LPS)-induced inflammation in Raw 264.7 macrophage cells. Transduction of Tat-BLVRA protein into Raw 264.7 cells and mice ear tissue was tested by Western blot analysis and immunohistochemical analysis. Tat-BLVRA protein was effective in inhibiting mitogen activated protein kinases (MAPKs), Akt and NF-κB activation, intracellular ROS production and DNA fragmentation. Also, Tat-BLVRA protein significantly inhibited the expression of cytokines, COX-2, and iNOS. In a 12-O-tetradecanoylphobol 13-acetate (TPA)-induced mouse model, mice ears treated with Tat-BLVRA protein showed decreased ear thickness and weight, as well as inhibited MAPKs activation and cytokine expression. Thus we suggested that Tat-BLVRA protein may provide an effective therapeutic agent for inflammatory skin diseases.


Effects of different regimes of corticosteroid treatment on calcium and bone metabolism in rheumatoid arthritis.
A clinical study of 30 patients with rheumatoid arthritis was undertaken in order to assess the acute effects of corticosteroids on calcium and bone metabolism. The patients were randomly divided into 3 groups. The first group was not treated with corticosteroids, the second group was treated with 3 oral pulses of 100 mg prednisolone and the third group received 3 intravenous pulses of 1000 mg methylprednisolone (MP) on alternate days during one week. In both steroid treated groups the serum parathyroid hormone concentration tended to increase. In the MP treated group an increase in the 1,25-dihydroxyvitamin D concentration after the first pulse was followed by a significant drop; this effect was also seen, but somewhat retarded and less distinct, in the orally treated group. In the MP treated group the urinary calcium excretion raised significantly 6 hrs after the first pulse and then dropped significantly. In all groups no changes were found in the serum calcium level and the urinary excretion of hydroxyproline. We conclude that, acute changes in calcium and bone metabolism occur during treatment with intravenous pulses of methylprednisolone and with oral pulses of prednisolone. These changes are small and reversible in a few days.


[Cyto-immunological study of the Pleurodele pituitary gland].
In the pituitary of an Amphibian (Urodela), various cell types were localized by cytoimmunological techniques: corticotrophs located in a rostral zone near the median eminence, ventral orangeophilic cells secreting a prolactin-like hormone and erythrosinophilic cells in a more dorso-caudal situation secreting growth hormone. Alpha-MSH and beta-MSH produceng cell were identified in the intermediate lobe; these cells were also labelled with antibodies against 1-24 ACTH and 17-39 ACTH. These data are in accordance with results obtained after an experimental study of the prolactin cells.


Comparison of the effects of bilateral and unilateral laparoscopic ovarian drilling on pregnancy rates in infertile patients with polycystic ovary syndrome.
This study aims to investigate the effects of unilateral and bilateral laparoscopic ovarian drilling (LOD) on pregnancy rates in patients with clomiphene citrate (CC) resistant infertile polycystic ovary syndrome. This prospective cohort study included 75 patients who were admitted to the Department of Obstetrics and Gynecology of the Antalya Training and Research Hospital between July 2016 and December 2017 and underwent LOD operation. Among these patients, 37 underwent unilateral laparoscopic ovarian drilling (ULOD) and 38 underwent bilateral laparoscopic ovarian drilling (BLOD). The drilling procedure was carried out using the following equation: Number of punctures (np) = 60 J/cm3 /30 watt × 4 s by selecting the larger ovary in the patients who underwent ULOD and by taking the ovarian volume of each ovary in the BLOD group. During the 1-year follow-up, 20 of the ULOD patients (54.1%) and 13 of the BLOD patients (34.2%) were observed to be pregnant. Although a higher number of pregnancies were obtained in the ULOD group, no statistically significant difference was found between the two groups (P = 0.083). The pregnancies occurred more in the first 6 months during the postoperative follow-ups of the patients. A total of 14 (70%) of the 20 pregnancies in the ULOD group and 9 (69.2%) of the 13 pregnancies in the BLOD group occurred in the first 6 months. ULOD with respect to a larger ovarian volume should be preferred to BLOD for CC-resistant PCOS patients because of the high pregnancy rates and fewer potential side effects.


Cardiologist's approach to the diabetic patient: No further delay for a paradigm shift.
Type 2 diabetes mellitus (DM) is constantly increasing worldwide and its most critical determinant of morbidity and mortality is still represented by cardiovascular (CV) complications. For years, cardiologists' approach to diabetic patients has been focused on risk factors optimization, with positive results. However, the management of DM per se was never truly considered in order to obtain prevention from major CV events, because medications used for glycemic control were not expected to gain CV benefit. Early trials concerning intensive versus conventional glycemia control did not prove useful in reducing the number of CV events. The introduction of new molecules led to a game change in DM treatment, as some new glucose-lowering drugs (GLDs), such as sodium-glucose linked transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA), showed not only to be safe but also to ensure CV benefit. A combination of anti-atherogenic effects and hemodynamic improvements are likely explanations of the observed reduction of CV events and mortality. These evidence opened a completely new era in the field of GLDs and of DM treatment. Nonetheless, the presence of residual cardiovascular risk despite optimal medical therapy remains an issue and an aggressive strategy against multiple risk factors is suggested. A paradigm shift toward a new approach to DM management should be made with no further delay with the use of medications that may prevent CV events in an integrated strategy of CV risk reduction.


Insight on a new indolinone derivative as an orally bioavailable lead compound against renal cell carcinoma.
A series of novel 3-indolinone-thiazolidinones and oxazolidinones 4a-k was synthesized via molecular hybridization approach and sequentially evaluated to explore its cytotoxic activity. The cytotoxicity screening pointed toward the N-cyclohexyl thiazolidinone derivative 4f that revealed promising renal cytotoxicity against CAKI-1 and UO-31 renal cancer cell lines with IC50 values 4.74 and 3.99 µM, respectively, which were comparable to those of sunitinib along with good safety threshold against normal renal cells. Further emphasis on compound 4f renal cytotoxicity was achieved via different enzyme assays and CAKI-1 and UO-31 cell cycle analysis. The results were supported by in silico studies to explore its physicochemical, pharmacokinetic and drug-likeness properties. Finally, compound 4f was subjected to an in vivo pharmacokinetic study through two different routes of administration showing excellent oral bioavailability. This research represents compound 4f as a promising candidate against renal cell carcinoma.