[Kinetic resonance in open biochemical reactions with genetic induction of enzyme biosynthesis].
It has been shown that the genetic induction of enzyme synthesis by the substrate, like the kinetic induction, may bring about resonance responses in an open biochemical reaction at periodic external disturbances. Joint action of genetic and kinetic inductions broadens the range of the system parameters, where the resonance phenomena are possible. Under the joint action of genetic and kinetic inductions the resonance frequency may be independent of the amplitude of external periodic disturbance.


Difficult action decisions reduce the sense of agency: A study using the Eriksen flanker task.
The sense of agency refers to the feeling that we are in control of our actions and, through them, of events in the outside world. Much research has focused on the importance of retrospectively matching predicted and actual action outcomes for a strong sense of agency. Yet, recent studies have revealed that a metacognitive signal about the fluency of action selection can prospectively inform our sense of agency. Fluent, or easy, action selection leads to a stronger sense of agency over action outcomes than dysfluent, or difficult, selection. Since these studies used subliminal priming to manipulate action selection, it remained unclear whether supraliminal stimuli affecting action selection would have similar effects. We used supraliminal flankers to manipulate action selection in response to a central target. Experiment 1 revealed that conflict in action selection, induced by incongruent flankers and targets, led to reduced agency ratings over an outcome that followed the participant's response, relative to neutral and congruent flanking conditions. Experiment 2 replicated this result, and extended it to free choice between alternative actions. Finally, Experiment 3 varied the stimulus onset asynchrony (SOA) between flankers and target. Action selection performance varied with SOA. Agency ratings were always lower in incongruent than congruent trials, and this effect did not vary across SOAs. Sense of agency is influenced by a signal that tracks conflict in action selection, regardless of the visibility of stimuli inducing conflict, and even when the timing of the stimuli means that the conflict may not affect performance.


Advanced glycation end-products and the progress of diabetic vascular complications.
Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of vascular complications, both in Type 1 and 2 diabetes mellitus. The formation of advanced glycation end-products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications including nephropathy, retinopathy, neuropathy and atherosclerosis. Recent studies have shown that increased formation of serum AGEs exists in diabetic children and adolescents with or without vascular complications. Furthermore, the presence of diabetic complications in children correlates with elevated serum AGEs. The level of serum AGEs could be considered as a marker of later developments of vascular complications in children with Type 1 and 2 diabetes mellitus. The careful metabolic monitoring of young diabetics together with monitoring of serum AGEs can provide useful information about impending AGE-related diabetic complications. It is becoming clear that anti-AGE strategies may play an important role in the treatment of young and older diabetic patients. Several potential drug candidates such as AGE inhibitors have been reported recently.


The proton-translocating a subunit of F0F1-ATP synthase is allocated asymmetrically to the peripheral stalk.
The position of the a subunit of the membrane-integral F0 sector of Escherichia coli ATP synthase was investigated by single molecule fluorescence resonance energy transfer studies utilizing a fusion of enhanced green fluorescent protein to the C terminus of the a subunit and fluorescent labels attached to specific positions of the epsilon or gamma subunits. Three fluorescence resonance energy transfer levels were observed during rotation driven by ATP hydrolysis corresponding to the three resting positions of the rotor subunits, gamma or epsilon, relative to the a subunit of the stator. Comparison of these positions of the rotor sites with those previously determined relative to the b subunit dimer indicates the position of a as adjacent to the b dimer on its counterclockwise side when the enzyme is viewed from the cytoplasm. This relationship provides stability to the membrane interface between a and b2, allowing it to withstand the torque imparted by the rotor during ATP synthesis as well as ATP hydrolysis.


The Role of Palliative Care in Heart Failure, Part 1: Referring Provider Perspectives About Opportunities in Advanced Cardiac Therapies.
Background: There are many ways that palliative care can support patients with heart failure, but the role of palliative care in supporting patients who are considering or are already using advanced cardiac therapies is less clear. Objective: To understand referring providers' perspectives about the role of palliative care in the treatment of patients with heart failure considering or using advanced cardiac therapies. Design: Qualitative study using a semistructured interview guide. Setting/Subjects: This study was conducted at an academic medical center in the United States with an integrated cardiac palliative care program. Interviews were conducted with cardiology providers, including cardiologists, cardiac surgeons, and nurse practitioners who care for patients with heart failure and who are considering or receiving advanced cardiac therapies. Measurements: Interview transcripts were analyzed deductively and inductively to reveal themes in providers' perspectives. Results: Five themes were identified about the role of palliative care when advanced therapies were considered or being used: (1) educating patients; (2) supporting goal-concordant care; (3) managing symptoms; (4) addressing psychosocial needs; and (5) managing end-of-life care. Providers suggested palliative care could be a facilitator of advanced therapies, rather than merely something to add to end-of-life care. Conclusions: Cardiology providers recognize the value of integrating palliative care across the heart failure disease trajectory to provide therapy options, support decision-making processes, and provide goal-concordant care for patients considering or receiving advanced therapies. Increasing awareness of opportunities to integrate palliative care throughout the treatment of these patients may help cardiology providers better coordinate with palliative care specialists to improve patient care.


Healthier mothers and babies.
At the beginning of the 20th century, for every 1000 live births, six to nine women in the United States died of pregnancy-related complications, and approximately 100 infants died before age 1 year. From 1915 through 1997, the infant mortality rate declined >90% to 7.2 per 1000 live births, and from 1900 through 1997, the maternal mortality rate declined almost 99% to <0.1 reported death per 1000 live births (7.7 deaths per 100,000 live births in 1997). Environmental interventions, improvements in nutrition, advances in clinical medicine, improvements in access to health care, improvements in surveillance and monitoring of disease, increases in education levels, and improvements in standards of living contributed to this remarkable decline. Despite these improvements in maternal and infant mortality rates, significant disparities by race and ethnicity persist. This report summarizes trends in reducing infant and maternal mortality in the United States, factors contributing to these trends, challenges in reducing infant and maternal mortality, and provides suggestions for public health action for the 21st century.


Temperature-dependent femtosecond photoinduced desorption in CO/Pd(111).
The desorption of CO from a Pd(111) surface following absorption of 120 fs pulses of 780 nm light occurs on two distinct and well-separated time scales. Two-pulse correlation measurements show a fast subpicosecond decay followed by a slower, approximately 40 ps decay. Simulations based on the two-temperature model of electron and phonon heat baths within the substrate, and an empirical friction model to treat coupling to the adsorbate, support the assignment of the desorption mechanism as an electron-mediated process. The photodesorption yield and overall width of the temporal response exhibit a marked dependence on the initial surface temperature in the 100-375 K range despite the much higher transient electronic temperatures (approximately 7000 K) achieved. The observed temperature dependences can be attributed directly to variations in the initial temperature within the frictional coupling picture. Simulations of this extended data set imply that the activation barrier to photoinduced desorption is equal in magnitude to that derived from thermal desorption experiments for this system within the limits of a one-dimensional Arrhenius desorption model. The simulations also imply that the slower decay is not the result of phonon-driven desorption. Though we cannot unambiguously determine the strength of the adsorbate-phonon coupling, our results suggest that its role is to moderate the degree of the adsorbate excitation.


Regenerative Capacity of Leukocyte-rich and Platelet-rich Fibrin in Indirect Sinus Elevation Procedure May be Dependent on Model-Specific Modification of the Centrifugation Cycle.
To compare optical density (OD) and fibrinogen content of leukocyte-rich and platelet-rich fibrin (L-PRF) generated by standard protocol (2700 rotations per minute [RPM] for 12 min) versus relative centrifugal force (RCF)-adjusted protocol across two widely used laboratory centrifuges with swing-out rotors. Centrifuges for PRF production generate forces in excess of 800 g. The study aimed to evaluate OD, fibrinogen content and effectiveness in bone-added osteotome sinus floor elevation (BAOSFE) of leukocyte-rich and platelet-rich fibrin (L-PRF) generated by the standard protocol (2700 RPM for 12 min) versus a RCF-adjusted protocol to generate precisely 400 g of force across two centrifuges with swing-out rotors. The outcomes were compared to a standard centrifuge configured to generate L-PRF as per the original Choukroun guidelines. Sample size for the present study was calculated using proportional power calculation. A minimum sample size of 8 per group was needed to detect a bone height difference of 2 mm when the power of the test is 0.80 at a significance level of 0.05. Based on the centrifuge and protocol used to generate L-PRF, 10 participants were assigned to each of the following groups are as follows: D group, fixed angle centrifuge (DUO Quattro®) at default setting. R-O group: Swing-out centrifuge (Remi 8C®) + standard protocol. R-A group: Remi 8C® centrifuge + RCF-adjusted protocol. C-O group: Swing-out centrifuge (Remi C854®) + standard protocol. and C-A group: Remi C854® + RCF-adjusted protocol. OD, fibrinogen content, and gain in bone fill and bone height after BAOSFE were the evaluated outcomes. Data were analyzed using GraphPad Prism® Software version 6.0 (GraphPad Software Inc., La Jolla, USA) and SAS Software® version 9.3 versions (SAS, New Delhi, India). Data were summarized by mean ± standard deviation for continuous data and median ± inter-quartile range for the score data. The comparison between different time points was done by analysis of one-way repeated measures test, followed by post hoc test for score data. The comparison between two groups for repeated data was made by analysis of two-way repeated measures test and followed by post hoc test. Spearman's Rho correlation test was used to test the correlation between prognosis and the other variables. L-PRF from the Remi C854® centrifuge with RCF-adjusted protocol showed OD (P = 0.152) and fibrinogen content (P = 0.232) identical to those from the DUO Quattro® centrifuge. L-PRF from Remi 8C® centrifuge with the RCF-adjusted protocol resulted in maximum postoperative bone height gain (7.01 ± 1.44 mm) and bone fill (13.50 ± 4.51 mm2) which was higher than that of the outcomes from the DUO Quattro® centrifuge (6.82 ± 2.92 mm and 12.32 ± 5.31 mm2). A reduction in RCF resulted in a less dense clot and had a positive influence on the regenerative potential of L-PRF in BAOSFE procedure.


Mutation of the GKS motif of the RNA-dependent RNA polymerase from potato virus X disables or eliminates virus replication.
The RNA-dependent RNA polymerase (RdRp) of potato virus X (PVX) contains a glycine-lysine-serine (GKS) motif. This motif is present in the replication enzyme of many RNA viruses and is thought to be required for nucleoside triphosphate-binding. Three single amino acid changes, glycine to alanine (AKS), lysine to asparagine (GNS) and lysine to glutamate (GES) within the GKS motif of the PVX RdRp were tested for their effect on PVX accumulation. The GNS and GES mutations rendered the virus unable to accumulate in either tobacco plants or protoplasts, whereas substitution of glycine with alanine had only a minor effect on accumulation of PVX. The glycine to alanine mutation reverted to wild-type after passage on Nicotiana clevelandii plants. These findings suggest that the GKS motif is required for PVX replication and that strong selection pressures are active to maintain necessary sequences of the viral RdRp.


Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation.
TBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown. We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network. 20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (D LCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma. PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.


Molecular characterization and expression of Onchocerca volvulus glutathione reductase.
Glutathione metabolism represents a potential target for anti-parasite drug design. The central role of glutathione reductase (GR) in maintenance of the thiol redox state and in anti-oxidative defence has to be evaluated in more detail in order to establish the essential function of this enzyme for the survival of the filarial parasite Onchocerca volvulus. The O. volvulus GR (OvGR) gene was cloned and sequenced. The gene is composed of 13 exons and 12 introns and spans 4065 bp. The first intron is located within the 5'-untranslated region of the gene, 16 nucleotides upstream of the translation initiation codon. Southern-blot analysis and structural characterization of the genomic sequence indicate that OvGR is encoded by a single-copy gene. Isolation of various cDNA clones revealed a polymorphism of polyadenylation initiation with no consensus polyadenylation sites in any of the cDNAs analysed. The entire cDNA is 1977 bp long and carries the nematode-specific spliced leader sequence SL1 at its 5' end, 236 nucleotides upstream of the first in-frame methionine. The cDNA codes for a polypeptide of 462 amino acids with 53.5% sequence identity with human GR (HsGR). A total of 18 out of 19 residues contributing to glutathione binding are identical in OvGR and HsGR. However, one of the arginine residues (Arg-224 in HsGR) involved in discrimination between NADPH and NADH in all known GRs is substituted by tryptophan (Trp-207 in OvGR). The coding region of OvGR was expressed in Escherichia coli as a histidine-fusion protein, and it was established that the parasite protein still favours the binding of NADPH (Km 10.9 microM) over NADH (Km 108 microM). The histidine-fusion protein has a subunit size of 54 kDa and is active as a homodimer of 110 kDa.


Predictors of mortality in chronic Chagas disease: a systematic review of observational studies.
Chagas disease is a major cause of morbidity and mortality in Latin America. Knowledge of the predictors of prognosis can help clinical decision making by identifying patients' level of risk. We reviewed the published literature on prognostic factors in patients with Chagas disease by performing a PubMed search for articles published in any language between 1985 and February 2006 and hand searches of the reference lists of retrieved articles. Studies were selected if they included patients in the chronic phase of Chagas disease, analyzed a clearly defined outcome (all-cause mortality, sudden cardiac deaths, and/or cardiovascular deaths), and used multivariable regression models of prognosis. From 606 potentially relevant studies, 12 met the inclusion criteria: 8 clinic-based studies including 3928 patients and 4 hospital-based studies including 349 patients. Impaired left ventricular function by echocardiogram or cineventriculogram was found to be the most common and consistent independent predictor of death. New York Heart Association functional class III/IV and cardiomegaly on the chest radiography also were independently associated with higher mortality. More recently, strong evidence was found that nonsustained ventricular tachycardia on 24-hour Holter monitoring indicated an adverse prognosis. The typical ECG abnormalities showed limited additional prognostic value. Other often-mentioned risk factors, advanced age and male sex, showed inconsistent results. A formal meta-analysis was not feasible because of the heterogeneity of published studies and the lack of minimal standards in reporting results. A systematic review of published studies indicates that impaired left ventricular function, New York Heart Association class III/IV, cardiomegaly, and nonsustained ventricular tachycardia indicate a poor prognosis in patients with chronic Chagas disease.


The effect of alpha-linolenic acid-rich emulsion on fatty acid metabolism and leukotriene generation of the colon in a rat model with inflammatory bowel disease.
The purpose of this study was to investigate the efficacy of alpha-linolenic acid-rich perilla oil emulsion (POE) in a rat model with trinitrobenzenesulfonic acid (TNB)-induced inflammatory bowel disease. Three different isocaloric solutions, which are glucose solution (FF), soybean oil emulsion (SOE) and POE, were infused for 14 days after instillation of TNB. After infusion, total cholesterol and phospholipid concentration in the plasma in the POE group were significantly decreased compared with the FF and SOE groups. Arachidonic acid level in the colonic phospholipids was significantly decreased and eicosapentaenoic acid level was significantly increased in the POE group compared with the FF and SOE groups. Thickness, damage score and leukotriene B4 content in the colon in the POE group were the lowest among the infusion groups. These results suggest that alpha-linolenic acid suppresses the synthesis of leukotriene B4 in the colon by changing the fatty acid composition in the colonic phospholipids and that POE may be effective in the improvement of inflammation in the colon.


Parallel inputs to memory in bee colour vision.
In the 19(th) century, it was found that attraction of bees to light was controlled by light intensity irrespective of colour, and a few critical entomologists inferred that vision of bees foraging on flowers was unlike human colour vision. Therefore, quite justly, Professor Carl von Hess concluded in his book on the Comparative Physiology of Vision (1912) that bees do not distinguish colours in the way that humans enjoy. Immediately, Karl von Frisch, an assistant in the Zoology Department of the same University of Münich, set to work to show that indeed bees have colour vision like humans, thereby initiating a new research tradition, and setting off a decade of controversy that ended only at the death of Hess in 1923. Until 1939, several researchers continued the tradition of trying to untangle the mechanism of bee vision by repeatedly testing trained bees, but made little progress, partly because von Frisch and his legacy dominated the scene. The theory of trichromatic colour vision further developed after three types of receptors sensitive to green, blue, and ultraviolet (UV), were demonstrated in 1964 in the bee. Then, until the end of the century, all data was interpreted in terms of trichromatic colour space. Anomalies were nothing new, but eventually after 1996 they led to the discovery that bees have a previously unknown type of colour vision based on a monochromatic measure and distribution of blue and measures of modulation in green and blue receptor pathways. Meanwhile, in the 20(th) century, search for a suitable rationalization, and explorations of sterile culs-de-sac had filled the literature of bee colour vision, but were based on the wrong theory.


Intrinsic differences between authentic and cryptic 5' splice sites.
Cryptic splice sites are used only when use of a natural splice site is disrupted by mutation. To determine the features that distinguish authentic from cryptic 5' splice sites (5'ss), we systematically analyzed a set of 76 cryptic 5'ss derived from 46 human genes. These cryptic 5'ss have a similar frequency distribution in exons and introns, and are usually located close to the authentic 5'ss. Statistical analysis of the strengths of the 5'ss using the Shapiro and Senapathy matrix revealed that authentic 5'ss have significantly higher score values than cryptic 5'ss, which in turn have higher values than the mutant ones. beta-Globin provides an interesting exception to this rule, so we chose it for detailed experimental analysis in vitro. We found that the sequences of the beta-globin authentic and cryptic 5'ss, but not their surrounding context, determine the correct 5'ss choice, although their respective scores do not reflect this functional difference. Our analysis provides a statistical basis to explain the competitive advantage of authentic over cryptic 5'ss in most cases, and should facilitate the development of tools to reliably predict the effect of disease-associated 5'ss-disrupting mutations at the mRNA level.


Mixing iron oxide nanoparticles with different shape and size for tunable magneto-heating performance.
Tuning the magnetic properties of nanoparticles is a strategic goal to use them in the most effective way to perform specific functions in the nanomedicine field. We report a systematic study carried out on a set of samples obtained by mixing together iron oxide nanoparticles with different shape: elongated with aspect ratio ∼5.2 and mean volume of the order of 103 nm3 (excluding the silica coating) and spherical with mean volume one order of magnitude larger. These structural features of the nanoparticles together with their aggregation state determine the magnetic anisotropy and the magnetic relaxation processes. In particular, the spherical nanoparticles turn out to be more stable against superparamagnetic relaxation. Mixing the nanoparticles in different proportions allows to modulate the magnetic response of the samples. The two populations of nanoparticles magnetically influence each other through a mean field mechanism, which depends crucially on temperature and rules the hysteretic magnetic properties and their thermal evolution. This magnetic phenomenology has a direct impact on the ability of the mixed samples to generate heat under an alternating magnetic field, a key function in view of nanomedicine applications. Under proper testing conditions, the heating efficiency of the mixed samples is larger compared to that obtained as the sum of those of the parent nanoparticles. This occurs thanks to the mean field produced by the magnetically blocked spherical nanoparticles that stabilizes the thermally fluctuating moments of the elongated ones, which therefore contribute more effectively to the heat production.


Current trends in digital camera-based bioassays for point-of-care tests.
Point-of-care and bedside tests are analytical devices suitable for a growing role in the current healthcare system and provide the opportunity to achieve an exact diagnosis by an untrained person and in various conditions and sites where it is necessary. Using a digital camera integrated into a well-accessible device like a smartphone brings a new way in which a colorimetric point-of-care diagnostic test can provide unbiased data. This review summarizes basic facts about the colorimetric point-of-care tests, principles of how to use a portable device with a camera in the assay, applications of digital cameras for the current tests, and new devices described in the recent papers. An overview of the recent literature and a discussion of recent developments and future trends are provided.


Substantial early changes in bone and calcium metabolism among adult pharmacoresistant epilepsy patients on a modified Atkins diet.
The aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone- and calcium (Ca) metabolism. Two groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25-OH vitamin D (25-OH vit D), 1,25-OH vitamin D (1,25-OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide collagen type 1 (CTX-1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle-stimulating hormone), sex hormone-binding globulin, and leptin. After 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX-1, P1NP, 1,25-OH vit D, and leptin. There was a significant increase in 25-OH vit D. These changes were most pronounced among patients <37 years old, and in those patients with the highest body mass index (≥25.8 kg/m²), whereas sex and type of antiseizure medication had no impact on the results. For the reference group, the changes were nonsignificant for all the analyses. In addition, the changes in sex hormones were nonsignificant. Twelve weeks of MAD treatment leads to significant changes in bone and Ca metabolism, with a possible negative effect on bone health as a result. A reduced level of leptin may be a triggering mechanism. The changes could be important for patients on MAD, and especially relevant for those patients who receive treatment with MAD at an early age before peak bone mass is reached.


Vortex flow during early and late left ventricular filling in normal subjects: quantitative characterization using retrospectively-gated 4D flow cardiovascular magnetic resonance and three-dimensional vortex core analysis.
LV diastolic vortex formation has been suggested to critically contribute to efficient blood pumping function, while altered vortex formation has been associated with LV pathologies. Therefore, quantitative characterization of vortex flow might provide a novel objective tool for evaluating LV function. The objectives of this study were 1) assess feasibility of vortex flow analysis during both early and late diastolic filling in vivo in normal subjects using 4D Flow cardiovascular magnetic resonance (CMR) with retrospective cardiac gating and 3D vortex core analysis 2) establish normal quantitative parameters characterizing 3D LV vortex flow during both early and late ventricular filling in normal subjects. With full ethical approval, twenty-four healthy volunteers (mean age: 20±10 years) underwent whole-heart 4D Flow CMR. The Lambda2-method was used to extract 3D LV vortex ring cores from the blood flow velocity field during early (E) and late (A) diastolic filling. The 3D location of the center of vortex ring core was characterized using cylindrical cardiac coordinates (Circumferential, Longitudinal (L), Radial (R)). Comparison between E and A filling was done with a paired T-test. The orientation of the vortex ring core was measured and the ring shape was quantified by the circularity index (CI). Finally, the Spearman's correlation between the shapes of mitral inflow pattern and formed vortex ring cores was tested. Distinct E- and A-vortex ring cores were observed with centers of A-vortex rings significantly closer to the mitral valve annulus (E-vortex L=0.19±0.04 versus A-vortex L=0.15±0.05; p=0.0001), closer to the ventricle's long-axis (E-vortex: R=0.27±0.07, A-vortex: R=0.20±0.09, p=0.048) and more elliptical in shape (E-vortex: CI=0.79±0.09, A-vortex: CI=0.57±0.06; <0.001) compared to E-vortex. The circumferential location and orientation relative to LV long-axis for both E- and A-vortex ring cores were similar. Good to strong correlation was found between vortex shape and mitral inflow shape through both the annulus (r=0.66) and leaflet tips (r=0.83). Quantitative characterization and comparison of 3D vortex rings in LV inflow during both early and late diastolic phases is feasible in normal subjects using retrospectively-gated 4D Flow CMR, with distinct differences between early and late diastolic vortex rings.


Age 85+ years accelerates large-fiber peripheral nerve dysfunction and diabetes contributes even in the oldest-old: the Women's Health and Aging Study.
Both diabetes mellitus and advancing age are associated with peripheral nerve dysfunction (PND). However, the independent and potentially synergistic effects of these factors in old age are poorly described, especially among the oldest-old and among people with an existing disability. A total of 894 women aged 65+ years participating in the Women's Health and Aging Study received a baseline home interview and clinical examination during which PND was evaluated by the Vibratron II. Age and diabetes were examined in relation to the level of PND (normal, mild, moderate, or severe). Height, alcohol consumption, smoking, report of neurologic symptoms, and diabetes duration were examined as potential confounders. Eighteen percent of the sample reported diabetes, 42% had normal nerve function, and 23.9%, 14.5%, and 19.5% had mild, moderate, and severe PND, respectively. Women aged 85+ years had 6.5, 7.5, and 13.3 times the odds of mild, moderate, and severe PND relative to women aged 65-74 years, adjusted for diabetes and height. Women who reported diabetes had 1.8, 2.4, and 1.6 times the risk of mild, moderate, and severe PND relative to those who did not, adjusted for age and height. No interaction between age and diabetes was observed. Age is strongly associated with decrements in large-fiber peripheral nerve function in disabled women aged 65+ years, with greatly accelerated risk among those aged 85+ years. Despite the overwhelmingly strong effects of advancing age on PND in this cohort, diabetes remains a significant correlate of PND. Future studies may determine whether prevention or control of diabetes is effective in reducing the occurrence of PND in old age and whether a reduction in PND will translate into reduced disability in this age group.


Attenuated Salmonella typhimurium-mediated tumour targeting imaging based on peptides.
Attenuated bacteria-mediated tumor targeting diagnosis will provide a novel strategy for further cancer treatments owing to the intrinsic facultative anaerobic characteristic of bacteria and rapid proliferation in the tumor sites. In this work, we firstly investigate the in vivo behaviour of the attenuated Salmonella typhimurium (S. typhimuriumΔppGpp/lux) after intravenous injection. S. typhimurium exhibits rapid proliferation in tumor sites after three days of injection through bioluminescence imaging, the Luria-Bertani plate and the Gram-staining assay. In contrast, S. typhimurium does not proliferate in the normal tissues and could be excreted from the body of mice. Afterwards, a targeting peptide ubiquicidin (UBI) labeled with fluorescent dye Cy5.5 or radionuclide 125I was intravenously injected into the mice with or without S. typhimurium treatments for in vivo fluorescence imaging and single-photon emission computed tomography (SPECT/CT) imaging, respectively. The results show that the peptide UBI could specifically target the two independent bacteria-infected tumor models, the 4T1 murine breast cancer model and the CT26 mouse colon cancer model, realizing the sensitive multimodal imaging of tumors. Such a strategy (bacteria-mediated tumor targeting) may further improve the sensitivity to early diagnosis of tumors. We hope that our developed strategy could further be extended to cancer theranostics in the future, bringing good news for cancer patients.


[Recent advances in prevention of sepsis in the preterm neonate].
An episode of sepsis occurs in 20 to 40% of all preterm patients, and such figures have been reported constantly increasing in Neonatal Intensive Care Units. Neonatal sepsis include bloodstream, urine, cerebrospinal, peritoneal infections, infections starting from burns and wounds, or from any other usually sterile sites. Many specific risk factors account for the increased risk of sepsis, including employment of broad-spectrum antibiotics selecting resistant microflora, parenteral nutrition, acid inhibitors and steroids, as well as the systematic and long-lasting use of invasive management. In preterm neonates, loss of gut commensals such as bifidobacteria and lactobacilli, due to the difficulties in oral feeding, or a slower acquisition of them, translates into an increased susceptibility to pathogenic gut colonization. Prompt diagnosis, effective treatment, and specific prophylaxis with antibacterial and antifungal drugs are the milestones of management of these life-threatening events. This article discusses the recent advances in prevention and shows how fluconazole for prevention of fungal sepsis, probiotics for prevention of necrotizing enterocolitis, and bovine lactoferrin for prevention of bacterial sepsis may be considered as effective preventive strategies.


Do calcium antagonists act directly on calcium channels to alter baroreceptor function?
This study examined the effects of antagonists known to act on voltage-dependent calcium channels (chiefly nitrendipine, diltiazem and verapamil) on arterial baroreceptor function. Single fiber discharge of aortic arch baroreceptor preparations of the rat was not altered at concentrations ranging from 10(-11) to 10(-6) M. Increasing pressure in an isolated perfused carotid sinus in the cat produced a reflex arterial pressure response which was not altered significantly when the carotid perfusate contained an antagonist concentration of 10(-7) to 10(-6) M. A higher concentration (10(-5) M) of all three antagonists decreased baroreceptor discharge and depressed the reflex response. In addition, nimodipine and nifedipine had uniformly similar dose-related effects. It is likely that the effects found at the elevated concentrations are nonspecific and probably are independent of voltage-dependent calcium channels. No differences between the dihydropyridine blockers and verapamil were found even at very high doses. Our results suggest that within the range of doses used clinically these antagonists do not directly affect baroreceptor function. In addition, the present results reinforce the notion that voltage-dependent calcium channels are not importantly involved in baroreceptor transduction as suggested by earlier studies of the effects of changing external calcium concentration.


Commensal microbiota induces colonic barrier structure and functions that contribute to homeostasis.
The intestinal barrier encompasses structural, permeability and immune aspects of the gut mucosa that, when disrupted, may contribute to chronic inflammation. Although gnotobiotic studies have demonstrated the effects of microbiota on mucosal and systemic immunity, as well as intestinal barrier architecture and innate immune characteristics, its impact on barrier function remains unclear. We compared germ-free and conventional mice, as well as mice colonized with human fecal microbiota that were followed for 21 days post-colonization. Colonic barrier structure was investigated by immunohistochemistry, molecular and electron microscopy techniques. Permeability was assessed in colon tissue by Ussing chambers, and by serum LPS and MDP detection using TLR4- and NOD2-NFκB reporter assays. Microbiota profile was determined by Illumina 16S rRNA gene sequencing. Low dose dextran sodium sulfate was administered to assess microbiota-induced barrier changes on resistance to colonic injury. Permeability to paracellular probes and mucus layer structure resembled that of conventional mice by day 7 post-colonization, coinciding with reduced claudin-1 expression and transient IL-18 production by intestinal epithelial cells. These post-colonization adaptations were associated with decreased systemic bacterial antigen exposure and reduced susceptibility to intestinal injury. In conclusion, commensal colonization promotes physiological barrier structural and functional adaptations that contribute to intestinal homeostasis.


Risk factors for headache, including TMD signs and symptoms, and their impact on quality of life. Results of the Study of Health in Pomerania (SHIP).
The aim of this investigation was to evaluate the role of various signs and symptoms of temporomandibular disorders (TMD), among other potential risk factors, in developing frequent headache in a population-based sample of the cross-sectional epidemiologic Study of Health in Pomerania (SHIP). The impact of headache and of myogenous and arthrogenous signs of TMD on the quality of life of this sample was evaluated. Medical history and dental and sociodemographic parameters of 4,255 subjects were checked for correlations with frequent headache using a multivariate logistic regression model. The quality of life of the headache sufferers was evaluated with a questionnaire on mental and physical health. Of the sample, 9% reported suffering from frequent headache. Significant values for the odds ratios for the whole sample were found for pain on palpation of the masticatory muscles; the anamnestic question on masticatory muscle pain; ear noises; lateral palpation pain of the temporomandibular joints (TMJ); several sleep disorders; psychosomatic complaints; and risk for women. Palpation pain of the muscles showed a dose/response effect. Subjects with a higher education level had a significantly reduced risk for developing frequent headache. Anamnestic questions for pain in the TMJ area, TMJ clicking, smoking, alcohol abuse, contraceptives, income, and chronic diseases did not correlate significantly with frequent headache. Subjects who reported frequent headache exhibited a significant reduction of physical and mental health scores. Pain upon muscle palpation showed significantly reduced scores on both scales for both genders. Within the limitations of this study, in addition to sensitive TMJs, mainly palpation-sensitive masticatory muscles showed a significant relation to the occurrence of frequent headache. Because of the number of tested covariates originally included in the model, this relation seems essential.


The Impact of Dobbs on Health Care Beyond Wanted Abortion Care.
While empirical evidence has exposed the harms and health disparities flowing from being denied a wanted abortion, we know less about how anti-abortion laws and policies impact health care more broadly. This article surveys the public health impacts of Dobbs on health care beyond wanted abortion care. The article argues that focusing the public's attention on the harmful consequences of abortion bans for healthcare beyond wanted abortion care could help to fend off further restrictions on abortion.


Coffee and nonalcoholic fatty liver disease: A review.
Nonalcoholic fatty liver disease (NAFLD) is widely prevalent globally and has no effective treatment. Coffee is one of the most popular beverages in the world and can therefore have a significant impact on public health on account of its health-promoting properties. Evidence from observational, clinical, and animal studies suggests that coffee may play an important role in human health. This article summarizes the effects of coffee on liver health, especially on nonalcoholic fatty liver disease (NAFLD) and its progression: liver fibrosis, cirrhosis and hepatocellular carcinoma. In addition, this article describes the pathogenesis, prevalence, diagnosis, and nutrition guidelines relating to NAFLD. Possible mechanisms responsible for the effects of coffee on the liver are also suggested.


Simultaneously hermaphroditic shrimp use lipophilic cuticular hydrocarbons as contact sex pheromones.
Successful mating is essentially a consequence of making the right choices at the correct time. Animals use specific strategies to gain information about a potential mate, which is then applied to decision-making processes. Amongst the many informative signals, odor cues such as sex pheromones play important ecological roles in coordinating mating behavior, enabling mate and kin recognition, qualifying mate choice, and preventing gene exchange among individuals from different populations and species. Despite overwhelming behavioral evidence, the chemical identity of most cues used in aquatic organisms remains unknown and their impact and omnipresence have not been fully recognized. In many crustaceans, including lobsters and shrimps, reproduction happens through a cascade of events ranging from initial attraction to formation of a mating pair eventually leading to mating. We examined the hypothesis that contact pheromones on the female body surface of the hermaphroditic shrimp Lysmata boggessi are of lipophilic nature, and resemble insect cuticular hydrocarbon contact cues. Via chemical analyses and behavioural assays, we show that newly molted euhermaphrodite-phase shrimp contain a bouquet of odor compounds. Of these, (Z)-9-octadecenamide is the key odor with hexadecanamide and methyl linoleate enhancing the bioactivity of the pheromone blend. Our results show that in aquatic systems lipophilic, cuticular hydrocarbon contact sex pheromones exist; this raises questions on how hydrocarbon contact signals evolved and how widespread these are in the marine environment.


Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19.
Introduction: An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin-converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow. Methods: We analysed clinical features in a cohort of 173 children with COVID-19 (0-15 yrs.-old) between January 22, 2020 and March 15, 2020. We systematically examined the expression and distribution of ACE2 in different developmental stages of children by using a combination of children's lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and ex vivo SARS-CoV-2 pseudoviral infections. Results: It revealed that infants (< 1yrs.-old), with a weaker potency of immune response, are more vulnerable to develop pneumonia whereas older children (> 1 yrs.-old) are more resistant to lung injury. The expression levels of ACE2 however do not vary by age in children's lung. ACE2 is notably expressed not only in Alveolar Type II (AT II) cells, but also in SOX9 positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants' lungs. The ACE2+SOX9+ cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children. Conclusions: Infants (< 1 yrs.-old) with SARS-CoV-2 infection are more vulnerable to lung injuries. ACE2 expression in multiple types of lung cells including SOX9 positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19. There is a need to continue monitoring lung development in young children who have recovered from SARS-CoV-2 infection.


Heritability and repeatability of milk coagulation properties predicted by mid-infrared spectroscopy during routine data recording, and their relationships with milk yield and quality traits.
The aim of this study was to estimate (co)variance components for milk coagulation properties (MCP) predicted by mid-infrared spectroscopy (MIRS) during routine milk recording, and to assess their relationships with yield and quality traits. A total of 63 470 milk samples from Holstein-Friesian cows were analyzed for MCP, pH and quality characteristics using MIRS. Casein to protein and protein to fat ratios were calculated from information obtained by MIRS. Records were collected across 1 year on 16 089 cows in 345 herds. The model used for genetic analysis included fixed effects of parity and stage of lactation, and random effects of herd-test-day, cow permanent environmental, animal additive genetic and residual. (Co)variance components were assessed in a Bayesian framework using the Gibbs Sampler. Estimates of heritabilities were consistent with those reported in the literature, being moderate for MCP (0.210 and 0.238 for rennet coagulation time (RCT) and curd firmness (a30), respectively), milk contents (0.213 to 0.333) and pH (0.262), and low for somatic cell score (0.093) and yield traits (0.098 to 0.130). Repeatabilities were 0.391 and 0.434 for RCT and a30, respectively, and genetic correlations were generally low, with estimates greater than 0.30 (in absolute value) only for a30 with fat, protein and casein contents. Overall, results suggest that genetic evaluation for MCP predicted by MIRS is feasible at population level, and several repeated measures per cow during a lactation are required to estimate reliable breeding values for coagulation traits.


LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.
LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.


Evaluation of toxicity and antitumor activity of cycloviolacin O2 in mice.
Cycloviolacin O2 is a small cyclic cysteine-rich protein belonging to the group of plant proteins called cyclotides. This cyclotide has been previously shown to exert cytotoxic activity against a variety of human tumor cell lines as well as primary cultures of human tumor cells in vitro. This study is the first evaluation of its tolerability and antitumor activity in vivo. Maximal-tolerated doses were estimated to 1.5 mg/kg for single intravenous (i.v.) dosing and 0.5 mg/kg for daily repeated dosing, respectively. Two different in vivo methods were used: the hollow fiber method with single dosing (i.v., 1.0 mg/kg) and traditional xenografts with repeated dosing over 2 weeks (i.v., 0.5 mg/kg daily, 5 days a week). The human tumor cell lines used displayed dose-dependent in vitro sensitivity (including growth in hollow fibers to confirm passage of cycloviolacin O2 through the polyvinylidene fluoride fibers), with IC5o values in the micromolar range. Despite this sensitivity in vitro, no significant antitumor effects were detected in vivo, neither with single dosing in the hollow fiber method nor with repeated dosing in xenografts. In summary, the results indicate that antitumor effects are minor or absent at tolerable (sublethal) doses, and cycloviolacin O2 has a very abrupt in vivo toxicity profile, with lethality after single injection at 2 mg/kg, but no signs of discomfort to the animals at 1.5 mg/kg. Repeated dosing of 1 mg/kg gave a local-inflammatory reaction at the site of injection after 2-3 days; lower doses were without complications.


Immunochemical and molecular characterization of regulatory idiotopes expressed by monoclonal antibodies exhibiting or lacking beta 2-6 fructosan binding activity.
Hybridomas secreting antibodies bearing the ABPC48 (A48) regulatory idiotype (Id) were generated from BALB/c mice treated at birth or as adults with minute amounts of anti-A48-Id antibodies. The majority of these antibodies were recognized by the syngeneic monoclonal anti-A48-Id and anti-UPC-10-Id antibodies, IDA10 and 10-1, respectively. In Northern blotting experiments, most of these hybridomas were shown to use VH (heavy chain variable region) genes related to the 441-4 germline VH gene that encodes the A48 VH region. Hybridization was detected between polyadenylated H chain mRNA, isolated from the majority of the hybridomas, and the VH probe. Southern blots confirmed these results by showing a rearrangement of VH-related sequences to the JH (H chain joining segment) clusters on these same hybridomas. The antibodies from all of the hybridomas that derived from neonatal mice and half of those derived from adult mice showed specificity for fructosan determinants that, in most cases, was different from the beta 2-6 fructosan linkage specificity of A48. Surprisingly, several of the non-fructosan-binding hybridomas generated from the adult mice and the MOPC-173 myeloma demonstrated a clear specificity for the beta 1-6-D-galactan determinant. Of four galactan-binding myeloma proteins studied. XRPC 44 alone shared idiotypy with the UPC-10 myeloma. These findings suggest a possible clonal crossreactive regulation mediated by regulatory idiotopes. The crossreactive regulation concept is discussed.


Development of the STAR evaluation system for football helmets: integrating player head impact exposure and risk of concussion.
In contrast to the publicly available data on the safety of automobiles, consumers have no analytical mechanism to evaluate the protective performance of football helmets. The objective of this article is to fill this void by introducing a new equation that can be used to evaluate helmet performance by integrating player head impact exposure and risk of concussion. The Summation of Tests for the Analysis of Risk (STAR) equation relates on-field impact exposure to a series of 24 drop tests performed at four impact locations and six impact energy levels. Using 62,974 head acceleration data points collected from football players, the number of impacts experienced for one full season was translated to 24 drop test configurations. A new injury risk function was developed from 32 measured concussions and associated exposure data to assess risk of concussion for each impact. Finally, the data from all 24 drop tests is combined into one number using the STAR formula that incorporates the predicted exposure and injury risk for one player for one full season of practices and games. The new STAR evaluation equation will provide consumers with a meaningful metric to assess the relative performance of football helmets.


Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database.
Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort. We analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC. MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002-2003, to 77.3% and 28.9% in 2018-2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006). The prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.


Is syncope a risk predictor in the general population?
Syncope in the general population is a frequent event often leading to hospitalization, but it is unclear whether syncope in the general population is an independent risk marker for adverse prognosis. In this review, we investigate the current literature and evaluate the prognosis and impact of syncope on adverse outcomes including death and recurrences across different populations with focus on the general population. In wide terms, a syncopal event is related to a higher risk of subsequent falls and injury and cardiac syncope is particularly associated with increased mortality as compared to non-cardiac syncope. The overall prognosis in the general population is by large determined by the underlying presence and severity of a given cardiac disease, but a given underlying cardiac disease can very well be unknown at the time of first syncope so that syncope is the presenting symptom resulting in an independent risk increase. Moreover, syncope is a significant risk predictor of a recurrence across populations. It is important to recognize several risk factors associated with adverse outcome in order to safely navigate in a population where most patients with syncope are healthy and low-risk but where a small number of patients have life-threatening conditions. Further research in the general population should attempt to categorize which patients with syncope need immediate referral and diagnostic testing, and whether this affects the outcome.


Markov chain aggregation and its applications to combinatorial reaction networks.
We consider a continuous-time Markov chain (CTMC) whose state space is partitioned into aggregates, and each aggregate is assigned a probability measure. A sufficient condition for defining a CTMC over the aggregates is presented as a variant of weak lumpability, which also characterizes that the measure over the original process can be recovered from that of the aggregated one. We show how the applicability of de-aggregation depends on the initial distribution. The application section is devoted to illustrate how the developed theory aids in reducing CTMC models of biochemical systems particularly in connection to protein-protein interactions. We assume that the model is written by a biologist in form of site-graph-rewrite rules. Site-graph-rewrite rules compactly express that, often, only a local context of a protein (instead of a full molecular species) needs to be in a certain configuration in order to trigger a reaction event. This observation leads to suitable aggregate Markov chains with smaller state spaces, thereby providing sufficient reduction in computational complexity. This is further exemplified in two case studies: simple unbounded polymerization and early EGFR/insulin crosstalk.


Parallelized edge-based droplet generation (EDGE) devices.
We here report on three parallelized designs of the new edge-based droplet generation mechanism, which, unlike existing mechanisms, produces many equally sized droplets simultaneously at a single droplet formation unit. Operation of the scaled-out systems is straight forward; only the oil inlet pressure has to be controlled to let all the units produce oil droplets, given certain basic design constraints. For systems with a typical nozzle depth of 1.2 microm, the mean droplet diameter is 7.5 microm and the coefficient of variation is below 10%. The number of droplets that is formed per unit can easily be increased by increasing the length of the unit. The stable pressure range in which monodisperse droplets are formed can be extended by small adjustments to the design. Overall, the EDGE devices are simple in design and robust in use, making them suitable for massive outscaling.


Pananx notoginseng saponins attenuate CCL2-induced cognitive deficits in rats via anti-inflammation and anti-apoptosis effects that involve suppressing over-activation of NMDA receptors.
HIV-associated neurocognitive disorders (HAND) are characterized by synaptic damage and neuronal loss in the brain, ultimately leading to progressive decline of cognitive abilities and memory. Chemokine CC motif ligand 2 (CCL2) is elevated in cerebrospinal fluid (CSF), and has been believed to contribute to HAND. Previous studies by our research team have shown that CCL2 enhances N-Methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) and causes nerve cell damage. However, there are few drugs currently available to treat nerve damage that is caused by CCL2. Panax notoginseng saponins (PNS) are isolated from Panax notoginseng and benefit the human body in various ways, including the neuroprotective effect. However, the protective effect of PNS on CCL2-induced neurotoxicity remains unknown. In this study, we found that PNS improved CCL2-induced learning and memory impairment, and inhibited CCL2-induced cell death. These effects may be due to inhibiting over-activation of NMDA receptors by alleviating the dysfunction of glutamate metabolism. Furthermore, PNS-modulated CCL2-inducd intracellular oxidative stress was found to attenuate cell inflammation. Additionally, PNS pretreatment evidently inhibited apoptotic pathways by reducing the Bax/BCL-2 ratio and caspase-3, 8, 9 expressions. In conclusion, this study demonstrates that PNS provides substantial neuroprotection against CCL2-induced neurotoxicity, and may be a novel therapeutic agent in CCL2-induced HAND or other neurodegenerative diseases.


Fine structure of the eggs of Anopheles (Anopheles) punctimacula.
The egg of Anopheles (Anopheles) punctimacula is described from scanning electron micrographs. Eggs of An. punctimacula are boat shaped, with lateral floats extending 70% of the length of the egg. Plastronlike polyhedral chorionic cells with distinctive boundaries and round tubercles in the cell field cover the dorsal, lateral, and ventral surfaces. Narrow decks enclosing a field of irregular jagged tubercles and 2-4 lobed tubercles are present at both egg poles.


Electroconductive Hydrogel Based on Functional Poly(Ethylenedioxy Thiophene).
Poly(ethylene dioxythiophene) with functional pendant groups bearing double bonds is synthesized and employed for the fabrication of electroactive hydrogels with advantageous characteristics: covalently cross-linked porous 3D scaffolds with notable swelling ratio, appropriate mechanical properties, electroactivity in physiological conditions, and suitability for proliferation and differentiation of C2C12 cells. This is a new approach for the fabrication of conductive engineered constructs.


Giant cell lesions of the maxilla.
A case of giant cell lesion arising from the maxilla is presented. The final clinical and pathological interpretation was of a true giant cell tumor. A review of the literature reveals giant cell lesions of the maxilla to be rare, with the dominant interpretation being giant cell reparative granuloma. On rare occasions, these lesions have been reported as true giant cell tumors. The histogenesis of these lesions in unknown. They may arise from cells of undifferentiated connective tissue, bone marrow, or from abnormal hyperplasia of osteoclasts. The modality of treatment and prognosis is dependent upon the final diagnosis.


Body mass index, physical activity, and risk of multiple myeloma.
Several studies have reported a positive relation of baseline body mass index (BMI) with multiple myeloma, but data on other correlates of energy balance are limited. We undertook the present analyses to further examine the role of energy balance in multiple myeloma etiology in two large prospective cohorts with biennially updated exposure data. We followed members of the Nurses' Health Study and Health Professionals Follow-up Study cohorts from baseline until multiple myeloma diagnosis, death, or 2002. Adult height and current weight were reported at enrollment, and weight every 2 years thereafter. Physical activity was queried at baseline and updated every 2 to 4 years. We computed age-adjusted relative risks (RR) of multiple myeloma for categories of BMI and physical activity using Cox proportional hazards regression. We conducted analyses on each cohort separately and on both cohorts combined. We confirmed 215 incident cases of multiple myeloma in the combined cohort of 136,623 individuals (>2.1 million person-years at risk). BMI was positively associated with multiple myeloma in all analyses. The association was strongest in men with a BMI of >or=30 kg/m2 (versus a BMI of <22.0 kg/m2; RR, 2.4; 95% confidence interval, 1.0-6.0) and modest in overweight (BMI, 25-29.9 kg/m2) and obese (BMI, >or=30 kg/m2) women [versus BMI of <22.0 kg/m2; RR (95% confidence interval), 1.6 (1.0-2.7) and 1.2 (0.7-2.2), respectively]. Physical activity was not significantly related to multiple myeloma risk, although an inverse association was suggested in women. In conclusion, obesity seems to have an etiologic role in multiple myeloma, but the role of other correlates of energy balance remains uncertain.


Restricted oncogenicity of BCR/ABL p190 in transgenic mice.
A chimeric BCR/ABL oncogene encoding the p190 protein has been introduced into the mouse germline using microinjection of one-cell fertilized eggs. Founder and progeny transgenic animals, when becoming ill, were found to develop lymphoblastic leukemia/lymphoma which was transplantable to compatible recipients. Lymphoblasts were arrested at the pre-B stage of development. Expression of BCR/ABL was not detected in peripheral blood during the early stages of leukemia but became evident as the disease progressed. However, the transgene was expressed early in development in bone marrow and was also transcribed in nonhematopoietic tissues although this did not result in tumorigenesis. These results strongly suggest that the oncogenicity of BCR/ABL is limited to hematopoietic cells, including pre-B cells or their progenitors.


Rv1106c from Mycobacterium tuberculosis is a 3beta-hydroxysteroid dehydrogenase.
New approaches are required to combat Mycobacterium tuberculosis (Mtb), especially the multi-drug resistant and extremely drug resistant organisms (MDR-TB and XDR-TB). There are many reports that mycobacteria oxidize 3beta-hydroxysterols to 3-ketosteroids, but the enzymes responsible for this activity have not been identified in mycobacterial species. In this work, the Rv1106c gene that is annotated as a 3beta-hydroxysteroid dehydrogenase in Mtb has been cloned and heterologously expressed. The purified enzyme was kinetically characterized and found to have a pH optimum between 8.5 and 9.5. The enzyme, which is a member of the short chain dehydrogenase superfamily, uses NAD+ as a cofactor and oxidizes cholesterol, pregnenolone, and dehydroepiandrosterone to their respective 3-keto-4-ene products. The enzyme forms a ternary complex with NAD+ binding before the sterol. The enzyme shows no substrate preference for dehydroepiandrosterone versus pregnenolone with second-order rate constants (kcat/Km) of 3.2 +/- 0.4 and 3.9 +/- 0.9 microM-1 min-1, respectively, at pH 8.5, 150 mM NaCl, 30 mM MgCl2, and saturating NAD+. Trilostane is a competitive inhibitor of dehydroepiandrosterone with a Ki of 197 +/- 8 microM. The expression of the 3beta-hydroxysteroid dehydrogenase in Mtb is intracellular. Disruption of the 3beta-hydroxysteroid dehydrogenase gene in Mtb abrogates mycobacterial cholesterol oxidation activity. These data are consistent with the Rv1106c gene being the one responsible for 3beta-hydroxysterol oxidation in Mtb.


Analyzing traffic conflicts and the behavior of motorcyclists at unsignalized three-legged and four-legged intersections in Cartagena, Colombia.
The global motorcycle market has grown significantly, with over 770 million vehicles estimated to be in use worldwide. Motorcycle-related road traffic deaths in low and middle-income countries (LMICs) like Colombia are concerning, comprising 30% of all reported fatalities. Cartagena has an average of 70 motorcycle-related deaths annually between 2019 and 2022, making it a high-risk area for motorcyclists. The study aimed to identify factors associated with motorcyclist safety at unsignalized three-legged and four-legged intersections in Cartagena by observing the behavior of the motorcyclists and the analysis of the potential traffic conflicts. The observational analysis focused on the access of motorcyclists from a secondary road to a main road since it is the behavior offered by the most significant road interaction and the potential risk of traffic conflicts due to crossing. The observational process was consolidated at ten three-legged intersections and seven four-legged intersections. Thirty-six hours of videos were collected considering different time slots and weekdays randomly distributed during September 2019 and March 2020. The selection of the intersections included different vehicular flows and road safety conditions. The variables considered in the study were: interaction with other road users, motorcyclist behavior, vehicle handling, potential distractors, and safety elements. The study used the Swedish Traffic Conflict Technique to analyze conflict analysis, incorporating the Post Encroachment Time (PET) measurement. The analysis was developed with descriptive and inferential statistical techniques. The collected variables were analyzed individually (frequency analysis), and contrasts were conducted with the PET values. The study evaluated associations between motorcycles and other motorized road actors at intersections about behaviors and crossroads. In the Records, 10,281 motorcycle accesses at three and four-Legged Intersections were interactions with other road users, where 2417 and 1903 resulted in potential traffic conflicts, respectively. Average potential conflicts per hour were 115 and 127 at three and four-legged intersections. At the two intersections, the average PET values in motorcycles were between 2.09 and 2.10 s, while in the other motorized road users, it averaged around 2.67 to 2.71 s. In the road conditions, it was identified that intersections with a traffic flow of<10,000 vehicles/day and poor visibility to the left of the intersection lead to more unsafe conditions for motorcyclists. Motorcycle taxi drivers were the user group most frequently involved in traffic conflicts. Actions on the part of motorcyclists, such as risky behaviors, not using helmets, not using turn signals, and not waiting patiently for access, showed a relationship with the potential for traffic conflicts. Finally, turns to the left, particularly the indirect turn to the left on the opposite road, showed a greater risk of traffic conflicts. The study found that motorcycles exhibit more severe traffic conflicts than motorized vehicles at intersections. Infrastructure conditions significantly impact the risk of intersection conflicts. Individual behaviors such as not stopping at intersections and driving recklessly increased the risk of traffic conflicts. The study recommends improving infrastructure such as visibility and signaling and implementing separators to reduce travel speed and traffic conflicts for motorcycles.


Effect of fractionated extracts and isolated pure compounds of Spondias mombin (L. Anacardiaceae) leaves on novelty-induced rearing and grooming behaviours in mice.
This study attempted to elucidate the neurotransmitter systems involved in the neurophysiological properties of ethanolic extract, fractions and pure isolates of Spondias mombin leaves in mice (n = 6) after intraperitoneal (i.p.) route of administration.The crude ethanolic extract of Spondian mombin leaves was fractionated using the partitioning method to obtain the ethylacetate, butanolic and aqueous fractions. Open column chromatographic fractionation of the ethylacetate fraction yielded seven sub-fractions, out of which the pure coumaroyl, quercetin and gallic acid derivatives were obtained after purification on Sephadex LH 20. The ethanolic extract, butanolic fraction, ethylacetate subfractions and pure isolates of the Spondian mombin leaves were tested on novelty-induced rearing and grooming behaviours in mice with standard pharmacological tools using the open field method. The extract and its fractions decreased novelty-induced rearing in a dose-dependent manner. While the Coumaroyl derivative had no effect on novelty-induced rearing, it significantly reversed the inhibitory effect of yohimbine, propranolol and haloperidol on novelty-induced rearing. Quercetin significantly potentiated the inhibitory effect of yohimbine on novelty-induced rearing. Naloxone significantly potentiated the quercetin-induced suppression of novelty-induced rearing. Gallic acid derivative significantly potentiated the inhibitory effect of yohimbine on novelty-induced rearing. Naloxone, atropine and haloperidol pretreatments significantly potentiated gallic acid derivative-induced suppression of novelty-induced rearing.The extract and its fractions had biphasic effect on novelty-induced grooming in mice. Coumaroyl derivative significantly increased novelty-induced grooming, while quercetin and gallic acid derivative decreased novelty-induced grooming significantly. The three pure isolates significantly reversed the effects of yohimbine and atropine on the novelty-induced grooming in mice. Propranolol-induced increase in novelty-induced grooming was significantly reversed by coumaroyl and gallic acid derivatives. Pre-treatment with naloxone significantly increased the gallic acid derivative-induced suppression of novelty-induced grooming. Pre-treatment with haloperidol reversed the effect of coumaroyl derivative and potentiated the inhibitory effect of quercetin derivative and gallic acid derivative significantly. This study suggested that adrenergic and dopaminergic neuro-transmissions are strongly involved in the neural mechanisms of the effect of the three pure isolates derivative, while opioid neuro-transmission is strongly linked with the neural mechanism of behavioural effect of coumaroyl derivative.


Impact of preoperative and postoperative membranous urethral length measured by 3 Tesla magnetic resonance imaging on urinary continence recovery after robotic-assisted radical prostatectomy.
We sought to investigate the impact of preoperative and postoperative membranous urethral length (MUL) on urinary continence using 3 Tesla (3T) magnetic resonance imaging (MRI) after robotic-assisted radical prostatectomy (RARP). Between 2008 and 2013, 190 men with RARP underwent preoperative and postoperative MRI. Patients who received adjuvant radiotherapy or who were lost to followup were excluded, leaving 186 patients eligible for analysis. Preoperative MUL was estimated from the prostate apex to the penile bulb, while postoperative MUL was estimated from the bladder neck to penile bulb. Patients with no pads or protection were considered to have complete continence. Logistic regression analysis was used to identify predictors associated with urinary incontinence at six and 12 months. Age was commonly associated with urinary incontinence at six and 12 months. In addition, diabetes mellitus (DM) was another factor associated with urinary incontinence at 12 months. When adjusting these variables, preoperative MUL ≤16 mm (95% confidence interval [CI] 1.01-1.14; p=0.022), postoperative MUL ≤14 mm (95% CI 1.16-9.80; p=0.025) and percent change of MUL >18% (95% CI 1.17-7.23; p=0.021) were significantly associated with urinary incontinence at six months. However, at 12 months, preoperative MUL ≤13.5 mm (95% CI 1.85-19.21; p=0.003) and postoperative MUL ≤13 mm (95% CI 1.24-13.84; p=0.021) had impacts on urinary incontinence, but not percent change of MUL. Preoperative and postoperative MUL were significantly associated with urinary continence recovery after RARP. Therefore, efforts to preserve MUL are highly recommended during surgery for optimal continence outcomes after RARP.


Randomized controlled studies and the treatment of middle-ear effusions and tonsillar pharyngitis: how random are the studies and what are their limitations?
To determine the applicability and external validity of randomized control studies (RCTs) in the light of patient susceptibilities and vulnerabilities to the sequelae of otitis media with effusion (OME) and tonsillar pharyngitis (T&A) and the composition of their cohorts. RCTs for OME and T&A were analyzed to determine which intrinsic and extrinsic susceptibilities to the otolaryngic disease and its sequelae were included or excluded and the composition of the cohort. A Medline and a Science Direct search were performed for all RCTs concerning OME and T&A through 2007. The articles selected to be included in this study are the OME RCTs that reported language and/or hearing outcomes and the T&A RCT studies in which the outcome measure was infection, alleviation of airway obstruction, and/or quality of life. These were analyzed for their inclusion or exclusion of intrinsic and extrinsic susceptibilities to the otolaryngic disease and their sequelae and the composition of the cohort. The pertinent otolaryngologic literature was assessed to determine applicable risk factors. The analysis of the inclusion or exclusion of risk factors showed that for OME 0 percent were included and 16 percent were excluded, and there were no data for 84 percent. The T&A findings were similar in that 1 percent of risk factors were included, 8 percent excluded, and there were no data for 92 percent. Both the OME and the T&A cohorts data were similar in that approximately half of the suitable candidates completed the study; 25 percent of the OME and 13 percent of the T&A enrolled subjects were either withdrawn or placed into a different experimental group. On the average, with data available, it took 4.6 years to recruit the OME sample and 5.5 years to recruit the T&A sample. The results of RCTs for these conditions are only applicable to narrowly defined and highly circumscribed populations. They cannot be generalized to the entire patient population because of their limited external validity. Future RCT protocols should be designed to control for the intrinsic and extrinsic susceptibilities that result in a propensity to acquire the disease and/or an exacerbation of the disease's sequelae. These studies would determine the most effective strategies for preventing disorders and/or their deleterious sequelae.


Fractalkine Modulates Microglia Metabolism in Brain Ischemia.
In the CNS, the chemokine CX3CL1 (fractalkine) is expressed on neurons while its specific receptor CX3CR1 is expressed on microglia and macrophages. Microglia play an important role in health and disease through CX3CL1/CX3CR1 signaling, and in many neurodegenerative disorders, microglia dysregulation has been associated with neuro-inflammation. We have previously shown that CX3CL1 has neuroprotective effects against cerebral ischemia injury. Here, we investigated the involvement of CX3CL1 in the modulation of microglia phenotype and the underlying neuroprotective effect on ischemia injury. The expression profiles of anti- and pro-inflammatory genes showed that CX3CL1 markedly inhibited microglial activation both in vitro and in vivo after permanent middle cerebral artery occlusion (pMCAO), accompanied by an increase in the expression of anti-inflammatory genes. Moreover, CX3CL1 induces a metabolic switch in microglial cells with an increase in the expression of genes related to the oxidative pathway and a reduction in those related to the glycolytic pathway, which is the metabolic state associated to the pro-inflammatory phenotype for energy production. The data reported in this paper suggest that CX3CL1 protects against cerebral ischemia modulating the activation state of microglia and its metabolism in order to restrain inflammation and organize a neuroprotective response against the ischemic insult.


Endoscopy for treating minor post-cholecystectomy biliary fistula A review of the literature.
Laparoscopic cholecystectomy for gallstone disease is the most common surgical procedures performed in Western countries and bile leaks remain a significant cause of morbidity. A recognized treatment for minor biliary injury is internal biliary decompression by endoscopic retrograde cholangiopancreatography. The aim of this study was to assess the effectiveness of endoscopic strategy in the management of minor biliary injuries. Twenty-two patients with a bile leak following laparoscopic cholecystectomy were recorded consecutively between 2007 and 2017 and they were all treated with endoscopic approach, with ERCP in order to confirm the nature of the injury and decompress the bile duct with sphincterotomy, stent insertion, or the placement of nasobiliary drains. In 15 patients, the leak was diagnosed by persistent bile drainage, in the other 7 patients without a drain the biliary leak was suspected because of symptoms in the immediate postoperative period. Controlled biliary fistulae were established in all 22 patients (100%), without further intervention. A complete cholangiogram was obtained in all patients (100%). The most common sites of minor leak were the cystic duct stump and the Luschka duct, but in one patients the site of the leak was unclear. Early in the series, sphincterotomy alone or nasobiliary tube placement was performed. Subsequently patients underwent sphincterotomy with stent insertion, in order to promote preferential drainage of bile into the duodenum. The median time to resolution after successful ERCP was 4 days. Two patients underwent ERCP complicated by mild pancreatitis. The median hospital stay was 15 days (range, 10-31 days) post-laparoscopic cholecystectomy. ERCP was performed 4-6 weeks later to document healing of the leaking point and to remove the stent. Routine follow was at median 50 days. This review confirms that postoperative minor biliary injuries can be successful managed by endoscopic ERCP biliary decompression. Bile leak, Bile duct injury, Biliary fistula, Endoscopy, ERCP, Laparoscopic cholecystectomy.


Energy partitioning between fat and bone mass is controlled via a hypothalamic leptin/NPY relay.
Maintaining energy balance is important to ensure a healthy organism. However, energy partitioning, coordinating the distribution of sufficient energy to different organs and tissues is equally important, but the control of this process is largely unknown. In obesity, an increase in fat mass necessitates the production of additional bone mass to cope with the increase in bodyweight and processes need to be in place to communicate this new weight bearing demand. Here, we investigate the interaction between leptin and NPY, two factors critically involved in the regulation of both energy metabolism and bone mass, in this process. We assessed the co-localization of leptin receptors on NPY neurons using RNAScope followed by a systematic examination of body composition and energy metabolism profiling in male and female mice lacking leptin receptors specifically in NPY neurons (Leprlox/lox;NPYCre/+). The effect of short-term switching between chow and high-fat diet was also examined in these mice. We uncovered that leptin receptor expression is greater on a subpopulation of NPY neurons in the arcuate that do not express AgRP. We further show that Leprlox/lox;NPYCre/+ mice exhibit significantly increased adiposity while bone mass is diminished. These body composition changes occur in the absence of alterations in food intake or energy expenditure, demonstrating a prominent role for leptin signaling in NPY neurons in the control of energy partitioning. Importantly however, when fed a high-fat diet, these mice display a switch in energy partitioning whereby they exhibit a significantly enhanced ability to increase their bone mass to match the increased bodyweight caused by higher caloric intake concurrent with attenuated adiposity. Taken together, these results demonstrate that leptin signaling in NPY neurons is critical for coordinating energy partitioning between fat and bone mass especially during situations of changes in energy balance.


Low thermal fluctuations in a system heated out of equilibrium.
We study the mechanical fluctuations of a micrometer sized silicon cantilever subjected to a strong heat flow, thus having a highly nonuniform local temperature. In this nonequilibrium steady state, we show that fluctuations are equivalent to the thermal noise of a cantilever at equilibrium around room temperature, while its mean local temperature is several hundred degrees higher. Changing the mechanical dissipation by adding a coating to the cantilever, we recover the expected rise of fluctuations with the mean temperature. Our work demonstrates that inhomogeneous dissipation mechanisms can decouple the amplitude of thermal fluctuations from the average temperature. This property could be useful to understand out-of-equilibrium fluctuating systems, or to engineer low noise instruments.


A multi-criteria decision analysis assessment of waste paper management options.
The use of Multi-criteria Decision Analysis (MCDA) was investigated in an exercise using a panel of local residents and stakeholders to assess the options for managing waste paper on the Isle of Wight. Seven recycling, recovery and disposal options were considered by the panel who evaluated each option against seven environmental, financial and social criteria. The panel preferred options where the waste was managed on the island with gasification and recycling achieving the highest scores. Exporting the waste to the English mainland for incineration or landfill proved to be the least preferred options. This research has demonstrated that MCDA is an effective way of involving community groups in waste management decision making.


Evaluation of contraindicated drug-drug interaction alerts in a hospital setting.
Risks associated with contraindicated drug-drug interaction alerts (CDDIAs) should always outweigh benefits. Misclassified CDDIAs should be eliminated. To review CDDIAs and determine if they are contraindicated according to Food and Drug Administration-approved product labeling and if there are circumstances in which contraindicated interactions are acceptable. A cross-sectional observational and quality improvement study was conducted over two 1-year periods. The 20 most common CDDIAs from May 2007 to May 2008 and all CDDIAs from April 2008 to April 2009 were collected at a large teaching hospital. Horizon Meds Manager used First DataBank as the knowledge base for decision support. Interactions were deemed truly contraindicated if listed in the contraindications section of the labeling of at least one of the interacting drugs. Alerts were grouped by drug and pharmacologic class to evaluate the evidence supporting the relevance of these interactions. An expert panel determined when an alert was misclassified. A medical advisory committee determined whether a contraindicated drug-drug combination was acceptable. Twelve (60%) of the most common 20 contraindicated interaction pairs from 2007 to 2008 were inappropriately classified. Half of the alerts were not truly contraindicated. The 8 truly contraindicated drug-drug pairs were ketorolac and other nonsteroidal antiinflammatory drugs or oral solid potassium products and anticholinergics. Half of these interactions were subsequently deemed acceptable under specific circumstances. Similar results were found in the second year, with only 55.1% of all CDDIAs being truly contraindicated despite eliminating some of the alerts that were misclassified in the first year. Nearly three fourths of legitimate CDDIAs were deemed acceptable under specific circumstances. Most contraindicated drug-drug interaction alerts from a commercial knowledge base were inappropriately categorized and could be downgraded. Some contraindicated drug combinations are permissible under specific circumstances. Alerts suggesting that certain drugs should never be used together, but their use together is sometimes acceptable, contribute to alert fatigue.


Endoscopic transcranial and intracranial resection: case series and design of a perioperative management protocol.
Purely endoscopic resections of transcranial/intracranial pathology represent an exciting minimally invasive option for some patients. There is an abundance of literature on surgical techniques, though very little deals with perioperative management, which is critical for good outcomes. We present a detailed case review and a perioperative management protocol with specific reference to skull base and neuroanatomy. We performed a retrospective chart review and analysis of outcomes and complications by approach and design and prospective employment of a perioperative management protocol in a major tertiary care referral hospital. We included patients undergoing endoscopic skull base approaches by the two senior surgeons from September 2005 to April 2009, selecting of transcranial/intracranial cases for detailed review. Our main outcome measures included perioperative morbidity, mortality, and complications; degree of resection; recurrence rate; and survival. Fifteen patients met study criteria. No perioperative mortality occurred. There were two major and four minor complications. Mean follow-up was 15 months; 11/13 patients with malignancies had no evidence of disease. A perioperative management protocol was designed from these data and has resulted in decreased lumbar drainage and increased fluid/electrolyte monitoring. Endoscopic transcranial/intracranial anterior skull base surgery is both safe and effective when a complete understanding of the surgery and perioperative management is achieved.


Anti-aging effects exerted by Tetramethylpyrazine enhances self-renewal and neuronal differentiation of rat bMSCs by suppressing NF-kB signaling.
In order to improve the therapeutic effects of mesenchymal stem cell (MSC)-based therapies for a number of intractable neurological disorders, a more favorable strategy to regulate the outcome of bone marrow MSCs (bMSCs) was examined in the present study. In view of the wide range of neurotrophic and neuroprotective effects, Tetramethylpyrazine (TMP), a biologically active alkaloid isolated from the herbal medicine Ligusticum wallichii, was used. It was revealed that treatment with 30-50 mg/l TMP for 4 days significantly increased cell viability, alleviated senescence by suppressing NF-κB signaling, and promoted bMSC proliferation by regulating the cell cycle. In addition, 40-50 mg/l TMP treatment may facilitate the neuronal differentiation of bMSCs, verified in the present study by presentation of neuronal morphology and expression of neuronal markers: microtubule-associated protein 2 (MAP-2) and neuron-specific enolase (NSE). The quantitative real-time polymerase chain reaction (qRT-PCR) revealed that TMP treatment may promote the expression of neurogenin 1 (Ngn1), neuronal differentiation 1 (NeuroD) and mammalian achaete-scute homolog 1 (Mash1). In conclusion, 4 days of 40-50 mg/l TMP treatment may significantly delay bMSC senescence by suppressing NF-κB signaling, and enhancing the self-renewal ability of bMSCs, and their potential for neuronal differentiation.


Clinical comparison of ertapenem and cefepime for treatment of infections caused by AmpC beta-lactamase-producing Enterobacteriaceae.
There are no comparative data evaluating outcomes of ertapenem treatment for infections with AmpC-producing Enterobacteriaceae. This retrospective matched case-control study was conducted between 2009 and 2012. Sixteen cases treated with ertapenem were matched 1:2 with 32 control cases treated with cefepime based on age, culture source, and hospital service. There were more cefepime-resistant organisms in the ertapenem group (cefepime resistance present in 44% of patients treated with ertapenem compared with 0% of control patients, p < 0.001). Ertapenem was used empirically in 25% of patients compared with 88% who received cefepime empirically (p < 0.001). Consequently, 56% of patients on ertapenem received inappropriate initial therapy compared with 9% of patients on cefepime (p < 0.001). No differences in clinical success were identified (69% for ertapenem vs 88% for cefepime, p = 0.138). Although a trend favoring cefepime could be suspected, it should be noted that no statistically significant difference in clinical success was detected despite the presence of more resistant organisms and delays in initiation of appropriate therapy among patients receiving ertapenem.


Modeling influences of dopamine on synchronization behavior of striatum.
A network model of striatum that comprises medium spiny neurons (MSNs) and fast spiking interneurons (FSIs) is constructed following the work of Humphries et al. (2009). The dynamic behavior of striatum microcircuit is investigated using a dopamine-modulated modified Izhikevich neuron model. The influences of dopamine on the synchronization behavior of the striatal microcircuit and the dependence on receptor type are investigated with and without time delay. To investigate the role of two types of dopamine receptors, D1 and D2, on the overall activity of the striatum microcircuit, the activities of two groups are considered as disconnected and connected. When the connection exists between D1 and D2 sub-networks with zero dopamine and time delay, neuronal activity decreases because of an inhibitory effect of the connected neurons of the other sub-network. In the presence of dopamine, an increase in the activity of D1 type MSNs and quiescent behavior of D2 type MSNs are observed when the time delay is zero. However, the diversity in synchronization of D1 and D2 type MSNs is observed for different synaptic time delays and synaptic strengths in the case that dopamine is present.


Clinico-Surgical Outcomes of Giant Intracranial Epidermoids: Gross Total Resection vs Subtotal Resection Which is Better?
To analyze the clinical and surgical outcomes following gross total resection (GTR) and planned subtotal resection (STR) of giant intracranial epidermoid tumors. In this retrospective cohort study, all patients who were diagnosed with and operated for giant intracranial epidermoid tumors between January 2007 and May 2016 were included. The demographics, clinical outcomes, and surgical outcomes of these patients were analyzed. Forty-eight patients were enrolled in this study, and multicompartmental epidermoid tumors were observed in 23% of the patients. The mean size of the tumors was 6.2 cm (range, 4.0?9.0 cm). GTR and near-total resection (NTR) were performed in 34 (71%) patients. Fourteen patients (29%) underwent STR. Most patients (89%) had Glasgow Outcome Scale (GOS) of 5, whereas 8% had GOS of 4. The GTR/NTR group (23.5%) had more permanent complications than the STR group (7.1%). The mean follow-up period was 5.2 years (range, eight months to nine years). In the STR group, four patients (29%) showed an increase in the residual tumor, and only one patient (7%) was symptomatic and required reoperation. STR of giant intracranial epidermoid tumors is a safe surgical strategy with good surgical outcome. The requirement for reoperation is usually late and seldom required but can be done safely. The average time to recurrence was more than seven years.


The Antimicrobial Activity of Essential Oil from Perovskia abrotanoides Karel and its Main Components.
In Iranian folk medicine, Perovskia abrotanoides is used for treatment of leishmaniasis. These patients may develop secondary infections with opportunistic microorganisms. Therefore, the antimicrobial activity of essential oil from aerial part of P. abrotanoides and its main components was evaluated against different microorganisms. Disc diffusion and broth micro dilution assays were used for in vitro antimicrobial screening. The antibacterial activity of this oil and main components on viability of S. aureus was determined. The oil showed antimicrobial activity against Candida albicans and Gram positive bacteria especially Staphylococcus aureus with zone inhibitions and minimal inhibitory concentration values in the range of 7.6 to 29 mm and 2 to 8 mul/ml respectively, whereas the least susceptible were Aspergillus niger and Gram negative bacteria. In viability test, the results showed that the antimicrobial activity of 1,8-cineole was more than that of alpha-pinene and camphor but after 60 min this effect gradually decreased only for 1,8-cineole and ultimately the antibacterial activity of camphor was more than that of alpha-pinene. 1,8-cineole had weak antimicrobial activity against all of the tested microorganisms. Hence the use of P. abrotanoides oil could be useful in fighting secondary infections in leishmaniasis especially against S. aureus.


Exo- and endoglycosidases revisited.
Many glycosidases, which work as useful reagents for the studies of structures and functions of free and conjugated oligosaccharides, have been found and thoroughly purified. These enzymes are classified into exo- and endoglycosidases by their glycon specificities. Their usefulness and limits as reagents are explained in detail in this review.Endoglycosidases, which were originally found in the culture fluid of bacteria and in the extracts of plants, are now widely found in the mammals including humans. The physiological roles of these enzymes are discussed in relation to the oligosaccharides accumulated in the urine of patients with exoglycosidase deficiencies. Furthermore, PNGase is found to play important roles in the ER-associated degradation pathway of glycoproteins.Recent studies of the glycosidases in Bifidobacteria have revealed that GNB/LNB pathway, which uniquely exist in this bacteria, works for the expression of Bifidus factor activity of human milk oligosaccharides, an important topic in the baby nutrition. This interesting field will be introduced in detail in one section of this article