Influence of spawn rate and commercial delayed release nutrient levels on Pleurotus cornucopiae (oyster mushroom) yield, size, and time to production.
Pleurotus cornucopiae 608 was grown on a mixture of pasteurized cottonseed hulls (75% dry wt). 24% chopped wheat straw, and 1% ground limestone. The substrate was spawned at various levels (1.25%, 2.5%, 3.75%, or 5% wet wt) and not supplemented or supplemented with commercial delayed release nutrient (Campbell's S-41) at various levels (0%, 3%, 6%, 9%, or 12%). Maximum yield (weight of fresh mushrooms harvested at maturity) was obtained at 3.75-5% spawn level and 6% S-41 supplement. As supplement levels exceeded 6%, yields declined significantly. There was a negative correlation (r=-0.81) between spawn rate and days to production. As the spawn rate increased, the number of days to production decreased. By using a spawn rate of 3.75% of the wet substrate wt, it was possible to reduce the time to production by a mean of 9.2 days compared with a spawn rate of 1.25%.


Neurotrophin-4/5 promotes dendritic outgrowth and calcium currents in cultured mesencephalic dopamine neurons.
Ca(2+) currents and their modulation by neurotrophin-4/5 were studied in cultured mesencephalic neurons. Tyrosine hydroxylase-positive neurons consistently had larger somas than tyrosine hydroxylase-negative neurons. Neurons with larger somas were therefore targeted for recording. In both control and neurotrophin-4/5-treated cultured neurons, isolation of Ca(2+) currents in cultured mesencephalic neurons revealed prominent low- and high-voltage-activated currents. These currents were separable based upon their voltage dependence of activation, the response to replacement of Ca(2+) with Ba(2+) and the response to Ca(2+) channel blockers. Replacement of Ca(2+) with Ba(2+) resulted in a slight reduction of low-voltage-activated currents and a significant enhancement of high-voltage-activated currents. Cd(2+) blocked a larger fraction of the high-voltage-activated current than Ni(2+). The synthetic conotoxins SNX-124 and SNX-230 selectively blocked high-voltage-activated currents. Morphological analysis of mesencephalic cultures pretreated with neurotrophin-4/5 revealed an increase in soma size and dendritic length in tyrosine hydroxylase-positive neurons. In agreement with the neurotrophin-4/5 induction of growth, neurotrophin-4/5 also increased cell capacitance in whole-cell recordings. Neurotrophin-4/5 significantly enhanced both low- and high-voltage-activated currents, but normalization for changes in capacitance revealed only a significant increase in high-voltage-activated current density. This study demonstrates the existence of low-voltage-activated and multiple classes of high-voltage-activated calcium currents in cultured mesencephalic neurons. Morphological and physiological data demonstrate that the increases in calcium currents due to neurotrophin-4/5 pretreatment are associated with somatodendritic growth, but an increase in high-voltage-activated Ca(2+) channel expression also occurred.


Neuronal activity controls transsynaptic geometry.
The neuronal synapse is comprised of several distinct zones, including presynaptic vesicle zone (SVZ), active zone (AZ) and postsynaptic density (PSD). While correct relative positioning of these zones is believed to be essential for synaptic function, the mechanisms controlling their mutual localization remain unexplored. Here, we employ high-throughput quantitative confocal imaging, super-resolution and electron microscopy to visualize organization of synaptic subdomains in hippocampal neurons. Silencing of neuronal activity leads to reversible reorganization of the synaptic geometry, resulting in a increased overlap between immunostained AZ and PSD markers; in contrast, the SVZ-AZ spatial coupling is decreased. Bayesian blinking and bleaching (3B) reconstruction reveals that the distance between the AZ-PSD distance is decreased by 30 nm, while electron microscopy shows that the width of the synaptic cleft is decreased by 1.1 nm. Our findings show that multiple aspects of synaptic geometry are dynamically controlled by neuronal activity and suggest mutual repositioning of synaptic components as a potential novel mechanism contributing to the homeostatic forms of synaptic plasticity.


Increased Wnt levels in the neural tube impair the function of adherens junctions during neurulation.
Wnt7a has been reported to signal via the canonical pathway, but also in non-canonical pathways acting on the cytoskeleton. Since Wnt7a is expressed after neurulation, we set to investigate the effects of Wnt7a on brain regionalization. We engineered transgenic mouse embryos that, under control of the nestin second intron, overexpressed Wnt7a in neural stem/progenitor cells. Surprisingly, transgenic embryos failed to complete cranial neurulation due to reduced levels and an impaired distribution of actin microfilaments, beta-catenin, and N-cadherin at the neural tube adherens junctions. These transgenic embryos expressed high levels of Vangl2, an essential component of non-canonical Wnt signaling. In agreement with a disregulation of this pathway, aberrant spinal neurulation was detected in the transgenic embryos, revealing a novel function regulated by Wnts. Thus, our findings suggest that Wnt7a overexpression disrupts normal Wnt signaling in the neural tube, resulting in defective adherens junctions and neurulation.


Effects of occupational exposure and smoking on respiratory symptomatology and PFT in healthy panelists and COPD patients.
A panel of 377 healthy adults and 920 COPD patients aged 30-65 years, is annually interviewed (ATS-NHLI health questionnaire) and performs pulmonary function test (PFT), which includes: FVC, FEV1, FEV1/FVC, PEF, FEF50 and FEF75. Baseline data analysis showed a more significant excess in respiratory symptoms (8.8% to 21.4%) and lower PFT (2.4% to 8.0%) among patients occupationally exposed to dust, than among healthy exposed panelists (-0.7% to 7.7% excess symptomatology and -0.3 to 5.8% lower PFT). Among patients a significant correlation between PFT and degree of occupational dust exposure was found. Significantly lower FEV1/FVC and excess in respiratory symptoms (with relative risks of 2.47-16.38) was present in healthy smokers vs. non smokers as compared with COPD patients.


The impact of the aortic valve impairment on the distant coronary arteries hemodynamics: a fluid-structure interaction study.
Atherosclerosis is still the leading cause of death in the developed world. Although its initiation and progression is a complex multifactorial process, it is well known that blood flow-induced wall shear stress (WSS) is an important factor involved in early atherosclerotic plaque initiation. In recent clinical studies, it was established that the regional pathologies of the aortic valve can be involved in the formation of atherosclerotic plaques. However, the impact of hemodynamic effects is not yet fully elucidated for disease initiation and progression. In this study, our developed 3D global fluid-structure interaction model of the aortic root incorporating coronary arteries is used to investigate the possible interaction between coronary arteries and aortic valve pathologies. The coronary hemodynamics was examined and quantified for different degrees of aortic stenosis varying from nonexistent to severe. For the simulated healthy model, the calculated WSS varied between 0.41 and 1.34 Pa which is in the atheroprotective range. However, for moderate and severe aortic stenoses, wide regions of the coronary structures, especially the proximal sections around the first bifurcation, were exposed to lower values of WSS and therefore they were prone to atherosclerosis even in the case of healthy coronary arteries.


Beyond patient-sharing: Comparing physician- and patient-induced networks.
The sharing of patients reflects collaborative relationships between various healthcare providers. Patient-sharing in the outpatient sector is influenced by both physicians' activities and patients' preferences. Consequently, a patient-sharing network arises from two distinct mechanisms: the initiative of the physicians on the one hand, and that of the patients on the other. We draw upon medical claims data to study the structure of one patient-sharing network by differentiating between these two mechanisms. Owing to the institutional requirements of certain healthcare systems rather following the Bismarck model, we explore different triadic patterns between general practitioners and medical specialists by applying exponential random graph models. Our findings imply deviation from institutional expectations and reveal structural realities visible in both networks.


Lipid and lipoprotein tracking in children.
Prospective studies in adults reveal that CHD risk is continuously related to total and LDL cholesterol levels (positively) and to HDL cholesterol levels (inversely) throughout their entire distribution. Such findings raise the possibility that children who tend to track in the lowest and highest decile for total and LDL cholesterol may mature to become adults respectively at reduced and increased CHD risk. Children who tend to track in the lowest and highest deciles for HDL cholesterol may also mature to become adults respectively at increased and reduced CHD risk. Although the degree of tracking at either extreme of the distribution, and for the group as a whole, appears to have adquate cohesiveness to be useful for prediction of future lipid and lipoprotein levels, individual children at the extremes of the distributions will need to be followed over longer periods of time, to identify the continuity of childhood and adult values, and eventual CHD risk.


Second peak in the distribution of age at onset of ulcerative colitis in relation to smoking cessation.
The prevalence of ulcerative colitis (UC) is increasing steadily in Japan. In Western countries, a bimodal distribution, with UC onset peaks in youth and middle age, is observed, and smoking cessation is reported as a risk factor for UC. However, there are few reports on a bimodal distribution of onset age among Japanese patients. Therefore, the distribution of onset age and factors related to late onset (i.e. onset at 50 years old or later) were investigated in UC patients in Japan. A questionnaire survey of UC patients was conducted to investigate the distribution of the age of onset and factors that may be related to UC onset in a Japanese university hospital. Among 465 UC patients, 343 patients responded. In the distribution of onset age, a large peak was seen in patients aged 10-20s, and small peaks were seen at age 40-44 years and then in 50-60s. In addition, the onset age was older in the UC patients diagnosed in 2001 or later than in those diagnosed in 2000 or earlier. Late onset was more common among the UC patients diagnosed in 2001 or later (vs 2000 or earlier: interaction odds ratio = 4.98, 95% CI: 2.21-11.25, P < 0.01) and among former smokers (vs never-smokers: interaction odds ratio = 2.93, 95% CI: 1.40-6.14, P < 0.01) on multivariate analysis. Similar to UC patients in Western countries, a bimodal distribution of onset age was also observed in Japanese UC patients, and smoking cessation may partly contribute to the increase in late-onset UC patients in recent years in Japan.


Inhibition of JAK-STAT and NF-κB signalling systems could be a novel therapeutic target against insulin resistance and type 2 diabetes.
Chronic inflammation is associated with the production of high levels of proinflammatory cytokines via the JAK-STAT and NF-κB signalling pathways which are known to be inhibited by tofacitinib and aspirin respectively. High levels of these cytokines increase the synthesis of suppressors of cytokines (SOCS), which at high levels inhibit insulin signalling leading to insulin resistance. The effects of tofacitinib and aspirin on the degree of insulin resistance in type 2 diabetic rats were determined. Rats were induced with type 2 diabetes (T2D) by administration of 10% fructose solution (ad libitum) followed by streptozotocin injection (40 mg/kg BW) and treated with different doses of tofacitinib (10 and 20 mg/kg BW), aspirin (100 and 200 mg/kg BW) and combination of the two drugs at both doses for 9 weeks. Results showed that separate treatment with 10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin significantly (P < 0.05) decreased tumour necrosis factor-α (TNF-α), interleukin 6 (IL-6) and serum amyloid A when compared to diabetic untreated rats. However, the combined therapy (10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin) significantly decreased the levels of TNF-α, IL-6, serum amyloid A, HOMA-IR, blood glucose level and SOC-3 gene expression but significantly (P < 0.05) improved glucose homoestasis, insulin secretion, HOMA-β and GLUT-4 gene expression when compared to diabetic untreated rat. It was concluded that simultaneous inhibition of the JAK-STAT and NF-κB signalling pathways with tofacitinib and aspirin respectively, could mitigate insulin resistance and hyperglycemia in T2D.


Antinuclear antibodies testing as a routine screening for systemic lupus erythematosus in patients presenting first-episode psychosis.
This report discusses the use of antinuclear antibody (ANA) detection as a screening test for neuropsychiatry systemic lupus erythematosus (NPSLE) in patients presenting a first-episode psychosis. We reviewed the medical records of 85 patients admitted to an emergency service due to first-episode psychosis, during a 1-year period, for whom ANA detection was performed through an IFI HEp2 cell assay. ANA-positive patients were subsequently evaluated for autoantibodies and neuroimaging exams. Three patients presented as ANA positive in the initial screening and further investigation confirmed NPSLE in two patients. The patients were treated with antipsychotics and cyclophosphamide pulses with satisfactory outcomes. Even though ANA detection is not specific, it is a low-cost procedure and could be an important screening test for NPSLE in the early-onset psychosis.


Resampling programs for multiway contingency tables with fixed marginal frequency totals.
A resampling algorithm is presented for analyzing multiway contingency tables with fixed marginal frequency totals. Applications are illustrated with extensions of Fisher's exact, Pearson's chi-squared, and likelihood-ratio tests to three-way contingency tables.


Neuron activity in the anterolateral motor cortex in operant food-acquiring and alcohol-acquiring behavior.
The interactions of the neuronal mechanisms of food-acquiring behavior and newly formed operant alcohol-acquiring behavior were studied by recording the activity of individual neurons in the anterolateral area of the motor cortex in chronically alcoholized rabbits. Adult animals learned food-acquiring behavior in a cage with two feeders and two pedals, in the comers (the food in the feeders was presented after pressing the corresponding pedal). After nine months of chronic alcoholization, the same rabbits learned an alcohol-acquiring behavior in the same experimental cage (gelatin capsules filled with 15% ethanol solution were placed in the feeders instead of food). Analysis of neuron activity showed that the set of neurons involved in supporting food-acquiring and alcohol-acquiring behaviors overlapped, though not completely. These experiments not only help us understand the neuronal mechanisms of the newly formed and the previously formed behaviors, but also facilitate the development of concepts of the similarity of the neuronal mechanisms of long-term memory and long-term modifications of the nervous system, occurring in conditions of repeated intake of addictive substances.


Effect of Combining the Ionophore Monensin with Natural Antimicrobials Supplemented in the Last Phase of Finishing of Lambs: Growth Performance, Dietary Energetics, and Carcass Characteristics.
With the aim of evaluating the effect of combining an antibiotic ionophore with plant extracts and probiotics on the productive efficiency (performance and carcass) during the last phase of lamb fattening, 24 Pelibuey × Katahdin male lambs (38.47 ± 3.92 kg, initial weight) were fed with a high-energy diet during for 56 days, and assigned, under a complete randomized block design experiment to one of the following supplement treatments: (1) 28 mg of monensin/kg diet DM supplemented alone (MON), (2) combination of MON plus 2 g/kg diet of a product contained Bacillus subtilis 2.2 × 108 CFU kg diet DM (MON + BS), (3) combination of MON + BS plus 300 mg essential oils/kg diet DM (MON + BS + EO), and (4) BS alone. At the end of the feeding trial (56-d), lambs were slaughtered and carcass variables were measured. Compared to the rest of the treatments, combining MON with BS improved dietary NE by 3.4% and the efficiency of utilization of dietary energy consumed. Inclusion of EO in the MON + BS combination resulted in a similar average daily weight gain (ADG) and feed efficiency (GF) when compared with MON + BS, but showed a lower dietary net energy (NE), hot carcass weight, and dressing percentage. Lambs receiving BS alone showed greater average ADG and dry matter intake (DMI) than lambs receiving MON + BS + EO, but similar feed GF and dietary NE. There were no treatment effects on tissue composition, whole cut, or visceral organ mass. It was concluded that combining probiotics with the ionophore monensin can improve the efficiency of dietary energy utilization in the last phase of finishing. Probiotics supplemented alone result in greater ADG without a difference in dietary energy efficiency when compared with MON alone. Inclusion of EO in the MON + BS combination did not show advantages; on the contrary, it reduced carcass weight and dressing percentage. It is necessary to further research the potential complementary effects of combining diverse sources of natural additives with synthetic antibiotics.


Tobacco intervention attitudes and practices among certified registered nurse anesthetists.
The period before surgery represents an opportunity for perioperative nurses, including certified registered nurse anesthetists (CRNAs), to address the tobacco use of their patients. To assess the current practices and attitudes of CRNAs toward tobacco interventions. A survey assessing current attitudes, practices and beliefs, and respondent demographics was mailed to 1,000 practicing CRNAs randomly selected from the membership of the American Association of Nurse Anesthetists, with one follow-up reminder. Summary statistics of survey responses were prepared. The response rate was 44% (N = 439). Almost all respondents (92%) reported routinely asking their patients if they smoke cigarettes, and the majority felt that it was their responsibility to advise their patients to quit smoking. However, most do not routinely do so. Identified barriers to intervention included a lack of time to intervene and a lack of training. Interest in learning more about tobacco interventions was high, with strong majorities willing to take an extra 5 minutes preoperatively to intervene and to refer patients to other intervention services. These results can inform efforts to promote tobacco use interventions in surgical patients by CRNAs. Increasing the frequency and effectiveness of tobacco use interventions provided by CRNAs would benefit not only immediate perioperative outcomes, but also the long-term health of surgical patients who take advantage of the surgical episode to initiate long-term tobacco abstinence.


Radiological and hormonal improvements in a 22-year-old patient with lymphocytic hypophysitis - the watchful waiting approach.
Not required for Clinical Vignette.


The effect of cross-spectrum correlation on the detectability of a noise band.
An experiment was performed to study the interaction of two narrow-band noises having correlated temporal envelopes. The detection threshold of a 100-Hz-wide noise-band signal was measured at different center frequencies in the presence of a continuous 100-Hz-wide noise band having a center frequency of 1000 Hz. The two noise bands had either correlated or independent temporal envelopes. Measured signal detection thresholds are lower when the two noise bands are independent, but the magnitude of this difference is not a simple function of the frequency separation between the two noise bands.


Expression of anti-inflammatory macrophage genes within skeletal muscle correlates with insulin sensitivity in human obesity and type 2 diabetes.
Low-grade systemic inflammation and adipose tissue inflammatory macrophages are frequently detected in patients with obesity and type 2 diabetes. Whether inflammatory macrophages also increase in skeletal muscle of individuals with metabolic disorders remains controversial. Here, we assess whether macrophage polarisation markers in skeletal muscle of humans correlate with insulin sensitivity in obesity and type 2 diabetes. Skeletal muscle biopsies were obtained from individuals of normal weight and with normal glucose tolerance (NGT), and overweight/obese individuals with or without type 2 diabetes. Insulin sensitivity was determined by euglycaemic-hyperinsulinaemic clamps. Expression of macrophage genes was analysed by quantitative RT-PCR. Gene expression of the inflammatory macrophage phenotype marker cluster of differentiation (CD)11c was higher in muscle of type 2 diabetes patients (p = 0.0069), and correlated with HbA1c (p = 0.0139, ρ = 0.48) and fasting plasma glucose (p = 0.0284, ρ = 0.43), but not after correction for age. Expression of TGFB1, encoding the anti-inflammatory marker TGF-β1, correlated inversely with HbA1c (p = 0.0095, ρ = -0.50; p = 0.0484, ρ = -0.50) and fasting plasma glucose (p = 0.0471, ρ = -0.39; p = 0.0374, ρ = -0.52) in two cohorts, as did HbA1c with gene expression of macrophage galactose-binding lectin (MGL) (p = 0.0425, ρ = -0.51). TGFB1 expression was higher in NGT individuals than in individuals with type 2 diabetes (p = 0.0303), and correlated with low fasting plasma insulin (p = 0.0310, ρ = -0.42). In exercised overweight/obese individuals, expression of genes for three anti-inflammatory macrophage markers, MGL (p = 0.0031, ρ = 0.71), CD163 (p = 0.0268, ρ = 0.57) and mannose receptor (p = 0.0125, ρ = 0.63), correlated with high glucose-disposal rate. Muscle expression of macrophage genes reveals a link between inflammatory macrophage markers, age and high glycaemia, whereas anti-inflammatory markers correlate with low glycaemia and high glucose-disposal rate.


The efficacy and safety of platelet-rich plasma in the tendon-exposed wounds: a preliminary study.
Currently, among wounds with large skin tissue defects caused by various reasons, the treatment of refractory wounds is still a major clinical problem. This study is aimed to preliminarily assess the therapeutic potentials of platelet-rich plasma (PRP) in refractory wounds with exposed tendons, as well as corresponding efficacy and safety. A total of 12 patients (5 males and 7 females) with refractory wounds and exposed tendons who were admitted to our hospital from June 2018 to December 2020 were included in this study. After the preparation of PRP, the included patients underwent the PRP injection after the debridement of wounds, and the efficacy and prognosis were assessed by the same group of senior surgeons. The average age of included patients was 42.7 ± 12.9 years, and the causes of injury included traffic accidents (3 cases), contusion (2 cases), burns (2 cases), diabetes complications (4 cases), and melanoma complications (1 cases). The average healing time was 23.0 ± 5.0 days, and the mean size of the wound was 3.1 × 5.1 cm2. During the whole treatment process, Vancouver Scar Scale (VSS) decreased from 7.4 ± 1.6 before PRP treatment to 3.6 ± 0.9 after treatment (P < 0.001), Manchester Scar Scale (MSS) decreased from 12.3 ± 4.5 before PRP treatment to 5.4 ± 1.2 after treatment (P < 0.001), and no redness and swelling were observed around wounds, the size and degree of wounds gradually reduced, the coverage rate of granulation tissue was acceptable, overall quality of scar was relatively good, skin sensitivity around wounds was normal, there was no local wounds secretion, and postoperative patient's satisfaction was relatively good during follow-up. Our study has preliminarily indicated that PRP can promote the wounds healing, reduce the inflammation around wounds, and improve the granulation tissue and angiogenesis, thereby effectively polishing up the safety and efficacy.


Anatomical study of the coffee berry borer (Hypothenemus hampei) using micro-computed tomography.
Traditionally, the study of anatomy in insects has been based on dissection techniques. Micro-computed tomography (micro-CT) is an X-ray based technique that allows visualization of the internal anatomy of insects in situ and does not require dissections. We report on the use of micro-CT scans to study, in detail, the internal structures and organs of the coffee berry borer (Hypothenemus hampei), the most damaging insect pest of coffee worldwide. Detailed images and videos allowed us to make the first description of the aedeagus and the first report of differences between the sexes based on internal anatomy (flight musculature, midgut shape, hindgut convolutions, brain shape and size) and external morphology (lateral outline of the pronotum and number of abdominal tergites). This study is the first complete micro-CT reconstruction of the anatomy of an insect and is also the smallest insect to have been evaluated in this way. High quality rendered images, and additional supplementary videos and 3D models are suitable for use with mobile devices and are useful tools for future research and as teaching aids.


Soil carbon dynamics: the effects of nitrogen input, intake demand and off-take by animals.
Elucidation of the drivers of soil carbon (C) change is required to enable decisions to be made on how to achieve soil C sequestration. Interactions between different components in the ecosystem in combination with feedback mechanisms mean that identifying drivers through conventional experimental approaches or by retro-fitting models to data are unlikely to result in the insights needed for the future. This paper explains soil C dynamics by using a process-based model. Drivers considered in the model include nitrogen (N) fertiliser inputs, intake demand, and off-take of animal products. The effect of the grazing animal in uncoupling the C and N cycles is explained, plus the implications of the farming system ('drystock' versus milk). The model enables depiction of the dynamic equilibrium achieved with time when a proposed change in the drivers is sustained. The results show that soil C loss under lactating cows is a result of N, rather than C, being removed in milk. Counter-intuitively, at the same intake demand, N loss under 'milk' is less than under 'dry-stock', as is C loss in animal respiration. Possibilities for changing the longevity of C in the soil are discussed, and the compromise between food production, N loss and C sequestration is considered.


HyFlex environment: addressing students' basic psychological needs.
Active learning strategies engage students and promote student-centered learning environments. Implementing active learning in a HyFlex environment during the Fall of 2020 global pandemic was challenging. We describe the Interactive Synchronous HyFlex approach to teaching design thinking at the introductory college level and explore impacts on students' basic psychological needs, including autonomy, competence, and relatedness. Aligned with Self-Determination Theory, active learning has been shown to motivate students and increase performance and retention in science, engineering, and mathematics disciplines, among others (Freeman et al., 2014; Lo & Hew, 2019). In active environments, the predominant mode of instruction is not lecture based and it engages students through student-to-student interactions and student-to-instructor interactions. The flipped classroom is a pedagogical model in which the typical lecture and homework elements of a course are reversed. This model of instruction is ideal for our design thinking course used as a context for this study because students are challenged to learn by doing. In active learning courses, students engage in video-recorded lectures or talks, text-based materials and online quizzes, or other preparation activities before and in preparation for class (Bishop & Verleger, 2013; Lo et al., 2017; O'Flaherty & Phillips, 2015). Scheduled class meeting time is used for engagement and interaction between students informed by a social constructivist learning theory. Students challenge each other to apply what they have learned with guidance and support from the instructor.


Effects of dose de-escalation following testosterone treatment and evoked resistance exercise on body composition, metabolic profile, and neuromuscular parameters in persons with spinal cord injury.
The dose de-escalation (DD) effects of testosterone and evoked resistance training (RT) on body composition, cardiometabolic, and neuromuscular variables were investigated. Thirteen men with chronic complete spinal cord injury (SCI) were followed for additional 16 weeks after receiving either testosterone treatment only (TT) or TT+RT. During the 16-week DD period, the TT+RT group underwent a program of once weekly electrical stimulation with gradually decreasing ankle weights and testosterone patches of 2 mg day-1 (TT+RT group). The TT only group did not receive any intervention throughout the detraining period (no-TT group). Body composition was tested using anthropometrics, dual energy X-ray absorptiometry, and magnetic resonance imaging. After an overnight fast, basal metabolic rate (BMR), lipid panel, serum testosterone, inflammatory biomarkers, glucose effectiveness, and insulin sensitivity were measured. Finally, peak isometric and isokinetic torques were measured only in the TT+RT group. All measurements were conducted at the beginning and at the end of DD. Absolute thigh muscle cross-sectional areas (CSAs) demonstrated interaction effects (p < 0.05) between the TT+RT (-8.15%, -6.5%) and no-TT (2.3%, 4.4%) groups. Similarly, absolute knee extensor muscle CSA demonstrated interaction effects (p < 0.05) between the TT+RT (-11%, -7.0%) and no-TT (2.6%, 3.8%) groups. There was a trend (p = 0.07) of increasing visceral adipose tissue (VAT) CSAs in the TT+RT (18%) and in the no-TT (16% cm2 ) groups. There was an interaction (p = 0.005) between TT+RT (decreased by 3.7%) and no-TT groups (increased by 9.0%) in BMR. No interactions were evident between groups over time for biomarkers related to carbohydrate, lipid metabolism, or inflammation. Finally, there were no changes (p > 0.05) in peak isometric or isokinetic torques and rise time following 16 weeks of the DD period in the TT+RT group. TT+RT during 16 weeks of DD was minimally effective at preventing detraining relative to no-TT on muscle size, BMR, and VAT. However, neuromuscular gains were successfully maintained.


Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans.
Ten patients were studied to determine the effect of spinal cord stimulation on CBF. In 5 patients using a cervical spinal cord stimulator, the stimulation produced a significant increase in CBF in the hemisphere ipsilateral to the induced paresthesia. Thoracic cord stimulation, used by the other 5 patients, had no effect on CBF. Atropine had no effect on the alteration in CBF produced by cervical cord stimulation. Indomethacin, however, partially blocked the effect. These heuristic observations may have implications for the future treatment of cerebrovascular insufficiency in humans.


Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion.
Ischemia triggers an inflammatory response that precipitates cell death during reperfusion. Several studies have shown that tissues are protected by ischemic preconditioning (IP) consisting of 10 min of ischemia followed by 10 min of reperfusion just before ischemia. The molecular basis of this protective effect is poorly understood. We used cDNA arrays (20K) to compare global gene expression in liver biopsies from living human liver donors who underwent IP (n=7) or not (n=7) just before liver devascularization. Microarray data were analyzed using pairedt test with a type I error rate fixed at alpha = 2.5 10(6) (Bonferroni correction). We found that 60 genes were differentially expressed (36 over- and 24 underexpressed in preconditioning group). After IP, the most significantly overexpressed gene was IL-1Ra. This was confirmed by immunoblotting. Differentially expressed were genes involved in apoptosis (NOD2, ephrin-A1, and calpain) and in the carbohydrate metabolism. A significant increase in the amount of the anti-apoptotic protein Bcl-2 in preconditioned livers but no change in the cleavage of procaspase-3, -8, and -9 was observed. We also observed an increase in the amount in the inducible nitric oxide synthase. Therefore, the benefits of IP may be associated with the overproduction of IL-1Ra, Bcl-2, and NO countering the proinflammatory and proapoptotic effects generated during ischemia-reperfusion.


The evolution of extracranial approaches to the pituitary and anterior skull base.
The development of extracranial approaches to the anterior skull base has been a process in development for over a 100 years. Many neurosurgical (and non-neurosurgical) pioneers have contributed to its evolution. In this paper, we will review the major contributors and contributions to this evolving field.


Circulating interleukin 6 concentrations and insulin resistance in patients with cancer.
The mechanism of insulin resistance in patients with cancer is not clear. This study was conducted to evaluate the possible role of circulating cytokines in inducing insulin resistance in patients with cancer. Twenty-three patients with a variety of cancers were studied, including one patient with oesophageal cancer, 12 with gastric cancer, four with colon cancer and six with lung cancer. Six normal volunteers served as controls. Insulin resistance was evaluated by euglycaemic hyperinsulinaemic glucose clamp with a high physiological insulin concentration of 100 microunits/ml. Metabolized glucose, the M value, was compared between patients with cancer and controls. Serum concentrations of interleukin (IL) 6 and other cytokines (tumour necrosis factor (TNF) alpha, IL-8 and IL-10) were measured by enzyme-linked immunosorbent assay. The mean(s.d.) M value for patients with cancer (5.47(1.59) mg per kg per min) was significantly lower than that for controls (8.23(0.79) mg per kg per min) (P< 0.001). There was no relationship between the M value and degree of body-weight loss. Serum IL-6 concentration was measurable in eight of 23 patients: four with lung cancer, two with gastric cancer, and one each with oesophageal and colon cancer. None of the controls had a measurable serum IL-6 concentration. There was no significant relationship between serum IL-6 concentration and body-weight loss. TNF-alpha was undetectable in the serum of both patients with cancer and controls. Serum IL-8 and IL-10 were detected in seven and one of 23 patients respectively. These cytokines were not detected in the serum of controls. The M value was significantly smaller in those with measurable serum IL-6 (4.01(1.22) mg per kg per min) than in those with no measurable IL-6 (6.26(1.16) mg per kg per min) (P< 0.001). IL-6 and IL-8 levels were raised more frequently in the same patient but there was no significant relationship between IL-8 and M values. These results may suggest that IL-6 is related to insulin resistance in patients with cancer.


Tamoxifen or aromatase inhibitors: which one is the culprit of urinary incontinence in premenopausal breast cancer patients receiving adjuvant hormone therapy?
The primary aim of this study was to compare tamoxifen versus aromatase inhibitors (AI) in terms of urinary incontinence (UI) in premenopausal female patients receiving adjuvant hormone therapy for breast cancer. A secondary aim was to investigate the prevalence and the affecting factors of UI. This study was designed as a multicenter, cross-sectional that included consecutive premenopausal breast cancer patients ≤50 years of age receiving tamoxifen (with/without LHRHa) or AI (with LHRHa) for at least 6 months, between June 2021 and September 2022. Patients with urinary incontinence before hormone treatments and metastatic patients were excluded from the study. Turkish validation of The International Consultation on Incontinence Modular Questionnaire Urinary Incontinence Short Form (ICIQ UI-SF) was used to determine the UI. Using logistic regression methods, we analyzed potential predictive factors for UI. A total of 206 breast cancer patients were included in this study. A total of 120 (58.2%) patients were receiving tamoxifen plus LHRHa, 40 (19.4%) patients were receiving aromatase inhibitor plus LHRHa, and 46 (22.3%) patients were receiving tamoxifen only. In this study, the prevalence of urinary incontinence was found to be 35.9% (n:74). 41% of the patients receiving tamoxifen and 15.0% of those receiving aromatase inhibitors had complaints of urinary incontinence. There was a statistically significant difference between patients receiving tamoxifen or aromatase inhibitor in terms of urinary incontinence (p=0.001). In the univariate analysis established to predict UI, parity (≥2 vs <2) (OR = 3.23, 95% CI: 1.62-6.46, p= 0.001), tamoxifen (vs AI) (OR = 3.97, 95% CI: 1.58-9.98, p= 0.003), age ( ≥40 vs. <40) (OR = 2.80, 95% CI: 1.37-5.71, p= 0.005), vaginal deliveries (≥2 vs. <2) (OR = 3.28, 95% CI: 1.44-7.46, p= 0.005), hypertension (OR = 3.59, 95% CI: 1.43-9.02, p= 0.007), diuretic use (OR = 2.55, 95% CI: 1.09-5.95, p= 0.031) ), and body mass index (≥25 vs <25) (OR = 1.94, 95% CI: 1.05-3.63), p= 0.034) was found to be predictive. Tamoxifen (OR = 4.71, 95% CI: 1.77-12.56, p= 0.002), hypertension (OR = 3.48, 95% CI: 1.27-9.52, p= 0.015), and age (OR = 2.35, 95% CI: 1.10-5.02, p= 0.027) remained independent predictors for incontinence in multivariate analyses. We found that tamoxifen had increased the risk of urinary incontinence compared to aromatase inhibitors in patients receiving hormone therapy for breast cancer. In addition, we showed that age and hypertension were also independent predictors for UI. In the context of quality of life, we recommend close follow-up of these patients, as drug adherence may be affected in the event of urinary incontinence.


Nidus localization in osteod osteoma by SPECT skeletal scintigraphy: Aid to diagnosis and surgical approach.
Osteod osteoma, although not a common clinical occurrence, does pose problems both in diagnosis and surgical management. Initial plain radiographic diagnosis is sometimes fraught with the limitation of not being able to differentiate from chronic osteomyelitis and stress fracture. CT-aided localization of the nidus is also often inconclusive. Radionuclide single photon emission computed tomography (SPECT) scintigraphy is highly sensitive in localizing the active nidus and also orients the lesion in a three-dimensional plane well, for effective surgical removal.


Tissue engineering of blood vessels.
Tissue engineering techniques have been employed successfully in the management of wounds, burns and cartilage repair. Current prosthetic alternatives to autologous vascular bypass grafts remain poor in terms of patency and infection risk. Growing biological blood vessels has been proposed as an alternative. This review is based on a literature search using Medline, PubMed, ISIS and CAS of original articles and reviews, and unpublished material and abstracts. Complete incorporation into host tissues and the maintenance of a viable and self-renewing endothelial layer are the fundamental goals to be achieved when developing a tissue-engineered blood vessel. Sourcing of cells and modulating their interaction with extracellular matrix and supporting scaffold have been the focus of intense research. Although the use of tissue-engineered blood vessels in humans is so far limited, advances in our knowledge of stem cell precursors and the development of new biomaterials should enable this technology to reach routine clinical practice within a decade.


Supplemental essential amino acids augment the somatomedin-C/insulin-like growth factor I response to refeeding after fasting.
Plasma somatomedin-C (Sm-C)/insulin-like growth factor I (IGF-I) concentrations have been shown to reflect changes in nitrogen balance induced by manipulation of nutrient intake. To assess the Sm-C/IGF-I response to refeeding a protein restricted diet in which the nitrogen source was supplemented with essential amino acids, six normal adults were fasted for five days, then refed for nine days diets consisting of 35 kcals/kg and 0.48 g protein/kg body weight. In one diet, 80% of the nitrogen was supplied as essential amino acids, and in the other, 80% was supplied as nonessential amino acids. Following the first fast/refeed cycle, a control diet was eaten for two weeks before the fast was repeated and the other test diet was ingested. The refeeding diets were given a random order. Plasma Sm-C/IGF-I fell from a pre-fast mean of 1.64 +/- 0.24 U/mL (mean +/- 1 SEM) to 0.67 +/- 0.18 (P less than 0.001) following fasting, and rose to 1.41 +/- 0.19 U/mL (P less than 0.001) following ingestion of the diet with supplemental essential amino acids. In contrast, when the same subjects were refed a diet in which 80% of the nitrogen was in the form of nonessential amino acids, the plasma Sm-C/IGF-I concentrations rose from 0.74 +/- 0.17 to 1.15 +/- 0.15 U/mL (P less than 0.01). This increase was significantly less than that observed after ingestion of the essential amino acid supplemented diet (0.74 +/- 0.10 U/mL v 0.40 +/- 0.11 U/mL; P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)


Enhanced direct fermentation of cassava to butanol by Clostridium species strain BOH3 in cofactor-mediated medium.
The main challenge of cassava-based biobutanol production is to enhance the simultaneous saccharification and fermentation with high hyperamylolytic activity and butanol yield. Manipulation of cofactor [e.g., Ca(2+) and NAD/(P)H] levels as a potential tool to modulate carbon flux plays a key role in the cassava hydrolysis capacity and butanol productivity. Here, we aimed to develop a technology for enhancing butanol production with simultaneous hydrolysis of cassava (a typical model as a non-cereal starchy material) using a cofactor-dependent modulation method to maximize the production efficacy of biobutanol by Clostridium sp. stain BOH3. Supplementing CaCO3 to the medium containing cassava significantly promotes activities of α-amylase responsible for cassava hydrolysis and butanol production due to the role of Ca(2+) cofactor-dependent pathway in conversion of cassava starch to reducing sugar and its buffering capacity. Also, after applying redox modulation with l-tryptophan (a precursor as de novo synthesis of NADH and NADPH), the levels of cofactor NADH and NADPH increased significantly by 67 % in the native cofactor-dependent system of the wild-type Clostridium sp. stain BOH3. Increasing availability of NADH and NADPH improved activities of NADH- and NADPH-dependent butanol dehydrogenases, and thus could selectively open the valve of carbon flux toward the more reduced product, butanol, against the more oxidized acid or acetone products. By combining CaCO3 and l-tryptophan, 17.8 g/L butanol with a yield of 30 % and a productivity of 0.25 g/L h was obtained with a hydrolytic capacity of 88 % towards cassava in a defined medium. The metabolic patterns were shifted towards more reduced metabolites as reflected by higher butanol-acetone ratio (76 %) and butanol-bioacid ratio (500 %). The strategy of altering enzyme cofactor supply may provide an alternative tool to enhance the stimulation of saccharification and fermentation in a cofactor-dependent production system. While genetic engineering focuses on strain improvement to enhance butanol production, cofactor technology can fully exploit the productivity of a strain and maximize the production efficiency.


A platform for efficient establishment and drug-response profiling of high-grade serous ovarian cancer organoids.
The broad research use of organoids from high-grade serous ovarian cancer (HGSC) has been hampered by low culture success rates and limited availability of fresh tumor material. Here, we describe a method for generation and long-term expansion of HGSC organoids with efficacy markedly improved over previous reports (53% vs. 23%-38%). We established organoids from cryopreserved material, demonstrating the feasibility of using viably biobanked tissue for HGSC organoid derivation. Genomic, histologic, and single-cell transcriptomic analyses revealed that organoids recapitulated genetic and phenotypic features of original tumors. Organoid drug responses correlated with clinical treatment outcomes, although in a culture conditions-dependent manner and only in organoids maintained in human plasma-like medium (HPLM). Organoids from consenting patients are available to the research community through a public biobank and organoid genomic data are explorable through an interactive online tool. Taken together, this resource facilitates the application of HGSC organoids in basic and translational ovarian cancer research.


Treatment of advanced head and neck cancer with concomitant radiation and chemotherapy.
Forty-four patients with predominantly inoperable or recurrent head and neck cancers were treated with combined chemotherapy (CT) and radiation therapy (RT) in a Phase I/II study. CT and RT were combined in a concomitant fashion to take advantage of radiosensitizing properties of the chemotherapeutic agents. Each treatment cycle consisted of cisplatin 60 mg/M2 on day 1, 5-FU infusion at a dose of 800 mg/M2 per day continuously for 5 days and RT at 200 cGy per day, days 1 through 5. The treatment cycle was repeated every 2 weeks for 7 cycles in patients treated curatively and for 2 to 6 cycles in patients treated palliatively due to prior radiation therapy or the presence of metastatic disease. Regional control was achieved in 98% of the patients. Regional control has persisted in 87% of the patients treated curatively with a minimum follow-up of 24 months. Distant failure occurred in 23% of this group. Actuarial survival of 2 years for the curative group is 66%. Concomitant combination of radiation with radiation potentiating chemotherapeutic agents shows promise of increase in local control.


Adrenal activity in anorexia nervosa.
Adrenocortical activity was studied in 19 emaciated women with anorexia nervosa. Relative to body size the patients' mean cortisol production rates of 0.591 mg/kg/day and 16.4 mg m2/day were significantly elevated compared to those of 0.322 mg/kg/day and 11.4 mg/m2/day for age and sex matched normal controls (p less than 0.001 and 0.02, respectively). The 24-hr mean plasma cortisol concentration in 18 patients was 10.6 microgram/dl and was significantly higher than that of the controls (6.8 microgram/dl, p less than 0.001). The average excretion of urinary free cortisol in nine patients was 205 microgram/day, significantly greater than that of 65 microgram/day in the controls (less than 0.01). Three patients underwent overnight suppression with 1 mg of dexamethasone and had inadequate responses. These data suggest that cortisol production is excessive in emaciated patients with anorexia nervosa due to a disturbance of the hypothalamic-pituitary mechanisms regulating adrenocortical function. The excessive adrenal activity may reflect certain psychobiological disturbances as well as the effects of malnutrition.


Systematic review of outcome measurements and reference group(s) to evaluate and compare implant success and failure.
There is a lack of consensus on measures to assess implant performance in clinical research. To investigate the outcomes measures and reference groups employed to evaluate and compare implant success and failure. MEDLINE (OVID) and Web of Science with searching reference lists of included papers. Inclusion: root form, titanium implants in dentate or edentulous individuals. Longitudinal studies reporting survival or success outcomes on at least 20 participants ≥ mean 5 years. Descriptive statistics. Two-hundred and sixteen studies were included. Implant survival was the most commonly reported primary outcome (60%) with success at 15.7%. Success constituted a wide variety of measures with little consistency. A percentage of 98.6% of studies employed the implant as the unit of analysis with little consideration of clustering within patients. The status of periodontal and general heath of study groups was unclear for more than 80% studies. The proportion of studies comprising randomized trials or using appropriate analytical methods increased from 1980 to 2011. Considers only English language and there was no author contact. In view of the disparate outcome measures employed to assess dental implant performance, agreement is needed both on a core set of implant outcomes and their statistical management.


Comparative proteomic analysis of tear fluid in Graves' disease with and without orbitopathy.
Graves' orbitopathy (GO) is a severe organ-specific autoimmune inflammatory ocular complication most often associated with Graves' disease (GD). Besides the cosmetic problems these patients develop, GO may also cause severe, sight-threatening complications. Additionally, GO complicates the treatment of patients with GD, making the identification of Graves patients at risk for eye disease before they develop symptoms a critical step in the clinical management and quality of life of these patients. The high concentration of proteins in tear fluid makes it an important source for studying potential protein biomarkers for GO. The aim of this study was to quantitatively compare tear fluid from GD patients with moderate/severe GO (GO) and patients with GD without GO (controls) using untargeted quantitative proteomics based on dimethyl labelling in combination with two-dimensional liquid chromatography-mass spectrometry. Among the 1212 proteins identified, 16 showed significant alterations in abundance between the two groups. Thus, in this study, we reveal a number of novel dysregulated proteins in GO which may contribute to a better understanding of the disease. In particular, upregulation of lacrimal gland proteins such as lysozyme C, lacritin, antileukoproteinase and zinc-alpha-2-glycoprotein 1 suggests involvement of the lacrimal gland in the pathogenesis of GO. It remains to be elucidated whether some of these proteins can be used as markers for patients at risk for developing GO as well as useful indicators for disease activity.


Dengue virus infection rate in field populations of female Aedes aegypti and Aedes albopictus in Singapore.
We developed a single-step reverse transcription-polymerase chain reaction (RT-PCR) followed by a semi-nested PCR using an upstream consensus primer and four type-specific primers within the non-structural protein gene (NS3) of dengue viruses to type dengue viruses in field populations of female Aedes mosquitoes. This yielded diagnostic fragments of 169, 362, 265 and 426 base pairs for dengue virus types 1, 2, 3 and 4, respectively. From 1997 to 2000, 54 (6.9%) of 781 Aedes aegypti and 67 (2.9%) of 2256 Aedes albopictus screened were positive for dengue viruses, with a declining trend. The most common dengue virus type detected in the Aedes mosquitoes was dengue-1. Details on the change of one serotype to another in the mosquito population over three consecutive years are discussed.


Pityriasis rosea in a patient with epidermolysis bullosa dystrophica.
A patient with clinical and histologic features of epidermolysis bullosa dystrophica-recessive (EBD-R) developed superimposed clinical lesions of pityriasis rosea (PR). Electron microscopy showed distinct "blebbing" of basal cells at the basement membrane zone in clinically normal skin of a non-predilected area, as well as in scarred skin from a predilected area and a lesion of PR. An increased susceptibility of the basement membrane zone to proteolytic enzymes is suggested as a possible hypothesis to explain these observations.


Static and dynamic analysis of five anterior instrumentation systems for thoracolumbar scoliosis.
A nondestructive biomechanical investigation among five anterior spinal instrumentation systems for scoliosis. The purpose of this study is to analyze the static and dynamic biomechanical stability of five different systems. Although a variety of anterior spinal instrumentation systems for scoliosis are available, very few attempts have been made at comparative biomechanical studies. Thirty calf spines were underwent static biomechanical tests, including flexion-extension, axial rotation, and lateral bending loading modes in the multisegmental spinal model. Five anterior instrumentation systems included: 1) Texas Scottish Rite Hospital system; 2) Bad Wildungen Metz; 3) anterior ISOLA; 4) Cotrel-Dubousset Hoph; and 5) Kaneda Anterior Scoliosis System. The initial and postfatigue stability after a cyclic loading test were analyzed by measuring the range of motion at instrumented segments compared to the intact within the same specimen (% to intact). Two-rod systems showed a significant decrease in range of motion compared to one-rod systems in flexion-extension (P < 0.001) and axial rotation (P < 0.05). In lateral bending, all systems demonstrated a significant decrease in range of motion of less than 40% to the intact (P < 0.001). After cyclical loading test, all systems increased in range of motion. In flexion-extension, one-rod systems depicted a significant increase in range of motion, compared to two-rod systems (P < 0.05). In the initial stability analysis, two-rod systems are superior to one-rod systems. For one-rod systems, repeated physiologic loading may result in reduced stability in flexion-extension.


Optimizing treatment sequencing of chemotherapy for patients with rectal cancer: The KIR randomized phase II trial.
Randomized studies have shown low compliance to adjuvant chemotherapy in rectal cancer patients receiving preoperative chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision. We hypothesize that giving neoadjuvant CT before local treatment would improve CT compliance. Between 2010-2017, 180 patients were randomized (2:1) to either Arm A (AA) with FOLFOX x6 cycles prior to high dose rate brachytherapy (HDRBT) and surgery plus adjuvant FOLFOX x6 cycles, or Arm B (AB), with neoadjuvant HDRBT with surgery and adjuvant FOLFOX x12 cycles. The primary endpoint was CT compliance to ≥85% of full-dose CT for the first six cycles. Secondary endpoints were ypT0N0, five-year disease free survival (DFS), local control and overall survival (OS). Patients were randomized to either AA (n = 120, median age (MA) 62 years) or AB (n = 60, MA 63 years). 175/180 patients completed HDRBT as planned (97.2%). In AA, two patients expired during CT; three patients post-randomization received short course EBRT because of progression under CT (n = 2, AA) or personal preference (n = 1, AB). ypT0N0 was 31% in AA and 28% in AB (p = 0.7). CT Compliance was 80% in AA and 53% in AB (p = 0.0002). Acute G3/G4 toxicity was 35.8% in AA and 27.6% in AB (p = 0.23). With a median follow-up of 48.5 months (IQR 33-72), the five-year DFS was 72.3% with AA and 68.3% with AB (p = 0.74), the five-year OS 83.8% for AA and 82.2% for AB (p = 0.53), and the five-year local recurrence was 6.3% for AA and 5.8% for AB (p = 0.71). We confirmed improved compliance to neoadjuvant CT in this study. Although there is no statistical difference in ypT0N0 rate, local recurrence, and DFS between the two arms, a trend towards favourable oncological outcomes is observed.


Immunological and enzymatic comparison of hepatic cytochrome P-450 fractions from phenobarbital-, 3-methylcholanthrene-, beta-naphthoflavone- and 2,3,7,8- tetrachlorodibenzo-p-dioxin-treated rats.
A comparison of the cytochrome P-450 forms induced in rat liver microsomes by phenobarbital on the one hand, and 3-methylcholanthrene, beta-naphthoflavone and 2,3,7,8-tetrachlorodibenzo-p-dioxin on the other hand, was performed using specific antibodies: anti-P-450 B2 PB IG (against the phenobarbital-induced cytochrome P-450) and anti-P-450 B2 BNF IG (against the beta-naphthoflavone-induced cytochrome P-450). On DEAE-cellulose chromatography, four cytochrome P-450 fractions were separated, called P-450 A (non-adsorbed), P-450 Ba, P-450 Bb and P-450 Bc, from control, phenobarbital-, 3-methylcholanthrene, beta-naphthoflavone- and 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats. Cytochrome P-450 A fractions appeared to be unmodified by the inducers, whereas the specifically induced cytochrome P-450 forms were always recovered in Bb fractions. The P-450 Bb fractions induced by 3-methylcholanthrene, beta-naphthoflavone and 2,3,7,8-tetrachlorodibenzo-p-dioxin exhibited common antigenic determinants, comparable catalytic activities (benzphetamine N-demethylase, benzo[a]pyrene hydroxylase) and similar mol. wts. Moreover, the inhibition patterns by the two antibodies of benzphetamine N-demethylase and benzo[a]pyrene hydroxylase activities catalysed by 3-methylcholanthrene, beta-naphthoflavone and 2,3,7,8-tetrachlorodibenzo-p-dioxin microsomes or by the corresponding P-450 Bb fractions in a reconstituted system were quite identical. By these different criteria, beta-naphthoflavone, 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin seem to induce a common cytochrome P-450 species in rat liver.


Behaviour of co-cultured human osteoclastic and osteoblastic cells exposed to endodontic sealers' extracts.
Bone tissue is constantly being moulded and shaped by the coordinated action of bone-resorbing osteoclasts and bone-synthesizing osteoblasts. This study addresses the long-term effects of endodontic sealers' extracts (AH Plus™, GuttaFlow™, Tubliseal™, Sealapex™ and RealSeal™) on co-cultures of human osteoclastic and osteoblastic cells. The sealers were mixed according to the manufacturer's instructions, freshly extracted with culture medium (1.3 cm(2)/ml; 24 h; 37 °C, 5% CO2/air) and diluted (1:20-1:2,500). Co-cultures of osteoclastic and osteoblastic cells, established from precursors present in human peripheral blood mononuclear cells and bone marrow cells, respectively, were exposed to the extracts for 21 days. Co-cultures were characterized for the osteoclastic and osteoblastic response. The sealers caused a dose-dependent decrease on TRAP and ALP activities, respectively, an osteoclastic and an osteoblastic marker. The resorbing ability of the osteoclastic cells and the expression of osteoclastic and osteoblastic genes were also decreased; in addition, the extracts affected several intracellular signalling pathways. Inhibition was higher during the two first weeks, followed by adaptive cell responses. Osteoblastic response was more sensitive to the extracts' toxicity and showed lower adaptive ability. A correlation to the clinical situation cannot be predicted; however, the results suggest that the sealers' eluents might disrupt the highly regulated interaction between osteoblastic and osteoclastic cells, compromising the local bone metabolism. Also, the higher susceptibility of the osteoblastic response might be particularly relevant in the initial stages of the healing of periapical lesions, due to the significant role of the bone formation events.


Isolation of CEA-like material from urinary bladder carcinoma.
Carcinoembryonic antigen (CEA)-like material from urinary bladder carcinoma was purified and compared with the immunological and physico-chemical properties of CEA isolated from colon cancer. After immunoadsorbent purification, the final step in a purification procedure similar to that adopted for colon cancer CEA, two main molecular species were identified: 1) Material identical with colon cancer CEA with respect to molecular size, PCA solubility, ability to bind to Con A, and most important the ability to bind to specific monkey anti-CEA serum. 2) Material with the same chromatographic and immunological properties as NCA.


Analyzing barriers and facilitators to the implementation of an action plan to strengthen the midwifery professional role: a Moroccan case study.
As part of a national strategy for reaching Millennium Development Goals 4 and 5 in Morocco, an action plan covering three systems (sociocultural, educational and professional) was developed to strengthen midwives' professional role in order to contribute to high quality maternity care. This study aimed to understand the implementation process by identifying the characteristics of this intervention and the dimensions of the three-systems which could act as barriers to/facilitators of the implementation process. We used a conceptual framework that builds on Hatem-Asmar's model that describes change in a health professional role; and on the Consolidated Framework for Implementation Research for our analysis. An embedded case study with three levels of analysis was conducted during June and July 2010. Data were collected through 11 semi-structured interviews, 20 focus groups, training session observations and documents. A purposive sample of 106 multi-stakeholders from two Moroccan regions (health professionals, academic staff, students, medical administrative officers and health programmers) and one international consultant were recruited. A thematic analysis was conducted using QDA Miner. Data showed a failure to carry out the plan as intended. Seventeen barriers and seven facilitators were identified. Misalignment of the values, methods, actors and targets of the sociocultural system with the values, methods and actors of the educational and professional systems, on one hand, and with the intervention, on the other hand, were likely the greatest impediments to implementing the plan. The bureaucratic structure and lack of readiness of the sociocultural system were among the most influential barriers to: dissemination of information, involvement of key actors in the process and readiness of the educational system. The main facilitators were the values promoted related to human rights, and the national and international policies to strengthen midwifery and reduce maternal mortality. The plan was perceived as beneficial, but complex and externally driven. The findings suggest that successful implementation requires redesigning the implementation strategy to adapt to the factors identified in our study. The results would be very useful to health planners seeking the expansion of such an intervention to other developing countries looking to strengthen midwives' role and to improve maternity health care services.


Mitochondrial Fission and Fusion.
Mitochondria are key cellular organelles responsible for many different functions. The molecular biology of mitochondria is continuously subject to comprehensive studies. However, detailed mechanisms of mitochondrial biogenesis are still unclear. Fusion and fission are among the most enigmatic processes connected with mitochondria. On the other hand, it has been shown that these events are of great biological importance for functioning of living cells. In this review, we summarize existing molecular data on mitochondrial dynamics and discuss possible biological functions of fusion and fission of these organelles.


Synchronous Reconstruction of a Total Mandibulectomy Defect With a Single Fibula Osteocutaneous Free Flap.
Osteoradionecrosis (ORN) is a well-known and usually late complication of radiation therapy in the treatment of head and neck cancer. Although the therapy can be life extending, it also produces tissue toxicity in ipsilateral and contralateral tissues in an acute and chronic fashion. In the most severe cases of ORN, such as the one presented in this report, bilateral disease results in the need for total mandibulectomy and creates a tremendous reconstructive challenge. The advent of microvascular surgery and free tissue transfer has caused an evolution of the management protocol for severe ORN cases. This report describes a unique case of total mandibulectomy with synchronous reconstruction using a single vascularized fibula osteocutaneous flap with subsequent dental implant reconstruction and prosthetic rehabilitation.


The collagen, fibrinogen and thrombin biological adhesive is effective in treating experimental liver injuries.
to evaluate the effectiveness of an collagen-based adhesive associated with fibrinogen and thrombin in experimental liver injuries in rats. we randomly divided 30 Wistar rats into three groups: A, B and C. All underwent a standard liver traumatic injury. In group A, the lesion was treated with the adhesive; in group B, with conventional, absorbable suture; group C received no treatment. We analyzed the time of hemostasis, mortality, occurrence of adhesions and any histological changes. there was no statistical difference in relation to mortality (p=0.5820). The adhesive treated group showed the lowest hemostasis times (p=0.0573, odds ratio 13.5) and lower incidence of adhesions (p=0.0119). The histological alterations of the Groups A and B were similar, with foreign body granuloma formation separating the adhesive material and the hepatic stroma suture. the collagen adhesive associated with fibrinogen and thrombin was effective in treating experimental hepatic injury, providing a lower incidence of adhesions between the liver and surrounding structures. avaliar a eficácia de um adesivo a base de colágeno associado ao fibrinogênio e trombina, no trauma hepático experimental em ratos. toram incluídos no estudo 30 ratos Wistar, igualmente divididos aleatoriamente em três grupos: A, B e C. Todos foram submetidos à lesão traumática hepática padronizada. No grupo A, a lesão foi tratada com o adesivo, no grupo B, com sutura convencional com fio absorvível, e no grupo C, não houve tratamento da lesão. Foram analisados o tempo de hemostasia, mortalidade, ocorrência de aderências e eventuais alterações histológicas. os resultados mostraram que não houve diferença estatística em relação à mortalidade (p=0,5820). O grupo tratado com adesivo apresentou os menores tempos de hemostasia (p=0,0573 e odds ratio 13,5) e menor ocorrência de aderências (p=0,0119). Microscopicamente as alterações histológicas dos grupos A e B foram semelhantes, com a formação de granuloma de corpo estranho separando o material do adesivo e do fio de sutura do estroma hepático. o adesivo de colágeno associado ao fibrinogênio e trombina foi eficaz no tratamento do trauma hepático experimental, proporcionado menor ocorrência de aderências entre o fígado e as estruturas vizinhas.


Spatial distribution of tumor vaccine improves efficacy.
Genetically engineered tumor cells were used as a vaccine in a murine model to compare tumor formation after inoculating multiple sites versus a single site. The effect of vaccinating draining lymph node basins was evaluated. Mice were vaccinated in either the floor of the mouth, the draining nodes of the front legs, the hind leg, or a combination of sites. Seven days later, the mice were challenged with parental tumor cells in the floor of the mouth and followed for tumor growth. A retroviral vector was used to transduce the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene into SCCFVII/SF tumor cells, which were then irradiated to prevent replication in vivo. Syngeneic C3H/HeJ mice were vaccinated with 1 x 10(6) cells in various sites, then challenged with 1 x 10(5) parental cells after 7 days. Animals vaccinated in multiple sites had better protection from later tumor challenge than those receiving single vaccinations. Of the animals receiving vaccination at multiple sites, those vaccinated in the site of tumor challenge (floor of the mouth) had more protection than those not vaccinated at the site. Mice vaccinated at multiple draining lymph node sites were better primed against tumor challenge than mice receiving single inoculations. Vaccination strategies that included the challenge site (floor of the mouth) and the nodes near this site were optimal.


Kinetics of photobleaching of protoporphyrin IX in the skin of nude mice exposed to different fluence rates of red light.
The purpose of the present study was to determine the kinetics and the fluence rate dependency of the photobleaching of protoporphyrin IX (PpIX) in normal skin of Balb/c nude mice after systemic and topical application of 5-aminolevulinic acid (ALA). ALA was administered systemically (200 mg/kg body weight, i.p.) and topically (20% w/w ALA cream) to the mice. Fluences of up to 40 J/cm2 were delivered by a dye laser (636 nm) at fluence rates of 37.5, 75, 150, 300 and 500 mW/cm2. The photo-bleaching rate was constant within this range of fluence rates. This result suggests that there is no oxygen effect for PpIX photobleaching in this region for the skin of Balb/c nude mice. During light exposure the fluorescence decay followed neither first- nor second-order kinetics. The decay rate was slightly faster after systemic application than after topical application of ALA, but did not depend on the time (1-8 h) between application and analysis.


Lifetime history of depression, type 2 diabetes, and endothelial reactivity to acute stress in postmenopausal women.
Coronary heart disease is a major cause of mortality in women and persons with diabetes. Mental stress and major depressive disorder have both been associated with coronary heart disease. Endothelial functioning is a clinically meaningful manifestation of CHD that is detectable in its earliest stages. This study aims to determine whether acute stress and lifetime history of major depressive disorder are associated with functional and biochemical markers of endothelial function and whether this relationship varies by diabetes status. Resting endothelial function was assessed for n = 215 postmenopausal women with no known or suspected coronary artery disease participated. Of these, 108 had a positive lifetime major depressive disorder (L-MDD; assessed through structured clinical interview) and had been free of major depressive disorder for >6 months; 103 had type 2 diabetes. Endothelial reactivity to acute mental stress was assessed for n = 114 of the participants. Endothelial function was assessed by flow-mediated dilation of the brachial artery (FMD) by total plasma nitrite, the cumulative molecule from nitric oxide (NO) generation, and by plasma endothelin-1 (ET-1). Participants with L-MDD had lower NO and lower FMD compared to never-depressed controls. Secondary analyses suggest that among participants with L-MDD, antidepressant medications are associated with higher NO. Participants with diabetes had higher NO but lower FMD than nondiabetic controls. Mental stress affected FMD in the entire sample. Diabetes moderated the effect of mental stress on NO and L-MDD moderated the effect of mental stress on ET-1. History of depression, even in full remission, is associated with impaired endothelial functioning regardless of diabetes status. Acute mental alters FMD, NO, and ET-1 differentially among subgroups.


Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.
Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.


A dynamic relationship between mucosal T helper type 17 and regulatory T-cell populations in nasopharynx evolves with age and associates with the clearance of pneumococcal carriage in humans.
Pneumococcal carriage is common in young children, which may account for the high incidence of disease in this age group. Host factors determining the clearance of carriage in humans remain unclear. We aimed to study the relationships between T helper type 17 (Th17) and Foxp3(+) regulatory T (Treg) cells in nasopharynx-associated lymphoid tissue (NALT) and carriage in children and adults. Frequencies of Th17 and Treg cells in NALT were analysed by flow cytometry in association with age and pneumococcal carriage status. Cytokine responses following pneumococcal stimulation were analysed by cytometric beads array. The frequencies of Th17 and Treg cells in NALT were inversely correlated (R -0.60). Whereas Treg cell frequency decreased with age (R -0.63), both Th17 and the Th17: Treg ratio increased with age (R 0.62 and R 0.64, respectively). Also, the Th17: Treg ratio was higher in carriage-negative than in carriage-positive children (p <0.01). Pneumococcal stimulation of tonsillar cells increased both Th17 and Treg cell numbers, but the Th17: Treg ratio and pattern of cytokine responses differed between carriage-negative and carriage-positive children. The former showed markedly higher Th17: Treg and interleukin-17A: interleukin-10 ratios than in the latter (p <0.01). Pneumococcal stimulation also induces Th17, although the capacity of this Th17 differentiation from naive T cells of young children was low, but increased with age. We demonstrated a dynamic relationship between Th17 and Treg cells in human nasopharynx that evolves with age. The balance between Th17 and Treg cells in NALT appears to be a major host factor closely associated with the clearance of Streptococcus pneumoniae from the nasopharynx.


The relative cost of biomass energy transport.
Logistics cost, the cost of moving feedstock or products, is a key component of the overall cost of recovering energy from biomass. In this study, we calculate for small- and large-project sizes, the relative cost of transportation by truck, rail, ship, and pipeline for three biomass feedstocks, by truck and pipeline for ethanol, and by transmission line for electrical power. Distance fixed costs (loading and unloading) and distance variable costs (transport, including power losses during transmission), are calculated for each biomass type and mode of transportation. Costs are normalized to a common basis of a giga Joules of biomass. The relative cost of moving products vs feedstock is an approximate measure of the incentive for location of biomass processing at the source of biomass, rather than at the point of ultimate consumption of produced energy. In general, the cost of transporting biomass is more than the cost of transporting its energy products. The gap in cost for transporting biomass vs power is significantly higher than the incremental cost of building and operating a power plant remote from a transmission grid. The cost of power transmission and ethanol transport by pipeline is highly dependent on scale of project. Transport of ethanol by truck has a lower cost than by pipeline up to capacities of 1800 t/d. The high cost of transshipment to a ship precludes shipping from being an economical mode of transport for distances less than 800 km (woodchips) and 1500 km (baled agricultural residues).


Health Care Professionals' Experiences and Perspectives on Using Telehealth for Home-Based Palliative Care: Protocol for a Scoping Review.
Telehealth seems feasible for use in home-based palliative care. However, acceptance among health care professionals (HCPs) is essential for the successful delivery of telehealth in practice. No scoping review has mapped the experiences and perspectives of HCPs on the use of telehealth for home-based palliative care. The aim of this review is to systematically map published studies on HCPs' experiences and perspectives on the use of telehealth in home-based palliative care. The proposed scoping review will employ the methodology of Arksey and O'Malley. This protocol is guided by the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol (PRISMA-P). A systematic search will be performed in MEDLINE, PsycINFO, EMBASE, CINAHL, Allied and Complementary Medicine (AMED), and Web of Science for studies published between January 2000 and July 5, 2021. We will also hand search the reference lists of included papers to identify additional studies of relevance. The search will be updated in 2022. Pairs of authors will independently assess the eligibility of studies and extract data. The first 2 stages of thematic synthesis will be used to thematically organize the data. Because the scoping review methodology consists of reviewing and collecting data from publicly available materials, this study does not require ethics approval. The database searches; testing of eligibility criteria; and screening of titles, abstracts, and full-text papers will be performed by fall 2021. The results from this scoping review will be presented as a descriptive summary of the results from all included papers, and will be inductively organized into descriptive themes. A frequency table illustrating which papers were included in which descriptive themes will be made. Results are anticipated by the fall of 2022. A mapping of studies could identify research gaps regarding HCPs' experiences and perspectives on the use of telehealth in home-based palliative care and may determine the value and feasibility of conducting a full systematic review. PRR1-10.2196/33305.


[Post-traumatic cortical defect: presentation of a case].
Post-traumatic cortical defect appears 3 months after greenstick or torus fractures in children. This entity is asymptomatic and usually located just proximal to the fracture site. The most frequently affected bone is the distal radius. The pathogenesis of this lesion remains unclear but it seems to be caused by an intramedullary fat and blood accumulation beneath a intact periostium. Its diagnosis is based on CT and MR images and no treatment is needed, because its resolution is the rule. There are only 25 cases reported in English literature, we present another one after an epiphisiolysis in the distal radius.


Gammadelta T-cells: potential regulators of the post-burn inflammatory response.
Severe burn induces an immunopathological response that contributes to the development of a systemic inflammatory response (SIRS) and subsequent multiple organ failure. While, multiple immune cells type (T-cells, macrophages, neutrophils) are involved in this response, recent evidence suggests that a unique T-cell subset, gammadelta T-cells are central in the response to injury. While gammadelta T-cells represent only a small percentage of the total T-cell population, they display specific functional characteristics that uniquely position them in the immune/inflammatory axis to influence a number of important aspects of the body's response to burn. This review will focus on the potential regulator role of gammadelta T-cells in immunopathological response following burn and thereby their potential as therapeutic targets for affecting inflammation and healing.


Association of low maternal education with neural tube defects in Colorado, 1989-1998.
Despite increasing use of folate prior to conception, neural tube defects remain among the most common birth defects in the United States. The Study objective was to investigate the maternal and child characteristics associated with having an infant born with a neural tube defect (NTD) in Colorado between 1989 and 1998. Data were derived from a population-based case control study of all live-born infants in Colorado from 1989 to 1998 (n=551,285), utilizing birth certificate records and a statewide neural tube defect registry. Chi-square analysis and multiple logistic regression were used to assess the strength of association between sociodemographic characteristics and the main outcome measure, the birth of a child with an NTD. Final analysis was limited to those children born to mothers who themselves were born in either the United States or Mexico. In this ten-year period, there were 251 confirmed cases of NTDs in Colorado, 224 of whom were born to women who were born in either the United States or Mexico. Significant bivariate associations were found between NTDs and the following: female sex of the child, lower maternal age, maternal country of birth in Mexico, and maternal education less than tenth grade. The single strongest predictor of having a child with an NTD was low maternal education (adjusted OR 1.8, 95% CI 1.1-3.1). Low maternal education is an important predictor of having a child with an NTD. In order to further reduce the incidence of neural tube defects, interventions should target women of low educational status.


Innovative process for facile dextran-bovine serum albumin conjugate synthesis: Mechanism, kinetics, and characterization.
Three process variations are developed to synthesize dextran-bovine serum albumin (BSA) model conjugate through the Maillard reaction and a Schiff base-Amadori solid phase rearrangement mechanism at 90 °C. The influences of lyophilization pH and dextran:BSA molar ratio on the reaction are investigated, with the highest yields achieved by absorbing heat evenly and continuously removing the water by-product under vacuum. Lyophilizing at pH 7.8 provides higher yields than materials lyophilized at pH 5.9, a result attributed to higher reactivity of deprotonated amine at pH 7.8. The purified dextran-BSA conjugate solution is heated to above the BSA denaturation temperature (80 °C) at pH 5.2 to form nanogels with a hydrodynamic diameter of 195-400 nm, with the size dependent on the conjugate composition estimated by bicinchoninic acid protein and glycoprotein carbohydrate assays.


A queueing Network approach for capacity planning and patient Scheduling: A case study for the COVID-19 vaccination process in Colombia.
This paper considers the problem of patient scheduling and capacity planning for the vaccination process during the COVID-19 pandemic. The proposed solution is based on a non-linear mathematical modeling approach representing the dynamics of an open Jackson Network and a Generalized Network. To test these models, we proposed three objective functions and analyzed different configurations of the process corresponding to various levels of the models' parameters as well as the conditions present in the case study. To assess the computational performance of the models, we also experimented with larger instances in terms of number of steps or stations used and number of patients scheduled. The computational results show how parameters such as the minimum percentage of patients served, the maximum occupation allowed per station and the objective functions used have an impact on the configuration of the process. The proposed approach can support the decision-making process in vaccination centers to efficiently assign human and material resources to maximize the number of patients vaccinated while ensuring reasonable waiting times, number of patients in queue and servers' utilization rates, which in turn are key to avoid overcrowding and other negative conditions in the system that could increase the risk of infections.


Automatic segmentation of vestibular schwannomas from T1-weighted MRI with a deep neural network.
Long-term follow-up using volumetric measurement could significantly assist in the management of vestibular schwannomas (VS). Manual segmentation of VS from MRI for treatment planning and follow-up assessment is labor-intensive and time-consuming. This study aims to develop a deep learning technique to fully automatically segment VS from MRI. This study retrospectively analyzed MRI data of 737 patients who received gamma knife radiosurgery for VS. Treatment planning T1-weighted isotropic MR and manually contoured gross tumor volumes (GTV) were used for model development. A 3D convolutional neural network (CNN) was built on ResNet blocks. Spatial attenuation and deep supervision modules were integrated in each decoder level to enhance the training for the small tumor volume on brain MRI. The model was trained and tested on 587 and 150 patient data, respectively, from this institution (n = 495) and a publicly available dataset (n = 242). The model performance were assessed by the Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), average symmetric surface (ASSD) and relative absolute volume difference (RAVD) of the model segmentation results against the GTVs. Measured on combined testing data from two institutions, the proposed method achieved mean DSC of 0.91 ± 0.08, ASSD of 0.3 ± 0.4 mm, HD95 of 1.3 ± 1.6 mm, and RAVD of 0.09 ± 0.15. The DSCs were 0.91 ± 0.09 and 0.92 ± 0.06 on 100 testing patients of this institution and 50 of the public data, respectively. A CNN model was developed for fully automated segmentation of VS on T1-Weighted isotropic MRI. The model achieved good performance compared with physician clinical delineations on a sizeable dataset from two institutions. The proposed method potentially facilitates clinical workflow of radiosurgery for VS patient management.


The pineal gland.
The pineal gland is located posterior to the midbrain and is the site of melatonin production. Research on pineal gland function in neonates is very limited. This article will discuss pineal gland development and the possible relationship between melatonin production and sudden infant death syndrome. Further research on pineal gland function is needed in order to establish its significance for the neonate.


A model of human microvascular exchange: parameter estimation based on normals and nephrotics.
A mathematical model is formulated and used to describe the distribution and transport of fluid and albumin in the human circulation, interstitium and lymphatics. Two transcapillary mass exchange mechanisms are investigated: a homoporous 'coupled Starling model', in which transcapillary albumin diffusion and convection occur within the same pathway, and a heteroporous 'plasma leak model', in which variations in structure and pressure are permitted along the length of the capillary. Parameters used in the transport models are determined based on statistical fitting of simulation predictions to experimental data from normal humans and nephrotic patients. The data consists of interstitial fluid volumes and interstitial colloid osmotic pressures as functions of plasma colloid osmotic pressure. Model validation is carried out based on comparison of (i) simulation predictions with experimental data used in parameter estimation, (ii) estimated transport parameters with experimentally determined values, and (iii) simulation predictions with a set of dynamic data from an albumin infusion study. While both models with their best-fit parameter estimates provide a good representation of experimental data, the drawbacks of the plasma leak model are three-fold: it requires more estimated parameters than the coupled Starling model, little experimental information exists with which to compare these parameters and, with the best fit values obtained, the plasma leak mechanism becomes insignificant. The model that employs a Starling-type exchange mechanism will therefore be favoured in future applications.


Glomerular actions of angiotensin II.
An abundance of evidence suggests that glomerular ultrafiltration is significantly influenced by alterations in circulating or local concentrations of a variety of vasoactive substances. Angiotensin II regulates whole kidney glomerular filtration rate by influencing one or more of the determinants of single nephron glomerular filtration rate, particularly the ultrafiltration coefficient and glomerular plasma flow rate. The glomerular mesangial cell may be an important target for angiotensin II by virtue of its ability to contract and thereby reduce glomerular capillary surface area and ultrafiltration coefficient. These control mechanisms are not only important under physiologic conditions but they may also be activated by a variety of insults and thereby contribute to the decrease in glomerular filtration rate observed in a broad spectrum of renal disease.


Global patterns and predictors of C:N:P in marine ecosystems.
Oceanic nutrient cycles are coupled, yet carbon-nitrogen-phosphorus (C:N:P) stoichiometry in marine ecosystems is variable through space and time, with no clear consensus on the controls on variability. Here, we analyze hydrographic, plankton genomic diversity, and particulate organic matter data from 1970 stations sampled during a global ocean observation program (Bio-GO-SHIP) to investigate the biogeography of surface ocean particulate organic matter stoichiometry. We find latitudinal variability in C:N:P stoichiometry, with surface temperature and macronutrient availability as strong predictors of stoichiometry at high latitudes. Genomic observations indicated community nutrient stress and suggested that nutrient supply rate and nitrogen-versus-phosphorus stress are predictive of hemispheric and regional variations in stoichiometry. Our data-derived statistical model suggests that C:P and N:P ratios will increase at high latitudes in the future, however, changes at low latitudes are uncertain. Our findings suggest systematic regulation of elemental stoichiometry among ocean ecosystems, but that future changes remain highly uncertain.


Anthranilate N-hydroxycinnamoyl/benzoyltransferase gene from carnation: rapid elicitation of transcription and promoter analysis.
Hydroxycinnamoyl/benzoyl-CoA:anthranilate N-hydroxycinnamoyl/benzoyltransferase (HCBT) catalyses the committed reaction of phytoalexin biosynthesis in carnation (Dianthus caryophyllus L.). Three HCBT cDNAs were cloned previously from suspension-cultured carnation cells that had been induced with fungal elicitor. A rapid, transient induction of hcbt transcripts upon elicitation, reaching maximal abundances within about 0.5 h and returning to basal levels within 4 h, suggested the involvement of unusual cis elements. A DNA fragment of 3.8 kb, spanning the hcbt2 gene with the 5'-flanking region of roughly 1.8 kb, was cloned from carnation plants. The gene encodes one long open reading frame lacking introns. The DNA sequence revealed a conserved TATA box, three elicitor response elements (EREs) and a 9 bp direct repeat as well as an interrupted direct repeat of 11 bp in the TATA distal region. EMSA revealed the binding of elicitor-inducible nuclear factors to the promoter region from -377 to -326 spanning two of the EREs, and their functional relevance was confirmed by transient expression assays of hcbt2 promoter-GUS reporter gene constructs in parsley protoplasts. Furthermore, an oligo(A) segment was present immediately preceding the start of translation (+140 to +150). Transient expression analysis demonstrated that the sequence upstream to -1157 at least is required in context with the 5'-UTR, particularly including the poly(A) segment, for strong expression and full elicitor induction of the hcbt2 gene. The results suggested that several sequence motifs scattered over a wide range of the 5'-flanking region and into the exonic sequence are responsible for the full elicitor regulation of the hcbt2 gene.


High energy phosphate metabolism in experimental permanent focal cerebral ischemia: an in vivo 31P magnetic resonance spectroscopy study.
Relative levels of phosphate metabolites in the brain were examined in vivo by 31P magnetic resonance spectroscopy (MRS) in 50 Sprague-Dawley rats before, during, and after induction of focal permanent cerebral ischemia. After acquisition of baseline spectra, rats were subjected to injury within the core of the MR spectrometer, and 31P spectra were collected for 60 min after injury: in 7 rats, permanent, acute focal cerebral ischemia was induced (ischemia group); in 6 rats, mild hypoxia (FiO2 14%) was induced at the time of the ischemic insult and was maintained for 20 min (ischemia-hypoxia group); in 6 rats, mild hypoxia (FiO2 14%) only was induced for 20 min (hypoxia group). Control studies were performed in 25 rats. Cerebral intracellular pH, calculated from the chemical shift of inorganic phosphate (Pi), decreased immediately after injury in the ischemia and ischemia-hypoxia groups. The first 31P spectrum obtained after injury was characterized by an increase in Pi and a decrease in phosphocreatine (PCr) in the ischemia and ischemia-hypoxia groups; these changes in spectra were significantly greater in the ischemia-hypoxia group. No significant changes in adenosine triphosphate (ATP) were found in either group. Within 60 min of occlusion, 31P spectra returned toward baseline spectra in both ischemia-hypoxia and ischemia groups. No significant changes were seen in spectra of rats subjected to hypoxia alone. These results confirm that 31P MRS is a sensitive measure of early changes of high energy metabolites in focal cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Ligand activation of peroxisome proliferator-activated receptor gamma induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity.
The peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily, is expressed at highest levels in adipose tissue and functions as a central regulator in the process of adipocyte differentiation. In the present study, we showed that human leukemic cell lines, not only myeloid but also lymphoid, express PPAR gamma and its activation by natural ligand (15-deoxy-Delta(12,14) - prostaglandin J(2)) and synthetic ligand (troglitazone) profoundly inhibited their proliferation by induction of apoptosis preferentially in the serum-free culture. We pursued its mechanism using the representative cell lines, and found that induction of apoptosis was accompanied by caspase-3 activation and specifically blocked by its inhibitor. While status of several apoptosis-related molecules remained unchanged, the c-Myc expression was markedly down-regulated within 24 h after troglitazone treatment. The c-myc mRNA levels were dramatically reduced at 1 h and became undetectable at 12 h after troglitazone treatment, which proved to be accompanied by complete blockade of the Tcf-4 activity in the electrophoretic mobility shift assay. We succeeded in establishing HL-60 cell lines growing well in the presence of troglitazone in the long-term serum-free culture. They showed neither induction of apoptosis nor down-regulation of the c-Myc expression via blockade of the Tcf-4 activity after troglitazone treatment. This is the first identification of the linkage between PPAR gamma-mediated apoptosis and down-regulation of the c-myc gene expression.


Thyroid profile during the alternative Sunitinib dosing 2/1 schedule in metastatic renal cell carcinoma.
Hypothyroidism is a common side effect of Sunitinib (SUN) treatment in metastatic renal cell carcinoma (mRCC) patients. We aimed to evaluate thyroid profile during the alternative 2/1 SUN treatment schedule and to assess the predictive value of hypothyroidism in terms of survival. We performed a prospective observational study enrolling 42 consecutive mRCC patients starting first-line alternative SUN dosing 2/1 schedule. Thyroid function was assessed at baseline and during the first three SUN cycles (1 cycle = 6 weeks = 2 ON/1 OFF + 2 ON/1 OFF), and then after 6 and 12 months. Thyroid ultrasound was performed at baseline and after 3, 6, and 12 months. Subclinical hypothyroidism developed in 24% of patients during the first cycle; in other 24% in the second cycle and in 14% in the third cycle. The highest TSH values were reached during the second cycle, ON phase (6.58 ± 5.74 μI U/l). We observed a reduction in thyroid size, in echogenicity and in parenchymal perfusion in all patients. Progression-free survival (PFS) tended to be longer in patients with TSH ≥ 5 μI U/ml during the second cycle (p = 0.069). TSH level was an independent risk factor for PFS in men (p = 0.009) but not in women (p = 0.285). This is the first study investigating functional and morphological effects on thyroid during the alternative 2/1 SUN schedule in mRCC patients. We detected an early onset of subclinical hypothyroidism, observing the association between TSH ≥ 5 μI U/ml and: (i) longer PFS in men; (ii) progressive decrease of thyroid size in absence of significant changes in autoimmune thyroid profile.


Characterization of nucleotide-binding oligomerization domain (NOD) protein expression in primary murine microglia.
We demonstrate that primary microglia express nucleotide-binding oligomerization domain (NOD) proteins that are thought to serve as novel pattern recognition receptors for bacterial peptidoglycan motifs. NOD2 is constitutively present in microglia and is upregulated following exposure to Borrelia burgdorferi or Neisseria meningitidis. Its expression is also elevated following exposure to Toll-like receptor (TLR) ligands and muramyl dipeptide (MDP), a putative ligand for NOD2. Microglia express essential downstream effector molecules for NOD2-mediated cell responses, and MDP augments TLR ligand-induced inflammatory cytokine production. Together these data suggest that NOD2 may contribute to microglial immune responses to bacterial pathogens.