Evaluation of the therapeutic effect of high-flow nasal cannula oxygen therapy on patients with aspiration pneumonia accompanied by respiratory failure in the post-stroke sequelae stage.
The aim of the present study was to evaluate the therapeutic effect of high-flow nasal cannula (HFNC) oxygen therapy on patients with aspiration pneumonia accompanied by respiratory failure in the post-stroke sequelae stage, with the goal of providing more effective oxygen therapy and improving patient prognosis. Retrospective analysis was conducted on 103 elderly patients with post-stroke aspiration pneumonia and moderate respiratory failure (oxygenation index: 100-200 mmHg) that had been admitted. The patients were divided into two groups according to the mode of oxygen therapy that was used: the Venturi mask group and the HFNC treatment group. The two groups were analyzed and compared in terms of the changes in the blood gas indices measured at different points in time (4, 8, 12, 24, 48, and 72 h), the proportion of patients that required transition to invasive auxiliary ventilation, and the 28-day mortality rate. A total of 103 patients were retrospectively analyzed; 16 cases were excluded, and 87 patients were included in the final patient group (42 in the HFNC group and 45 in the Venturi group). There was a statistically significant difference in the oxygenation indices of the HFNC group and the Venturi group (F = 546.811, P < 0.05). There was a statistically significant interaction between the monitored oxygenation indices and the mode of oxygen therapy (F = 70.961, P < 0.05), and there was a statistically significant difference in the oxygenation indices for the two modes of oxygen therapy (F = 256.977, P < 0.05). HFNC therapy contributed to the improvement of the oxygenation indices at a rate of 75.1%. The Venturi and HFNC groups also differed significantly in terms of the proportion of patients that required transition to invasive auxiliary ventilation within 72 h (P < 0.05). The HFNC group's risk for invasive ventilation was 0.406 times that of the Venturi group (P < 0.05). There was no statistical difference in the 28-day mortality rate of the two groups (P > 0.05). HFNC could significantly improve the oxygenation state of patients with post-stroke aspiration pneumonia and respiratory failure, and it may reduce the incidence of invasive ventilation.


Multiple effects of TRAIL in human carcinoma cells: induction of apoptosis, senescence, proliferation, and cytokine production.
TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ml, apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL-stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by the altered morphology and expression of several senescence markers: SA-beta-gal, p21Waf1/Cip1, p16INK4a, and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased the yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL-induced proapoptotic and prosurvival responses correlate with the strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects.


Twinning of aragonite - the crystallographic orbit and sectional layer group approach.
The occurrence frequency of the {110} twin in aragonite is explained by the existence of an important substructure (60% of the atoms) which crosses the composition surface with only minor perturbation (about 0.2 Å) and constitutes a common atomic network facilitating the formation of the twin. The existence of such a common substructure is shown by the C2/c pseudo-eigensymmetry of the crystallographic orbits, which contains restoration operations whose linear part coincides with the twin operation. Furthermore, the local analysis of the composition surface in the aragonite structure shows that the structure is built from slices which are fixed by the twin operation, confirming and reinforcing the crystallographic orbit analysis of the structural continuity across the composition surface.


Potassium chloride versus voltage clamp contractures in ventricular muscle.
In frog ventricle, developed tension was markedly larger in response to depolarization caused by a voltage clamp step than to depolarization induced by high concentrations of potassium chloride. Measurement of extracellular potassium activity at the surface and at the depth of muscle during the development of contractures showed that the diffusion of potassium is much slower than the spread of depolarization through the cross section of muscle. These two observations suggest that competition between the depolarizing and the negative inotropic effects of an increase in the extracellular potassium ion concentration may determine the time course and magnitude of contractile tension in heart muscle.


The Future Role of Machine Learning in Clinical Transplantation.
The use of artificial intelligence and machine learning (ML) has revolutionized our daily lives and will soon be instrumental in healthcare delivery. The rise of ML is due to multiple factors: increasing access to massive datasets, exponential increases in processing power, and key algorithmic developments that allow ML models to tackle increasingly challenging questions. Progressively more transplantation research is exploring the potential utility of ML models throughout the patient journey, although this has not yet widely transitioned into the clinical domain. In this review, we explore common approaches used in ML in solid organ clinical transplantation and consider opportunities for ML to help clinicians and patients. We discuss ways in which ML can aid leverage of large complex datasets, generate cutting-edge prediction models, perform clinical image analysis, discover novel markers in molecular data, and fuse datasets to generate novel insights in modern transplantation practice. We focus on key areas in transplantation in which ML is driving progress, explore the future potential roles of ML, and discuss the challenges and limitations of these powerful tools.


Antibiotic repeat prescriptions: are patients not re-filling them properly?
This study aimed to explore patients' utilization of repeat prescriptions for antibiotics indicated in upper respiratory tract infections (URTI). An emphasis was placed on whether the current system of repeat prescriptions contributes to patients self-diagnosing infections and if so, identify the common reasons for this. This is a prospective study of self-reported use of repeat antibiotic prescriptions by pharmacy consumers presenting with repeat prescriptions for antibiotics commonly indicated in URTIs. Data were collected via self-completed surveys in Perth metropolitan pharmacies. A total of 123 respondents participated in this study from 19 Perth metropolitan pharmacies. Of the respondents, approximately a third of them (33.9%) presented to the pharmacy to fill their antibiotic repeat prescription one month or more from the time the original prescription was written (i.e. time when original diagnosis was made by a doctor). Over two thirds of respondents indicated to not have consulted their doctor prior to presenting to the pharmacy to have their antibiotic repeat prescription dispensed (i.e. 68.3%). The most common reasons for this were that their 'doctor had told them to take the second course' (38%), followed by potential self-diagnosis (29%), i.e. 'they had the same symptoms as the last time they took the antibiotics'. Approximately one third (33.1%) of respondents indicated they 'were not told what the repeat prescription was needed for' when they were originally prescribed the antibiotic. Respondents who presented to fill their repeat prescription more than 2 weeks after the original prescription written were more likely not have consulted their doctor (p = 0.006, 95% CI [1.16, 2.01]) and not to know why their repeat was needed (p = 0.010, 95% CI [1.07, 2.18]). Findings of this study suggested that the current 12 month validity of antibiotics repeat prescriptions is potentially contributing to patients' self-diagnosis of URTIs and therefore potential misuse of antibiotics. This may be contributing to the rise of antimicrobial resistance. The study also outlines some common reasons for patients potentially self-diagnosing URTIs when using repeat prescriptions. Larger Australian studies are needed to confirm these findings.


Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry.
Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.


Radiomics, machine learning, and artificial intelligence-what the neuroradiologist needs to know.
Artificial intelligence (AI) is playing an ever-increasing role in Neuroradiology. When designing AI-based research in neuroradiology and appreciating the literature, it is important to understand the fundamental principles of AI. Training, validation, and test datasets must be defined and set apart as priorities. External validation and testing datasets are preferable, when feasible. The specific type of learning process (supervised vs. unsupervised) and the machine learning model also require definition. Deep learning (DL) is an AI-based approach that is modelled on the structure of neurons of the brain; convolutional neural networks (CNN) are a commonly used example in neuroradiology. Radiomics is a frequently used approach in which a multitude of imaging features are extracted from a region of interest and subsequently reduced and selected to convey diagnostic or prognostic information. Deep radiomics uses CNNs to directly extract features and obviate the need for predefined features. Common limitations and pitfalls in AI-based research in neuroradiology are limited sample sizes ("small-n-large-p problem"), selection bias, as well as overfitting and underfitting.


[Alogliptin (Vipidia): a selective DPP-4 inhibitor with a good cardiovascular safety].
Alogliptin (Vipidia) is a new selective inhibitor of dipeptidyl peptidase-4. By potentiating insulin secretion and by inhibiting glucagon secretion, both in a glucose-dependent manner, it improves glucose control of type 2 diabetic patients, without increasing the risk of hypoglycaemia and inducing weight gain, with an excellent clinical and biological tolerance. Both efficacy and safety have been demonstrated in randomised controlled trials, in monotherapy or in combination with other oral antidiabetic agents or even insulin. These results were obtained independently of clinical or demographic patient characteristics, including in elderly subjects and in patients with renal insufficiency. However, because alogliptin is eliminated through the kidneys, the usual dose of 25 mg once daily should be reduced to 12.5 mg per day in case of moderate renal impairment and to 6.25 mg per day in case of severe renal failure. Cardiovascular safety of alogliptin has been demonstrated in a large prospective study (EXAMINE) showing non-inferiority versus placebo in type 2 diabetic patients following an acute coronary syndrome.


A Comparison of China's Risk Communication in Response to SARS and H7N9 Using Principles Drawn From International Practice.
China's emergency management of severe acute respiratory syndrome (SARS) was heavily criticized, whereas the H7N9 response was praised by the international community.AimsThe aims of this study were to examine and compare the strengths and weaknesses of risk communication conducted in response to SARS and H7N9 and their associated social impacts on affected communities in China. A qualitative comparative case study approach was employed in the present study, using a set of 8 risk communication principles selected from international literature to suit the Chinese context for the comparative analysis of emergency responses of SARS and H7N9. The study found significant differences in the risk communication conducted in the 2 cases. The SARS outbreak fully exposed China's lack of experience in public health risk communication. By contrast, the Chinese government's risk communication strategies had improved significantly during the H7N9 outbreak.DiscussionTrust is the basis for communication. Maintaining an open and honest attitude and actively engaging stakeholders to address their risk information needs will serve to build trust and facilitate multi-sector collaborations in dealing with a public health crisis. From SARS to H7N9, risk communication practices in China greatly improved, which, in turn, lessened adverse social impacts and improved outcomes in emergency management of public health crises. (Disaster Med Public Health Preparedness. 2018;12:587-598).


Breast development in the newborn.
Breast size and milk secretion was studied in term and preterm infants. Breast nodules were palpable in most of the mature infants, both boys and girls. In 6 term infants without palpable breast tissue there was a high incidence of complications during late pregnancy or delivery. In light-for-gestational age infants the breast diameter was generally appropriate for gestation. None of the infants under 31 weeks' gestation had palpable breast tissue at birth, but some in the first weeks of life developed breast tissue and secreted milk. Milk had been secreted by most of the mature infants by age 7 days, and the onset was earlier in light-for-dates infants. The breast does not regress rapidly after birth. The nodules persist into the second half of the first year by which time sex differences have emerged. Clearly the growth and activity of the neonatal breast cannot be explained solely in terms of the influence of maternal hormones towards the end of gestation. Further studies on early breast tissue development may indicate the other endocrine factors concerned.


[The use of the aquarium fishes Danio rerio and Poecilia reticulata as highly sensitive species for testing the carcinogenicity of chemical compounds].
Aquarium fishes Danio rerio and Poecilia reticulata are recommended as test-objects for testing carcinogenic chemical agents. 30 compounds were tested for their action on these objects. The analysis of the incidence of induced tumors, period of their appearance and Iball index shows high sensitivity of the aquarium fishes to the carcinogenic action. Data are presented on the dynamics of experimental carcinogenesis, morphology of induced tumours, as well as on modifications of carcinogenesis (the role of environmental temperature, age, dose, exposition, etc.). Advantages and limitations of the "fish model" are compared with those found in the experiments carried on mammals.


CD4+ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors.
During acute human immunodeficiency virus (HIV) infection, there is a massive depletion of CD4(+) T cells in the gut mucosa that can be reversed to various degrees with antiretroviral therapy. Th17 cells have been implicated in mucosal immunity to extracellular bacteria, and preservation of this subset may support gut mucosal immune recovery. However, this possibility has not yet been evaluated in HIV-1-infected long-term nonprogressors (LTNPs), who maintain high CD4(+) T cell counts and suppress viral replication in the absence of antiretroviral therapy. In this study, we evaluated the immunophenotype and function of CD4(+) T cells in peripheral blood and gut mucosa of HIV-uninfected controls, LTNPs, and HIV-1-infected individuals treated with prolonged antiretroviral therapy (ART) (VL [viral load]<50). We found that LTNPs have intact CD4(+) T cell populations, including Th17 and cycling subsets, in the gut mucosa and a preserved T cell population expressing gut homing molecules in the peripheral blood. In addition, we observed no evidence of higher monocyte activation in LTNPs than in HIV-infected (HIV(-)) controls. These data suggest that, similar to nonpathogenic simian immunodeficiency virus (SIV) infection, LTNPs preserve the balance of CD4(+) T cell populations in blood and gut mucosa, which may contribute to the lack of disease progression observed in these patients.


Abomasal size and emptying time in healthy lambs and in lambs affected by watery mouth.
Contrast radiography (barium sulphate suspension fed by stomach tube) was used to assess abomasal profile area (a reflection of tone in the abomasal wall) and the rate of abomasal emptying in healthy lambs aged four to 144 hours and in lambs affected by watery mouth. In healthy lambs abomasal profile area increased from 15.1 +/- 0.56 cm2/kg at four hours of age to 23.1 +/- 1.07 cm2/kg at 24 to 48 hours (P less than 0.001). There was no change up to 48 to 72 hours but after this age there was a substantial decrease to 12.8 +/- 0.76 cm2/kg at 120 to 144 hours (P less than 0.001). The rate of abomasal emptying decreased as abomasal profile area increased. Complete emptying of the abomasum was observed within three hours of feeding in the majority of lambs aged four hours (seven out of eight) and 120 to 144 hours (13 out of 16) but only in a minority of lambs aged 24 to 48 hours (one out of 11). In lambs affected by watery mouth (mean age [+/- se] 33 +/- 2.8 hours, n = 34) abomasal profile area was greater and the rate of abomasal emptying was slower than in healthy lambs aged 24 to 48 hours. These findings confirm the previous suspicion that watery mouth is associated with an impairment of gut motility. Abomasal emptying time was prolonged in lambs aged four hours when either ewe or cow colostrum was included with the contrast medium. A similar effect was observed in lambs aged 24 to 48 hours when cow colostrum was included. The castration of lambs aged four hours with rubber rings immediately before the administration of contrast medium had no effect on the rate of abomasal emptying.


Optical concatenation of a large number of beads with a single-beam optical tweezer.
Optical tweezers consist of the spatial confinement of microscopic dielectric particles by the action of forces produced by the change in momentum of the photons of a highly focused laser beam that are deviated by the particle. In experiments that use a single laser beam, it is common to capture not only one but a few particles in the optical trap. However, to our knowledge, the formation of a long chain of beads optically confined with a single laser beam has never been reported. In this work, up to 73 silica spheres immersed in water are seen concatenated along the propagation direction of a 976-nm wavelength Gaussian laser of 300 mW of power. This long chain of beads is obtained when the laser is focused through an oil-immersion DIN microscope objective with 100× magnification and a numerical aperture of 1.25. When performing the same experiment using an infinity-corrected UplanFLN 100× objective with a numerical aperture of 1.3, the maximum number of concatenated beads is only 14. Our results suggest that the mechanisms responsible for the observed phenomena involve successive refocusing of the laser beam by each trapped sphere, optically induced dipole coupling (commonly referred to as optical binding), and aberrations generated by the DIN microscope objective.


Modelling the energy balance of an anaerobic digester fed with cattle manure and renewable energy crops.
Knowledge of the net energy production of anaerobic fermenters is important for reliable modelling of the efficiency of anaerobic digestion processes. By using the Anaerobic Digestion Model No. 1 (ADM1) the simulation of biogas production and composition is possible. This paper shows the application and modification of ADM1 to simulate energy production of the digestion of cattle manure and renewable energy crops. The paper additionally presents an energy balance model, which enables the dynamic calculation of the net energy production. The model was applied to a pilot-scale biogas reactor. It was found in a simulation study that a continuous feeding and splitting of the reactor feed into smaller heaps do not generally have a positive effect on the net energy yield. The simulation study showed that the ratio of co-substrate to liquid manure in the inflow determines the net energy production when the inflow load is split into smaller heaps. Mathematical equations are presented to calculate the increase of biogas and methane yield for the digestion of liquid manure and lipids for different feeding intervals. Calculations of different kinds of energy losses for the pilot-scale digester showed high dynamic variations, demonstrating the significance of using a dynamic energy balance model.


Atrial fibrillation and cardiac resynchronization therapy.
Atrial fibrillation and heart failure are commonly encountered in current clinical practice. This review aims to revisit the complex interaction of these two common situations and the best treatment whenever both occurs, especially focusing on heart failure patients undergoing cardiac resynchronization therapy (CRT). It has been recently confirmed that in patients undergoing cardiac resynchronization therapy, 100% biventricular pacing percentage should be pursued. Large observational studies confirmed that atrioventricular junction ablation is very often the only way to gain 100% biventricular pacing in atrial fibrillation. On the basis of the recent observational extensive data, in patients presenting intermediate or elevated atrial tachycardia-atrial fibrillation burden, atrioventricular junction ablation may represent a fundamental tool to achieve full CRT delivery, thus, conferring marked improvements in global cardiac function, and by extension, in survival. Atrial fibrillation patients should not be excluded from CRT, provided that maximal biventricular pacing is warranted.


Enhanced expression of ATP-binding cassette transporter A1 in non-rafts decreases the sensitivity of vascular endothelial cells to Shiga toxin.
Shiga toxin (Stx) binds to globotriaosyl ceramide (Gb3) receptors on the surface of vascular endothelial cells, which is followed by Gb3-dependent endocytosis, and initiates a cascade leading to cell damage. The Gb3 receptor is localized in lipid rafts, in which cholesterol is tightly packed primarily with sphingolipids in a liquid-ordered state. Recent studies have indicated that phosphodiesterase (PDE) type 4 inhibitors enhance the expression of ATP-binding cassette 1 (ABCA1) which promotes cholesterol efflux from non-rafts at the plasma membrane. Here we report that rolipram, a PDE4 inhibitor, reduced the sensitivity to Stx2 of human umbilical vascular endothelial cells in association with increased apolipoproteinA-I (apoA-I)-mediated cholesterol efflux, and shift of some Gb3 molecules from lipid rafts into non-rafts. Although rolipram treatment did not reduce Gb3 content at the plasma membrane and Stx binding to whole cells of HUVECs, it reduced Stx2 endocytosis. Knockdown of ABCA1 by transfection with siRNA ABCA1 in vascular endothelial cells abrogated the protective effect of rolipram on Stx2-exposed cells. Our present results suggest that the expression level of ABCA1 protein is one of critical determinants of Stx sensitivity levels in vascular endothelial cells.


Development of a bacterial challenge test for gnotobiotic Nile tilapia Oreochromis niloticus larvae.
Gastrointestinal microbiota have an important impact on fish health and disease, stimulating interest in a better understanding of how these gastrointestinal microbial communities are composed and consequently affect host fitness. In this respect, probiotic microorganisms have been extensively used in recent aquaculture production. To study the use of probiotics in the treatment of infectious diseases, the establishment of a method of experimental infection to obtain consistent results for mortality and infection in challenge tests is important. In pathogen-screening tests, 4 candidate pathogenic bacteria strains (Edwardsiella ictaluri gly09, E. ictaluri gly10, E. tarda LMG2793 and Streptococcus agalactiae LMG15977) were individually tested on xenic Nile tilapia larvae. Only Edwardsiella strains delivered via Artemia nauplii, with or without additional pathogen delivery via the culture water, led to increased mortality in fish larvae. A gnotobiotic Nile tilapia larvae model system was developed to provide a research tool to investigate the effects and modes-of-action of probiotics under controlled conditions. A double disinfection procedure using hydrogen peroxide and sodium hypochlorite solution was applied to the fish eggs, which were subsequently incubated in a cocktail of antibiotic and antifungal agents. In the gnotobiotic challenge test, E. ictaluri gly09R was added to the model system via Artemia nauplii and culture water, resulting in a significant mortality of the gnotobiotic fish larvae. The developed gnotobiotic Nile tilapia model can be used as a tool to extend understanding of the mechanisms involved in host-microbe interactions and to evaluate new methods of disease control.


Russell Viper Venom: A Journey from the Bedside to the Bench and Back to the Bedside.
Russel Viper Venom (RVV) is widely used as a diagnostic test for antiphospholipid syndrome (APS). But the history of how this venom came to be discovered is well known. Dr Patrick Russel is responsible for the identification of the venom during his work on snake bites in India while Dr Robert Macfarlane used it to staunch bleeding in persons with haemophilia. The ability to directly activate factor X led RVV to the laboratory diagnosis of APS. More recently, it has come back to clinical world with a potential for an engineered factor X activator from RVV to be used in the treatment of haemophilia.


Magnetic direction finding: evidence for its use in migratory indigo buntings.
The orientational capabilities of caged migratory indigo buntings were studied under differing magnetic field conditions. When tested in a situation allowing minimal exposure to visual cues but in the presence of the normal geomagnetic field, the birds demonstrated a significant orientation in the appropriate migratory direction (to the north). When the horizontal component of the magnetic field was deflected clockwise 120 degrees by activation of Helmholtz coils surrounding the cage, the orientation of the buntings shifted accordingly (clockwise to geographic east-southeast). These results suggest that indigo buntings are not only able to detect the geomagnetic field, but also can use this information in the finalization of their migratory direction.


Effects of eprosartan on target organ protection.
Hypertension is the most important cardiovascular risk factor for stroke. Blood pressure reduction by antihypertensive treatment is clearly efficacious in the prevention of stroke (both primary and secondary), although no clear differences have yet been observed between antihypertensive drug classes. However, a recent study reported the clear superiority of the angiotensin-receptor blocker eprosartan over the calcium channel blocker nitrendipine in cardiovascular protection of hypertensive patients with a previous stroke. Comparative studies using angiotensin-receptor blockers have also suggested the superiority of this class of drugs on primary stroke prevention. This effect may be linked to their beneficial actions on left ventricular hypertrophy, atrial enlargement, and supraventricular arrhythmias, endothelial dysfunction, inflammation, and remodelling, as well as a direct neuroprotective effect mediated through the stimulation of the angiotensin II type-2 receptor. In addition, a sympathoinhibition observed with the renin-angiotensin system blockers and particularly demonstrated with eprosartan, may help to explain the better cardiovascular and cerebrovascular protection in comparison with the calcium antagonist nitrendipine.


Toilet Training: Common Questions and Answers.
Toilet training is a significant developmental milestone in early childhood. Most U.S. children achieve the physiologic, cognitive, and emotional development necessary for toilet training by 18 to 30 months of age. Markers of readiness for toilet training include being able to walk, put on and remove clothing, and follow parental instruction; expressive language; awareness of a full bladder or rectum; and demonstrated dissatisfaction with a soiled diaper. Other readiness cues include imitating toileting behavior, expressing desire to toilet, and demonstrating bladder or bowel control (staying dry through a nap or through the night). Physicians should provide anticipatory guidance to parents beginning at about 18 to 24 months of age, noting the signs of toilet training readiness, and setting realistic expectations for parents. Parents should be counseled that no training method is superior to another. Parents should choose a method that is best suited to them and their child, and the method should use positive reinforcement. Complications of toilet training include stool toileting refusal, stool withholding, encopresis, hiding to defecate, and enuresis. These problems typically resolve with time, although some may require further investigation and treatment. Medical comorbidities such as Down syndrome, autism spectrum disorder, and cerebral palsy reduce the likelihood of successfully attaining full toilet training and often require early consultation with occupational therapists, developmental pediatricians, or other subspecialists to aid in toilet training.


Short- and long-term effects of highly active antiretroviral therapy on Kaposi sarcoma-associated herpesvirus immune responses and viraemia.
To investigate the effect of highly active antiretroviral therapy (HAART) on Kaposi sarcoma-associated herpesvirus (KSHV) DNA load, anti-KSHV antibody responses and KSHV-specific CD8 T cell responses in HIV-infected individuals over a 2 year period. Prospective study of 27 HIV-infected antiretroviral therapy-naive individuals, with (n = 4) and without KS (n = 23), before HAART and at 3-month intervals, during treatment with HAART. Sequential blood samples were collected for anti-KSHV antibody detection, KSHV DNA load in peripheral blood mononuclear cells (PBMC) and plasma, HIV Gag-specific and KSHV-specific CD8 T cell responses, HIV-1 plasma RNA load and CD4 and CD8 T cell counts. KSHV DNA in PBMC and plasma became less detectable over time during HAART, in particular after 12 months. KSHV DNA was undetectable in plasma after 24 months on HAART. Anti-KSHV lytic, but not latent, antibody levels increased within 12 months of treatment. KSHV-specific CD8 T cell responses were absent prior to HAART but became detectable in some patients within 6 months of starting treatment, and continued to increase thereafter. HAART (both protease inhibitor-based and non-nucleoside reverse transcriptase inhibitor-based antiretroviral combinations) is associated with immune reconstitution to KSHV and with undetectable KSHV viraemia. However, this restoration is apparent (in particular) only after a relatively long (> 24 months) period of treatment. These immune responses could contribute to the decreased incidence of KS during HAART, but it is unlikely to be a complete explanation for the often rapid resolution of KS when HAART is started.


Predicting Patients at Risk of 30-Day Unplanned Hospital Readmission.
We developed a machine learning model to predict 30-day readmissions using the model types; XGBoost, Random Forests and Adaboost with decision stumps as a base learner with different feature combinations and preprocessing procedures. The proposed model achieved the F1-score (0.386 ± 0.006), sensitivity (0.598 ± 0.013), positive predictive value (PPV) (0.285 ± 0.004) and negative predictive value (NPV) (0.932 ± 0.002). When compared with LACE and PARR (NZ) models, the proposed model achieved better F1-score by 12.5% compared to LACE and 22.9% compared to PARR (NZ). The mean sensitivity of the proposed model was 6.0% higher than LACE and 42.4% higher than PARR (NZ). The mean PPV was 15.9% and 13.5% higher than LACE and PARR (NZ) respectively.


Development and characterization of a long-term murine model of Streptococcus pneumoniae infection of the lower airways.
Chronic obstructive pulmonary disease (COPD) is characterized by long periods of stable symptoms, but exacerbations occur, which result in a permanent worsening of symptoms. Previous studies have shown a link between bacterial colonization of the lower airways of COPD sufferers and an increase in exacerbation frequency. One of the most frequent bacterial colonizers is Streptococcus pneumoniae. To mimic this aspect of COPD, a murine model of low-level pneumococcal colonization in the lung has been developed, in which S. pneumoniae persisted in the lungs for at least 28 days. From day 14 postinfection, bacterial numbers remained constant until at least 28 days postinfection, and animals showed no outward signs of disease. The bacterial presence correlated with a low-level inflammatory response that was localized to small foci across the left and inferior lobes of the lung. The cellular response was predominantly monocytic, and focal fibroplasia was observed at the airway transitional zones. Physiological changes in the lungs were investigated with a Forced Maneuvers system. This new model provides a means of study of a long-term pulmonary infection with a human pathogen in a rodent system. This is an excellent tool for the development of future models that mimic complex respiratory diseases such as COPD and asthma.


Systemic Mastocytosis and Essential Thrombocythemia: Case Report and Literature Overview.
Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.


TRPV4-associated skeletal dysplasias.
Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis.


Electron dynamics in inhomogeneous magnetic fields.
This review explores the dynamics of two-dimensional electrons in magnetic potentials that vary on scales smaller than the mean free path. The physics of microscopically inhomogeneous magnetic fields relates to important fundamental problems in the fractional quantum Hall effect, superconductivity, spintronics and graphene physics and spins out promising applications which will be described here. After introducing the initial work done on electron localization in random magnetic fields, the experimental methods for fabricating magnetic potentials are presented. Drift-diffusion phenomena are then described, which include commensurability oscillations, magnetic channelling, resistance resonance effects and magnetic dots. We then review quantum phenomena in magnetic potentials including magnetic quantum wires, magnetic minibands in superlattices, rectification by snake states, quantum tunnelling and Klein tunnelling. The third part is devoted to spintronics in inhomogeneous magnetic fields. This covers spin filtering by magnetic field gradients and circular magnetic fields, electrically induced spin resonance, spin resonance fluorescence and coherent spin manipulation.


Surface charge manipulation and electrostatic immobilization of synaptosomes for super-resolution imaging: a study on tau compartmentalization.
Synaptosomes are subcellular fractions prepared from brain tissues that are enriched in synaptic terminals, widely used for the study of neural transmission and synaptic dysfunction. Immunofluorescence imaging is increasingly applied to synaptosomes to investigate protein localization. However, conventional methods for imaging synaptosomes over glass coverslips suffer from formaldehyde-induced aggregation. Here, we developed a facile strategy to capture and image synaptosomes without aggregation artefacts. First, ethylene glycol bis(succinimidyl succinate) (EGS) is chosen as the chemical fixative to replace formaldehyde. EGS/glycine treatment makes the zeta potential of synaptosomes more negative. Second, we modified glass coverslips with 3-aminopropyltriethoxysilane (APTES) to impart positive charges. EGS-fixed synaptosomes spontaneously attach to modified glasses via electrostatic attraction while maintaining good dispersion. Individual synaptic terminals are imaged by conventional fluorescence microscopy or by super-resolution techniques such as direct stochastic optical reconstruction microscopy (dSTORM). We examined tau protein by two-color and three-color dSTORM to understand its spatial distribution within mouse cortical synapses, observing tau colocalization with synaptic vesicles as well postsynaptic densities.


The use of external fixators for finger injuries: pin placement and tethering of the extensor hood.
External fixation is useful for the treatment of selected injuries to the hand. Some authors have suggested that external fixation of a phalanx may tether the extensor hood, thereby hindering active movements and predisposing to permanent adhesions. There is no consensus as to the best site for placement of the pin to minimise these problems. This study was performed on cadaver specimens to investigate the influence of the pin site on the range of simulated active movement of the interphalangeal joint. The dorsal midline position produces least interference with the extensor mechanism; radial and ulnar to this, interdigitating oblique fibres prevent a clean longitudinal split in the direction of gliding thus limiting movement of the extensor hood. At the proximal phalanx, positioning of the pin just off the midline avoids the thickening of the proximal median hood, whereas at the middle phalanx, a true midline position utilises the bare area at its base.


Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic.
Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.


Mobility overestimation due to gated contacts in organic field-effect transistors.
Parameters used to describe the electrical properties of organic field-effect transistors, such as mobility and threshold voltage, are commonly extracted from measured current-voltage characteristics and interpreted by using the classical metal oxide-semiconductor field-effect transistor model. However, in recent reports of devices with ultra-high mobility (>40 cm(2) V(-1) s(-1)), the device characteristics deviate from this idealized model and show an abrupt turn-on in the drain current when measured as a function of gate voltage. In order to investigate this phenomenon, here we report on single crystal rubrene transistors intentionally fabricated to exhibit an abrupt turn-on. We disentangle the channel properties from the contact resistance by using impedance spectroscopy and show that the current in such devices is governed by a gate bias dependence of the contact resistance. As a result, extracted mobility values from d.c. current-voltage characterization are overestimated by one order of magnitude or more.


Increased volume and collagen crosslinks drive soft tissue contribution to post-traumatic elbow contracture in an animal model.
Post-traumatic joint contracture (PTJC) in the elbow is a biological problem with functional consequences. Restoring elbow motion after injury is a complex challenge because contracture is a multi-tissue pathology. We previously developed an animal model of elbow PTJC using Long-Evans rats and showed that the capsule and ligaments/cartilage were the primary soft tissues that caused persistent joint motion loss. The objective of this study was to evaluate tissue-specific changes within the anterior capsule and lateral collateral ligament (LCL) that led to their contribution to elbow contracture. In our rat model of elbow PTJC, a unilateral surgery replicated damage that commonly occurs due to elbow dislocation. Following surgery, the injured limb was immobilized for 42 days. The capsule and LCL were evaluated after 42 days of immobilization or 42 days of immobilization followed by 42 days of free mobilization. We evaluated extracellular matrix protein biochemistry, non-enzymatic collagen crosslink content, tissue volume with contrast-enhanced micro-computed tomography, and tissue mechanical properties. Increased collagen content, but not collagen density, was observed in both injured limb capsules and LCLs, which was consistent with the increased tissue volume. Injured limb LCLs exhibited decreased normalized maximum force, and both tissues had increased immature collagen cross-links compared to control. Overall, increased tissue volume and immature collagen crosslinks in the capsule and LCL drive their contribution to elbow contracture in our rat model.


Mental health of college students and their non-college-attending peers: results from a large French cross-sectional survey.
The great majority of mental disorders begin during adolescence or early adulthood, although they are often detected and treated later in life. To compare mental health status of college students and their non-college-attending peers whether working, attending a secondary school, or non-college-attending peers who are neither employed nor students or trainees (NENST) will allow to focus on high risk group. Data were drawn from a large cross-sectional survey conducted by phone in 2005 in four French regions in a randomly selected sample of 22,138 adults. Analyses were restricted to the college-age subsample, defined as those aged 18 to 24 (n = 2424). Sociodemographic, educational, and occupational status were determined. In addition, respondents were administered standardized instruments to assess mental health and well-being (CIDI-SF, SF-36, Sheehan Disability Scale, CAGE), mastery, social support, and isolation. The four occupational groups were compared. All analyses were stratified by gender. Mental health disorders were more prevalent among the NENST group, with significant differences among men for anxiety disorders including phobias, post-traumatic stress disorder (PTSD) and panic disorder, impairing at least one role in their daily life. This was also true among women except for panic disorder. The NENST group also reported the lowest level of mastery and social support for both genders and the highest level of social isolation for women only. After adjustment, occupational status remained an independent correlate of PTSD (OR = 2.92 95 % CI = 1.4-6.1), agoraphobia (OR = 1.86 95 % CI 1.07-3.22) and alcohol dependence (OR = 2.1 95 % CI = 1.03-4.16). Compared with their peers at work or in education/training, the prevalence of certain common mental health disorders was higher among college-aged individuals in the NENST group. Efforts should be made to help young adults in the transition between school or academic contexts and joining the workforce. It is also important to help youths with psychiatric disorders find an occupational activity and provide them information, care, support and counseling, particularly in times of economic hardship. Schools and universities may be adequate institutional settings to set health promotion programs in mental health and well-being.


[Increased incidence of coronary artery disease and cardiac death in elderly diabetic nephropathy patients undergoing chronic hemodialysis therapy].
The incidence of coronary artery disease and cardiac death was investigated in elderly diabetic patients undergoing chronic hemodialysis therapy. Three hundred thirty-five patients who began hemodialysis therapy since 1992 were followed up by echocardiography and treadmill exercise testing. Coronary angiography was also performed in patients with angina pectoris. Angina pectoris was defined as clinical symptoms > Canadian Cardiovascular Society classification II, and asynergy findings by echocardiography or ST depression > 0.1 mV during the treadmill exercise test. Coronary artery stenosis was defined as narrowing > or = 75%. Patients were divided into 4 groups: diabetic nephropathy (DN) > or = 65 years old (Group O/DN, n = 56), DN < 65 years old (Group Y/DN, n = 84), non-DN > or = 65 years old (Group O/non-DN, n = 76) and non-DN < 65 years old (Group Y/non-DN, n = 119). Between 1992 and 1998, there were 137 patients with angina pectoris (40.9%), 79 with coronary artery stenosis (23.6%) and 37 with cardiac death (11.0%). Cumulative incidences of angina pectoris, coronary artery stenosis and cardiac death were significantly higher in the following order of groups; O/DN > Y/DN > O/non-DN > Y/non-DN. Five-year cumulative incidences of angina pectoris, coronary artery stenosis and cardiac death in Groups O/DN vs Y/non-DN were 72.2% vs 38.6%, 53.7% vs 12.2% and 50.6% vs 3.5%, respectively. Relative risks of aging and diabetic nephropathy for angina pectoris, coronary artery stenosis and cardiac death were 3.8, 7.9 and 22.4, respectively (p < 0.0001). Aging and the presence of diabetes are strong risk factors for coronary artery disease and cardiac death in hemodialysis patients. Therefore, diagnosis and treatment of coronary artery disease should be achieved at the early stage of hemodialysis therapy.


No evidence of somatotopic place of articulation feature mapping in motor cortex during passive speech perception.
The motor theory of speech perception has experienced a recent revival due to a number of studies implicating the motor system during speech perception. In a key study, Pulvermüller et al. (2006) showed that premotor/motor cortex differentially responds to the passive auditory perception of lip and tongue speech sounds. However, no study has yet attempted to replicate this important finding from nearly a decade ago. The objective of the current study was to replicate the principal finding of Pulvermüller et al. (2006) and generalize it to a larger set of speech tokens while applying a more powerful statistical approach using multivariate pattern analysis (MVPA). Participants performed an articulatory localizer as well as a speech perception task where they passively listened to a set of eight syllables while undergoing fMRI. Both univariate and multivariate analyses failed to find evidence for somatotopic coding in motor or premotor cortex during speech perception. Positive evidence for the null hypothesis was further confirmed by Bayesian analyses. Results consistently show that while the lip and tongue areas of the motor cortex are sensitive to movements of the articulators, they do not appear to preferentially respond to labial and alveolar speech sounds during passive speech perception.


Effects of Sad and Happy Music on Mind-Wandering and the Default Mode Network.
Music is a ubiquitous phenomenon in human cultures, mostly due to its power to evoke and regulate emotions. However, effects of music evoking different emotional experiences such as sadness and happiness on cognition, and in particular on self-generated thought, are unknown. Here we use probe-caught thought sampling and functional magnetic resonance imaging (fMRI) to investigate the influence of sad and happy music on mind-wandering and its underlying neuronal mechanisms. In three experiments we found that sad music, compared with happy music, is associated with stronger mind-wandering (Experiments 1A and 1B) and greater centrality of the nodes of the Default Mode Network (DMN) (Experiment 2). Thus, our results demonstrate that, when listening to sad vs. happy music, people withdraw their attention inwards and engage in spontaneous, self-referential cognitive processes. Importantly, our results also underscore that DMN activity can be modulated as a function of sad and happy music. These findings call for a systematic investigation of the relation between music and thought, having broad implications for the use of music in education and clinical settings.


RNA function and phosphorus use by photosynthetic organisms.
Phosphorus (P) in RNA accounts for half or more of the total non-storage P in oxygenic photolithotrophs grown in either P-replete or P-limiting growth conditions. Since many natural environments are P-limited for photosynthetic primary productivity, and peak phosphorus fertilizer production is inevitable, the paper analyses what economies in P allocation to RNA could, in principle, increase P-use efficiency of growth (rate of dry matter production per unit organism P). The possibilities of decreasing P allocation to RNA without decreasing growth rate include (1) more widespread down-regulation of RNA production in P-limited organisms, (2) optimal allocation of P to RNA, both spatially among cell compartments and organs, and temporally depending on the stage of growth, and (3) a constant rate of protein synthesis through the diel cycle. Acting on these suggestions would, however, be technically demanding.


The development of a promising photosensitive Schottky barrier diode using a novel Cd(ii) based coordination polymer.
A novel 1D Cd(ii) based coordination polymer (complex 1) has been synthesized involving an 8-aminoquinoline based Schiff base ligand and cyanate ion. It has been characterized by elemental analysis, different spectroscopy methods and X-ray single crystal diffraction technique. Most interestingly it exhibits unique properties like electrical conductivity and photosensitivity which shows its potential in optoelectronic device application. We prove both experimentally and theoretically that electrical conduction under irradiation of visible light increases many fold in comparison with that under dark condition. Our synthesized material based device shows some paramount behaviour under irradiance of light which is obvious in light sensing Schottky devices. The rectification ratio of our complex based device was found to be 12.44 and 27.74 under dark and photoirradiation conditions respectively. The discovery of such type of coordination polymer advances the area of optoelectronic devices.


Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila.
Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINSC96Y and hINSLB15YB16delinsH, neither of which secreted from the β-cells, could not stimulate the Drosophila growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent Xbp1 mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of Growth arrest and DNA-damage-inducible 45 (Gadd45) in imaginal disc cells. ER stress induced by hINSC96Y also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.


The role of dynamic stimulation pattern in the analysis of bistable intracellular networks.
Bistable systems play an important role in the functioning of living cells. Depending on the strength of the necessary positive feedback one can distinguish between (irreversible) "one-way switch" or (reversible) "toggle-switch" type behavior. Besides the well- established steady-state properties, some important characteristics of bistable systems arise from an analysis of their dynamics. We demonstrate that a supercritical stimulus amplitude is not sufficient to move the system from the lower (off-state) to the higher branch (on-state) for either a step or a pulse input. A switching surface is identified for the system as a function of the initial condition, input pulse amplitude and duration (a supercritical signal). We introduce the concept of bounded autonomy for single level systems with a pulse input. Towards this end, we investigate and characterize the role of the duration of the stimulus. Furthermore we show, that a minimal signal power is also necessary to change the steady state of the bistable system. This limiting signal power is independent of the applied stimulus and is determined only by systems parameters. These results are relevant for the design of experiments, where it is often difficult to create a defined pattern for the stimulus. Furthermore, intracellular processes, like receptor internalization, do manipulate the level of stimulus such that level and duration of the stimulus is conducive to characteristic behavior.


A mathematical model of immune activation with a unified self-nonself concept.
The adaptive immune system reacts against pathogenic nonself, whereas it normally remains tolerant to self. The initiation of an immune response requires a critical antigen(Ag)-stimulation and a critical number of Ag-specific T cells. Autoreactive T cells are not completely deleted by thymic selection and partially present in the periphery of healthy individuals that respond in certain physiological conditions. A number of experimental and theoretical models are based on the concept that structural differences discriminate self from nonself. In this article, we establish a mathematical model for immune activation in which self and nonself are not distinguished. The model considers the dynamic interplay of conventional T cells, regulatory T cells (Tregs), and IL-2 molecules and shows that the renewal rate ratio of resting Tregs to naïve T cells as well as the proliferation rate of activated T cells determine the probability of immune stimulation. The actual initiation of an immune response, however, relies on the absolute renewal rate of naïve T cells. This result suggests that thymic selection reduces the probability of autoimmunity by increasing the Ag-stimulation threshold of self reaction which is established by selection of a low number of low-avidity autoreactive T cells balanced with a proper number of Tregs. The stability analysis of the ordinary differential equation model reveals three different possible immune reactions depending on critical levels of Ag-stimulation: a subcritical stimulation, a threshold stimulation inducing a proper immune response, and an overcritical stimulation leading to chronic co-existence of Ag and immune activity. The model exhibits oscillatory solutions in the case of persistent but moderate Ag-stimulation, while the system returns to the homeostatic state upon Ag clearance. In this unifying concept, self and nonself appear as a result of shifted Ag-stimulation thresholds which delineate these three regimes of immune activation.


Vascular function in kidneys preserved by simple cold storage in Sacks' or Collins' solutions.
Vascular resistance was determined in 40 kidneys after preservation in Collins' or Sacks' solution for 24 and 48 hours. Kidneys without warm ischaemia and kidneys with up to 60 min of warm ischaemia prior to preservation were investigated, vascular resistance was determined during short time perfusion with Tis-U-Sol at 4 degrees. The experiments showed that cold preservation of kidneys with no warm ischaemia or 15 min of warm ischaemia gave a small increase in vascular resistance, independent of the solution used. 30 and 60 min of warm ischaemia gave a considerable increase in vascular resistance, but less increase was found in kidneys preserved in Sacks' solution. Determination of the weights and thereby formation of oedema showed slight dehydration in kidneys preserved in Sacks' solution. Kidneys preserved in Collins' solution showed small increase in weight. No correlation was, however, found between the vascular resistance and degree of oedema.


Active idiopathic ulcerative colitis in a patient with ongoing HIV-related immunodepression.
It is suspected that immune mechanisms are important in the pathogenesis of ulcerative colitis. The following is a case report of a patient with human immunodeficiency virus-related immunodeficiency whose ulcerative colitis ran a course independent of the depression of his peripheral CD4 cells. Thus, peripheral CD4 cells may have little role in the pathogenesis of ulcerative colitis.


A phase I/II study of continuous intra-arterial chemotherapy using an implantable reservoir for the treatment of liver metastases from breast cancer: a Japan Clinical Oncology Group (JCOG) study 9113. JCOG Breast Cancer Study Group.
Liver metastasis from breast cancer has a poor prognosis. While there are some reports of good response rates of hepatic metastasis from breast cancer by hepatic intra-arterial infusion chemotherapy, no phase I study including pharmacokinetic analysis has been reported. We performed a phase I/II study of intra-arterial infusion chemotherapy using adriamycin and 5-fluorouracil to find the maximum tolerated dose and response rate in patients with advanced or recurrent breast cancer. A hepatic arterial catheter with an access port was inserted into the proper hepatic artery. Patients received 30 mg/m2 adriamycin on days 1 and 8 and 100 mg/m2 5-fluorouracil at level 1, 200 mg/m2 at level 2,300 mg/m2 at level 3 and 400 mg/m2 at level 4 continuously from day 1 through day 14 every 28 days. At least two cycles were required before evaluation. Twenty-eight patients were entered into this study and 26 patients were evaluable. Seventeen patients had hepatic metastasis only, although nine patients had additional metastasis to other sites. Dose-limiting toxicity of thrombocytopenia and neurotoxicity occurred at level 4. Leukocytopenia (ECOG grade 3-4) was observed in five (19%), thrombocytopenia in three (12%) and anemia in two (8%) patients. There were 11 catheter-related complications which were not dose dependent. Seven out of 13 evaluable patients (54%) responded at level 3. The median duration of response was 5.8 months (range, 1-23+) and median survival was 25.3 months (range, 6.2-54.7+). Hepatic arterial infusion therapy appears to be safe and effective but catheter-related complications must be overcome before starting a phase III trial.


Detection of direct binding of human herpesvirus 8-encoded interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and -independent signaling.
Human herpesvirus 8 (HHV-8) is associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease; in all of these diseases, interleukin-6 (IL-6) has been implicated as a likely mitogenic and/or angiogenic factor. HHV-8 encodes a homologue of IL-6 (viral IL-6 [vIL-6]) that has been shown to be biologically active in several assays and whose activities mirror those of its mammalian counterparts. Like these proteins, vIL-6 mediates its effects through the gp130 signal transducer, but signaling is not dependent on the structurally related IL-6 receptor (IL-6R; gp80) subunit of the receptor-signal transducer complex. However, as we have shown previously, IL-6R can enhance vIL-6 signal transduction and can enable signaling through a gp130 variant (gp130.PM5) that is itself unable to support vIL-6 activity, indicating that IL-6R can form part of the signaling complex. Also, our analysis of a panel of vIL-6 mutants in transfection experiments in Hep3B cells (that express IL-6R and gp130) showed that most were able to function normally in this system. Here, we have used in vitro vIL-6-receptor binding assays to demonstrate direct binding of vIL-6 to both gp130 and IL-6R and vIL-6-induced gp130-IL-6R complex formation, and we have extended our functional analyses of the vIL-6 variants to identify residues important for IL-6R-independent and IL-6R-dependent signaling through native gp130 and gp130.PM5, respectively. These studies have identified residues in vIL-6 that are important for IL-6R-independent and IL-6R-mediated functional complex formation between vIL-6 and gp130 and that may be involved directly in binding to gp130 and IL-6R.


MR imaging in the differential diagnosis of neurogenic foot drop.
Prolonged T2 relaxation time of denervated muscle has been described in several clinical and experimental studies. The purpose of this study was to evaluate the utility of MR imaging in the diagnosis of neurogenic muscle disorders compared with that of clinical and electrophysiologic examination. In a prospective study, 40 consecutive patients clinically presenting with a foot drop were included. MR imaging of the lower leg included axial T1-weighted and axial turbo inversion recovery magnitude (TIRM) sequences. Two readers blinded to clinical data evaluated T1-weighted images for anatomic localization of affected muscles and TIRM images for patterns of signal intensity increase. After MR imaging, a detailed neurophysiologic examination was performed. Cause of foot drop was independently determined on the basis of MR and electrophysiologic data. Clinical examination and electromyography (EMG) disclosed 20 peroneal nerve lesions, nine cases of L5 radiculopathy, and 11 nerve lesions extending beyond neural structures. MR imaging revealed three distinct patterns of signal intensity increase on TIRM images: peroneal nerve pattern, L5 pattern, and unspecific pattern. MR imaging and EMG findings were in agreement in 37 (92%) of 40 patients. In three patients, MR imaging revealed a more widespread involvement than did EMG. In one of these patients, denervation in the corresponding muscle was validated by follow-up EMG. No false-negative diagnoses were made by use of MR imaging as compared with use of EMG. MR imaging improves accuracy in the differential diagnosis of peripheral nerve lesions compared with that of EMG and can supplement EMG in the diagnosis of denervated muscles.


Behavior problems antecede the development of wheeze in childhood: a birth cohort study.
It is not clear to what extent behavior problems observed in children with asthma antecede asthma development, or are a consequence of the disease. We investigated psychologic factors at age 3 years and subsequent development of wheeze by age 5 in an unselected birth cohort study. Children were recruited prenatally, followed prospectively, and reviewed at age 3 and 5 years. The rate of significant behavior problems at age 3 (above the clinically relevant cut-off on the Eyberg Child Behavior Inventory) was compared between children who had never wheezed (n = 397) and those developing late-onset wheezing (after age 3 years; n = 39). Late-onset wheezers were more likely to be above cut-offs for behavior problems at 3 years (before wheeze onset), compared with children who never wheezed, on Intensity (23.1% vs. 6.0%, p < 0.001) and Problem scores (10.8% vs. 1.3%, p < 0.001). Families of late-onset wheezers had poorer scores on family functioning variables, but we found no evidence of increased anxiety or depression scores in parents. In the multivariate analysis, significant and independent associates of late-onset wheeze were as follows: maternal asthma (odds ratio [OR] 5.4, 95% confidence intervals [CI] 2.1-13.8, p < 0.001), maternal smoking when child was 3 years (OR 3.3, CI 1.2-8.7, p = 0.02), expressiveness (OR 0.71, CI 0.55-0.9, p = 0.005), and significant behavior problems at age 3 years (OR 3.5, CI 1.2-9.9, p = 0.02). Behavior problems in early life are associated with increased risk of subsequent development of wheeze.


Analysis of Authorship in Hepatopancreaticobiliary Surgery: Women Remain Underrepresented.
Given the need to increase female representation in hepatopancreatobiliary (HPB) surgery, as well as the need to increase the academic pipeline of women in this subspecialty, we sought to characterize the prevalence of female authorship in the HPB literature. In particular, the objective of the current study was to determine the proportion of women who published HPB research articles as first, second, or last author over the last decade. All articles pertaining to hepatopancreaticobiliary (HPB) surgery appearing in seven surgical journals (Annals of Surgery, British Journal of Surgery, JAMA Surgery, Annals of Surgical Oncology, HPB (Oxford), Surgery, and Journal of Gastrointestinal Surgery) were reviewed for the years 2008 and 2018. Information on sex of author, country of author's institution, and article type was collected and entered into a computerized database. Among the 1473 index articles included in the final analytic cohort, 414 (28%) publications had a woman as the first or last author, while the vast majority (n = 1,059, 72%) had a man as the first or last author. The number of female first authors increased from 15.6% (n = 92/591) in 2008 to 25.7% (n = 227/882) in 2018 (p < 0.001). There were no differences in the proportion of second (n = 123/536, 23.0% vs n = 214/869, 24.6%, p = 0.47) or last (n = 44/564, 7.8% vs n = 88/875, 10.1%, p = 0.15) authors. Women were more likely to publish papers appearing in medium-impact journals (OR 1.40, 95% CI 1.04-1.88) and articles with a female author were more likely to be from a North American institution (referent: North America, Asia OR 0.43, 95% CI 0.31-0.59 vs Europe OR 0.67, 95% CI 0.51-0.87). Women first/last authors in HPB research articles have increased over the past 10 years from 22 to 32%. Women as last authors remain low, however, as only 1 in 10 papers had a senior woman author. These data should prompt HPB leaders to find solutions to the gap in female authorship including mentorship of young female researchers and surgeons.


Evaluation of the Persian version of modified fatigue impact scale in Iranian patients with multiple sclerosis.
Fatigue, a major cause of disability in individuals with multiple sclerosis (MS), is associated with reduced quality of life. The aim of this study was to evaluate the reliability and reproducibility of the Persian version of Modified Fatigue Impact Scale (MFIS) in Iranian patients with MS. This study included 15 subjects with clinically definite MS, 15 hospitalized patients with MS, and 15 hospitalized patients with other chronic illnesses (as controls). They filled in the Persian version of the MFIS twice with a three-day interval. MFIS items were analyzed and the correlation coefficient was calculated. THERE WAS A GOOD CORRELATION BETWEEN THE SCORES OF THE TWO MEASUREMENTS (CORRELATION COEFFICIENT: 0.984, P < 0.001) especially in physical and cognitive subgroups. The reproducibility of psychosocial subscale was lower than physical and cognitive subscales. According to our findings, the Persian version of the MFIS has a good reliability and reproducibility for assessment of fatigue in patients with MS.


Catalyst-free one step synthesis of large area vertically stacked N-doped graphene-boron nitride heterostructures from biomass source.
A procedure for the one-step preparation of films of few-layer N-doped graphene on top of nanometric hexagonal boron nitride sheets ((N)graphene/h-BN) based on the pyrolysis at 900 °C under an inert atmosphere of a film of chitosan containing about 20 wt% of ammonium borate salt as a precursor is reported. During the pyrolysis a spontaneous segregation of (N)graphene and boron nitride layers takes place. The films were characterized by optical microscopy that shows a thin graphene overlayer covering the boron nitride layer, the latter showing characteristic cracks, and by XPS measurements at different monitoring angles from 0° to 50° where an increase in the proportion of C vs. B and N was observed. The resulting (N)graphene/h-BN films were also characterized by Raman, HRTEM, SEM, FIB-SEM and AFM. The thickness of the (N)graphene and h-BN layers can be controlled by varying the concentration of precursors and the spin coating rate and is typically below 5 nm. Electrical conductivity measurements using microelectrodes can cause the burning of the graphene layer at high intensities, while lower intensities show that (N)graphene/h-BN films behave as capacitors in the range of positive voltages.


Changes in diagnostic investigation and improved detection of colon cancer, Manitoba 1964-1984.
Detection of colon cancer has improved in Manitoba over the last 20 years with decreases in diagnostic delay and failure. Between 1981 and 1984 diagnostic delay, resulting from initial false-negative examinations, occurred in 5.7% of patients. Diagnostic failure, because all investigations were negative in patients found to have cancer of the colon within one year, was 0.66%, compared with 9.5% and 5.8% respectively between 1964 and 1969. In the intervening time double-contrast barium examinations and colonoscopy were introduced and became more widely used, with a corresponding decline in single-contrast examinations. The mortality rate in the general population was unchanged despite an increased incidence, while 1980 survival rates suggested that women cancer patients were living longer than previously as well as longer than their male counterparts.


Texture classification by statistical learning from morphological image processing: application to metallic surfaces.
A classification method based on textural information for metallic surfaces displaying complex random patterns is proposed. Because these kinds of textures show fluctuations at a small scale and some uniformity at a larger scale, a probabilistic approach is followed, considering textural variations as realizations of random functions. Taking into account information of pixel neighbourhoods, the texture for each pixel is described at different scales. By means of statistical learning, the most relevant textural descriptors are selected for each application. The performance of this approach is established on a real data set of steel surfaces.


Enhancement of diazepam and gamma-aminobutyric acid binding by (+)etomidate and pentobarbital.
(+)Etomidate and pentobarbital enhance [3H]diazepam and [3H]gamma-aminobutyric acid [( 3H]GABA) binding to cerebral cortex membranes. Both (+)etomidate and pentobarbital increase the affinity of [3H]diazepam for its binding sites. In contrast, they increase the Bmax of both the high- and low-affinity GABA receptor sites. The enhancement of [3H]diazepam and [3H]GABA by (+)etomidate and pentobarbital is blocked by GABA antagonists. These results indicate that hypnotic drugs such as (+)etomidate and pentobarbital, which are not structurally related, modulate diazepam and GABA binding sites via similar mechanisms.


Chronic monitoring of vascular progression after ischemic stroke using multiexposure speckle imaging and two-photon fluorescence microscopy.
Monitoring the progression of the vascular structure and cerebral blood flow (CBF) after brain injury is vital to understand the neurovascular recovery process. Multiexposure speckle imaging (MESI) provides a quantitatively accurate technique for chronically measuring the postocclusion CBF perfusion of the infarct and peri-infarct regions in rodent stroke models, while multiphoton microscopy offers direct visualization of the microvascular structure. In this paper, we present imaging outcomes extending 35 days after photo-thrombotic occlusion, tracking the progression of the vasculature throughout this period. We compare MESI flow estimates within the unresolvable parenchyma with subsurface microvascular volume fractions taken with two-photon microscopy in the same regions to assess how the vascular density influences the surface-integrated MESI flow values. The MESI flow measurements and volume fractions are shown to have high correlations (r=0.90) within areas of recovering vasculature in the peri-infarct region. We also observe vascular reorientation occurring within the microvascular structure throughout the 35-day postocclusion period. With the combination of a chronic mouse model and relatively noninvasive optical imaging techniques, we present an imaging protocol for monitoring long-term vascular progression after photo-thrombotic occlusion with the potential to test the efficacy of rehabilitation and pharmacological therapies.


[Clinico-pathogenetic role of hormones of the pituitary-adrenal system and somatotropin in the development of immunosuppression in chronic hepatitis B and delta infection in children and the approach to its correction].
The basal level of secretion of hypophyseal (ACTH, STH) and peripheral glucocorticoid (cortisol, corticosterone) hormones as related to the immune status (lymphocyte subpopulations, serum immunoglobulins, circulating immune complexes, macrophagal component) and specific marker profiles of viruses B and delta was measured in 142 children with different forms of chronic virus hepatitis B and delta (D). The patients with chronic persistent hepatitis was characterized by the "cortisol" type response of stressor adaptation hormones in parallel with the genetically determined weak immune response, demanding no correction. The patients with chronic active hepatitis B and D demonstrated the "central" type of hormonal response with a primary increase in the content of ACTH and CTH and a moderate rise of the cortisol level, which correlated with pronounced secondary immunodeficiency of the T cell and macrophagal components of immune response. In the patients with chronic virus hepatitis B and D, the hormonal profile, as liver cirrhosis develops, is characterized by an increase in corticosterone and blood somatotropin and by a relatively low cortisol content. This reflects depletion of the mechanisms of adaptation and correlates with deep insufficiency of all the three components of immune response. The use of human leukocytic interferon and T-activin exert a well-defined effect on hormonal adaptation of immune response, promotes completion of HB-virus infection replication and the onset of a stable remission.


Isolation of an integral membrane glycoprotein by chloroform-methanol extraction and C3-reversed-phase high-performance liquid chromatography.
Methodology is presented for the isolation of integral membrane proteins and applied to the purification of the major myelin glycoprotein, P0. This isolation scheme depends on the detergent solubilization of an isoosmotically extracted membrane fraction from sciatic nerve endoneurium, followed by the removal of lipids and detergent by chloroform/methanol extraction. The resulting membrane proteins are readily dissolved in acetic acid/water (1/1) and directly analyzed by reversed-phase high-performance liquid chromatography. The hydrophobic nature of the intrinsic membrane protein mixture results in strong binding to a C8 stationary phase, leading to poor resolution and yields. These problems can be eliminated by employing a C3 alkylsilane column, thereby allowing separation of the protein components and the isolation of P0. The purified P0 has an amino-terminal sequence that matches that predicted from nucleotide sequencing, and the glycoprotein contains the expected amount of sialic acid. This latter finding indicates that the isolation procedure is not detrimental to the complex-type oligosaccharide structure of P0 and should make the methodology readily applicable to the purification of other integral membrane proteins and glycoproteins.


Regulation of TRPC6 Channels by Non-Steroidal Anti-Inflammatory Drugs.
Family focal segmental glomerulosclerosis (FSGS) is characterized by sclerosis and hyalinosis of particular loops of glomeruli and is one of the causes of the nephrotic syndrome. Certain mutations in the structure of TRPC6 channels are the genetic impetus for FSGS development resulting in podocytes functional abnormalities and various nephropathies. We have recently demonstrated that non-steroid anti-inflammatory drugs (NSAID) ibuprofen and diclofenac decrease the activity of endogenous TRPC like cal cium channels in the podocytes of the freshly isolated rat glomeruli. It has also been shown that TRPC6 chan nels are expressed in the podocytes. In the current study we have functionally reconstituted TRPC6 channels in mammalian cells to investigate the effects of diclofenac on the activity of wild type TRPC6 channel and TRPC6P112Q channel containing a mutation in the N-terminus that was described in FSGS patients. Intracellular calcium level measurements in transfected cells revealed a more intensive carbachol induced increase of calcium concentration in HEK 293 cells expressing TRPC6P112Q versus the cells expressing wild-type TRPC6. We also performed patch-clamp experiments to study TRPC6 channels reconstituted in Chinese hamster ovary (CHO) cell line and found that application of diclofenac (500 μM) acutely reduced single channel activity. Preincubation with diclofenac (100 μM) also decreased the whole cell current in CHO cells overexpressing TRPC6P112Q. Therefore, our previously published data on the effects of NSAID on TRPC-like channels in the isolated rat glomeruli, along with this current investigation on the cultured overexpressed mammalian cells, allows hypothesizing that TRPC6 channels may be a target for NSAID that can be impor tant in the treatment of FSGS.


A proof-of-concept study comparing tinnitus and neural connectivity changes following multisensory perceptual training with and without a low-dose of fluoxetine.
Background. This proof-of-concept study investigated a method of multisensory perceptual training for tinnitus, and whether a short, low-dose administration of fluoxetine enhanced training effects and changed neural connectivity.Methods. A double-blind, randomized placebo controlled design with 20 participants (17 male, 3 female, mean age = 57.1 years) involved 30 min daily computer-based, multisensory training (matching visual, auditory and tactile stimuli to perception of tinnitus) for 20 days, and random allocation to take 20 mg fluoxetine or placebo daily. Behavioral measures of tinnitus and correlations between pairs of a priori regions of interest (ROIs), obtained using resting-state functional magnetic resonance imaging (rs-fMRI), were performed before and after the training.Results. Significant changes in ratings of tinnitus loudness, annoyance, and problem were observed with training. No statistically significant changes in Tinnitus Functional Index, Tinnitus Handicap Inventory or Depression Anxiety Stress Scales were found with training. Fluoxetine did not alter any of the behavioural outcomes of training compared to placebo. Significant changes in connectivity between ROIs were identified with training; sensory and attention neural network ROI changes correlated with significant tinnitus rating changes. Rs-fMRI results suggested that the direction of functional connectivity changes between auditory and non-auditory networks, with training and fluoxetine, were opposite to the direction of those changes with multisensory training and placebo.Conclusions. Improvements in tinnitus measures were correlated with changes in sensory and attention networks. The results provide preliminary evidence for changes in rs-fMRI accompanying a multisensory training method in persons with tinnitus.


L+-lactic acid production from starch by a novel amylolytic Lactococcus lactis subsp. lactis B84.
A new Lactococcus lactis subsp. lactis B84, capable of utilizing starch as a sole carbon source and producing L(+)-lactate, was isolated from spontaneously fermented rye sourdough. Aiming at maximum lactic acid productivity, the components of the media and the cultivation conditions were varied. In MRS-starch medium (with absence of yeast and meat extracts), at 33 degrees C, agitation 200 rpm and pH 6.0 for 6 days complete starch hydrolysis occurred and 5.5 gl(-1) lactic acid were produced from 18 gl(-1) starch. The identification of strain B84 was based on genetic criteria. Amplified ribosomal DNA restriction analysis (ARDRA), PCR with species-specific primers and sequencing of the 16S rDNA proved its species affiliation. Four genes for enzymes, involved in starch degradation were detected in B84 genome: amyL, amyY, glgP and apu, coding cytoplasmic and extracellular alpha-amylases, glycogen phosphorylase and amylopullulanase, respectively. Reverse transcription PCR experiments showed that both genes, encoding alpha-amylases (amyL and amyY) were expressed into mRNAs, whereas apu and glgP were not. Amylase activity assay was performed at different pH and temperatures. The cell-bond amylase proved to be the key enzyme, involved in the starch hydrolysis with maximum activity at 45 degrees C and pH 5.4.


The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo.
The TGFbeta-related growth factor Nodal governs anteroposterior (AP) and left-right (LR) axis formation in the vertebrate embryo. A conserved intronic enhancer (ASE), containing binding sites for the fork head transcription factor Foxh1, modulates dynamic patterns of Nodal expression during early mouse development. This enhancer is responsible for early activation of Nodal expression in the epiblast and visceral endoderm, and at later stages governs asymmetric expression during LR axis formation. We demonstrate ASE activity is strictly Foxh1 dependent. Loss of this autoregulatory enhancer eliminates transcription in the visceral endoderm and decreases Nodal expression in the epiblast, but causes surprisingly discrete developmental abnormalities. Thus lowering the level of Nodal signaling in the epiblast disrupts both orientation of the AP axis and specification of the definitive endoderm. Targeted removal of the ASE also dramatically reduces left-sided Nodal expression, but the early events controlling LR axis specification are correctly initiated. However loss of the ASE disrupts Lefty2 (Leftb) expression and causes delayed Pitx2 expression leading to late onset, relatively minor LR patterning defects. The feedback loop is thus essential for maintenance of Nodal signals that selectively regulate target gene expression in a temporally and spatially controlled fashion in the mouse embryo.


The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms.
Enhanced quantitative urine culture (EQUC) detects live microorganisms in the vast majority of urine specimens reported as "no growth" by the standard urine culture protocol. Here, we evaluated an expanded set of EQUC conditions (expanded-spectrum EQUC) to identify an optimal version that provides a more complete description of uropathogens in women experiencing urinary tract infection (UTI)-like symptoms. One hundred fifty adult urogynecology patient-participants were characterized using a self-completed validated UTI symptom assessment (UTISA) questionnaire and asked "Do you feel you have a UTI?" Women responding negatively were recruited into the no-UTI cohort, while women responding affirmatively were recruited into the UTI cohort; the latter cohort was reassessed with the UTISA questionnaire 3 to 7 days later. Baseline catheterized urine samples were plated using both standard urine culture and expanded-spectrum EQUC protocols: standard urine culture inoculated at 1 μl onto 2 agars incubated aerobically; expanded-spectrum EQUC inoculated at three different volumes of urine onto 7 combinations of agars and environments. Compared to expanded-spectrum EQUC, standard urine culture missed 67% of uropathogens overall and 50% in participants with severe urinary symptoms. Thirty-six percent of participants with missed uropathogens reported no symptom resolution after treatment by standard urine culture results. Optimal detection of uropathogens could be achieved using the following: 100 μl of urine plated onto blood (blood agar plate [BAP]), colistin-nalidixic acid (CNA), and MacConkey agars in 5% CO2 for 48 h. This streamlined EQUC protocol achieved 84% uropathogen detection relative to 33% detection by standard urine culture. The streamlined EQUC protocol improves detection of uropathogens that are likely relevant for symptomatic women, giving clinicians the opportunity to receive additional information not currently reported using standard urine culture techniques.


Developmental shift from local to central control of norepinephrine release in the cardiac-sympathetic axis: effects of cocaine and related drugs.
Developmental exposure to cocaine is associated with cardiovascular abnormalities as well as neurobehavioral disturbances. Because of the profound influence of cocaine on noradrenergic neurotransmission, we examined its acute effects on norepinephrine release from cardiac nerve terminals in the neonatal rat, as assessed by turnover measurements. Cocaine reduced norepinephrine turnover at all ages studied, but with an apparent transition in the mechanism of action related to the development of central control of sympathetic tone. At 1 day of age, before the establishment of functional connections between the central nervous system and sympathetic neurons, cocaine acted primarily through blockade of norepinephrine reuptake and consequent activation of alpha-2 adrenergic autoreceptors that inhibit transmitter release. Accordingly, its effects were shared by the uptake inhibitor, desmethylimipramine and the alpha-2 agonist, clonidine, but not by drugs whose actions depend upon sympathetic activity or high tonic release of transmitter (yohimbine, pargyline or chlorisondamine). By 21 days, when neuronal activity is under dynamic control by the central nervous system, cocaine was still effective in shutting off norepinephrine release, but the effect was no longer dependent upon blockade of reuptake; desmethylimipramine did not reduce turnover at this age, but clonidine, pargyline and chlorisondamine did. Yohimbine evoked a profound increase in turnover by 21 days.(ABSTRACT TRUNCATED AT 250 WORDS)


Screening for NUP98 rearrangements in hematopoietic malignancies by fluorescence in situ hybridization.
The aim of this study was to determine the incidence of rearrangements of NUP98 (the gene coding for nucleoporin 98kDa protein) in childhood acute myeloid leukemia (AML) and selected patients with 11p13-15 rearrangements. This aim was achieved using a fluorescence in situ hybridization (FISH) assay that allows the detection of NUP98 aberrations independently of the partner gene involved. Screening of 59 consecutive patients enrolled in the Austrian AML-BFM93 clinical trial was performed by dual-color FISH. In addition, 14 selected cases with various hematologic malignancies and 11p13-15 aberrations were analyzed. NUP98-positive cases were further investigated by fusion gene-specific FISH and reverse transcription polymerase chain reaction assays. Among the 59 AML patients, one NUP98-NSD1 positive case (1.7%) was detected. Among the 14 selected patients, five new NUP98 positive cases were determined. Two cases showed an inv(11)(p15q22)/NUP98-DDX10 fusion, one each displayed a t(5;11)(q35;p15)/NUP98-NSD1 and a t(11;20)(p15;q12)/NUP98-TOP1 fusion, and one case with a putative new fusion partner gene at 3p24 was identified. The observed frequency of 1.7% confirmed the low incidence of NUP98 rearrangements in childhood AML. The low occurrence of NUP98 rearrangements in selected samples with 11p13-15 alterations suggests the existence of variable chromosomal breakpoints and affected genes in this region. The identification of a new NUP98 fusion partner region confirms the evident promiscuity of NUP98. Thus, analysis of NUP98 aberrations by FISH seems to be the method of choice for determining the presence of these genetic lesions in unselected patients, and to confirm the involvement of NUP98 in cases with 11p15 aberrations.


Resveratrol improves motoneuron function and extends survival in SOD1(G93A) ALS mice.
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1(G93A) ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests. We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1(G93A) mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1(G93A) spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.


Presence of digestible starch impacts in vitro fermentation of resistant starch.
Starch is an important energy source for humans. Starch escaping digestion in the small intestine will transit to the colon to be fermented by gut microbes. Many gut microbes express α-amylases that can degrade soluble starch, but only a few are able to degrade intrinsic resistant starch (RS), which is insoluble and highly resistant to digestion (≥80% RS). We studied the in vitro fermentability of eight retrograded starches (RS-3 preparations) differing in rapidly digestible starch content (≥70%, 35-50%, ≤15%) by a pooled adult faecal inoculum and found that fermentability depends on the digestible starch fraction. Digestible starch was readily fermented yielding acetate and lactate, whereas resistant starch was fermented much slower generating acetate and butyrate. Primarily Bifidobacterium increased in relative abundance upon digestible starch fermentation, whereas resistant starch fermentation also increased relative abundance of Ruminococcus and Lachnospiraceae. The presence of small fractions of total digestible starch (±25%) within RS-3 preparations influenced the fermentation rate and microbiota composition, after which the resistant starch fraction was hardly fermented. By short-chain fatty acid quantification, we observed that six individual faecal inocula obtained from infants and adults were able to ferment digestible starch, whereas only one adult faecal inoculum was fermenting intrinsic RS-3. This suggests that, in contrast to digestible starch, intrinsic RS-3 is only fermentable when specific microbes are present. Our data illustrates that awareness is required for the presence of digestible starch during in vitro fermentation of resistant starch, since such digestible fraction might influence and overrule the evalution of the prebiotic potential of resistant starches.


Challenges in pressure ulcer prevention.
Although this article is a stand-alone article, it sets the scene for later articles in this issue. Pressure ulcers are considered to be a largely preventable problem, and yet despite extensive training and the expenditure of a large amount of resources, they persist. This article reviews the current understanding of pressure ulcer aetiology: pressure, shear and microclimate. Individual risk factors for pressure ulceration also need to be understood in order to determine the level of risk of an individual. Such an assessment is essential to determine appropriate prevention strategies. The main prevention strategies in terms of reducing pressure and shear and managing microclimate are studied in this article. The problem of pressure ulceration related to medical devices is also considered as most of the standard prevention strategies are not effective in preventing this type of damage. Finally, the possibility of using dressings as an additional preventive strategy is raised along with the question: is there enough evidence to support their use?


Single crystalline Co3O4 nanocrystals exposed with different crystal planes for Li-O2 batteries.
Single crystalline Co3O4 nanocrystals exposed with different crystal planes were synthesised, including cubic Co3O4 nanocrystals enclosed by {100} crystal planes, pseudo octahedral Co3O4 enclosed by {100} and {110} crystal planes, Co3O4 nanosheets exposed by {110} crystal planes, hexagonal Co3O4 nanoplatelets exposed with {111} crystal planes, and Co3O4 nanolaminar exposed with {112} crystal planes. Well single crystalline features of these Co3O4 nanocrystals were confirmed by FESEM and HRTEM analyses. The electrochemical performance for Li-O2 batteries shows that Co3O4 nanocrystals can significantly reduce the discharge-charge over-potential via the effect on the oxygen evolution reaction (OER). From the comparison on their catalytic performances, we found that the essential factor to promote the oxygen evolution reactions is the surface crystal planes of Co3O4 nanocrystals, namely, crystal planes-dependent process. The correlation between different Co3O4 crystal planes and their effect on reducing charge-discharge over-potential was established: {100} < {110} < {112} < {111}.