Healthcare utilization and costs associated with persistent post-concussive symptoms.
To describe the healthcare utilization and costs associated with the interdisciplinary treatment of pediatric persistent post-concussive symptoms (PPCS). A retrospective chart review was conducted with 461 youth referred by community physicians to an interdisciplinary pediatric PPCS outpatient clinic in Ontario, Canada. Healthcare utilization parameters included accessibility, continuity, comprehensiveness, and service productivity. Direct healthcare costs included those incurred by physicians and other interdisciplinary services. Indirect costs per client included travel to the clinic and caregiver productivity loss. Data analyses were completed using descriptive statistics. The median age of clients was 15 years (range = 3 to 18). The median wait time for an initial PPCS clinic physician consultation was 71 days, and less than 2 months for other interdisciplinary services. Eighty-two percent of clients were referred to at least one other service after an initial physician consultation. Occupational therapy received the highest proportion of referrals (79%). Total median direct costs per client were approximately $915, with a final accumulated cost of $532 623 for all clients. Caregiver productivity loss was approximately $387 per family. Our findings suggest that interdisciplinary PPCS care represents an accessible, comprehensive and cost-saving healthcare model from the client and societal perspectives.


Taking a step back: Self-distancing dynamics in adolescent writing about peer problems.
Can the retelling of an unpleasant experience help adolescents cope with that experience? This study answers that question by looking at the role of psychological self-distancing when adolescents write about recently untold stressful events with peers using either a traditional expressive writing (EW) intervention or a cognitively oriented expressive writing (CEW) intervention. Extent of self-distancing (i.e., low and high) as well as its variability (i.e., increasing or stable) were taken into account. Data, obtained from 292 written essays from 78 Italian adolescents (mean age was 12.9; 50% was female), were collected longitudinally on four occasions. Group-based trajectory modeling determined the extent and variability in self-distancing for the two writing interventions (i.e., EW and CEW) and two baseline peer problem conditions (i.e., low and high). Findings indicate that, for adolescents who experience high peer problems at baseline, CEW intervention fosters meaning-making through self-distancing, resulting in being more beneficial than traditional EW.


Effect of counter ions on the silica oligomerization reaction.
The silicate oligomerization reaction is key to sol-gel chemistry and zeolite synthesis. Numerous experimental and theoretical studies have addressed the physical chemistry of silicate oligomers in the prenucleation stage of siliceous zeolite formation. Here we report a study of a silica condensation reaction in aqueous solution in the presence of counter ions (Li(+) and NH(4)(+)). Ab-initio molecular dynamics simulations have been used to construct reaction energy diagrams including transition state free energies. Contact with Li+ as well as NH(4)(+) increases the activation energies of the dimerization step compared to the situation in the absence of counterions. The presence of NH(4)(+) has no effect on consecutive oligomerization steps. Hence NH(4)(+) will increase the relative formation rate of larger oligomers.


Clinical therapeutic analysis of vitiligo phase--II.
The incidence of vitiligo varies from country to country. In the present study, seventy cases of vitiligo have been studied from skin out patient department of the Institute of Post-graduate Medicine & Research over a period of 2 years. The prevalence rate of vitiligo among the total out patient attendent was 0.4 per cent. 85 per cent of the cases belonged to the age group to 11-40 years. Male and female ratio was 2:1. Precipitating factors like physical injury, mental stress and strain had close link with development of skin lesion. In 11.4 per cent cases near relations were involved. Skin lesions according to the site showed lower extremity to be the maximally involved area and the genital areas were least involved.


Continuous Glucose Monitors and Automated Insulin Dosing Systems in the Hospital Consensus Guideline.
This article is the work product of the Continuous Glucose Monitor and Automated Insulin Dosing Systems in the Hospital Consensus Guideline Panel, which was organized by Diabetes Technology Society and met virtually on April 23, 2020. The guideline panel consisted of 24 international experts in the use of continuous glucose monitors (CGMs) and automated insulin dosing (AID) systems representing adult endocrinology, pediatric endocrinology, obstetrics and gynecology, advanced practice nursing, diabetes care and education, clinical chemistry, bioengineering, and product liability law. The panelists reviewed the medical literature pertaining to five topics: (1) continuation of home CGMs after hospitalization, (2) initiation of CGMs in the hospital, (3) continuation of AID systems in the hospital, (4) logistics and hands-on care of hospitalized patients using CGMs and AID systems, and (5) data management of CGMs and AID systems in the hospital. The panelists then developed three types of recommendations for each topic, including clinical practice (to use the technology optimally), research (to improve the safety and effectiveness of the technology), and hospital policies (to build an environment for facilitating use of these devices) for each of the five topics. The panelists voted on 78 proposed recommendations. Based on the panel vote, 77 recommendations were classified as either strong or mild. One recommendation failed to reach consensus. Additional research is needed on CGMs and AID systems in the hospital setting regarding device accuracy, practices for deployment, data management, and achievable outcomes. This guideline is intended to support these technologies for the management of hospitalized patients with diabetes.


Tissue distribution of indium after repeated intratracheal instillations of indium-tin oxide into the lungs of hamsters.
The aim of this study was to analyze the tissue distribution of indium after intratracheally instilling indium-tin oxide (ITO) into the lungs of hamsters. Male Syrian hamsters received an intratracheal dose of 3 mg/kg or 6 mg/kg of ITO particles containing 2.2 mg/kg or 4.5 mg/kg of indium, twice weekly for 8 weeks. In parallel, control hamsters received only an intratracheal dose of distilled water. A subset of hamsters was euthanized periodically throughout the study from 8 up to 78 weeks after the final instillation. The distribution of indium in the lungs, liver, kidneys and spleen, as well as pathological changes in the liver, kidneys, and spleen, was determined. The contents of indium in the lungs in the two ITO groups gradually decreased over the 78-week observation period, with elimination half-lives of approximately 142 weeks for the 3 mg/kg ITO group and 124 weeks for the 6 mg/kg ITO. The indium concentrations in the liver, kidneys, and spleen gradually increased throughout the observation period. Although foci of the lesions were observed histopathologically in the extrapulmonary organs among the two ITO groups, the control group showed similar lesions. The results clearly demonstrate that the clearance of indium from the body is extremely slow after intratracheal instillation in hamsters.


Imaging diagnosis-CT myelography in a dog with intramedullary intervertebral disc herniation.
A 5-year-old Chihuahua was examined for peracute pain and paraparesis. Neuroanatomic localization was consistent with a symmetric T3-L3 myelopathy. Computed tomography (CT) of the T9-L5 vertebrae was normal. Myelography disclosed attenuation of the subarachnoid space from T11 to L1, consistent with spinal cord swelling. CT following the myelogram disclosed a focal area of intramedullary iodinated contrast medium at T13-L1. At surgery, intervertebral disc material was removed from the spinal cord. Based on the findings in this patient, intramedullary disc herniation should be considered a cause for focal intramedullary contrast medium accumulation.


Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands.
The eukaryotic 20S proteasome is known to associate with the IFN gamma-inducible regulator PA28. We analyzed the kinetics of product generation by 20S proteasomes with and without PA28. In the absence of PA28, the 20S proteasome rapidly generates peptides that have been cleaved only once, while internal fragments accumulate only slowly. In the presence of PA28, products generated by two flanking cleavages appear immediately as main products while the generation of single-cleavage products is strongly reduced. Kinetic data support a PA28-induced, coordinated double-cleavage mechanism. In particular, degradation of peptides derived from mouse cytomegalovirus pp89 and JAK1 kinase in the presence of PA28 leads to strongly enhanced production of the respective major histocompatibility complex ligands and potential precursors. These results show that PA28 profoundly alters the cleavage mechanism of the proteasome and appears to optimize the generation of dominant T-cell epitopes.


Transient Receptor Potential Vanilloid 4-Dependent Microglial Function in Myelin Injury and Repair.
Microglia are found pathologically at all stages of multiple sclerosis (MS) lesion development and are hypothesized to contribute to both inflammatory injury and neuroprotection in the MS brain. Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed, play an important role as environmental sensors, and are involved in calcium homeostasis for a variety of cells. TRPV4 modulates myeloid cell phagocytosis in the periphery and microglial motility in the central nervous system. We hypothesized that TRPV4 deletion would alter microglia phagocytosis in vitro and lessen disease activity and demyelination in experimental autoimmune encephalitis (EAE) and cuprizone-induced demyelination. We found that genetic deletion of TRPV4 led to increased microglial phagocytosis in vitro but did not alter the degree of demyelination or remyelination in the cuprizone mouse model of MS. We also found no difference in disease in EAE following global or microglia-specific deletion of Trpv4. Additionally, lesioned and normal appearing white matter from MS brains exhibited similar TRPV4 expression compared to healthy brain tissue. Taken together, these findings indicate that TRPV4 modulates microglial activity but does not impact disease activity in mouse models of MS, suggesting a muted and/or redundant role in MS pathogenesis.


Two-Team Surgical Approach to Improve Retroperitoneal Nerve Identification in the Treatment of Groin Pain.
An estimated 700,000 groin hernia repairs are performed in the United States each year. Studies have shown that up to 50% of patients who undergo groin hernia repair are affected by persistent pain beyond the first few days after surgery. At 2 to 5 years after either open or laparoscopic, mesh or without mesh, 10% to 12% of these patients will have persistent and disabling pain. If the ilioinguinal, iliohypogastric, or genitofemoral nerves are injured below the transversalis muscle layer, the traditional external, open approach to nerve resection will not help these patients. The traditional internal, laparoscopic, approach to the retroperitoneum can be used for nerve resection, but identification of the correct nerve is difficult. Therefore, we have developed a 2-team, dual approach, combining open and endoscopic approaches to solve this problem. A retrospective review of the electronic medical records was performed to identify all patients who underwent a dual approach for groin denervation after persistent postherniorraphy pain. This dual approach included an external incision paired with a laparoscopic, retroperitoneal approach to identify and/or transect the ilioinguinal, iliohypogastic, lateral femoral cutaneous, and genital branch of the genitofemoral nerve. Inclusion criteria are persistent groin pain with alleviation after preoperative nerve block and either a failed attempt at an external approach groin denervation or pain after a primary laparotomy/laparoscopy procedure. Thirteen patients met the inclusion criteria. All patients underwent a dual approach, and nerves were identified and confirmed in both the external groin and laparoscopic approaches. When placed on a scale from excellent/good to fair/poor relief of pain, 10 patients (77%) described excellent/good relief and 3 (23%) continued to have persistent pain. A combined open surgical procedure, to identify the lateral femoral cutaneous nerve, and a laparoscopic procedure in the retroperitoneum have demonstrated the feasibility of this approach to identify correctly the nerve to be resected to relieve disabling groin pain.


A recurrent neural network for closed-loop intracortical brain-machine interface decoders.
Recurrent neural networks (RNNs) are useful tools for learning nonlinear relationships in time series data with complex temporal dependences. In this paper, we explore the ability of a simplified type of RNN, one with limited modifications to the internal weights called an echostate network (ESN), to effectively and continuously decode monkey reaches during a standard center-out reach task using a cortical brain-machine interface (BMI) in a closed loop. We demonstrate that the RNN, an ESN implementation termed a FORCE decoder (from first order reduced and controlled error learning), learns the task quickly and significantly outperforms the current state-of-the-art method, the velocity Kalman filter (VKF), using the measure of target acquire time. We also demonstrate that the FORCE decoder generalizes to a more difficult task by successfully operating the BMI in a randomized point-to-point task. The FORCE decoder is also robust as measured by the success rate over extended sessions. Finally, we show that decoded cursor dynamics are more like naturalistic hand movements than those of the VKF. Taken together, these results suggest that RNNs in general, and the FORCE decoder in particular, are powerful tools for BMI decoder applications.


Two-Dimensional Phononic Crystals: Disorder Matters.
The design and fabrication of phononic crystals (PnCs) hold the key to control the propagation of heat and sound at the nanoscale. However, there is a lack of experimental studies addressing the impact of order/disorder on the phononic properties of PnCs. Here, we present a comparative investigation of the influence of disorder on the hypersonic and thermal properties of two-dimensional PnCs. PnCs of ordered and disordered lattices are fabricated of circular holes with equal filling fractions in free-standing Si membranes. Ultrafast pump and probe spectroscopy (asynchronous optical sampling) and Raman thermometry based on a novel two-laser approach are used to study the phononic properties in the gigahertz (GHz) and terahertz (THz) regime, respectively. Finite element method simulations of the phonon dispersion relation and three-dimensional displacement fields furthermore enable the unique identification of the different hypersonic vibrations. The increase of surface roughness and the introduction of short-range disorder are shown to modify the phonon dispersion and phonon coherence in the hypersonic (GHz) range without affecting the room-temperature thermal conductivity. On the basis of these findings, we suggest a criteria for predicting phonon coherence as a function of roughness and disorder.


An approach for Ewing test selection to support the clinical assessment of cardiac autonomic neuropathy.
This article addresses the problem of determining optimal sequences of tests for the clinical assessment of cardiac autonomic neuropathy (CAN). We investigate the accuracy of using only one of the recommended Ewing tests to classify CAN and the additional accuracy obtained by adding the remaining tests of the Ewing battery. This is important as not all five Ewing tests can always be applied in each situation in practice. We used new and unique database of the diabetes screening research initiative project, which is more than ten times larger than the data set used by Ewing in his original investigation of CAN. We utilized decision trees and the optimal decision path finder (ODPF) procedure for identifying optimal sequences of tests. We present experimental results on the accuracy of using each one of the recommended Ewing tests to classify CAN and the additional accuracy that can be achieved by adding the remaining tests of the Ewing battery. We found the best sequences of tests for cost-function equal to the number of tests. The accuracies achieved by the initial segments of the optimal sequences for 2, 3 and 4 categories of CAN are 80.80, 91.33, 93.97 and 94.14, and respectively, 79.86, 89.29, 91.16 and 91.76, and 78.90, 86.21, 88.15 and 88.93. They show significant improvement compared to the sequence considered previously in the literature and the mathematical expectations of the accuracies of a random sequence of tests. The complete outcomes obtained for all subsets of the Ewing features are required for determining optimal sequences of tests for any cost-function with the use of the ODPF procedure. We have also found two most significant additional features that can increase the accuracy when some of the Ewing attributes cannot be obtained. The outcomes obtained can be used to determine the optimal sequences of tests for each individual cost-function by following the ODPF procedure. The results show that the best single Ewing test for diagnosing CAN is the deep breathing heart rate variation test. Optimal sequences found for the cost-function equal to the number of tests guarantee that the best accuracy is achieved after any number of tests and provide an improvement in comparison with the previous ordering of tests or a random sequence.


Cannabis and exercise: Effects of Δ9-tetrahydrocannabinol on preference and motivation for wheel-running in mice.
Recent surveys have revealed close links between cannabis and exercise. Specifically, cannabis usage before and/or after exercise is an increasingly common habit primarily aimed at boosting exercise pleasure, motivation, and performance whilst facilitating post-exercise recovery. However, whether these beliefs reflect the true impact of cannabis on these aspects of exercise is unknown. This study has thus examined the effects of cannabis' main psychoactive ingredient, namely Δ9-tetrahydrocannabinol (THC), on (i) mouse wheel-running preference and performance and (ii) running motivation and seeking behaviour. Wheel-running preference and performance were investigated using a T-maze with free and locked wheels located at the extremity of either arm. Running motivation and seeking were assessed by a cued-running operant task wherein wheel-running was conditioned by nose poking. Moreover, because THC targets cannabinoid type 1 (CB1) receptors, i.e. receptors previously documented to control running motivation, this study also assessed the role of these receptors in running preference, performance, and craving-like behaviour. Whilst acute blockade or genetic deletion of CB1 receptors decreased running preference and performance in the T-maze, THC proved ineffective on either variable. The failure of THC to affect running variables in the T-maze extended to running motivation, as assessed by cued-running under a progressive ratio (PR) reinforcement schedule. This ineffectiveness of THC was not related to the treatment protocol because it successfully increased motivation for palatable food. Although craving-like behaviour, as indexed by a cue-induced reinstatement of running seeking, was found to depend on CB1 receptors, THC again proved ineffective. Neither running motivation nor running seeking were affected when CB1 receptors were further stimulated by increasing the levels of the endocannabinoid 2-arachidonoylglycerol. These results, which suggest that the drive for running is insensitive to the acute stimulation of CB1 receptors, raise the hypothesis that cannabis is devoid of effect on exercise motivation. Future investigation using chronic administration of THC, with and without other cannabis ingredients (e.g. cannabidiol), is however required before conclusions can be drawn.


Dopexamine and dopamine in the prevention of low gastric mucosal pH following cardiopulmonary by-pass.
The effect of low-dose dopexamine and dopamine on gastric intramucosal pH (pHi) during cardiac surgery and 16 hours postoperatively was studied in 35 adults patients (coronary artery bypass grafting and/or valve replacement). The patients were assigned randomly to treatment groups with either dopexamine (1 microgram.kg-1.min-1 (n = 12), dopamine 2.5 micrograms.kg-1.min-1 (n = 11) or to a control group (n = 12). The infusions were started after induction of anaesthesia and were continued until 16 hours after CPB. pHi and arterial pH (pHa) did not differ between groups and remained unchanged during cardiopulmonary by-pass and for the first four postoperative hours. Both the carbon dioxide tension of arterial blood (PaCO2) and of the saline in the tonometer (PtonCO2) changed in parallel with a decrease during CPB and an increase after CPB and surgery with maximal values 12 hours after termination of CPB. A significant correlation was noted between pHi and pHa and between arterial and tonometric PCO2. It is concluded that low dose dopexamine and dopamine have no influence on pHi during and after cardiac surgery. The observed changes in pHi and PtonCO2 were due to changes in pHa and in PaCO2 and not a sign of gastric mucosal ischemia.


Stimulation-Induced Transient Nonmotor Psychiatric Symptoms following Subthalamic Deep Brain Stimulation in Patients with Parkinson's Disease: Association with Clinical Outcomes and Neuroanatomical Correlates.
The clinical and neurobiological underpinnings of transient nonmotor (TNM) psychiatric symptoms during the optimization of stimulation parameters in the course of subthalamic nucleus deep brain stimulation (STN-DBS) remain under intense investigation. Forty-nine patients with refractory Parkinson's disease underwent bilateral STN-DBS implants and were enrolled in a 24-week prospective, naturalistic follow-up study. Patients who exhibited TNM psychiatric manifestations during DBS parameter optimization were evaluated for potential associations with clinical outcome measures. Twenty-nine TNM+ episodes were reported by 15 patients. No differences between TNM+ and TNM- groups were found in motor outcome. However, unlike the TNM- group, TNM+ patients did not report improvement in subsyndromal depression or quality of life. TNM+ episodes were more likely to emerge during bilateral monopolar stimulation of the medial STN. The occurrence of TNM psychiatric symptoms during optimization of stimulation parameters was associated with the persistence of subsyndromal depression and with lower quality of life ratings at 6 months. The neurobiological underpinnings of TNM symptoms are investigated yet remain difficult to explain.


Blood oxygenation during hyperpressure intraperitoneal fluid administration in a rabbit model of severe liver injury: Evaluation of a novel concept for control of pre-hospital liver bleeding.
Oxygen is an essential part of the most important metabolic pathways in aerobic organisms. Oxygen delivery is merely dependent on blood, rendering blood loss a devastating event. Traumatic pre-hospital liver bleeding is a major cause of early trauma deaths in human and animals, with no established therapeutic method yet. Increasing intra-abdominal pressure (IAP) has been shown to reduce liver bleeding by half. Although reduction of blood loss could be in favor of blood oxygen delivery, however, the complex interaction between increased IAP and respiratory mechanics during severe hemorrhagic shock remained unclear. We used a novel model of liver trauma in 16 rabbits and randomly assigned them to either normotensive abdomen group or increased IAP by fluid infusion (HA) groups (n=8 each). Liver size and the amount of liver injury were evaluated. Various blood oxygenation parameters were recorded. Both groups were identical in terms of the liver size and injury. The HA group had significantly lower shock index. Arterial oxygen capacity and oxygen content were higher in the HA group. No significant statistical difference was seen between groups in terms of abdominal perfusion pressure; alveolar pressure of oxygen; dissolved oxygen in blood plasma; alveolar to arterial oxygen tension gradient; arterial to alveolar oxygen pressure ratio; the ratio between partial pressure of arterial oxygen and fraction of inspired oxygen; and respiratory index. In conclusion, the novel therapeutic method of increasing IAP by fluid infusion in a rabbit model of liver hemorrhage preserved blood oxygenation better than the classic therapeutic method.


Intersection Syndrome: The Subtle Squeak of an Overused Wrist.
Patient histories that include wrist pain can be pivotal in the distinction between intersection syndrome (IS) and the more common de Quervain's tenosynovitis (DQT). Presented here is a 26-year-old pregnant woman with a history of rowing who developed left radial/dorsal wrist pain and a rubbing/squeaking sensation. Nine months of conservative DQT therapy and a landmark-guided corticosteroid injection failed to relieve her symptoms. An in-clinic ultrasound showed tenosynovitis at the intersection of the first and second compartments, confirming a diagnosis of IS. She found immediate relief with ultrasound-guided saline hydrodissection, the injection of saline into the intercompartmental space to reduce adhesions. Both DQT and IS are overuse injuries caused by repetitive wrist extension, as occurs in rowing, and either condition can worsen after pregnancy. Distinguishing the subtleties between DQT and IS can be challenging. Close attention to the patient's description of the pain can guide treatment, potentially expediting recovery. In addition, saline hydrodissection can be both a diagnostic tool and a potentially therapeutic alternative to steroid injections for such tendinopathies.


Aloin Protects Against Blood-Brain Barrier Damage After Traumatic Brain Injury in Mice.
Aloin is a small-molecule drug well known for its protective actions in various models of damage. Traumatic brain injury (TBI)-induced cerebral edema from secondary damage caused by disruption of the blood-brain barrier (BBB) often leads to an adverse prognosis. Since the role of aloin in maintaining the integrity of the BBB after TBI remains unclear, we explored the protective effects of aloin on the BBB using in vivo and in vitro TBI models. Adult male C57BL/6 mice underwent controlled cortical impact injury, and mouse brain capillary endothelial bEnd.3 cells underwent biaxial stretch injury, then both received aloin treatment. In the animal experiments, we found 20 mg/kg aloin to be the optimum concentration to decrease cerebral edema, decrease disruption of the BBB, and improve neurobehavioral performance after cortical impact injury. In the cellular studies, the optimum concentration of 40 μg/mL aloin reduced apoptosis and reversed the loss of tight junctions by reducing the reactive oxygen species levels and changes in mitochondrial membrane potential after stretch injury. The mechanisms may be that aloin downregulates the phosphorylation of p38 mitogen-activated protein kinase, the activation of p65 nuclear factor-kappa B, and the ratios of B cell lymphoma (Bcl)-2-associated X protein/Bcl-2 and cleaved caspase-3/caspase-3. We conclude that aloin exhibits these protective effects on the BBB after TBI through its anti-oxidative stress and anti-apoptotic properties in mouse brain capillary endothelial cells. Aloin may thus be a promising therapeutic drug for TBI.


Pathway for the elimination of melamine in lactating dairy cows.
Melamine might be degraded into cyanuric acid and some other analogs by the rumen microorganism. Thus, the metabolism of melamine in ruminants may be different from that in monogastric animals. The objective of this study was to investigate the pathway for the elimination of melamine in lactating dairy cows. Four late-lactation dairy cows (body weight=524±17 kg, days in milk=265±14 d) fitted with ruminal cannulas were dosed with melamine (purity ≥99.5%) at 800 mg/d per cow that divided into 2 equal daily doses. The trial lasted for 20 d (13-d preliminary period, followed by a 7-d sample-collecting period). The method of liquid chromatography and tandem mass spectrometry was used to determine melamine and cyanuric acid contents simultaneously. Before the trial started, no melamine or cyanuric acid was detected in samples of total mixed ration, milk, plasma, urine, and feces. The melamine concentration in rumen fluid (Y, mg/L) decreased exponentially after the morning feeding (X, h) (Y=3.85591e(-X/9.25674)+1.35924, R(2)=0.99), but no cyanuric acid was detected. Plasma melamine concentration (0.296±0.014 mg/L) was relatively stable in the 3 different sampling times. The percentages of melamine excreted through milk, urine, and feces were 0.48±0.06, 44.07±10.79 and 10.98±3.88%, respectively. It could be inferred that 44.47±7.98% of ingested melamine was degraded in the rumen, because cyanuric acid was detected in plasma, urine, and feces on the condition that no melamine was contained in the total mixed ration fed to the dairy cows. The results of the present study implied that the elimination pathway of melamine in lactating dairy cows was different from that in monogastric animals. A high percentage of melamine was degraded into cyanuric acid gradually by rumen microorganisms. Most ingested melamine was excreted in urine and feces, which are the main elimination pathways for melamine in lactating dairy cows.


Stability and in vivo evaluation of pullulan acetate as a drug nanocarrier.
To develop pullulan acetate nanoparticles (PANs) as a drug nanocarrier, pullulan acetate (PA) was synthesized and characterized. Its acetylation degree determined by the proton nuclear magnetic resonance ((1)H NMR) was 2.6. PANs were prepared by the solvent diffusion method and characterized by transmission electron microscope (TEM), size distribution, and zeta potential techniques. PANs had nearly spherical shape with a size range of 200-450 nm and low zeta potentials both in distilled water and in 10% FBS. The storage stability of PANs was observed in distilled water. PANs were stored for at least 2 months with no significant size and zeta potential changes. The safety of PANs was studied through single dose toxicity test in mice, and the result showed that PANs were well tolerated at the dose of 200 mg/kg in mice. Epirubicin-loaded PANs (PA/EPI) were also prepared and characterized in this study. Moreover, the in vivo pharmacokinetics of PA/EPI was investigated. Compared with the free EPI group, the PA/EPI group exhibited higher plasma drug concentration, longer half-life time (t(1/2)) and the larger area under the curve (AUC). All results suggested that PANs were stable, safe, and showed a promising potential on improving the bioavailability of the loaded drug of the encapsulated drug.


Salivary creatinine as a diagnostic tool for evaluating patients with chronic kidney disease.
Preliminary studies have shown the potential use of salivary creatinine concentration in the diagnosis of chronic kidney disease (CKD). For saliva to replace serum as a diagnostic tool, studies must be done to determine its effectiveness in the diagnosis and staging of CKD. The aim of the present study was to evaluate the use of salivary creatinine as a safe and non-invasive alternative for identifying patients with CKD. A cross-sectional study was conducted at Tygerberg Hospital in Cape Town, on 230 patients, across all stages of CKD. Ethical approval to conduct the study was obtained from the University of the Western Cape Biomedical Research Ethics Committee, and written informed consent was provided by each participant. Saliva and serum samples were collected for creatinine analysis and the correlation determined using Spearman's correlation. Receiver operating characteristics (ROC) analysis was used to determine the diagnostic ability of salivary creatinine. A cut-off value for optimal sensitivity and specificity of salivary creatinine to diagnose CKD with glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 was obtained. Serum creatinine values ranged from 46 μmol/L to 1581 μmol/L, with a median value of 134 μmol/L. Salivary creatinine values ranged from 3 μmol/L to 400 μmol/L, with a median of 11 μmol/L. There was a strong positive correlation (r = 0.82) between serum and salivary creatinine values. Linear regression analysis of serum and salivary creatinine for CKD patients was significant in all CKD stages, except for stage 1. Area under the curve for salivary creatinine was 0.839. A cut-off value of 8.5 μmol/L yielded a sensitivity of 78.3% and specificity of 74.0% for classifying patients as having CKD based on estimated GFR < 60 mL/min/1.73 m2. The results support the potential of salivary creatinine as a non-invasive diagnostic tool for estimating GFR and identifying patients with CKD.


Phosphorylation of CDC25A on SER283 in late S/G2 by CDK/cyclin complexes accelerates mitotic entry.
The Cdc25A phosphatase is an essential activator of CDK-cyclin complexes at all steps of the eukaryotic cell cycle. The activity of Cdc25A is itself regulated in part by positive and negative feedback regulatory loops performed by its CDK-cyclin substrates that occur in G1 as well as during the G1/S and G2/M transitions. However, the regulation of Cdc25A during G2 phase progression before mitotic entry has not been intensively characterized. Here, we identify by mass spectrometry analysis a new phosphorylation event of Cdc25A on Serine283. Phospho-specific antibodies revealed that the phosphorylation of this residue appears in late S/G2 phase of an unperturbed cell cycle and is performed by CDK-cyclin complexes. Overexpression studies of wild-type and non-phosphorylatable mutant forms of Cdc25A indicated that Ser283 phosphorylation increases the G2/M-promoting activity of the phosphatase without impacting its stability or subcellular localization. Our results therefore identify a new positive regulatory loop between Cdc25A and its CDK-cyclin substrates which contributes to accelerate entry into mitosis through the regulation of Cdc25A activity in G2.


Affective and cooperative social interactions modulate effective connectivity within and between the mirror and mentalizing systems.
Decoding the meaning of others' actions, a crucial step for social cognition, involves different neural mechanisms. While the "mirror" and "mentalizing" systems have been associated with, respectively, the processing of biological actions versus more abstract information, their respective contribution to intention understanding is debated. Processing social interactions seems to recruit both neural systems, with a different weight depending on cues emphasizing either shared action goals or shared mental states. We have previously shown that observing cooperative and affective social interactions elicits stronger activity in key nodes of, respectively, the mirror (left posterior superior temporal sulcus (pSTS), superior parietal cortex (SPL), and ventral/dorsal premotor cortex (vPMC/dPMC)) and mentalizing (ventromedial prefrontal cortex (vmPFC)) systems. To unveil their causal organization, we investigated the effective connectivity underlying the observation of human social interactions expressing increasing cooperativity (involving left pSTS, SPL, and vPMC) versus affectivity (vmPFC) via dynamic causal modeling in 36 healthy human subjects. We found strong evidence for a model including the pSTS and vPMC as input nodes for the observed interactions. The extrinsic connectivity of this model undergoes oppositely valenced modulations, with cooperativity promoting positive modulations of connectivity between pSTS and both SPL (forward) and vPMC (mainly backward), and affectivity promoting reciprocal positive modulations of connectivity between pSTS and vmPFC (mainly backward). Alongside fMRI data, such divergent effective connectivity suggests that different dimensions underlying the processing of social interactions recruit distinct, although strongly interconnected, neural pathways associated with, respectively, the bottom-up visuomotor processing of motor intentions, and the top-down attribution of affective/mental states.


In vivo absorption and metabolism of leptosperin and methyl syringate, abundantly present in manuka honey.
Manuka honey, which shows strong nonperoxide-dependent antibacterial activity, contains unique components, such as methyl syringate 4-O-β-D-gentiobioside (leptosperin) and its aglycone, methyl syringate (MSYR). To determine the potential for biological activity evoked by the ingestion of leptosperin and MSYR, we investigated the absorption and metabolism of these components in manuka honey. The incubation of MSYR with liver microsomes or S9 fractions in vitro resulted in the formation of MSYR-glucuronide (MSYR-GA), MSYR-sulfate (MSYR-S), and syringic acid as metabolites. Then, manuka honey (15 g) was fed to healthy human volunteers. MSYR-GA, MSYR-S, and MSYR were detected in both plasma and urine. Within plasma, their levels were highest within 0.5 h to 1 h post-ingestion, and most metabolites disappeared within 3 h. In conjunction with the disappearances, a significant amount of metabolites along with trace leptosperin was excreted in urine within 4 h. To elucidate the detailed metabolisms of leptosperin and MSYR, each compound was separately administered to mice. In each case, MSYR-GA, MSYR-S, and MSYR were detected in both plasma and urine. This study shows the major molecular pathway for leptosperin and MSYR metabolism and could facilitate an understanding of biological functions of manuka honey post ingestion.


Remodeling in myocardium adjacent to an infarction in the pig left ventricle.
Changes in the structure of the "normal" ventricular wall adjacent to an infarcted area involve all components of the myocardium (myocytes, fibroblasts and the extracellular matrix, and the coronary vasculature) and their three-dimensional structural relationship. Assessing changes in these components requires tracking material markers in the remodeling tissue over long periods of time with a three-dimensional approach as well as a detailed histological evaluation of the remodeled structure. The purpose of the present study was to examine the hypotheses that changes in the tissue adjacent to an infarct are related to myocyte elongation, myofiber rearrangement, and changes in the laminar architecture of the adjacent tissue. Three weeks after myocardial infarction, noninfarcted tissue adjacent to the infarct remodeled by expansion along the direction of the fibers and in the cross fiber direction. These changes are consistent with myocyte elongation and myofiber rearrangement (slippage), as well as a change in cell shape to a more elliptical cross section with the major axis in the epicardial tangent plane, and indicate that reorientation of fibers either via "cell slippage" or changes in orientation of the laminar structure of the ventricular wall are quantitatively important aspects of the remodeling of the normally perfused myocardium.


Dietary patterns and risk of squamous-cell carcinoma and adenocarcinoma of the esophagus and adenocarcinoma of the gastric cardia: a population-based case-control study in Sweden.
We conducted a large population-based case-control study in Sweden to examine the association of dietary patterns and the development of cancers from the esophagus or gastroesophageal junction. In total 185 patients with esophageal adenocarcinoma, 165 with esophageal squamous-cell carcinoma, 258 with gastric cardia adenocarcinoma, and 815 randomly selected population controls underwent face-to-face interviews. Exploratory factor analysis was used to identify possible dietary patterns. Multivariate logistic regression with adjustments for age, sex, years of education, body mass index, physical activity, symptomatic gastroesophageal reflux, smoking, and total energy intake was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). We identified three major dietary patterns in this population, for example, "healthy diet" (high in vegetables, tomato, fruits, fish, and poultry), "Western diet" (high in processed meat, red meat, sweets, high-fat dairy, and high-fat gravy), and "alcohol drinker" (high in intakes of beer, liquor, and French fries). We found that a healthy diet tended to moderately decrease the risk of all three cancers under study, although none of the associations was statistically significant. A high score of Western diet was associated with increased risks of gastric cardia adenocarcinoma (high 3rd tertile vs. low 1st quartile, OR = 1.8, 95% CI = 1.1-2.9, P for trend = 0.04) and esophageal adenocarcinoma (high 3rd tertile vs. low 1st tertile, OR = 1.6, 95% CI = 0.9-3.1, P for trend = 0.13), whereas a dietary pattern characterized by high beer and liquor intake (alcohol drinker) significantly increased the risk of squamous-cell carcinoma of the esophagus (3rd tertile vs. low 1st tertile, OR = 3.5, 95% CI = 1.9-6.3, P for trend < 0.0001). Our study confirms the important role of diet in the carcinogenesis of esophageal and cardia cancer.


A distinct transcriptional signature of antidepressant response in hippocampal dentate gyrus granule cells.
Major depressive disorder is the most prevalent mental illness worldwide, still its pharmacological treatment is limited by various challenges, such as the large heterogeneity in treatment response and the lack of insight into the neurobiological pathways underlying this phenomenon. To decode the molecular mechanisms shaping antidepressant response and to distinguish those from general paroxetine effects, we used a previously established approach targeting extremes (i.e., good vs poor responder mice). We focused on the dentate gyrus (DG), a subregion of major interest in the context of antidepressant mechanisms. Transcriptome profiling on micro-dissected DG granule cells was performed to (i) reveal cell-type-specific changes in paroxetine-induced gene expression (paroxetine vs vehicle) and (ii) to identify molecular signatures of treatment response within a cohort of paroxetine-treated animals. We identified 112 differentially expressed genes associated with paroxetine treatment. The extreme group comparison (good vs poor responder) yielded 211 differentially expressed genes. General paroxetine effects could be distinguished from treatment response-associated molecular signatures, with a differential gene expression overlap of only 4.6% (15 genes). Biological pathway enrichment and cluster analyses identified candidate mechanisms associated with good treatment response, e.g., neuropeptide signaling, synaptic transmission, calcium signaling, and regulation of glucocorticoid secretion. Finally, we examined glucocorticoid receptor (GR)-dependent regulation of selected response-associated genes to analyze a hypothesized interplay between GR signaling and good antidepressant treatment response. Among the most promising candidates, we suggest potential targets such as the developmental gene Otx2 or Htr2c for further investigations into antidepressant treatment response in the future.


Cytomorphological findings and histological correlation of low-grade cribriform cystadenocarcinoma of salivary gland in fine-needle aspiration: a case study.
Low-grade cribriform cystadenocarcinoma (LGCCC) of the salivary gland is a rare tumor. We report the cytologic features and histologic correlation of a patient with LGCCC. A 57-year-old man had a hardly palpable, nontender mass in the right cheek area followed over nine months. Radiologic analysis revealed a 1.2 cm multiseptated, cystic, solid nodule in an anterior superficial lobe of the right parotid gland. Fine-needle aspiration cytology revealed many irregular overlapping sheets or clusters of ductal epithelial cells forming solid, pseudopapillary, and cribriform architectures. Nuclei of the tumor cells revealed inconspicuous atypia with minimal size variation. On the basis of these findings, we confirmed a diagnosis of ductal epithelial proliferative lesion, favoring neoplasm, with uncertain malignant potential. Tumor excision was performed, revealing a tiny multicystic nodule (0.7 cm). Histopathologically, this tumor showed the characteristic morphology of LGCCC. This is the first report of cytomorphological findings of LGCCC in Korea.


Multimerization of Drosophila sperm protein Mst77F causes a unique condensed chromatin structure.
Despite insights on the cellular level, the molecular details of chromatin reorganization in sperm development, which involves replacement of histone proteins by specialized factors to allow ultra most condensation of the genome, are not well understood. Protamines are dispensable for DNA condensation during Drosophila post-meiotic spermatogenesis. Therefore, we analyzed the interaction of Mst77F, another very basic testis-specific protein with chromatin and DNA as well as studied the molecular consequences of such binding. We show that Mst77F on its own causes severe chromatin and DNA aggregation. An intrinsically unstructured domain in the C-terminus of Mst77F binds DNA via electrostatic interaction. This binding results in structural reorganization of the domain, which induces interaction with an N-terminal region of the protein. Via putative cooperative effects Mst77F is induced to multimerize in this state causing DNA aggregation. In agreement, overexpression of Mst77F results in chromatin aggregation in fly sperm. Based on these findings we postulate that Mst77F is crucial for sperm development by giving rise to a unique condensed chromatin structure.


What is known about infant colic?
The ancient Greeks were the first to mention infant colic in recorded history; yet in 2002, the cause of infant colic is still unknown. Review of the infant colic literature suggests there are at least five possible explanations-cow's milk/soy protein allergy or intolerance; immature gastrointestinal system; immature central nervous system; difficult infant temperament; and parent-infant interaction problems consisting of either the transfer of parental anxiety to the infant or the inability of the infant to give clear cues about needs to the caregiver. It is likely the cause of infant colic is multifactorial because it has proven to be so elusive. One or more of the above explanations (or as yet an undiscovered explanation) is likely to play a role in the development of colic in a given infant. Determining the most probable explanation for each infant and then selecting interventions based on this explanation is likely to be more successful in preventing or decreasing the length or frequency of episodes than the various trial-and-error approaches to treatment currently recommended by healthcare providers. Infant colic is an important clinical problem that is amenable to nursing intervention.


Practice patterns for the prophylaxis and treatment of acute radiation dermatitis in the United States.
Due to the inconclusive evidence for available treatment options, management of radiation dermatitis (RD) varies among practitioners. This study defines and reviews the current treatment patterns for RD in the USA, providing guidance for practicing physicians as well as directions for future research. An online survey of 21 questions was emailed to all 5626 members of the 2013 American Society for Radiation Oncology (ASTRO) directory, which included radiation oncologists, residents, fellows, physician assistants, nurse practitioners, registered nurses and other care providers. The questions were designed to evaluate demographics of responders, their training and comfort in the management RD, and their patterns of care regarding prophylaxis and treatment of RD. Data was analyzed using simple summary and descriptive statistics. Out of the 5626 emails sent, we were left with 709 physician respondents for our analysis, or a response rate of 12.9%. Although 84.7% of physicians felt that RD had a moderate or large impact on patients' quality of life during cancer treatment, only 30.1% received special training or specific instructional courses in treating RD during their medical training in residency or fellowship. Eighty-nine percent of surveyed physicians rely on observational and/or anecdotal findings to guide treatment decisions, and 51.4% reported using evidence-based treatments. The results of our study show that there is great variability in the topical agents and dressings used in practice by radiation oncologists to prevent and treat RD. This information may be useful to other practitioners to develop their own personal recommendations and can guide further research into strategies to prevent and treat radiation dermatitis.


Diagnosis in schizophrenia and manic-depressive illness: a reassessment of the specificity of 'schizophrenic' symptoms in the light of current research.
Present clinical and research methods of differential diagnosis of schizophrenia and affective psychoses rely very heavily on presenting symptoms and signs, especially in acute psychosis. We have reviewed studies bearing on this issue, including studies of the phenomenology of psychotic illness, outcome, family history, response to treatment with lithium carbonate, and cross-national and historical diagnostic comparisons. We conclude that most so-called schizophrenic symptoms, taken alone and in cross section, have remarkably little, if any, demonstrated validity in determining diagnosis, prognosis, or treatment response in psychosis. In the United States, particularly, overreliance on such symptoms alone results in overdiagnosis of schizophrenia and underdiagnosis of affective illnesses, particularly mania. This compromises both clinical treatment and research.


Plant growth-promoting bacteria Kosakonia radicincitans mediate anti-herbivore defense in Arabidopsis thaliana.
This study demonstrates that the application of the PGPB strain, Kosakonia radicincitans enhances a plant's resistance against phloem-feeding and chewing insects in Arabidopsis thaliana. The plant growth-promoting bacterial strain K. radicincitans DSM 16656 applied to A. thaliana reduced the number of phloem-feeding insects of both the specialist Brevicoryne brassicae and the generalist Myzus persicae. While weight gain of the generalist chewing insect Spodoptera exigua was reduced by 30% on A. thaliana plants treated with K. radicincitans, growth of the specialist caterpillar Pieris brassicae was not affected when compared with caterpillars from control plants. Since generalist and specialist chewing insects responded differentially to PGPB application, the implication of signaling pathways in PGPB mediated changes in plant defense was studied using two signaling pathway mutants impaired in their salicylic acid (npr1-1 mutant) or jasmonic acid (coi1-1 mutant) pathway. We found that the jasmonic acid pathway is relevant for upregulation of aliphatic glucosinolates and suppression of the chewing generalist S. exigua larval growth. Chewing from generalist P. brassicae increased glucosinolate content in A. thaliana leaves mediated via both signaling pathways. However, only in the npr1-1 mutant, which contains the highest aliphatic glucosinolate content, the P. brassicae induced further enrichment of glucosinolates, resulting in a reduction of larval growth. Effects of K. radicincitans on plant resistance could not be explained by changes in glucosinolate contents or composition. Our results demonstrate the distinct role played by K. radicincitans in suppressing insect performance in A. thaliana.


High sensitivity C-reactive protein associated with different health predictors in middle-aged and oldest old Chinese.
To describe the distribution of plasma high sensitivity C-reactive protein (hsCRP) and explore the relationship between hsCRP and metabolic risk factors among residents living in longevity areas of China. 268 individuals aged between 40 and 59 years and 506 individuals aged over 90 years were selected from 5 longevity areas of China to participate in a cross section longitudinal cohort study. The participants were interviewed with general health related questionnaire to collect their demographic, behavioral and lifestyle data, as well as their chronic conditions, and meanwhile their physical and biomedical parameters including waist circumference (WC), blood pressure (BP), hsCRP, plasma lipids, and fasting blood glucose (FBG) were measured. The median of hsCRP was 0.99 mg/L in the middle-aged group and 1.76 mg/L in the oldest old group. No significant gender difference was observed between the above two groups. Among the oldest old individuals, 36.56% had an hsCRP level >3.0 mg/L. The prevalence of high hsCRP was 16.79% in the middle-aged group. The results of stepwise multiple linear regression analyses showed that HDL-C was independently associated with ln (hsCRP) concentration in the middle-aged group, whereas ln (TG), HDL-C and FBG were correlated after adjustment for gender, study site, smoking, drinking, education and BMI in the oldest old group. HDL-C is a stronger predictor of elevated hsCRP than other metabolic factors in the middle-aged population. For the oldest old persons, high TG, low HDL-C, and FBG predict elevated plasma hsCRP.


Iodixanol 320 results in better renal tolerance and radiodensity than do gadolinium-based contrast media: arteriography in ischemic porcine kidneys.
To prospectively compare nephrotoxicity and radiodensity of plasma hyperosmotic gadolinium chelates (attenuation-osmotic ratio of 1:1) with those of plasma iso-osmotic iodine-based contrast media (attenuation-osmotic ratio of 3:1 or 6:1) after renal arteriography in ischemic porcine kidneys. The local animal care committee approved this study. The following contrast media were used: (a) iodixanol (150 mg of iodine per milliliter and 320 mg I/mL, 0.29 osm/kg H(2)O), (b) iopromide (150 mg I/mL, 0.34 osm/kg), (c) 0.5 mol/L gadodiamide (0.78 osm/kg), and (d) 1.0 mol/L gadobutrol (1.6 osm/kg). After left-sided nephrectomy, contrast media (3 mL per kilogram of body weight) were injected (20 mL/min) in a noncrossover design into the right renal artery of pigs during a 10-minute ischemic period. There were eight pigs in each group and one group for each contrast medium. We compared histomorphology, radiographic contrast medium excretion, subjective radiodensity of nephrograms (70 kVp) at the end of injection, and contrast medium plasma half-life elimination times 1-3 hours after injection. Longer elimination times resulted in lower glomerular filtration rates. Gadobutrol caused extensive tubular necrosis and moderate glomerular necrosis; gadodiamide and iopromide, minimal to mild tubular necrosis; and iodixanol, no necrosis. Gadobutrol was the only contrast medium to show no sign of excretion, and its plasma half-life elimination time (median, 1103 minutes; P < .001) was significantly longer than that of other contrast agents. Gadodiamide had a significantly longer plasma half-life elimination time (median, 209 minutes; P = .01) than did iodine-based contrast media (median, 136-142 minutes). The 320 mg I/mL dose of iodixanol had the highest radiodensity, whereas gadodiamide had the lowest radiodensity. The radiodensity of the 320 mg I/mL dose of iodixanol was greater than that of the 150 mg I/mL dose of iodixanol, which was equal to the radiodensities of the 150 mg I/mL dose of iopromide and 1.0 mol/L gadobutrol, which in turn were greater than that of 0.5 mol/L gadodiamide. Plasma iso-osmotic iodine-based contrast media used at commercially available concentrations have superior attenuation and nephrotoxic profiles compared with equal volumes of hyperosmotic nonionic 0.5-1.0 mol/L gadolinium-based contrast media when performing renal arteriographic procedures.


Hepatitis C virus antibody status, sociodemographic characteristics, and risk behaviour among injecting drug users in Croatia.
The study was conducted among 76 injecting drug users (IDU) from seven Croatian cities during a three-year period (2005-2007). Each participant completed a questionnaire on sociodemographic characteristics and potential risk factors for hepatitis C virurs (HCV) infection followed by anti-HCV and anti-HIV antibody testing. The mean patient age was 30. The majority of patients (69.8%) reported more than one potential exposure to HCV: 97.1% had shared injecting equipment, 75% reported risk sexual behaviour, and 56.3% reported a history of travelling abroad. The overall HCV seroprevalence was 51.3% (95% CI = 40-63%). HCV seroprevalence increased with increasing number of risk behaviours (p = 0.026). Needle sharing frequency was the most important risk factor for hepatitis C. The HCV seroprevalence rate ranged from 27.3% in IDUs who answered that they shared needles occasionally to 100% in IDUs who always shared needles (p < 0.001). No other risk factors (age, gender, educational level, marital and employment status, history of travelling abroad and sexual risk behaviour) were associated with HCV seropositivity.


Genetic diversity and fingerprinting of 33 standard flue-cured tobacco varieties for use in distinctness, uniformity, and stability testing.
At present, the distinctness, uniformity, and stability (DUS) testing of flue-cured tobacco (Nicotiana tabacum L.) depends on field morphological identification, which is problematic in that it is labor intensive, time-consuming, and susceptible to environmental impacts. In order to improve the efficiency and accuracy of tobacco DUS testing, the development of a molecular marker-based method for genetic diversity identification is urgently needed. In total, 91 simple sequence repeats (SSR) markers with clear and polymorphic amplification bands were obtained with polymorphism information content, Nei index, and Shannon information index values of 0.3603, 0.4040, and 0.7228, respectively. Clustering analysis showed that the 33 study varieties, which are standard varieties for flue-cured tobacco DUS testing, could all be distinguished from one another. Further analysis showed that a minimum of 25 markers were required to identify the genetic diversity of these varieties. Following the principle of two markers per linkage group, 48 pairs of SSR markers were selected. Correlation analysis showed that the genetic relationships revealed by the 48 SSR markers were consistent with those found using the 91 SSR markers. The genetic fingerprints of the 33 standard varieties of flue-cured tobacco were constructed using 48 SSR markers, and an SSR marker-based identification technique for new tobacco varieties was developed. This study provides a reliable technological approach for determining the novelty of new tobacco varieties and offers a solid technical basis for the accreditation and protection of new tobacco varieties.


Socioemotional effects of fathers' incarceration on low-income, urban, school-aged children.
The goal was to evaluate whether children of incarcerated fathers are more likely to report or exhibit behavioral symptoms than their equally disadvantaged peers without an incarcerated father. During an ongoing longitudinal study of intrauterine cocaine exposure involving 102 children (50% male and 89% black) from urban, low-income homes, questions regarding incarceration of the child's father were asked of the child's primary caregiver at each visit during school age. Children were administered the Children's Depression Inventory between the ages of 6 and 11 years, and their primary caregivers completed the Child Behavior Checklist. In addition, the children's teachers completed the Teacher Report Form. Children's Depression Inventory, Child Behavior Checklist, and Teacher Report Form data obtained at the oldest available age after the first report of paternal incarceration were analyzed. In bivariate analyses, children whose fathers were in jail had higher Children's Depression Inventory total scores compared with children without incarcerated fathers, indicating more depressive symptoms. This finding was robust in multivariate analyses after adjustment for children's age, gender, prenatal cocaine and alcohol exposure, and school-age violence exposure. Teachers reported higher Teacher Report Form externalizing scores for children whose fathers were in jail, after adjustment for age, gender, prenatal cocaine and marijuana exposure, and school-age violence exposure. Children of incarcerated fathers reported more depressive symptoms and their teachers noted more externalizing behaviors, after controlling for other biopsychosocial risks. Interventions targeted to ameliorate the distress of children with incarcerated fathers should be considered.


RankMap: A Framework for Distributed Learning From Dense Data Sets.
This paper introduces RankMap, a platform-aware end-to-end framework for efficient execution of a broad class of iterative learning algorithms for massive and dense data sets. Our framework exploits data structure to scalably factorize it into an ensemble of lower rank subspaces. The factorization creates sparse low-dimensional representations of the data, a property which is leveraged to devise effective mapping and scheduling of iterative learning algorithms on the distributed computing machines. We provide two APIs, one matrix-based and one graph-based, which facilitate automated adoption of the framework for performing several contemporary learning applications. To demonstrate the utility of RankMap, we solve sparse recovery and power iteration problems on various real-world data sets with up to 1.8 billion nonzeros. Our evaluations are performed on Amazon EC2 and IBM iDataPlex servers using up to 244 cores. The results demonstrate up to two orders of magnitude improvements in memory usage, execution speed, and bandwidth compared with the best reported prior work, while achieving the same level of learning accuracy.


Calpain and Cardiometabolic Diseases.
Calpain is defined as a member of the superfamily of cysteine proteases possessing the CysPC motif within the gene. Calpain-1 and -2, which are categorized as conventional isozymes, execute limited proteolysis in a calcium-dependent fashion. Accordingly, the calpain system participates in physiological and pathological phenomena, including cell migration, apoptosis, and synaptic plasticity. Recent investigations have unveiled the contributions of both conventional and unconventional calpains to the pathogenesis of cardiometabolic disorders. In the context of atherosclerosis, overactivation of conventional calpain attenuates the barrier function of vascular endothelial cells and decreases the immunosuppressive effects attributed to lymphatic endothelial cells. In addition, calpain-6 induces aberrant mRNA splicing in macrophages, conferring atheroprone properties. In terms of diabetes, polymorphisms of the calpain-10 gene can modify insulin secretion and glucose disposal. Moreover, conventional calpain reportedly participates in amino acid production from vascular endothelial cells to induce alteration of amino acid composition in the liver microenvironment, thereby facilitating steatohepatitis. Such multifaceted functionality of calpain underscores its potential as a promising candidate for pharmaceutical targets for the treatment of cardiometabolic diseases. Consequently, the present review highlights the pivotal role of calpains in the complications of cardiometabolic diseases and embarks upon a characterization of calpains as molecular targets.


Consistency of microvascular and autonomic abnormalities in diabetes.
The progression of early measures of microvascular disease and autonomic neuropathy were studied in a group of 81 children with insulin dependent diabetes mellitus over a mean interval of 4.2 years. Repeated measurements were made of blood pressure, albumin excretion, joint mobility, and pupillary dilatation in darkness. Over the years between the first and the second study, systolic and diastolic blood pressure showed positive tracking correlations (r = 0.38 and r = 0.32) with a small but significant deviation from normality; albumin/creatinine ratio was significantly increased (0.79 v 0.55); a greater number of children were identified in the second study as having limitation of mobility of the fifth metacarpophalangeal joint; and pupillary dilatation in darkness significantly decreased (61.5% v 62.9%); 62% of the children with one or more abnormal measurements in the first study were found to have measurements outside the normal ranges in the second study, indicating a consistency in observations over time. It remains to be seen with what accuracy these measurements predict adult onset clinical disease.


The hepatoprotective effect of oxygen during halothane anesthesia.
The effects of halothane anesthesia on liver function, as reflected by postanesthetic changes in serum glutamic pyruvic transaminase (SGPT) levels, were evaluated in 2 groups of 40 patients. All patients had 2 halothane anesthetics. In 1 group, both anesthetics were administered at 1 atmosphere pressure with 30% O2 in the inspired air. In the 2nd group, both anesthetics were administered at 2 to 3 atmospheres (absolute) of pressure with 97 to 98% O2 in the inspired air. While the SGPT levels remained within the normal range in all cases, there was a significant rise in SGPT levels in patients undergoing surgery under 1 atmospheric pressure. Patients undergoing surgery at 2 to 3 atmospheres pressure (absolute) had SGPT levels which remained at low normal values. The difference in response of SGPT in the 2 groups was statistically significant. We conclude that increased O2 tensions alter the normal response of SGPT to halothane anesthesia and that increased O2 tensions appear to protect the liver from possible adverse responses to halothane or its metabolites.


Myosin light chain phosphorylation-dephosphorylation in mammalian skeletal muscle.
Phosphorylation of the myosin light chain 2 (LC2) subunit was examined in rat fast-twitch and slow-twitch skeletal muscles in response to repetitive stimulation at 23 and 35 degrees C and on incubation of fast-twitch skeletal muscle with isoproterenol. After a 1-s tetany at 35 degrees C, LC2 phosphate content in extensor digitorum longus muscle increased rapidly and transiently from 0.21 to 0.51 mol phosphate/mol LC2. This pattern of phosphorylation was similar to that observed at 23 degrees C. Increases in LC2 phosphate content were dependent on the frequency and duration of stimulation. In soleus muscle LC2 phosphate content was minimal following a 1-s tetany but increased markedly following more prolonged tetanies. On incubation of extensor digitorum longus muscle with isoproterenol (20 microM), LC2 phosphate content did not change, whereas phosphorylase a levels increased. A positive correlation existed between LC2 phosphate content and potentiation of peak twitch tension in both types of muscles, suggesting a physiological function for LC2 phosphorylation.


Anti-inflammatory Elafin in human fetal membranes.
Elafin is a low molecular weight protein with antileukoproteinase, anti-inflammatory, antibacterial and immunomodulating properties. The profile of Elafin in fetal membranes is not well characterized. This study determined the changes in Elafin expression and concentration in human fetal membrane from patients with preterm prelabor rupture of membranes (PPROM) and in vitro in response to intra-amniotic polymicrobial pathogens. Elafin messenger RNA (mRNA) expressions were studied in fetal membranes from PPROM, normal term as well as in normal term not in labor membranes in an organ explant system treated (24 h) with lipopolysaccharide (LPS), using quantitative reverse transcription-polymerase chain reaction (RT-PCR). Enzyme-linked immunosorbent assay (ELISA) measured Elafin concentrations in culture supernatants from tissues treated with LPS and polybacterial combinations of heat-inactivated Mycoplasma hominis (MH), Ureaplasma urealyticum (UU) and Gardnerella vaginalis (GV). Elafin mRNA expression in fetal membranes from women with PPROM was significantly higher compared to women who delivered at term after normal pregnancy (5.09±3.50 vs. 11.71±2.21; P<0.05). In vitro, LPS-stimulated membranes showed a significantly increased Elafin m-RNA expression (P<0.05). However, the protein levels after LPS stimulation was not changed. Similarly, polymicrobial-treated fetal membranes also showed no changes in Elafin protein concentrations compared to untreated controls. Higher Elafin expression in PPROM fetal membranes suggests a host response to an inflammatory pathology. However, lack of Elafin response to LPS and polymicrobial treatment is indicative of the minimal anti-inflammatory impact of this molecule in fetal membranes.


Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals.
Although primarily regarded as being intracellular, this study has identified the presence of heat shock protein 60 (Hsp60) in the peripheral circulation of normal individuals. The median Hsp60 concentration was approximately 3.5-fold higher in females than in males and significantly higher levels of anti-human Hsp60 antibodies were also detected in females. There were no differences in the levels of antibodies to mycobacterial Hsp60 between males and females, nor did antibody levels correlate with Hsp60 concentrations. Hsp60 was not released from mitogenically stimulated peripheral blood mononuclear cells. The potential physiological roles for circulating Hsp60 are unknown. Given the emerging evidence that inappropriate reactivity to heat shock proteins is involved in autoimmune disease and that T cells responsive to self Hsp60 appear to be protective, these findings suggest that circulating Hsp60 may be involved in the regulation of tolerance to self and immunity to bacterial forms of these widely expressed and structurally conserved proteins.


Probucol attenuates hyperoxia-induced lung injury in mice.
Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol-a commercially available drug for treating hypercholesterolemia-has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O2 for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2'-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome.


New adhesive protocol improves shear bond strength of Polyetherketoneketone (PEKK).
Inert surface of Polyetherketoneketone (PEKK) jeopardizes resin bonding. This study aimed to present a new adhesive protocol to improve PEKK bonding. A total of 360 PEKK blocks were milled, polished (maximum roughness of 0.20 µm), and randomly assigned to groups. The new protocol was applied (n = 36) and compared to conventional treatments (no treatment; sandblasting (110-µm Al2O3 and silica); no adhesive; Visiolink (Bredent); and PEKKbond (AnaxDent)) (n = 36). For the new protocol, the surface was blasted (110 µm Al2O3 and 96% isopropyl alcohol at 60 psi), followed by 96% isopropyl alcohol washing, and air drying. PEKKbond was applied (dried for 3 min at 77 °C), followed by Visiolink (dried for 3 min at 60 °C); both light-cured for 3 min (800 mW/cm2). Preopaque (GC Europe) and Opaque (AnaxDent) were applied and light-cured (5 min). Morphological topography was analyzed, and flowable gingiva-colored composite (AnaxGum, AnaxDent) was bonded. All specimens were aged for 24 h and thermocycled (5000 cycles, 5-55 °C). Shear bond strength (SBS) was measured (MPa) and data were analyzed by two-way ANOVA, Tukey, and Weibull moduli estimation (α = 0.05). The highest SBS values were found in the new protocol (p < 0.05), regardless of aging. Thermocycling reduced SBS (p < 0.05), while Al2O3 and PEKKbond produced higher SBS values than silica and Visiolink, respectively (p < 0.05). The new protocol strongly improves PEKK adhesiveness, and this can reflect in the longevity of prostheses.


Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation.
Two major goals of regenerative medicine are to reproducibly transform adult somatic cells into a pluripotent state and to control their differentiation into specific cell fates. Progress toward these goals would be greatly helped by obtaining a complete picture of the RNA isoforms produced by these cells due to alternative splicing (AS) and alternative promoter selection (APS). To investigate the roles of AS and APS, reciprocal exon-exon junctions were interrogated on a genome-wide scale in differentiating mouse embryonic stem (ES) cells with a prototype Affymetrix microarray. Using a recently released open-source software package named AltAnalyze, we identified 144 genes for 170 putative isoform variants, the majority (67%) of which were predicted to alter protein sequence and domain composition. Verified alternative exons were largely associated with pathways of Wnt signaling and cell-cycle control, and most were conserved between mouse and human. To examine the functional impact of AS, we characterized isoforms for two genes. As predicted by AltAnalyze, we found that alternative isoforms of the gene Serca2 were targeted by distinct microRNAs (miRNA-200b, miRNA-214), suggesting a critical role for AS in cardiac development. Analysis of the Wnt transcription factor Tcf3, using selective knockdown of an ES cell-enriched and characterized isoform, revealed several distinct targets for transcriptional repression (Stmn2, Ccnd2, Atf3, Klf4, Nodal, and Jun) as well as distinct differentiation outcomes in ES cells. The findings herein illustrate a critical role for AS in the specification of ES cells with differentiation, and highlight the utility of global functional analyses of AS.


Compartmentalized Cytokine Responses in Hidradenitis Suppurativa.
Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS). Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs) were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured. CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1β and IL-17 by PBMCs at week 8. Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF.


Rapid evolutionary response to a transmissible cancer in Tasmanian devils.
Although cancer rarely acts as an infectious disease, a recently emerged transmissible cancer in Tasmanian devils (Sarcophilus harrisii) is virtually 100% fatal. Devil facial tumour disease (DFTD) has swept across nearly the entire species' range, resulting in localized declines exceeding 90% and an overall species decline of more than 80% in less than 20 years. Despite epidemiological models that predict extinction, populations in long-diseased sites persist. Here we report rare genomic evidence of a rapid, parallel evolutionary response to strong selection imposed by a wildlife disease. We identify two genomic regions that contain genes related to immune function or cancer risk in humans that exhibit concordant signatures of selection across three populations. DFTD spreads between hosts by suppressing and evading the immune system, and our results suggest that hosts are evolving immune-modulated resistance that could aid in species persistence in the face of this devastating disease.


Image Denoising Based on Nonlocal Bayesian Singular Value Thresholding and Stein's Unbiased Risk Estimator.
Singular value thresholding (SVT)- or nuclear norm minimization (NNM)-based nonlocal image denoising methods often rely on the precise estimation of the noise variance. However, most existing methods either assume that the noise variance is known or require an extra step to estimate it. Under the iterative regularization framework, the error in the noise variance estimate propagates and accumulates with each iteration, ultimately degrading the overall denoising performance. In addition, the essence of these methods is still least squares estimation, which can cause a very high mean-squared error (MSE) and is inadequate for handling missing data or outliers. In order to address these deficiencies, we present a hybrid denoising model based on variational Bayesian inference and Stein's unbiased risk estimator (SURE), which consists of two complementary steps. In the first step, the variational Bayesian SVT performs a low-rank approximation of the nonlocal image patch matrix to simultaneously remove the noise and estimate the noise variance. In the second step, we modify the conventional SURE full-rank SVT and its divergence formulas for rank-reduced eigen-triplets to remove the residual artifacts. The proposed hybrid BSSVT method achieves better performance in recovering the true image compared with state-of-the-art methods.


Transmission of mitochondrial DNA following assisted reproduction and nuclear transfer.
Mitochondria are the organelles responsible for producing the majority of a cell's ATP and also play an essential role in gamete maturation and embryo development. ATP production within the mitochondria is dependent on proteins encoded by both the nuclear and the mitochondrial genomes, therefore co-ordination between the two genomes is vital for cell survival. To assist with this co-ordination, cells normally contain only one type of mitochondrial DNA (mtDNA) termed homoplasmy. Occasionally, however, two or more types of mtDNA are present termed heteroplasmy. This can result from a combination of mutant and wild-type mtDNA molecules or from a combination of wild-type mtDNA variants. As heteroplasmy can result in mitochondrial disease, various mechanisms exist in the natural fertilization process to ensure the maternal-only transmission of mtDNA and the maintenance of homoplasmy in future generations. However, there is now an increasing use of invasive oocyte reconstruction protocols, which tend to bypass mechanisms for the maintenance of homoplasmy, potentially resulting in the transmission of either form of mtDNA heteroplasmy. Indeed, heteroplasmy caused by combinations of wild-type variants has been reported following cytoplasmic transfer (CT) in the human and following nuclear transfer (NT) in various animal species. Other techniques, such as germinal vesicle transfer and pronuclei transfer, have been proposed as methods of preventing transmission of mitochondrial diseases to future generations. However, resulting embryos and offspring may contain mtDNA heteroplasmy, which itself could result in mitochondrial disease. It is therefore essential that uniparental transmission of mtDNA is ensured before these techniques are used therapeutically.


Isolation and antisense suppression of flavonoid 3', 5'-hydroxylase modifies flower pigments and colour in cyclamen.
Cyclamen is a popular and economically significant pot plant crop in several countries. Molecular breeding technologies provide opportunities to metabolically engineer the well-characterized flavonoid biosynthetic pathway for altered anthocyanin profile and hence the colour of the flower. Previously we reported on a genetic transformation system for cyclamen. Our aim in this study was to change pigment profiles and flower colours in cyclamen through the suppression of flavonoid 3', 5'-hydroxylase, an enzyme in the flavonoid pathway that plays a determining role in the colour of anthocyanin pigments. A full-length cDNA putatively identified as a F3'5'H (CpF3'5'H) was isolated from cyclamen flower tissue. Amino acid and phylogeny analyses indicated the CpF3'5'H encodes a F3'5'H enzyme. Two cultivars of minicyclamen were transformed via Agrobacterium tumefaciens with an antisense CpF3'5'H construct. Flowers of the transgenic lines showed modified colour and this correlated positively with the loss of endogenous F3'5'H transcript. Changes in observed colour were confirmed by colorimeter measurements, with an overall loss in intensity of colour (C) in the transgenic lines and a shift in hue from purple to red/pink in one cultivar. HPLC analysis showed that delphinidin-derived pigment levels were reduced in transgenic lines relative to control lines while the percentage of cyanidin-derived pigments increased. Total anthocyanin concentration was reduced up to 80% in some transgenic lines and a smaller increase in flavonol concentration was recorded. Differences were also seen in the ratio of flavonol types that accumulated. To our knowledge this is the first report of genetic modification of the anthocyanin pathway in the commercially important species cyclamen. The effects of suppressing a key enzyme, F3'5'H, were wide ranging, extending from anthocyanins to other branches of the flavonoid pathway. The results illustrate the complexity involved in modifying a biosynthetic pathway with multiple branch points to different end products and provides important information for future flower colour modification experiments in cyclamen.


Development of a novel efficient fluorescence-based plaque reduction microneutralization assay for measles virus immunity.
The measurement of functional measles virus-specific neutralizing antibodies is of considerable interest for vaccine-related research. In this study, we developed and standardized a simple, rapid, highly sensitive, and reproducible fluorescence-based plaque reduction microneutralization (PRMN) assay with visual and automated readout, using a recombinant measles virus engineered to express enhanced green fluorescent protein. The assay is performed in micro format, requires less time to complete (2 versus 4 to 7 days), and is less labor-intensive and less costly than the classical plaque reduction neutralization (PRN) test, widely accepted as the "gold standard" in measles serology. Two available WHO international anti-measles virus standards and one in-house reference serum were used to develop and standardize the new assay. The mean PRMN values from repeated assays were found to be similar to those reported in the literature or assigned to the WHO standards by the classical PRN assay. For validation, we used three groups of low, moderate, and high measles virus vaccine responders' sera with moderate values of correlation in antibody levels (mIU/ml) between PRMN and the Dade Behring immunoglobulin G enzyme immunoassay (EIA). The PRMN assay was more sensitive at low antibody levels and more informative in terms of protection than this commercial EIA. In conclusion, we have developed and validated a sensitive and high-throughput measles virus-specific PRMN that can be readily used in large population-based measles studies.


Freezing promoted hybridization of very short DNA oligonucleotides.
Shorter DNA probes provide better specificity for hybridization, but they may not form stable duplexes at room temperature. In this study, we used thiazole orange to follow DNA hybridization upon freezing and achieved stable 5-mer duplex DNA. Using multiple short probes in tandem, long DNA could also be studied. This study provides insights into DNA hybridization in the frozen state and expands the application of freezing for nucleic acid chemistry.


Flexible coding of time or distance in hippocampal cells.
Analysis of neuronal activity in the hippocampus of behaving animals has revealed cells acting as 'Time Cells', which exhibit selective spiking patterns at specific time intervals since a triggering event, and 'Distance Cells', which encode the traversal of specific distances. Other neurons exhibit a combination of these features, alongside place selectivity. This study aims to investigate how the task performed by animals during recording sessions influences the formation of these representations. We analyzed data from a treadmill running study conducted by Kraus et al., 2013, in which rats were trained to run at different velocities. The rats were recorded in two trial contexts: a 'fixed time' condition, where the animal ran on the treadmill for a predetermined duration before proceeding, and a 'fixed distance' condition, where the animal ran a specific distance on the treadmill. Our findings indicate that the type of experimental condition significantly influenced the encoding of hippocampal cells. Specifically, distance-encoding cells dominated in fixed-distance experiments, whereas time-encoding cells dominated in fixed-time experiments. These results underscore the flexible coding capabilities of the hippocampus, which are shaped by over-representation of salient variables associated with reward conditions.


Expression of translationally controlled tumour protein is regulated by calcium at both the transcriptional and post-transcriptional level.
We have investigated how the programme of protein synthesis is altered in response to a loss of calcium homoeostasis in Cos-7 cells using a differential proteome mapping approach. Exposure of the cells to the calcium ionophore A23187 or thapsigargin, or alternatively, expression of a viral glycoprotein reported to deplete intracellular calcium stores, resulted in the up-regulated expression of a characteristic set of proteins. One of these is the translationally controlled tumour protein (TCTP), a cytoplasmic protein whose expression has not previously been linked to calcium perturbation. Quantitative Northern blot assay demonstrated that steady-state mRNA abundance of TCTP was also increased under these conditions. Clamping the cytosolic calcium concentration by the introduction of bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetra-acetic acid (BAPTA) into cells did not affect the increase in steady-state levels of TCTP mRNA observed in response to ionophore. Therefore depletion of endoplasmic reticulum (ER) calcium, but not elevation of the cytosolic calcium concentration, was responsible for increased transcription of the TCTP gene. However, the presence of BAPTA significantly attenuated the ionophore-mediated increase in levels of the protein. Moreover, the level of TCTP in ionophore-treated cells increased in advance of a detectable increase in the corresponding mRNA abundance. These results indicate that expression of TCTP is regulated at two distinct levels in response to the concentration of calcium in different cellular compartments. Whereas depletion of the ER store causes an increase in TCTP mRNA abundance, increased cytosolic calcium concentrations regulate gene expression at the post-transcriptional level.


AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.
We investigated the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), prosurvival kinase Akt, oxidative stress, and autophagy in the cytotoxicity of parkinsonian neurotoxin 1-methyl-4-phenyl piridinium (MPP+) towards SH-SY5Y human neuroblastoma cells. MPP+-mediated oxidative stress, mitochondrial depolarization, and apoptotic cell death were associated with rapid (within 2 h) activation of AMPK, its target Raptor, and prosurvival kinase Akt. Antioxidants N-acetylcysteine and butylated hydroxyanisole suppressed MPP+-induced cytotoxicity, AMPK, and Akt activation. A genetic or pharmacological inhibition of AMPK increased MPP+-triggered production of reactive oxygen species and cell death, and diminished Akt phosphorylation, while AMPK activation protected SH-SY5Y cells from MPP+. On the other hand, genetic or pharmacological inactivation of Akt stimulated MPP+-triggered oxidative stress and neurotoxicity, but did not affect AMPK activation. At later time-points (16-24 h), MPP+ inhibited the main autophagy repressor mammalian target of rapamycin, which coincided with the increase in the levels of autophagy marker microtubule-associated protein 1 light-chain 3B. MPP+ also increased the concentration of a selective autophagic target sequestosome-1/p62 and reduced the levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification, suggesting that MPP+-induced autophagy was coupled with a decrease in autophagic flux. Nevertheless, further pharmacological inhibition of autophagy sensitized SH-SY5Y cells to MPP+-induced death. Antioxidants and AMPK knockdown reduced, whereas genetic inactivation of Akt potentiated neurotoxin-triggered autophagy. These results suggest that MPP+-induced oxidative stress stimulates AMPK, which protects SH-SY5Y cells through early activation of antioxidative Akt and late induction of cytoprotective autophagy.


Binocular competition in the control of geniculate cell size depends upon visual cortical N-methyl-D-aspartate receptor activation.
The lateral geniculate nucleus relays visual information from the retina to cortex. One well-known anatomical consequence of monocular deprivation during early postnatal development is a shrinkage of neurons in the lamina of the lateral geniculate nucleus that receive input from the deprived eye. This is thought to reflect the competition of afferents subserving the two eyes, possibly at the level of the visual cortex. We find that blockade of N-methyl-D-aspartate receptors in kitten visual cortex disrupts this process of binocular competition. These data provide direct evidence that postsynaptic activation of cortical neurons is required for competitive changes in lateral geniculate cell size and suggest a role for N-methyl-D-aspartate receptors in anatomical as well as physiological plasticity in the mammalian visual system.


M-idempotent and self-dual morphological filters.
In this paper, we present a comprehensive analysis of self-dual and m-idempotent operators. We refer to an operator as m-idempotent if it converges after m iterations. We focus on an important special case of the general theory of lattice morphology: spatially variant morphology, which captures the geometrical interpretation of spatially variant structuring elements. We demonstrate that every increasing self-dual morphological operator can be viewed as a morphological center. Necessary and sufficient conditions for the idempotence of morphological operators are characterized in terms of their kernel representation. We further extend our results to the representation of the kernel of m-idempotent morphological operators. We then rely on the conditions on the kernel representation derived and establish methods for the construction of m-idempotent and self-dual morphological operators. Finally, we illustrate the importance of the self-duality and m-idempotence properties by an application to speckle noise removal in radar images.


P16 expression and recurrent cervical intraepithelial neoplasia after cryotherapy among women living with HIV.
The expression of p16 protein, a surrogate marker for high-risk human papillomavirus (hrHPV), is associated with cervical dysplasia. We evaluated correlates of p16 expression at treatment for high-grade cervical lesions and its utility in predicting the recurrence of cervical intraepithelial lesions grade 2 or higher (CIN2+) following cryotherapy among women with HIV. This is a subgroup analysis of women with HIV in Kenya with baseline cervical biopsy-confirmed CIN2+ who were randomized to receive cryotherapy and followed every six-months for two-years for biopsy-confirmed recurrence of CIN2+. P16 immunohistochemistry was performed on the baseline cervical biopsy with a positive result defined as strong abnormal nuclear expression in a continuous block segment of cells (at least 10-20 cells). Among the 200 women with CIN2+ randomized to cryotherapy, 160 (80%) had a baseline cervical biopsy specimen available, of whom 94 (59%) were p16-positive. p16 expression at baseline was associated with presence of any one of 14 hrHPV genotypes [Odds Ratio (OR) = 3.2; 95% Confidence Interval (CI), 1.03-9.78], multiple lifetime sexual partners (OR = 1.6; 95% CI, 1.03-2.54) and detectable plasma HIV viral load (>1,000 copies/mL; OR = 1.43; 95% CI, 1.01-2.03). Longer antiretroviral therapy duration (≥2 years) at baseline had lower odds of p16 expression (OR = 0.46; 95% CI, 0.24-0.87) than <2 years of antiretroviral therapy. Fifty-one women had CIN2+ recurrence over 2-years, of whom 33 (65%) were p16-positive at baseline. p16 was not associated with CIN2+ recurrence (Hazard Ratio = 1.35; 95% CI, 0.76-2.40). In this population of women with HIV and CIN2+, 41% of lesions were p16 negative and baseline p16 expression did not predict recurrence of cervical neoplasia during two-year follow up.


When Technology Fails: Getting Back to Nature.
Research on substance use disorders has produced a slew of disappointments in studies designed to confirm basic principles of the technology approach to treatment dissemination. These setbacks should inspire addictions science to pursue complementary paths of inquiry that focus on evidence-based practices delivered under naturalistic conditions. This will require larger accommodations to, and closer partnerships with, the indigenous cultures of everyday care.


Series on pharmacology in practice. 9. Glucocorticoids in rheumatic disease.
Glucocorticoids are potent anti-inflammatory agents that play an important role in the therapy of many patients with connective tissue diseases, including systemic lupus erythematosus, polymyalgia rheumatica, various types of vasculitis, and complications of rheumatoid arthritis. Glucocorticoids reduce the number and influence the function of lymphocytes, monocytes, and eosinophils in peripheral blood. Prolonged high doses of glucocorticoids result in decreased levels of immunoglobulins, particularly IgG. Granulocytes are increased in the peripheral blood, but their migration to sites of inflammation is diminished. Glucocorticoids inhibit release of lysosomal enzymes. Although they have no effect on the factor or factors that initiate inflammation, glucocorticoids have proved to be effective in the treatment of inflammatory manifestations of disease. Among significant adverse effects of glucocorticoid therapy are osteoporosis, aseptic necrosis of bone, and steroid myopathy.


The Role of chemokine receptor CXCR4 in breast cancer metastasis.
Breast cancer is one of the leading causes of cancer related deaths worldwide. Breast cancer-related mortality is associated with the development of metastatic potential of primary tumor lesions. The chemokine receptor CXCR4 has been found to be a prognostic marker in various types of cancer, including breast cancer. Recent advances in the field of cancer biology has pointed to the critical role that CXCR4 receptor and its ligand CXCL12 play in the metastasis of various types of cancer, including breast cancer. Breast tumors preferentially metastasize to the lung, bones and lymph nodes, all of which represent organs that secrete high levels of CXCL12. CXCL12 acts as a chemoattractant that drives CXCR4-positive primary tumor cells towards secondary metastatic sites leading to the onset of metastatic lesions. Since its discovery in 2001, the CXCR4 field has progressed at a very fast rate and further studies have pointed to the role of CXCR4 in dissemination of tumor cells from primary sites, transendothelial migration of tumor cells as well as the trafficking and homing of cancer stem cells. This review summarizes the information that has been obtained over the years regarding the role of CXCL12-CXCR4 signaling in breast cancer, discusses its potential application to the development of new therapeutic tools for breast cancer control, and elucidates the potential therapeutic challenges which lie ahead and the future directions that this field can take for the improvement of prognosis in breast cancer patients.


Extraarticular infection 9 years after Anterior Cruciate Ligament reconstruction. Case Report.
Extraarticular infection after Anterior Cruciate Ligament reconstruction (ACLr) is a rare condition with challenging diagnosis because the symptoms are milder and more insidious when compared to septic arthritis. When late (>2 months after surgery) it tends to be associated to osteomyelitis, requiring more extensive surgical debridement and hardware removal. We report a case of extraarticular infection after ACLr, in the acute phase affecting the tibial site and 9 years after index surgery affecting around the femur site. There was no progression to osteomyelitis at any of the sites. The infection developed a large posterolateral encapsulated abscess, with the endobutton plate loose inside it with its loop intact. In addition to the absence of osteomyelitis progression, there was no sinus tract formation, graft or joint involvement. With open debridement and antibiotic therapy, the patient returned to his activities without limitations. The reported case highlights that extraarticular infection after ACLr, while rare, can be challenging to diagnose and treat. However, with appropriate treatment, it can lead to good results with no functional limitations.