Deep Unfolding for Topic Models.
Deep unfolding provides an approach to integrate the probabilistic generative models and the deterministic neural networks. Such an approach is benefited by deep representation, easy interpretation, flexible learning and stochastic modeling. This study develops the unsupervised and supervised learning of deep unfolded topic models for document representation and classification. Conventionally, the unsupervised and supervised topic models are inferred via the variational inference algorithm where the model parameters are estimated by maximizing the lower bound of logarithm of marginal likelihood using input documents without and with class labels, respectively. The representation capability or classification accuracy is constrained by the variational lower bound and the tied model parameters across inference procedure. This paper aims to relax these constraints by directly maximizing the end performance criterion and continuously untying the parameters in learning process via deep unfolding inference (DUI). The inference procedure is treated as the layer-wise learning in a deep neural network. The end performance is iteratively improved by using the estimated topic parameters according to the exponentiated updates. Deep learning of topic models is therefore implemented through a back-propagation procedure. Experimental results show the merits of DUI with increasing number of layers compared with variational inference in unsupervised as well as supervised topic models.


Impaired Excitatory Neurotransmission in the Urinary Bladder from the Obese Zucker Rat: Role of Cannabinoid Receptors.
Metabolic syndrome (MS) is a known risk factor for lower urinary tract symptoms. This study investigates whether functional and expression changes of cannabinoid CB1 and CB2 receptors are involved in the bladder dysfunction in an obese rat model with insulin resistance. Bladder samples from obese Zucker rat (OZR) and their respective controls lean Zucker rat (LZR) were processed for immunohistochemistry and western blot for studying the cannabinoid receptors expression. Detrusor smooth muscle (DSM) strips from LZR and OZR were also mounted in myographs for isometric force recordings. Neuronal and smooth muscle CB1 and CB2 receptor expression and the nerve fiber density was diminished in the OZR bladder. Electrical field stimulation (EFS) and acetylcholine (ACh) induced frequency- and concentration-dependent contractions of LZR and OZR DSM. ACh contractile responses were similar in LZR and OZR. EFS-elicited contractions, however, were reduced in OZR bladder. Cannabinoid receptor agonists and antagonists failed to modify the DSM basal tension in LZR and OZR In LZR bladder, EFS responses were inhibited by ACEA and SER-601, CB1 and CB2 receptor agonists, respectively, these effects being reversed by ACEA plus the CB1 antagonist, AM-251 or SER-601 plus the CB2 antagonist, AM-630. In OZR bladder, the inhibitory action of ACEA on nerve-evoked contractions was diminished, whereas that SER-601 did not change EFS responses. These results suggest that a diminished function and expression of neuronal cannabinoid CB1 and CB2 receptors, as well as a lower nerve fiber density is involved in the impaired excitatory neurotransmission of the urinary bladder from the OZR.


Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs.
The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies 'outside the box' of current antibiotic paradigms.


Vagus Nerve Stimulation for Pediatric and Adult Patients with Pharmaco-resistant Epilepsy.
Over past two decades, vagus nerve stimulation (VNS) has been widely used and reported to alleviate seizure frequency worldwide, however, so far, only hundreds of patients with pharmaco-resistant epilepsy (PRE) have been treated with VNS in mainland China. The study aimed to evaluate the effectiveness of VNS for Chinese patients with PRE and compare its relationship with age cohort and gender. We retrospectively assessed the clinical outcome of 94 patients with PRE, who were treated with VNS at Beijing Fengtai Hospital and Beijing Tiantan Hospital between November 2008 and April 2014 from our database of 106 consecutive patients. The clinical data analysis was retrospectively examined. Seizure frequency significantly decreased with VNS therapy after intermittent stimulation of the vagus nerve. At last follow-up, we found McHugh classifications of Class I in 33 patients (35.1%), Class II in 27 patients (28.7%), Class III in 20 patients (21.3%), Class IV in 3 patients (3.2%), and Class V in 11 patients (11.7%). Notably, 8 (8.5%) patients were seizure-free while ≥50% seizure frequency reduction occurred in as many as 60 patients (63.8%). Furthermore, with regard to the modified Engel classification, 12 patients (12.8%) were classified as Class I, 11 patients (11.7%) were classified as Class II, 37 patients (39.4%) were classified as Class III, 34 patients (36.2%) were classified as Class IV. We also found that the factors of gender or age are not associated with clinical outcome. This comparative study confirmed that VNS is a safe, well-tolerated, and effective treatment for Chinese PRE patients. VNS reduced the seizure frequency regardless of age or gender of studied patients.


Mechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular Cage.
Supramolecular coordination cages show a wide range of useful properties including, but not limited to, complex molecular machine-like operations, confined space catalysis, and rich host-guest chemistries. Here we report the uptake and release of non-covalently encapsulated, pharmaceutically-active cargo from an octahedral Pd cage bearing polymer chains on each vertex. Six poly(ethylene glycol)-decorated bipyridine ligands are used to assemble an octahedral PdII6 (TPT)4 cage. The supramolecular container encapsulates progesterone and ibuprofen within its hydrophobic nanocavity and is activated by shear force produced by ultrasonication in aqueous solution entailing complete cargo release upon rupture, as shown by NMR and GPC analyses.


Advances in LDL-apheresis for the treatment of severe hypercholesterolemia.
LDL-apheresis is an extracorporeal plasma-perfusion method that selectively removes apolipoprotein B-containing lipoproteins from the blood. It is indicated for patients with homozygous and drug-resistant heterozygous familial hypercholesterolemia. Clinical and angiographic regression of coronary artery disease has been demonstrated in patients treated with cholesterol-lowering programs that include LDL-apheresis.


[New avenues for pharmacotherapy of type 2 diabetes mellitus].
Pharmaceutical products reviewed in this paper markedly extend possibilities for the management of DM-2 and create prerequisites for diferential therapy of this disease. Exenatide and DPP-4 inhibitors do not cause hypoglycemia and may be prescribed to subjects in whom this condition may affect the ability to drive or operate machinery (drivers, pilots, etc.). The mechanism of action of DPP-4 inhibitors make them especially suitable for the treatment of early stages of DM-2 when B-cells are still capable of insulin secretion. They can be used at a dose of 100 mg once daily both for monotherapy and in combination with other oral hypoglycemic agents. These drugs are well tolerated by the patients but contraindicated to those with severe renal insuficiency. Exenatid is more eficacious than DPP-4 inhibitors and has advantages over insulin therapy because it does not increase body weight and do not require as frequent blood glucose monitoring. However, it produces side effects. Therefore, the treatment should be started with a low dose of the drug (5 mg subcutaneously twice daily) that can be doubled in 4 weeks. Bearing in mind the mechanism of action of exanatide, it is indicated largely to patients with DM-2 associated with obesity and a moderately elevated HbAlc level. Rimonabant is especially efficient due to its effect on the endocannabioid system of DM-2 patients with obesity, however it has a drawback of frequently producing adverse affects.


On the Relation Between Marr's Levels: A Response to Blokpoel (2017).
Blokpoel reminds us of the importance of consistency of function across Marr's levels, but we argue that the approach to ensuring consistency that he advocates-a strict relation through exact implementation of the higher level function at the lower level-is unnecessarily restrictive. We show that it forces overcomplication of the computational level (by requiring it to incorporate concerns from lower levels) and results in the sacrifice of the distinct responsibilities associated with each level. We propose an alternative, no less rigorous, potential characterization of the relation between levels.


[Congenital pain insensitivity].
A case showing multiple lesions that make it very illustrative is reported. Differential diagnosis is made with some other diseases that are similar in some isolated facts. Mention is also made on the pathophysiology of the disease as well as on the necessity of the intercourse of several medicosurgical specialties in the management of these patients. A brief review of the literature is made.


Modulation-format-transparent IQ imbalance estimation of dual-polarization optical transmitter based on maximum likelihood independent component analysis.
We propose and experimentally demonstrate a modulation-format-transparent dual-polarization (DP) transmitter (Tx) in-phase/quadrature (IQ) imbalance estimation scheme based on maximum likelihood independent component analysis (ML-ICA). The proposed scheme can separate Tx IQ imbalance from polarization crosstalk and phase noise and achieve accurate IQ imbalance estimation without training data and the information of modulation format. Firstly, the complex-ML-ICA is used to implement format-transparent polarization de-multiplexing to remove polarization crosstalk; then the real-ML-ICA is employed to estimate inverse IQ mixing matrix and compensate Tx IQ imbalance/phase noise on each polarization channel. Inverse IQ mixing matrix contains the information of phase noise and Tx IQ imbalance; Finally, Tx IQ imbalance is derived from the inverse matrix by analytic method. The impact of Tx IQ imbalance on polarization demultiplexing and carrier phase recovery (CPE) is investigated by numerical simulation from three aspects of Jones space, Stokes space, and Kurtosis. The simulation results demonstrate the proposed scheme has strong robustness to phase noise, quantization noise, and amplified spontaneous emission (ASE) noise. The proposed ML-ICA algorithm is verified experimentally in polarization division multiplexing (PDM) quadrature phase-shift keying (QPSK)/8 quadrature amplitude modulation (QAM)/16QAM/64QAM systems. The experimental results show the scheme can accurately estimate Tx IQ imbalance within wide range in a format transparent manner.


Formulation and characterization of clozapine and risperidone co-entrapped spray-dried PLGA nanoparticles.
In the current study, polylactide-co-glycolide (PLGA) nanoparticles entrapping both clozapine (CLZ) and risperidone (RIS) were formulated by spray-drying using Buchi Nano Spray Dryer B-90 (Flawil, Switzerland). Parameters such as inlet temperature, spray mesh diameter, sample flow rate, spray rate and applied pressure were optimized to produce nanoparticles having desired release profile using both low- and high-molecular weight PLGA polymer. Smallest size nanoparticle of size around 248 nm could be prepared using a 4.0 μm mesh diameter with low-molecular weight polymer. The load of CLZ and RIS was 126.3 and 58.2 μg/mg of polymer particles, respectively. Entrapment efficiency of drugs in PLGA nanoparticles was 94.74% for CLZ and 93.12% for RIS. Both the drugs released continuously from the nanoparticle formulations. PLGA nanoparticles formulated using low-molecular weight polymer released around 80% of the entrapped drug over 10 days of time. Nature of drug inside polymer particles was amorphous, and there was no chemical interaction of CLZ and RIS with polymer. Polymeric nanoparticles were found to be non-toxic in nature using PC12 cell line. This nanospray drying process proved to be suitable for developing polymeric nanoformulation delivering dual drugs for the treatment of Schizophrenia.


Monitoring Cerebral Oxygenation in Neonates: An Update.
Cerebral oxygenation is not always reflected by systemic arterial oxygenation. Therefore, regional cerebral oxygen saturation (rScO2) monitoring with near-infrared spectroscopy (NIRS) is of added value in neonatal intensive care. rScO2 represents oxygen supply to the brain, while cerebral fractional tissue oxygen extraction, which is the ratio between rScO2 and systemic arterial oxygen saturation, reflects cerebral oxygen utilization. The balance between oxygen supply and utilization provides insight in neonatal cerebral (patho-)physiology. This review highlights the potential and limitations of cerebral oxygenation monitoring with NIRS in the neonatal intensive care unit.


[The selected risk factors of the metabolic syndrome in children].
Obesity is the main component of the metabolic syndrome, which appears to be one of the biggest social problems nowadays. The metabolic syndrome can start even in childhood and then risk factors of cardiovascular diseases should be diagnosed and a prophylaxis should be undertaken. was the evaluation of the selected lipid parameters in the serum in children and adolescents with simple obesity. The study was conducted on 305 children (156 boys and 149 girls) aged 6.5-17.9 years. The state of nutrition was estimated on the basis of anthropometrical measurements with the evaluation of body weight and height as well as the evaluation of BMI. The obesity was found in 119 children (61 boys and 58 girls) whose BMI was over 95 percentiles. There were 186 children (95 boys and 91 girls) whose BMI was between 25 and 75 percentiles in the control group. In 90 children with the diagnosed simple obesity 10 skinfolds were measured. In all of the studied children concentrations of triglycerides, total cholesterol and HDL cholesterol were determined in the blood serum. The concentration of LDL and VLDL cholesterol were calculated by the Friedewald formula. The obtained research results were analysed statistically. The values of BMI and the lipid parameters among children and adolescents with simple obesity were compared with the control group. Within the group of boys and girls with obesity higher concentration of total cholesterol (p<0.001) and girls (p<0.05) and LDL cholesterol (p<0.001; p<0.001) were found. However, the significantly lower concentration of HDL cholesterol was found within the girls with obesity in comparison to the control group (p<0.05). The significant negative correlation between the sum of 3 skinfold thickness and concentration of HDL cholesterol were found. The existence of atherogenic lipids profile in children with obesity allows us to conclude that the children may constitute a group within which there exist risk factors characteristic for the metabolic syndrome.


Static frictional resistances of polycrystalline ceramic brackets with metal slot inserts.
To compare the static frictional resistances of polycrystalline ceramic brackets with a gold slot insert (Desire), a stainless steel slot insert (Clarity), a conventional polycrystalline ceramic bracket (Transcend 6000) and a stainless steel bracket (Ultratrimm). Twenty five brackets of each type were tested by sliding against straight lengths of 0.019 x 0.025 inch rectangular stainless steel wire. During the tests the brackets and wire were lubricated with artificial saliva. Static frictional forces at three different binding angulations (0, 5 and 10 degrees) were measured for all brackets. Statistically significant increases in static frictional resistance were found as the bracket/wire angulation increased from 0 through 5 to 10 degrees for all bracket types. At angulations below the critical binding angle the Ultratrimm brackets produced the greatest friction and the Transcend 6000 brackets produced the least friction. As the angulation increased the Transcend 6000 brackets produced greater friction than the other brackets. At the highest angulation (10 degrees), the Ultratrimm brackets produced significantly less friction and the Transcend 6000 brackets produced significantly more friction than the other brackets. The Desire and Clarity brackets produced comparable results: there were no statistically significant differences between these two brackets for static friction at any of the angulations. Polycrystalline ceramic brackets with either stainless steel or gold slot inserts produced similar static frictional resistances to sliding. At binding angulations, the brackets with inserts demonstrated consistently lower static frictional resistances than a conventional ceramic bracket.


Infectious mononucleosis as a disease of early childhood in Japan caused by primary Epstein-Barr virus infection.
The present study investigated 54 pediatric patients with acute Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM) in Japan. Most of the acute cases clustered within the first 5 years of life, and the peak incidence was observed at around 4 years of age. These patients were arbitrarily separated into three age groups (less than 3 years, 3-5 years, and 6-14 years). Fever, pharyngitis, lymphadenopathy and hepatomegaly were detected in more than 80% of all cases. Tonsillitis and splenomegaly were present in about 60% of cases. Skin manifestations and eyelids edema were less often detected in the older age group than in the young age groups. In addition to an increase of total white blood cell and lymphocyte counts in the peripheral blood, a significant increase in the percentage of CD3+ CD8+ HLA-DR+ T cells was always observed. Epstein-Barr virus seropositivity increased soon after birth and reached approximately 70% around 3 years of age. Close to 100% of the adult controls were EBV seropositive. The results suggest that EBV-induced acute IM is a disease of early childhood in Japan.


Fibronectin anchorage to polymer substrates controls the initial phase of endothelial cell adhesion.
Early stages of the adhesion of human endothelial cells onto a set of smooth polymer films were analyzed to reveal the modulation of cell-matrix interactions by the physicochemical constraints of predeposited fibronectin (FN). Hydrophobic and hydrophilic polymer substrates, consisting of poly(octadecene-alt-maleic anhydride) and poly(propene-alt-maleic anhydride) films, were coated with similar amounts of FN at conditions of either covalent or noncovalent immobilization. The well-defined substrates permit variation of the anchorage of FN at invariant topography, pliability, and molecular composition. Although all of the compared FN coatings were effective in stimulating attachment of endothelial cells, the initial formation of cell-matrix adhesions was found to be controlled by the type of interaction between predeposited FN and the underlying substrate. Covalent linkage and hydrophobic interactions of the predeposited FN with the polymer films interfered with the rapid generation of focal and fibrillar adhesions. It was demonstrated that this was caused by the fact that only weakly bound FN could become readily reorganized by the adherent cells. Upon prolonged culture periods at standard cell culture conditions, secretion and deposition of organized extracellular matrix by the attached cells was found to balance out the differences of the substrates.


T-cell responses to the Mycobacterium tuberculosis-specific antigens in active tuberculosis patients at the beginning, during, and after antituberculosis treatment.
The objectives of the study were to assess the performance of the QuantiFERON-TB Gold In-Tube (QFN-G-IT) and the T-SPOT.TB tests in the immunodiagnosis of active tuberculosis (TB) in adult patients, and to study the T-cell interferon gamma (IFN-gamma) responses during treatment and in patients who have recovered after curative treatment and self-healed TB patients. When only analyzing patients included at the beginning of treatment, the sensitivity was 83.3% for T-SPOT.TB and 69.4% for QFN-G-IT. In contrast, when evaluating patients during treatment, the sensitivity of the T-SPOT.TB and QFN-G-IT decreased to 69.8% and 48.8%, respectively. The response to the specific antigens increased after finishing the treatment compared with the values during the treatment. The T-SPOT.TB was more sensitive in diagnosing active TB than the QFN-G-IT. The IFN-gamma tests could be used as a complementary method in the diagnosis of active TB.


A rapid rise in hormone receptor-positive and HER2-positive breast cancer subtypes in Southern Thai women: A population-based study in Songkhla.
The incidence of breast cancer is increasing in low- and middle-income countries, including Thailand. However, its molecular immunohistochemical (M-IHC) subtypes have not been summarized in a population-based cancer registry. Thus, we aimed to estimate the breast cancer incidence and trends based on the hormone receptor and human epidermal growth factor receptor 2 (HER2) status. This cross-sectional study included 2,883 women diagnosed with primary invasive breast cancer between 2009 and 2018 from the Songkhla Cancer Registry. After imputing the missing values of estrogen receptor (ER), progesterone receptor (PR), and HER2 status, the cases were classified into four subtypes: HR+/HER2-, HR+/HER2+, HR-/HER2-, and HR-/HER2+. The age-specific incidence rate of 5-year age groups and age-standardized incidence rate (ASR) were calculated. An age-period-cohort (APC) model was used to describe the effects of age, birth cohort, and period of diagnosis. Finally, the incidence trends were extrapolated to 2030 based on the APC and joinpoint models. The results showed, HR+/HER2- had the highest ASR in breast cancer. The incidence trends of HR+/HER2- and HR+/HER2+ increased with an annual percent change of 5.4% (95%CI: 2.5% to 8.3%) and 10.1% (95%CI: 4.9% to 15.5%), respectively. The rate ratio was high in the younger generation and recent period of diagnosis. The joinpoint and APC model projections showed that the ASR of HR+/HER2- would reach 30.0 and 29.2 cases per 100,000 women, while ASR of the HR+/HER2+ would reach 8.8 and 10.4 cases per 100,000 women in 2030. On the other hand, the incidence trends of the HR-/HER2- and HR-/HER2+ subtypes were stable. The rising trends of HR-positive and a part of HER2-positive breast cancer forecast a dynamicity of the future health care budgeting, resource allocation, and provision of facilities.


Transient hyponatremia of prematurity caused by mild Bartter syndrome type II: a case report.
Bartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle's loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy. We describe a case of a prematurely born female infant presenting with antenatal polyhydramnios, and postnatal dehydration and hyponatremia. After 7 weeks of sodium supplementation, the patient demonstrated complete resolution of her hyponatremia and developed only transient metabolic alkalosis at 2 months of age but continues to be polyuric and exhibits hypercalciuria, without development of nephrocalcinosis. She was found to have two pathogenic variants in the KCNJ1 gene: a frameshift deletion, p.Glu334Glyfs*35 and a missense variant, p. Pro110Leu. While many features of classic ROMK mutations have resolved, the child does have Bartter syndrome type II and needs prolonged pediatric nephrology follow-up. Transient neonatal hyponatremia warrants a multi-system workup and genetic variants of KCNJ1 should be considered.


Photonic dual RF beam reception of an X band phased array antenna using a photonic crystal fiber-based true-time-delay beamformer.
We report dual RF beam reception of an X band phased array antenna using a photonic crystal fiber (PCF)-based delay network. Each incoming RF signal can be independently received, and the angle of arrival can be determined based on the delay time-dependent wavelength. Two RF signals with frequencies 8.4 and 12 GHz impinge upon an X-band antenna array from -7.4 degrees and -21.2 degrees . These signals are detected, and the angle of arrival is determined with a very good degree of accuracy using PCF-based true-time delay. The total number of RF beams that can be simultaneously detected is limited by the hardware availability and the bandwidth of the wavelength differentiation capability of the system.


Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis.
The proteasome is emerging as a target for cancer therapy because small molecule inhibitors of its catalytic activity induce apoptosis in both in vitro and in vivo models of human malignancies and are proving to have efficacy in early clinical trials. To further elucidate the mechanism of action of these inhibitors, their impact on signaling through the p44/42 mitogen-activated protein kinase (MAPK) pathway was studied. Proteasome inhibition with either carbobenzoxy-leucyl-leucyl-phenylalaninal or lactacystin led to a loss of dually phosphorylated, activated p44/42 MAPK in A1N4-myc human mammary and MDA-MB-231 breast carcinoma cells in a dose- and time-dependent fashion. This correlated with an induction of the dual specificity MAPK phosphatases (MKP)-1 and -2, and blockade of MKP induction using either actinomycin D or Ro-31-8220 significantly decreased loss of activated p44/42 MAPK. Inhibition of p44/42 MAPK signaling by use of the MAPK kinase inhibitors PD 98059 or U0126, or by use of a dominant negative MAPK construct, enhanced proteasome inhibitor-mediated apoptosis. Conversely, activation of MAPK by epidermal growth factor, or use of a mutant MAPK resistant to MKP-mediated dephosphorylation, inhibited apoptosis. These studies support a role for inactivation of signaling through the p44/42 MAPK pathway in proteasome inhibitor-mediated apoptosis.


E-Waste and Harm to Vulnerable Populations: A Growing Global Problem.
Electronic waste (e-waste) is produced in staggering quantities, estimated globally to be 41.8 million tonnes in 2014. Informal e-waste recycling is a source of much-needed income in many low- to middle-income countries. However, its handling and disposal in underdeveloped countries is often unsafe and leads to contaminated environments. Rudimentary and uncontrolled processing methods often result in substantial harmful chemical exposures among vulnerable populations, including women and children. E-waste hazards have not yet received the attention they deserve in research and public health agendas. We provide an overview of the scale and health risks. We review international efforts concerned with environmental hazards, especially affecting children, as a preface to presenting next steps in addressing health issues stemming from the global e-waste problem. The e-waste problem has been building for decades. Increased observation of adverse health effects from e-waste sites calls for protecting human health and the environment from e-waste contamination. Even if e-waste exposure intervention and prevention efforts are implemented, legacy contamination will remain, necessitating increased awareness of e-waste as a major environmental health threat. Global, national, and local levels efforts must aim to create safe recycling operations that consider broad security issues for people who rely on e-waste processing for survival. Paramount to these efforts is reducing pregnant women and children's e-waste exposures to mitigate harmful health effects. With human environmental health in mind, novel dismantling methods and remediation technologies and intervention practices are needed to protect communities. Heacock M, Kelly CB, Asante KA, Birnbaum LS, Bergman AL, Bruné MN, Buka I, Carpenter DO, Chen A, Huo X, Kamel M, Landrigan PJ, Magalini F, Diaz-Barriga F, Neira M, Omar M, Pascale A, Ruchirawat M, Sly L, Sly PD, Van den Berg M, Suk WA. 2016. E-waste and harm to vulnerable populations: a growing global problem. Environ Health Perspect 124:550-555; http://dx.doi.org/10.1289/ehp.1509699.


Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism.
Among various factors, such as an unhealthy diet or a sedentarity lifestyle, excessive fructose consumption is known to favor nonalcoholic fatty liver disease (NAFLD), as fructose is both a substrate and an inducer of hepatic de novo lipogenesis. The present review presents some well-established mechanisms and new clues to better understand the pathophysiology of fructose-induced NAFLD. Beyond its lipogenic effect, fructose intake is also at the onset of hepatic inflammation and cellular stress, such as oxidative and endoplasmic stress, that are key factors contributing to the progression of simple steatosis to nonalcoholic steatohepatitis (NASH). Beyond its hepatic effects, this carbohydrate may exert direct and indirect effects at the peripheral level. Excessive fructose consumption is associated, for example, with the release by the liver of several key mediators leading to alterations in the communication between the liver and the gut, muscles, and adipose tissue and to disease aggravation. These multifaceted aspects of fructose properties are in part specific to fructose, but are also shared in part with sucrose and glucose present in energy- dense beverages and foods. All these aspects must be taken into account in the development of new therapeutic strategies and thereby to better prevent NAFLD.


Investigation of the human H3.3B (H3F3B) gene expression as a novel marker in patients with colorectal cancer.
H3.3 histone is a replacement histone subtype that is express in entire cell cycle phases and overexpress in transcriptionally active regions, promoter regions, and intergenic or intragenic regulatory elements. This histone encoded by two genes termed H3.3A (H3F3A) and H3.3B (H3F3B). Mutations of these two genes lead to some human cancers such as chondroblastoma, osteosarcoma, and epithelial ovarian cancer. The aims of this study were to quantitatively examine the expression of H3.3B gene in colorectal cancer (CRC) and to correlate their expression level with demographics and clinicopathological characteristics. We investigated H3.3B gene expression in CRC by relative quantitative real-time polymerase chain reaction (real-time PCR) technique for the first time. For this purpose, total RNA extracted, then cDNA synthesized and H3.3B gene expression was evaluated with specific primers by real-time PCR in tumoral tissues and adjacent normal tissues of 36 patients with CRC, then statistical analysis was performed using SPSS software. The results of this study indicated that H3.3B gene significantly overexpressed in tumoral tissue than adjacent normal tissue. Furthermore, statistical analysis represented the significant correlation between the H3.3B gene expression and some of the clinicopathological characteristics. Our study showed that H3.3B gene expression changes can be useful as a probable prognosis biomarker in the early stages of CRC before it metastasized.


Crystal Structures of the Putative Isocitrate Dehydrogenase from Sulfolobus tokodaii Strain 7 in the Apo and NADP+-Bound Forms.
Isocitrate dehydrogenase is a catabolic enzyme that acts during the third step of the tricarboxylic acid cycle. The hypothetical protein ST2166 from the archaeon Sulfolobus tokodaii was isolated and crystallized. It shares high primary structure homology with prokaryotic NADP+-dependent IDHs, suggesting that these enzymes share a common enzymatic mechanism. The crystal structure of ST2166 was determined at 2.0 Å resolution in the apo form, and then the structure of the crystal soaked with NADP+ was also determined at 2.4 Å resolution, which contained NADP+ bound at the putative active site. Comparisons between the structures of apo and NADP+-bound forms and NADP-IDHs from other prokaryotes suggest that prokaryotic NADP-IDHs recognize their cofactors using conserved Lys335, Tyr336, and Arg386 in ST2166 at the opening cleft before the domain closure.


[Acute results of left ventricular endocardial pacing for cardiac resynchronization therapy obtained with a transapical approach].
Although cardiac resynchronization therapy (CRT) is considered a milestone in the treatment of patients affected with chronic congestive heart failure, reduced left ventricular ejection fraction and enlarged QRS, up to 30% of patients can be considered clinical non-responders to this treatment. In these patients, optimization of atrioventricular and interventricular intervals could be of some help, but results of trials are not univocal on the benefit of this procedure. In the last years, left ventricular endocardial pacing for CRT has emerged as a possible solution in non-responders. Several studies have demonstrated its feasibility and safety, and some reports suggest its incremental efficacy in comparison with traditional epicardial pacing, both obtained transvenously or surgically. We describe the cases of two patients already implanted with a CRT device who came to our attention for clinical non-responsiveness to CRT and who have been successfully treated with the addition of a left endocardial lead. A brief literature review on this topic is also reported.


Timing of hepatitis B vaccination and impact of non-simultaneous vaccination with DTP vaccine following introduction of a hepatitis B birth dose in the Philippines.
Timely administration of hepatitis B vaccine beginning at birth prevents up to 95 per cent of perinatally acquired hepatitis B virus infections in infants of infected mothers. The Philippines changed its national HepB schedule in 2007 to include a dose at birth. We evaluated vaccination schedule change by reviewing infant records at selected health facilities to measure completeness and timeliness of HepB administration and frequency of recommended, simultaneous vaccination with diphtheria-tetanus-pertussis (DTP) vaccine. Of 1431 sampled infants, 1106 (77 per cent) completed the HepB series and 10 per cent followed the national schedule. The proportion with timely vaccination declined with successive doses: HepB1 (71 per cent), HepB2 (47 per cent), and HepB3 (26 per cent). Twentysix per cent received HepB2 simultaneously with DTP1 and 34 per cent received HepB3 simultaneously with DTP3. If HepB and DTP vaccination were given simultaneously,10 per cent more infants could have received all HepB doses. Program implementers should monitor vaccination timeliness and increase simultaneous administration to improve vaccination coverage and decrease disease incidence.


Transsphenoidal hypophysectomy in disseminated breast cancer.
Sixty patients with metastatic breast cancer had transsphenoidal hypophysectomy at Emory University Hospital. Median survival for the entire group was ten months. Survival was increased (longer than 14 months) in good responders as compared to nonresponders (three months). Pain was significantly relieved in the majority of those patients who had severe pain. Operative complications were minimal. The technic of transsphenoidal hypophysectomy offers a substantial chance of objective and subjective palliation with minimal morbidity in advanced breast cancer.


Interplay between the p53 tumor suppressor protein family and Cdk5: novel therapeutic approaches for the treatment of neurodegenerative diseases using selective Cdk inhibitors.
Cyclin-dependent kinases (Cdks) play a key role in orchestrating the coordination of cell cycle progression in proliferating cells. The escape from the proper control of the cell cycle by the upregulation of cyclins or aberrant activation of Cdks leads to malignant transformation. In quiescent cells and/or terminally differentiated cells, the expression pattern and activity of Cdks is altered. In postmitotic neurons, expression of mitotic kinases is downregulated, whereas Cdk5 expression becomes upregulated. Similarly to other Cdks, free Cdk5 displays no enzymatic activity and requires complex formation with a specific regulatory subunit. Two activators of Cdk5 have been identified. p35 and its isoform p39 bind to, and thereby activate, Cdk5. Unlike mitotic kinases, Cdk5 does not require activating phosphorylation within the T-loop. Because p35 is a short-lived protein, the p35/Cdk5 complexes are unstable. The stability of the p35 protein is regulated by its Cdk5-mediated phosphorylation of p35. Activated p35/Cdk5 kinase phosphorylates numerous physiological targets. The proper phosphorylation of the most important substrates, such as tau protein and neurofilament H, is essential for the correct regulation of the cytoskeletal organization, thereby regulating cell adhesion, motility, and synaptic plasticity. Moreover, Cdk5 regulates the activity of the p53 tumor suppressor via phosphorylation. p53 is upregulated in multiple neuronal death paradigms, including hypoxia, ischemia, and excitotoxicity, and plays a key role in the induction of apoptosis. On the other hand, an abnormally high expression and elevated activity of Cdk5 was observed in neurodegenerative diseases, suggesting the application of Cdk inhibitors for their therapy. Considering the action of some Cdk inhibitors on the expression and activity of the p53 protein, their therapeutic efficacy must be carefully evaluated.


Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors.
Multiple myeloma (MM) is still a fatal plasma cell cancer. Novel compounds are currently clinically tested as a single agent in relapsing patients, but in best cases with partial response of a fraction of patients, emphasising the need to design tools predicting drug efficacy. Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression and are in clinical development in MM. To create a score predicting HDACi efficacy, five MM cell lines were treated with trichostatin A (TSA) and gene expression profiles were determined. The expression of 95 genes was found to be upregulated by TSA, using paired supervised analysis with Significance Analysis of Microarrays software. Thirty-seven of these 95 genes had prognostic value for overall survival in a cohort of 206 newly diagnosed MM patients and their prognostic information was summed up in a histone acetylation score (HA Score); patients with the highest HA Score had the shorter overall survival. It is worth noting that MM cell lines or patients' primary MM cells with a high HA Score had a significant higher sensitivity to TSA, valproic acid, panobinostat or vorinostat. In conclusion, the HA Score allows identification of MM patients with poor survival, who could benefit from HDACi treatment.


Distribution of butyltins at dredged material dumping sites around the coast of China and the potential ecological risk.
Previous research has found butyltin pollution at dumping sites, which are the final fate of dredged material mostly originating from harbors and navigation systems. The distribution and impacts of butyltins were assessed in sediments at 12 dumping sites of China. Total butyltins (monobutyltin, dibutyltin, and tributyltin) concentrations ranged from 1.76 to 486.62 ng Sn g-1 dw. This study also presents evidence of considerable historic inputs of tributyltin (TBT) to Dumping sites 01, 05, 06, 08, 09 and 11, with evidence of heavier recent TBT input at Dumping site 04 and 10. The butyltin contamination at dumping sites was comparatively light and historic compared to research in other countries, but was more serious than other sea regions. TBT levels at Dumping site 09 probably have negative effects on biological systems. Overall, more attention should be paid to the level and impacts of butyltins in the sediment at dumping sites in China.


Efficacy and Tolerability of Asenapine Compared with Olanzapine in Borderline Personality Disorder: An Open-Label Randomized Controlled Trial.
Asenapine is a new second-generation antipsychotic that is understudied in borderline personality disorder (BPD). Only one study investigating the use of the drug in this indication (an open-label pilot study) has been conducted to date. The present open-label, randomized, controlled trial aimed to evaluate the efficacy and tolerability of asenapine in comparison with olanzapine, the most broadly studied antipsychotic in BPD. A total of 51 outpatients aged between 18 and 50 years with a diagnosis of BPD based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were assigned for 12 weeks to asenapine (5-10 mg/day) or olanzapine (5-10 mg/day). Participants were assessed at baseline and after 12 weeks with the following instruments: the Clinical Global Impression Scale, Severity item (CGI-S), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Social Occupational Functioning Assessment Scale (SOFAS), Borderline Personality Disorder Severity Index (BPDSI), Barratt Impulsiveness Scale, version 11 (BIS-11), Modified Overt Aggression Scale (MOAS), Self-Harm Inventory (SHI), and Dosage Record and Treatment Emergent Symptom Scale (DOTES). Analysis of variance repeated measures was performed. Intention-to-treat analysis with last observation carried forward was conducted. There were 11 drop-outs (21.57%): six patients taking asenapine and five patients receiving olanzapine. Two patients who received asenapine stopped the drug, one due to oral hypoesthesia and the other due to moderate anxiety. Two patients receiving olanzapine discontinued the treatment because of significant weight gain (≥3 kg). The remaining seven drop-outs resulted from the lack of compliance with the trial prescription. Forty out of the 51 patients (78%) completed the trial: 19 patients received asenapine, while 21 patients received olanzapine. We found a significant within-subject effect (trial duration) for all rating scales, except from the HAM-D, the MOAS, and two items of the BPDSI, namely, "identity disturbance" and "parasuicidal behaviors." A significant effect between subjects was found for the two items of the BPDSI "affective instability" and "dissociation/paranoid ideation." Asenapine was found superior to olanzapine in reducing the affective instability score (P = 0.001), whereas olanzapine was found superior to asenapine in reducing dissociation/paranoid ideation (P = 0.012). However, the study was found to be underpowered to detect a difference between the drugs on the dissociation/paranoid ideation item of the BPDSI. Two patients receiving asenapine experienced akathisia and another two restlessness/anxiety, while three patients receiving olanzapine reported somnolence and two fatigue. Asenapine and olanzapine were demonstrated to have a similar efficacy. While asenapine was found to be more efficacious than olanzapine in treating affective instability, olanzapine was superior to asenapine in treating paranoid ideation and dissociation. However, the study was underpowered to detect a difference between groups on the dissociation/paranoid ideation item. Both medications were well tolerated, with asenapine being related to a higher frequency of oral hypoesthesia and akathisia, and olanzapine being prone to induce weight gain. The open-label study design, lack of a placebo group, and small sample size constitute major limitations of this trial. Our findings need to be replicated in further studies. Clinical Trials Registry code: ACTRN12614000551695.


Molecular control of stomatal development.
Plants have evolved developmental plasticity which allows the up- or down-regulation of photosynthetic and water loss capacities as new leaves emerge. This developmental plasticity enables plants to maximise fitness and to survive under differing environments. Stomata play a pivotal role in this adaptive process. These microscopic pores in the epidermis of leaves control gas exchange between the plant and its surrounding environment. Stomatal development involves regulated cell fate decisions that ensure optimal stomatal density and spacing, enabling efficient gas exchange. The cellular patterning process is regulated by a complex signalling pathway involving extracellular ligand-receptor interactions, which, in turn, modulate the activity of three master transcription factors essential for the formation of stomata. Here, we review the current understanding of the biochemical interactions between the epidermal patterning factor ligands and the ERECTA family of leucine-rich repeat receptor kinases. We discuss how this leads to activation of a kinase cascade, regulation of the bHLH transcription factor SPEECHLESS and its relatives, and ultimately alters stomatal production.


Dissociation Energies of Sulfur-Centered Hydrogen-Bonded Complexes.
In this work we have determined dissociation energies of O-H···S hydrogen bond in the H2S complexes of various phenol derivatives using 2-color-2-photon photofragmentation spectroscopy in combination with zero kinetic energy photoelectron (ZEKE-PE) spectroscopy. This is the first report of direct determination of dissociation energy of O-H···S hydrogen bond. The ZEKE-PE spectra of the complexes revealed a long progression in the intermolecular stretching mode with significant anharmonicity. Using the anharmonicity information and experimentally determined dissociation energy, we also validated Birge-Sponer (B-S) extrapolation method, which is an approximate method to estimate dissociation energy. Experimentally determined dissociation energies were compared with a variety of ab initio calculations. One of the important findings is that ωB97X-D functional, which is a dispersion corrected DFT functional, was able to predict the dissociation energies in both the cationic as well as the ground electronic state very well for almost every case.


Prevalence of vitamin D depletion among subjects seeking advice on osteoporosis: a five-year cross-sectional study with public health implications.
We assessed vitamin D nutritional status in unselected consecutive patients seeking advice on osteoporosis. The prevalence of vitamin D depletion ranged from 15-72% depending upon the cut-off levels used for serum 25-hydroxyvitamin D, and the prevalence did not change over the 5 years of the study. Vitamin D depletion is a significant public health problem and has been studied in different populations using different cut-off levels, but the optimal level is yet to be established. In a cross-sectional study of 2,924 patients seen for osteoporosis advice we determined the prevalence of vitamin D depletion, as assessed by 25-hydroxyvitamin D (25-OHD), using three different cut-off levels stratified by gender, race and the year of the study over 5 years. Mean age was 68.3 +/- 10.0 years; 90% women and 88% white. Mean 25-OHD level was 24.6 +/- 10 ng/ml and mean PTH was 48.4 +/- 32 pg/ml. The prevalence of vitamin D depletion was 15% with a cut-off level of <15 ng/ml, and rose to 32% and 72% with cut-off levels <20 ng/ml and <30 ng/ml, respectively. The prevalence was higher in men and blacks and remained constant over 5 years, regardless of the cut-off level. The expected inverse relationship between 25-OHD and PTH was observed irrespective of gender or ethnicity. The prevalence of vitamin D depletion in patients seeking advice for osteoporosis is high and did not change over the 5 years of the study.


NKCC1 (SLC12a2) induces a secondary axis in Xenopus laevis embryos independently of its co-transporter function.
NKCC1 is a broadly expressed Na(+)-K(+)-Cl(-) co-transporter involved in regulation of ion flux across the cell membrane and in regulating cell volume. Whilst much is known about the co-transporter activity of NKCC1 and its regulation by protein kinases and phosphatases, little is known about the activities of NKCC1 that are co-transporter independent. In this report we show that over-expression of NKCC1 in embryos of Xenopus laevis induces secondary axes, independently of its co-transporter activity. In addition, over-expression of NKCC1 results in the formation of neural tissue in ectodermal explants. We also show that NKCC1 is expressed broadly but non-uniformly in embryos of Xenopus laevis and Xenopus tropicalis, with prominent expression in the notochord, nervous system and stomach. These results provide insights into an additional, previously unreported activity of NKCCl.


Automated source of squeezed vacuum states driven by finite state machine based software.
In the last few decades, much effort has been made for the production of squeezed vacuum states in order to reduce quantum noise in the audio-frequency band. This technique has been implemented in all running gravitational-wave interferometric detectors and helped to improve their sensitivity. While the detectors are acquiring data for astrophysical observations, they must be kept in the operating condition, also called "science mode," that is, a state that requires the highest possible duty-cycle for all the instrumental parts and controls. We report the development of a highly automated setup for the generation of optical squeezed states, where all the required control loops are supervised by a software based on finite state machines; we took special care to grant ease of use, stability of operation, and possibility of auto-recovery. Moreover, the setup has been designed to be compatible with the existing software and hardware infrastructure of the Virgo detector. In this paper, we discuss the optical properties of this squeezing setup, the locking techniques, and the automation algorithms.


Analgesic effect and possible mechanism of SCH772984 intrathecal injection on rats with bone cancer pain.
This study is to establish a model of rat tibial osteocarcinoma pain, intrathecally inject specific ERK1/2 inhibitors SCH772984, observe the analgesic effect, and discuss the influence of ERK-P90RSK-Fos signal path in bone cancer pain. Forty female SD rats were randomly divided into 5 groups. Establish a bone cancer pain model after putting the intrathecal tube 5d and determine the rats' mechanical withdrawal threshold (MWT) after tube 5d; 40 SD rats with intrathecal tube back 5d were randomly divided into 5 groups. Sham Group receives no medication, the other four respectively receive 5% DMSO 10 μl, SCH 0.1, 1.0, 10 μg (SCH dissolved in 10 μl 5% DMSO) intrathecally. Determine the rats' mechanical withdrawal threshold (MWT) before and after giving medication 1, 3, 6, 9, 12, 15, 18, 24 h, and 2 min spontaneous paw withdrawal. Western blot and immuno-fluorescence determine the expression condition of spinal cord dorsal horn of p-ERK, p-p90RSK and Fos protein. Intrathecal injection of SCH772984 has analgesic effects on rats with bone cancer pain, and the effects enhance with increasing dose; intrathecal injection of SCH772984 10 μg could greatly reduce the expression of spinal dorsal horn Fos protein. Injecting walker 256 tumor cells into rats' tibia could cause behavior changes, such as idiopathic pain sensitivity and pain; the intrathecal tube almost has no effect on motor function of rats; ERK1/2 is involved in bone cancer pain, and intrathecal injection of ERK1/2 specific inhibitors SCH772984 10 μg may effectively relieve bone cancer pain.


Functional Effects of Prebiotic Fructans in Colon Cancer and Calcium Metabolism in Animal Models.
Inulin-type fructans are polymers of fructose molecules and are known for their capacity to enhance absorption of calcium and magnesium, to modulate gut microbiota and energy metabolism, and to improve glycemia. We evaluated and compared the effects of Chicory inulin "Synergy 1®" and inulin from Mexican agave "Metlin®" in two experimental models of colon cancer and bone calcium metabolism in mice and rats. Inulins inhibited the development of dextran sulfate sodium-induced colitis and colon cancer in mice; these fructans reduced the concentration of tumor necrosis factor alpha and prevented the formation of intestinal polyps, villous atrophy, and lymphoid hyperplasia. On the other hand, inulin treatments significantly increased bone densitometry (femur and vertebra) in ovariectomized rats without altering the concentration of many serum biochemical parameters and urinary parameters. Histopathology results were compared between different experimental groups. There were no apparent histological changes in rats treated with inulins and a mixture of inulins-isoflavones. Our results showed that inulin-type fructans have health-promoting properties related to enhanced calcium absorption, potential anticancer properties, and anti-inflammatory effects. The use of inulin as a prebiotic can improve health and prevent development of chronic diseases such as cancer and osteoporosis.


[Effects of reproductive hormones on spermatogenesis].
Spermatogenesis, a continuous course of cell proliferation and differentiation, depends on reproductive hormones. FSH and LH-induced T are the main hormones regulating spermatogensis. Intratesticular T is one of the key factors in maintaining spermatogenesis, while FSH is just as important for origination and maintenance of normal spermatogenesis. Sertoli cells are the pivot of hormonal regulation. Interestingly, these reproductive hormones also regulate sperm cell apoptosis spermatogenesis. Further studies on the hormonal regulation of spermatogenesis provide a base for the development of safe and recoverable contraceptives for males.


[Milk intolerance, lactose intolerance and lactase deficiency in partial resection of the stomach].
Of 40 patients with a partial gastrectomy (Billroth-II) 10 developed a milk intolerance and 11 had a lactase deficiency, the latter in 4 cases appearing together with a decrease in other disaccharidases. Only 2 of the 11 lactase-deficient patients complained of milk intolerance. The Ethanol lactose tolerance test (ELTT) was performed in 21 patients and was found to be abnormal in 6. Whereas cases of abnormal ELTT usually (4 of 6 cases) showed a lactase deficiency, only 2 patients with milk intolerance showed an abnormal ELTT and lactase deficiency. Milk intolerance can therefore only exceptionally be explained by lactase deficiency, and lack of lactase in the upper jejunum usually does not produce intolerance symptoms. Moreover, in comparable determinations from the afferent and efferent jejunal loop no differences in enzyme activities could be observed.


The effects of thymoquinone and Doxorubicin on leukemia and cardiomyocyte cell lines.
Acute Lymphoblastic Leukemia remains the most common cancer for children, and if left untreated is rapidly fatal. The gold standard for treatment of ALL in children is with a class of drugs known as the antracyclines. Long term outcomes following treatment of leukemia with antracylines can result in cardiac abnormalities including arrhythmias, congestive heart failure, myocardial infarction, hypertension and left ventricular failure. Thymoquinone is a natural product that has demonstrated anti-proliferative, anti-inflammatory, anti-cancer, and chemo-protective effects in control trials as well as a reduction in cardiotoxicity in antracyline treated rats. The aims of the study were to determine if thymoqunione could be used to reduce leukemia cell viability without injuring primary cardiomyocyte, and to determine its effects if used in conjunction with a known chemotherapeutic agent. Cellular viability and morphological changes were observed in the, RAW leukemia cells and cardiac myocytes following treatment with thymoquinone, antracyline (doxorubicin), alone and in combination for 24, 48 and 72 hours. The results suggest that thymoquinone treatment in RAW leukemia cells reduced the cell number without altering the morphology, while doxorubicin reduced cell number and induced spindle cell formation and increased cellular damage. Findings also suggest RAW cell apoptosis increased in combination therapy with thymoquinone and doxorubicin. Thymoquinone administered to cardiomyocytes showed similar morphological changes as control over time in culture; whereas doxorubicin treated cells showed evidence of loss of connectivity and disruption of cell membranes. Combination treatment with doxorubicin and thymoquinone demonstrated significant cardiac myocyte survival at concentrations when used alone were able to reduce the leukemia cells. Overall, the data is promising and may provide a treatment regime to protect the heart tissue. Additional work is warrant to understand the mechanisms involved to reduce cardio toxicity by combining thymoquinone with doxorubicin.