An "enigmatic" L-carnosine (β-alanyl-L-histidine)? Cell proliferative activity as a fundamental property of a natural dipeptide inherent to traditional antioxidant, anti-aging biological activities: balancing and a hormonally correct agent, novel patented oral therapy dosage formulation for mobility, skeletal muscle power and functional performance, hypothalamic-pituitary- brain relationship in health, aging and stress studies.
Hypothalamic releasing and inhibiting hormones are major neuroendocrine regulators of human body metabolism being driven directly to the anterior pituitary gland via hypothalamic-hypophyseal portal veins. The alternative physiological or therapeutic interventions utilizing the pharmaco-nutritional boost of imidazole-containing dipeptides (non-hydrolized oral form of carnosine, carcinine, N-acetylcarnosine lubricant eye drops) can maintain health, enhance physical exercise performance and prevent ageing. Carnosine (β-alanyl-L-histidine) is synthesized in mammalian skeletal muscle. There is an evidence that the release of carnosine from the skeletal muscle sarcomeres moieties during physical exercise affects autonomic neurotransmission and physiological functions. Carnosine released from skeletal muscle during exercise acts as a powerful afferent physiological signaling stimulus for hypothalamus, may be transported into the hypothalamic tuberomammillary nucleus (TMN), specifically to TMN-histamine neurons and hydrolyzed herewith via activities of carnosine-degrading enzyme (carnosinase 2) localized in situ. Through the colocalized enzymatic activity of Histidine decarboxylase in the histaminergic neurons, the resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and physiological function. Carnosine and its imidazole-containing dipeptide derivatives are renowned for their anti-aging, antioxidant, membrane protective, metal ion chelating, buffering, anti-glycation/ transglycating activities used to prevent and treat a spectrum of age-related and metabolic diseases, such as neurodegenerative disease, sight threatening eye diseases, Diabetes mellitus and its complications, cancers and other disorders due to their wide spectrum biological activities. The precursor of carnosine (and related imidazole containing compounds) synthesis in skeletal muscles beta-alanine is used as the oral supplement by athletes to achieve the fine sporting art results due to the buffering activities of carnosine and its related imidazole- containing compounds which contribute to the maintenance of the acid-base balance in the acting muscles. This work originally emphasizes that overall data indicate the signaling activities of carnosine in skeletal and cardiac muscles switching on the mechanisms of exercise-induced telomere protection and point to the stress response and growth/cellular proliferation pathways as high-priority candidates for the ongoing studies and therapeutic concepts. The therapeutic interventions utilizing the specific oral formulation (Can-C Plus), timing dosing and pharmaco-nutritional boost of imidazolecontaining dipeptides can maintain health, enhance physical exercise performance and prevent aging. The patented therapeutic concept protects the existence of the interesting physiological major activities, better controls and therapeutic treatments for aging/age-related disorders (including age-related loss of muscle mass and muscle function) using carnosine dipeptide for cellular rejuvenation and manipulating telomeres and enzyme telomerase activity that may reduce some of the physiological declines that accompany aging.


An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway.
Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin-induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.


Information gap: can health insurer personal health records meet patients' and physicians' needs?
Personal health records (PHRs), centralized places for people to electronically store and organize their health information, can benefit both patients and doctors. This qualitative study of health insurers' PHRs for enrollees reveals potential benefits and challenges. Insurers' ability to put claims-based data into the PHR offers an advantage. However, consumers are concerned about sharing personal health information with insurers and about Internet security. Physicians question (1) the validity of claims data in making treatment decisions and (2) whether accessing these PHRs is worth the disruptions to their workflow. This paper offers possible solutions that may lead to more widespread adoption of insurer PHRs.


Pedal manifestations of Milroy's disease.
A pedal complication of Milroy's disease has been presented. With a history of multiple debridement procedures as in this case, there is the risk of recurrent infections and the possibility of permanent vascular compromise, particularly with respect to the thin pedal skin on the dorsal aspect. When the toes are recurrently involved with infection, a patient may be best served with a transmetatarsal amputation using a skin flap on the plantar aspect.


HIV induces production of IL-18 from intestinal epithelial cells that increases intestinal permeability and microbial translocation.
Interleukin-18 (IL-18) is a pleiotropic cytokine of the IL-1 family with multiple context dependent functions. We and others have shown that HIV infection is accompanied by increased circulating levels of IL-18 along with decreased levels of its antagonist, Interleukin-18 Binding Protein (IL-18BP). The infection is also accompanied by intestinal inflammation and decreased intestinal integrity as measured by intestinal permeability, regeneration and repair. However, little is known concerning the relation between high level of IL-18 associated with the viral infection and intestinal permeability. Here we demonstrate that HIV treatment increases production of IL-18 and decreases that of IL-18BP production in human intestinal epithelial cell (IEC) lines. IL-18 causes apoptosis of the IEC by activating caspase-1 and caspase-3. It induces epithelial barrier hyperpermeability by decreasing and disrupting both tight and adherens junction proteins, occludin, claudin 2 and beta-catenin. Disorganization of F-actin was also observed in the IEC that were exposed to the cytokine. Moreover IL-18 decreases transepithelial electrical resistance (TEER) in Caco-2 and increases permeability in HT29 monolayers. The cells' treatment with IL-18 causes an increase in the expression of phosphorylated myosin II regulatory light-chain (p-MLC) and myosin light-chain kinase (MLCK), and a decrease in phosphorylated Signal Transducer and Activator of Transcription (p-STAT)-5. This increase in p-MLC is suppressed by a Rho-kinase (ROCK)-specific inhibitor. Interestingly, the levels of the cytokine correlate with those of LPS in the circulation in three different categories of HIV infected patients (HAART-naïve and HAART-treated HIV-infected individuals, and Elite controls) as well as in healthy controls. Collectively, these results suggest that the HIV-induced IL-18 plays a role in increased intestinal permeability and microbial translocation observed in HIV-infected individuals.


A high diversity of Eurasian lineage low pathogenicity avian influenza A viruses circulate among wild birds sampled in Egypt.
Surveillance for influenza A viruses in wild birds has increased substantially as part of efforts to control the global movement of highly pathogenic avian influenza A (H5N1) virus. Studies conducted in Egypt from 2003 to 2007 to monitor birds for H5N1 identified multiple subtypes of low pathogenicity avian influenza A viruses isolated primarily from migratory waterfowl collected in the Nile Delta. Phylogenetic analysis of 28 viral genomes was performed to estimate their nearest ancestors and identify possible reassortants. Migratory flyway patterns were included in the analysis to assess gene flow between overlapping flyways. Overall, the viruses were most closely related to Eurasian, African and/or Central Asian lineage low pathogenicity viruses and belonged to 15 different subtypes. A subset of the internal genes seemed to originate from specific flyways (Black Sea-Mediterranean, East African-West Asian). The remaining genes were derived from a mixture of viruses broadly distributed across as many as 4 different flyways suggesting the importance of the Nile Delta for virus dispersal. Molecular clock date estimates suggested that the time to the nearest common ancestor of all viruses analyzed ranged from 5 to 10 years, indicating frequent genetic exchange with viruses sampled elsewhere. The intersection of multiple migratory bird flyways and the resulting diversity of influenza virus gene lineages in the Nile Delta create conditions favoring reassortment, as evident from the gene constellations identified by this study. In conclusion, we present for the first time a comprehensive phylogenetic analysis of full genome sequences from low pathogenic avian influenza viruses circulating in Egypt, underscoring the significance of the region for viral reassortment and the potential emergence of novel avian influenza A viruses, as well as representing a highly diverse influenza A virus gene pool that merits continued monitoring.


Media participation and mental health in terrorist attack survivors.
Terrorism and disasters receive massive media attention, and victims are often approached by reporters. Not much is known about how terror and disaster victims perceive the contact with media and whether such experiences influence mental health. In this study, we describe how positive and negative experiences with media relate to posttraumatic stress (PTS) reactions among survivors of the 2011 Utøya Island terrorist attack in Norway. Face-to-face interviews were conducted with 285 survivors (47.0% female and 53.0% male) 14-15 months after the terrorist attack. Most survivors were approached by reporters (94%), and participated in media interviews (88%). The majority of survivors evaluated their media contact and participation as positive, and media participation was unrelated to PTS reactions. Survivors who found media participation distressing had more PTS reactions (quite distressing: B = 0.440, extremely distressing: B = 0.611, p = .004 in adjusted model). Perceiving media participation as distressing was slightly associated with lower levels of social support (r = -.16, p = .013), and regretting media participation was slightly associated with feeling let down (r = .18, p = .004). Reporters should take care when interviewing victims, and clinicians should be aware of media exposure as a potential additional strain on victims.


Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.
Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene. We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein. Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test). Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.


Statin therapy in heart failure.
The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. Mounting experimental and clinical evidence also suggest a potential benefit as well as theoretical harm of statin therapy in patients with heart failure. This article briefly summarizes the therapeutic properties of statins that may be of benefit to patients with heart failure and the theoretical adverse effects of cholesterol reduction in this group of patients. A number of nonrandomized clinical studies over the past several years have shown an association between statin use and reduced overall mortality. Several large-scale randomized studies designed to confirm these findings are currently under way. Statin therapy appears to improve clinical outcomes in patients with both ischemic and nonischemic cardiomyopathy independently of their cholesterol-lowering properties. The theoretical adverse properties of statins in heart failure patients have not been substantiated in small to medium-sized clinical trials. Although the encouraging results of these preliminary studies suggest a role for statin therapy in heart failure, larger studies are needed to validate these findings. Several ongoing randomized trials are currently under way to evaluate the effect of statin therapy on cardiovascular outcomes in heart failure patients. The results of these studies, expected in the next several years, should provide scientific evidence for the role of statins in the treatment of failure.


Mineral balance in horses fed two supplemental silicon sources.
Numerous studies suggest that silicon (Si) supplementation is beneficial for mineral metabolism and bone health. Mineral balance studies have not been performed in horses to determine how these supplements affect absorption of other minerals. The purpose of these studies was to investigate the effects of two different Si supplements on mineral absorption and retention in horses. Eight geldings were randomly placed in one of two groups: control (CO) or supplemental Si, which was provided by one of two supplements. The first, sodium aluminium silicate (SA), contains a bioavailable form of Si and is high in aluminium (Al). The second supplement contains oligomeric orthosilicic acid (OSA). All horses received textured feed and ad libitum access to hay. Supplemented horses received either 200 g of SA or 28.6 ml of OSA per day. Following a 10-day adaptation period, the horses underwent a 3-day total collection. Blood samples were taken on days 0 and 13. The two balance studies were conducted 4 months apart to reduce carryover effects. Intakes of Al and Si were greater with SA supplementation (p < 0.05). Sodium aluminium silicate increased faecal and urinary Si excretion (p < 0.05). Calcium retention and apparent digestion were increased by SA (p < 0.05). It also maintained plasma Si compared with the CO which tended to have a decrease in plasma Si (p = 0.08). Supplemental OSA increased retention of Ca and B (p < 0.05) and apparent digestion of B (p < 0.01). Orthosilicic acid tended to increase Si retention (p = 0.054), apparent digestion (p < 0.065), and also increased plasma Si. Both supplements were able to alter Ca retention and B metabolism, however, only OSA was able to alter Si retention, digestibility and plasma concentration. Orthosilicic acid, an Si supplement without substantial Al, appears to be a viable option for Si supplementation as it increased Si retention and digestibility.


Detection of interleukin-6 and interleukin-1 production in human thyroid epithelial cells by non-radioactive in situ hybridization and immunohistochemical methods.
Human endocrine thyroid epithelial cells have been described to produce cytokines in vitro. In order to determine whether they do so in vivo during thyroiditis, parallel studies on mRNA expression with a non-radioactive in situ hybridization technique and immunohistochemical detection for the protein were performed on frozen sections of thyroid samples from autoimmune thyroiditis (Graves' disease and Hashimoto's thyroiditis), non-toxic goitre and normal thyroid tissue. cDNA probes were sulphonated and their hybridization with mRNA was detected with a sulphonyl-specific monoclonal antibody. This signal was amplified and visualized with the alkaline phosphatase-anti-alkaline phosphatase (APAAP) system. The protein products were detected with immuno-purified rabbit F(ab')2 antibody fragments recognizing recombinant human cytokines, visualized by the immunoperoxidase technique. Each sample was studied at the two levels. Both interleukin-6 mRNA and protein were found in the endocrine cells. There was no obvious difference between autoimmune thyroiditis and non-toxic goitre. However, normal thyroid epithelial cells produced less interleukin-6. Interleukin-1 alpha mRNA and its protein were found in epithelial cells from Hashimoto's thyroiditis samples, but not in the others, except one Graves' disease sample, in which only mRNA was detected. Interleukin-1 beta was not detected in these cells, its mRNA was only found in one of the Graves' disease samples. These cytokines were also detected in some infiltrating cells.


Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model.
Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to the potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human-relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organs-on-Chips technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.


Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes.
Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study.


[Possible connection between gastroesophageal reflux and interstitial pulmonary fibrosis in patients with systemic sclerosis].
Interstitial lung disease represents the main cause of morbidity and mortality in patients with systemic sclerosis. The mechanisms leading to interstitial lung disease are poorly understood and thus current strategies have little effect on this progressive and fatal disease. Therefore, it appears relevant the importance to assess the possible risk factors involved in its pathogenesis. Previous studies in vivo and in vitro suggested that pulmonary fibrosis can occur after repeated aspiration of small amounts of gastric contents over long periods of time. Recently, our group observed that patients with systemic sclerosis and pulmonary fibrosis have a more severe degree of gastroesophageal reflux with a greater number of reflux events and a higher percentage of reflux episodes reaching the proximal esophagus, causing an increasing risk of microaspiration, compared to patients with systemic sclerosis without lung involvement. Further larger controlled studies are necessary to evaluate whether or not the development of interstitial lung disease in systemic sclerosis patients can be prevented by treating gastroesophageal reflux.


Switchable double wavelength generating vertical external cavity surface-emitting laser.
Switchable, double wavelength generation is demonstrated from a single vertical external cavity surface-emitting laser chip. Power of ~0.5 W for two wavelengths λ≈967 nm and 1,018 nm i.e. within the spectral distance of 51 nm were registered. In the semiconductor heterostructure a single set of nominally identical quantum wells was enclosed in a single, two-mode resonant microcavity. The wavelength switching was induced by the change of the pump power. The increase or decrease of the pump power changes the active region temperature and thus tunes spectrally the gain spectrum to the one of two modes.


Do tumor necrosis factor inhibitors increase cancer risk in patients with chronic immune-mediated inflammatory disorders?
Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune-mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person-years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person-years in adalimumab users on non-melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person-years regarding melanoma to the highest rate 63.20 per 1000 person-years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person-years in TNFi users on lymphoma to 34.0 per 1000 person-years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non-TNFi users.


Dietary Interventions in Liver Cirrhosis.
Liver cirrhosis is associated with significant nutritional risks that often result in serious hepatic complications and poor survival rates. Diet is an important but underutilized aspect in the treatment modality of cirrhosis. Therefore, the aims of this review are to ascertain nutritional risks associated with its pathophysiology and to summarize existing evidence that support dietary recommendations for managing this patient population. Alterations in substrate utilization for energy production is a main feature of liver cirrhosis, resulting in increased catabolism of protein stores and a predisposition toward protein-energy malnutrition, even in the early stages of the disease. The body of evidence suggests that a high energy and protein (>1.2 g/kg body weight/d) diet consumed frequently and late in the evening is effective in improving nutritional status of these patients and has been associated with improved hospitalization and mortality rates. The use of branched-chain amino acid supplementation shows promise in reducing cirrhosis-related complications but are currently limited by adverse gastrointestinal symptoms and poor palatability. Furthermore exploration of dietary manipulation of branched-chain amino acid warrants further examination. Evidence is also accumulating that protein intake should not be restricted in patients with hepatic encephalopathy with earlier studies of protein restriction neglecting to account for the relative increase in fermentable fiber which would reduce the absorption of ammonia into the portal system in a way similar to supplementation with lactulose. Finally, a major finding of this review is the need to improve the quality and quantity of dietary intervention studies for patients with liver cirrhosis, particularly with the use of partial or whole dietary sources. In conclusion, dietary management of cirrhosis is not a one-size fits all approach but should be implemented earlier on in the treatment algorithm to improve the clinical prognosis of cirrhosis.


A stripe-to-droplet transition driven by conformational transitions in a binary lipid-lipopolymer mixture at the air-water interface.
We report the observation of an unusual stripe-droplet transition in precompressed Langmuir monolayers consisting of mixtures of poly(ethylene) glycol (PEG) amphiphiles and phospholipids. This highly reproducible and fully reversible transition occurs at approximately zero surface pressure during expansion (or compression) of the monolayer following initial compression into a two-dimensional solid phase. It is characterized by spontaneous emergence of an extended, disordered stripe-like morphology from an optically homogeneous phase during gradual expansion. These stripe patterns appear as a transient feature and continuously progress, involving gradual coarsening and ultimate transformation into a droplet morphology upon further expansion. Furthermore, varying relative concentrations of the two amphiphiles and utilizing amphiphiles with considerably longer ethylene glycol headgroups reveal that this pattern evolution occurs in narrow concentration regimes, values of which depend on ethylene oxide headgroup size. These morphological transitions are reminiscent of those seen during a passage through a critical point by variations in thermodynamic parameters (e.g., temperature or pressure) as well as those involving spinodal decomposition. While the precise mechanism cannot be ascertained using present experiments alone, our observations can be reconciled in terms of modulations in competing interactions prompted by the pancake-mushroom-brush conformational transitions of the ethylene glycol headgroup. This in turn suggests that the conformational degree of freedom represents an independent order parameter, or a switch, which can induce large-scale structural reorganization in amphiphilic monolayers. Because molecular conformational changes are pervasive in biological membranes, we speculate that such conformational transition-induced pattern evolution might provide a physical mechanism by which membrane processes are amplified.


TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability.
The innate immune response is influenced by the nutrient status of the host. Mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase 1 (ERK1) and ERK2, are activated after the stimulation of macrophages with bacterial lipopolysaccharide (LPS) and are necessary for the optimal production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). We uncovered a role for the extracellular nutrient arginine in the activation of ERK1/2 in LPS-stimulated macrophages. Arginine facilitated the activation of MAPKs by preventing the dephosphorylation and inactivation of the MAPK kinase kinase tumor-promoting locus 2 (TPL-2). Starvation of mice decreased the concentration of arginine in the plasma and impaired the activation of ERK1/2 by LPS. Supplementation of starved mice with arginine promoted the subsequent activation of ERK1/2 and the production of TNF-alpha in response to LPS. Thus, arginine is critical for two aspects of the innate immune response in macrophages: It is the precursor used in the generation of the antimicrobial mediator nitric oxide, and it facilitates MAPK activation and consequently cytokine production.


Gut Microbiome and Gastrointestinal Cancer: Les liaisons Dangereuses.
Gastrointestinal (GI) cancers are the leading cause of mortality worldwide. These cancers are the end result of a complex interplay between gene and environment. Bacteria, parasites, and viruses have been implicated in some cancers. Recent data have put at focus the gut microbiome as the key player firing tumorigenesis. Experimental and human studies have provided evidence on the role of microbiota in cancer development. Although subject to changes in different settings such as antibiotic treatment, diet or lifestyle, our microbiome is quite stable and is capable of increasing susceptibility to cancer or decrease and halt its progression. The crucial event in carcinogenesis triggered by microbiome seems to be chronic inflammation influencing the genomic stability of host cells and activating immune mechanisms. Infection-related cancers represent 5.5% of the global cancer burden. Chronic inflammation predisposes to cancer in various GI organs, including hepatocellular carcinoma caused by hepatitis B or hepatitis C virus-related chronic hepatitis, gastric cancer (GC) caused by Helicobacter pylori-associated chronic gastritis, colorectal cancer caused by inflammatory bowel disease, bile duct cancer by primary sclerosing cholangitis, and esophageal cancer caused by Barrett esophagus. Apart from its impact in GI cancer development microbiota can also play an important role in the progression of cancer, response to chemotherapy or cancer prevention. In this review we will discuss the role of microbiome in GI cancers in the light of the current literature and the possible therapeutic options targeting microbiota in the near future.


Neofunctionalization within the Omp85 protein superfamily during chloroplast evolution.
The Toc75 and OEP80 proteins reside in the chloroplast outer envelope membrane. Both are members of the Omp85 superfamily of β-barrel proteins, and both are essential in Arabidopsis plants with important roles throughout development. Toc75 forms the translocation channel of the TOC complex, which is responsible for importing nucleus-encoded proteins into chloroplasts, while the function of OEP80 remains uncertain. Deficiency of Toc75 in plants that have artificially reduced OEP80 levels suggests that the latter may be involved in the biogenesis of β-barrel proteins, in similar fashion to Omp85-related proteins in other systems. To elucidate the evolutionary relationship between the two proteins, we conducted a phylogenetic analysis using 48 sequences from diverse species. This indicated that Toc75 and OEP80 belong to sister groups in the Omp85 superfamily, and originate from a gene duplication in an ancient eukaryotic organism > 1.2 billion years ago. Our analysis also supports the notion that the Toc75 family has undergone a phase of neofunctionalization to accommodate the organelle's newly acquired need to import proteins.


Neurological symptoms and blood neurofilament light levels.
Neurofilament light chain (NfL) is an incredibly specific marker of neuronal injury that is not specific for cause or location of the neuronal damage. NfL is increasingly considered as possible biomarker of disease activity in neurological conditions. Several works reviewed the utility of NfL in the different diseases. Nonetheless, NfL is a universal marker of neuronal damage, which interpretation spaces beyond the single disease. Because of this, the interpretation of NfL may benefit by also considering how neurological symptoms relate to its blood concentration. Here, we review how different neurological symptoms can be associated with blood NfL levels with a practical interpretation of it.


Blood stream infections in patients in the burn intensive care unit.
The study on bacteremia helps empirically select the proper antibiotics before the results of culture test about causative pathogen. The purpose of this study is to investigate causative pathogen in bloodstream infection, changing aspects based on elapsed time after burn, relationship with other sites and resistance of important causative pathogen against antibiotics through analysis on bacteria isolated from blood culture of patients hospitalized in burn intensive care unit (BICU). A retrospective study was conducted targeting patients hospitalized in BICU from January 2007 to June 2011. Changes of causative pathogen in bloodstream infection based on elapsed time after injury were analyzed. We would like to examine the relationship between bloodstream infection and infection on other body parts by comparing results of cultures in burn wound site, sputum, urine and catheter tip. Antibiotics resistance patterns of Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus species, and Klebsiella pneumoniae were studied. A total of 2,337 burn patients were hospitalized in BICU for 54 months. Causative pathogen was cultured in blood cultures from 397 patients (17.0%). P. aeruginosa (169, 30.1%) was the most cultured and A. baumannii (107, 19.0%) and S. aureus (81, 14.4%) were followed. It was confirmed that the relative frequency of A. baumannii tended to get lower as the period got longer after injury, but the relative frequency of K. pneumoniae got higher as the period got longer after injury. With comparison without bacteremia, P. aeruginosa bacteremia showed high probability in which the same bacteria were cultured in wound site, sputum and cathether tip, and A. baumannii bacteremia and candida bacteremia had high probability in sputum, and urine and catheter tip, respectively. 95.9% of P. aeruginosa and 95.3% of A. baumannii showed the resistance against carbapenem. 96.3% of S. aureus was methicillin resistant and 36.2% of Enterococcus species were vancomycin resistant. 75.0% of K. pneumonia were extended-spectrum beta-lactamase (ESBL)-producing bacteria. Since the highly antibiotic resistant microorganisms were isolated from the patients hospitalized in BICU during early phase, the empirical selection of antibiotics targeting these pathogens should be considered before the results of microbiologic culture test. In addition, use of empirical antifungal agent after 1 week of injury can be considered for patients who have risk factor of fungal infection.


Wnt3a induces exosome secretion from primary cultured rat microglia.
Microglia, the immune effector cells of the CNS and the signaling molecule Wnt, both play critical roles in neurodevelopment and neurological disease. Here we describe the inducible release of exosomes from primary cultured rat microglia following treatment with recombinant carrier-free Wnt3a. Wnt3a was internalised into microglia, being detectable in early endosomes, and secreted in exosomes through a GSK3-independent mechanism. Electron microscopy demonstrated that exosomes were elliptical, electron-dense (100 nm) vesicles that coalesced with time in vitro. In contrast to microglia, primary cortical neurons released exosomes constitutively and the quantity of exosomes released was not altered by Wnt3a treatment. The proteomic profile of the microglial-derived exosomes was characterised using liquid chromatography-tandem mass spectrometry (LC/MS/MS) and the vesicles were found to be associated with proteins involved in cellular architecture, metabolism, protein synthesis and protein degradation including β-actin, glyceraldehyde-3-phosphate dehydrogenase, ribosomal subunits and ubiquitin (45 proteins in total). Unlike lipopolysaccharide, Wnt3a did not induce a neurotoxic, pro-inflammatory phenotype in primary microglia. These findings reveal a novel mechanism through which Wnt3a signals in microglia resulting in the release of exosomes loaded with proteinaceous cargo.


Activation of endogenous protein kinase C by halothane in synaptosomes.
Protein kinase C is a signal transducing enzyme that is an important regulator of multiple physiologic processes and a potential molecular target for general anesthetic actions. However, the results of previous studies of the effects of general anesthetics on protein kinase C activation in vitro have been inconsistent. The effects of halothane on endogenous brain protein kinase C activation were analyzed in isolated rat cerebrocortical nerve terminals (synaptosomes) and in synaptic membranes. Protein kinase C activation was monitored by the phosphorylation of MARCKS, a specific endogenous substrate. Halothane stimulated basal Ca2+ dependent phosphorylation of MARCKS (Mr = 83,000) in lysed synaptic membranes (2.1-fold; P< 0.01) and in intact synaptosomes (1.4-fold; P< 0.01). The EC50 for stimulation of MARCKS phosphorylation by halothene in synaptic membranes was 1.8 vol%. A selective peptide protein kinase C inhibitor, but not a protein phosphatase inhibitor (okadaic acid) or a peptide inhibitor of Ca2+/calmodulin-dependent protein kinase II, another Ca2+/-dependent signal transducing enzyme, blocked halothane-stimulated MARCKS phosphorylation in synaptic membranes. Halothane did not affect the phosphorylation of synapsin 1, a synaptic vesicle-associated protein substrate for Ca2+/calmodulin-dependent protein kinase II and AMP-dependent protein kinase, in synaptic membranes or intact synaptosomes subjected to KC1-evoked depolarization. However, halothane stimulated synapsin 1 phosphorylation evoked by ionomycin (a Ca2+ ionophore that permeabilizes membranes to Ca2+) in intact synaptosomes. Halothane acutely stimulated basal protein kinase C activity in synaptosomes when assayed with endogenous nerve terminal substrates, lipids, and protein kinase C. This effect appeared to be selective for protein kinases C, because two other structurally similar second messenger-regulated protein kinases were not affected. Direct determinations of anesthetic effects on endogenous protein kinase C activation, translocation, and/or down-regulation are necessary to determine the ultimate effect of anesthetics on the protein kinase C signaling pathway in intact cells.


Use and Content of Primary Care Office-Based vs Telemedicine Care Visits During the COVID-19 Pandemic in the US.
Little is known about the association between the coronavirus disease 2019 (COVID-19) pandemic and the level and content of primary care delivery in the US. To quantify national changes in the volume, type, and content of primary care delivered during the COVID-19 pandemic, especially with regard to office-based vs telemedicine encounters. Analysis of serial cross-sectional data from the IQVIA National Disease and Therapeutic Index, a 2-stage, stratified nationally representative audit of outpatient care in the US from the first calendar quarter (Q1) of 2018 to the second calendar quarter (Q2) of 2020. Visit type (office-based or telemedicine), overall and stratified by patient population and geographic region; assessment of blood pressure or cholesterol measurement; and initiation or continuation of prescription medications. In the 8 calendar quarters between January 1, 2018, and December 31, 2019, between 122.4 million (95% CI, 117.3-127.5 million) and 130.3 million (95% CI, 124.7-135.9 million) quarterly primary care visits occurred in the US (mean, 125.8 million; 95% CI, 121.7-129.9 million), most of which were office-based (92.9%). In 2020, the total number of encounters decreased to 117.9 million (95% CI, 112.6-123.2 million) in Q1 and 99.3 million (95% CI, 94.9-103.8 million) in Q2, a decrease of 21.4% (27.0 million visits) from the average of Q2 levels during 2018 and 2019. Office-based visits decreased 50.2% (59.1 million visits) in Q2 of 2020 compared with Q2 2018-2019, while telemedicine visits increased from 1.1% of total Q2 2018-2019 visits (1.4 million quarterly visits) to 4.1% in Q1 of 2020 (4.8 million visits) and 35.3% in Q2 of 2020 (35.0 million visits). Decreases occurred in blood pressure level assessment (50.1% decrease, 44.4 million visits) and cholesterol level assessment (36.9% decrease, 10.2 million visits) in Q2 of 2020 compared with Q2 2018-2019 levels, and assessment was less common during telemedicine than during office-based visits (9.6% vs 69.7% for blood pressure; P < .001; 13.5% vs 21.6% for cholesterol; P < .001). New medication visits in Q2 of 2020 decreased by 26.0% (14.1 million visits) from Q2 2018-2019 levels. Telemedicine adoption occurred at similar rates among White individuals and Black individuals (19.3% vs 20.5% of patient visits, respectively, in Q1/Q2 of 2020), varied by region (low of 15.1% of visits [East North Central region], high of 26.8% of visits [Pacific region]), and was not correlated with regional COVID-19 burden. The COVID-19 pandemic has been associated with changes in the structure of primary care delivery, with the content of telemedicine visits differing from that of office-based encounters.


Intracranial bleeding following induction of anesthesia in a patient undergoing elective surgery for refractory epilepsy.
A patient with refractory epilepsy due to underlying mesial temporal sclerosis underwent general anesthesia for an elective anterior temporal lobectomy and amgydalo-hippocampectomy. He was a known hypertensive and his blood pressure was well controlled on medication. Following induction of general anesthesia and subsequent opening of the craniotomy flap it was noted that the patient had a very swollen brain that herniated out of the dural defect. There was an underlying spontaneous intraparenchymal bleed encountered in the region of the left temporal lobe with associated subarachnoid hemorrhage within the sylvian fissure. The clot was evacuated and subsequently brain swelling reduced allowing us to proceed with the intended surgery. Despite the intracranial findings there was no overt abnormality in the hemodynamic status from the time of induction of anesthesia to the craniotomy opening excepting a mild nonsustained elevation of blood pressure at the outset. This case is of interest due to the fact that spontaneous intraparenchymal bleeding after induction of anesthesia has not been reported before in literature and should be considered in any patient in which brain swelling occurs in a setting of elective neurosurgery in which the primary lesion does not cause elevated intracranial pressure.


The Protective Effect of Brown-, Gray-, and Blue-Tinted Lenses against Blue LED Light-Induced Cell Death in A2E-Laden Human Retinal Pigment Epithelial Cells.
A2E-laden ARPE-19 cells were exposed to a blue light to induce cytotoxicity, in order to investigate the protective effects of various tinted ophthalmic lenses against photo-induced cytotoxicity in human retinal pigment epithelial (RPE) cells laden with A2E, known to be among the etiologies of age-related macular degeneration (AMD). Different-colored tinted lenses with varying levels of tint and different filtering characteristics, such as polarized, blue-cut, and photochromatic lenses, were placed over the cells, and the protective efficacies thereof were evaluated by lactate dehydrogenase assay. When tinted lenses were placed over ARPE-19 cells, there were different reductions in cytotoxicity according to the colors and tint levels. The level of protection afforded by brown-tinted lenses was 6.9, 36.1, and 49% with a tint level of 15, 50, and 80%, respectively. For gray-tinted lenses, the protective effect was 16.3, 35, and 43.4% for the corresponding degree of tint, respectively. In the case of blue-tinted lenses, a protective effect of 20% was observed with 80% tinted lenses, but 15 and 50% tinted lenses provided no significant protection. In addition, photochromic lenses showed a protective effect but blue-cut lenses and polarized lenses provided no significant protection. Tinted lenses significantly reduced cytotoxicity in RPE cells irradiated with blue light. The protection was more efficient in lenses with a brown or gray tint than in blue-tinted lenses. Tinted glasses may provide significant protection against potential blue-light-induced photochemical and photo-oxidative damage in RPE cells.


MicroRNA expression and clinical outcome of small cell lung cancer.
The role of microRNAs in small-cell lung carcinoma (SCLC) is largely unknown. miR-34a is known as a p53 regulated tumor suppressor microRNA in many cancer types. However, its therapeutic implication has never been studied in SCLC, a cancer type with frequent dysfunction of p53. We investigated the expression of a panel of 7 microRNAs (miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a) in 31 SCLC tumors, 14 SCLC cell lines, and 26 NSCLC cell lines. We observed significantly lower miR-21, miR-29b, and miR-34a expression in SCLC cell lines than in NSCLC cell lines. The expression of the 7 microRNAs was unrelated to SCLC patients' clinical characteristics and was neither prognostic in term of overall survival or progression-free survival nor predictive of treatment response. Overexpression or downregulation of miR-34a did not influence SCLC cell viability. The expression of these 7 microRNAs also did not predict in vitro sensitivity to cisplatin or etoposide in SCLC cell lines. Overexpression or downregulation of miR-34a did not influence sensitivity to cisplatin or etoposide in SCLC cell lines. In contrast to downregulation of the miR-34a target genes cMET and Axl by overexpression of miR-34a in NSCLC cell lines, the intrinsic expression of cMET and Axl was low in SCLC cell lines and was not influenced by overexpression of miR-34a. Our results suggest that the expression of the 7 selected microRNAs are not prognostic in SCLC patients, and miR-34a is unrelated to the malignant behavior of SCLC cells and is unlikely to be a therapeutic target.


Uncovering the Modulatory Interactions of Brain Networks in Cognition with Central Thalamic Deep Brain Stimulation Using Functional Magnetic Resonance Imaging.
Deep brain stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. It acts by altering brain networks and facilitating synaptic plasticity. For enhancing cognitive functions, the central thalamus (CT) has been shown to be a potential DBS target. The network-level mechanisms contributing to the effect exerted by DBS on the CT (CT-DBS) remain unknown. Combining CT-DBS with functional magnetic resonance imaging (fMRI), this study explored brain areas activated while applying CT-DBS in rats, using a newly developed neural probe that was compatible with MRI and could minimize the image distortion and resolve safety issues. Results showed activation of the anterior cingulate cortex, motor cortex, primary and secondary somatosensory cortices, caudate putamen, hypothalamus, thalamus, and hippocampus, suggesting that the corticostriatal, corticolimbic, and thalamocortical brain networks were affected. Behaviorally, the CT-DBS group required a shorter time than sham controls to learn a water-reward lever-pressing task and made more correct choices in a T-maze task. Concurrent with enhanced learning performance, bilateral CT-DBS resulted in alteration in the functional connectivity of brain networks determined by resting-state fMRI. Western blot analyses showed that the protein level of both dopamine D1 and α4-nicotinic acetylcholine receptors was increased, and dopamine D2 receptor was decreased. These data suggest that CT-DBS can enhance cognitive performance as well as brain connectivity through the modulation of synaptic plasticity, such that CT is a target providing high potential for the remediation of acquired cognitive learning and memory disabilities.


The clinical effectiveness and cost-effectiveness of clinical nurse specialist-led hospital to home transitional care: a systematic review.
Clinical nurse specialists (CNSs) are major providers of transitional care. This paper describes a systematic review of randomized controlled trials (RCTs) evaluating the clinical effectiveness and cost-effectiveness of CNS transitional care. We searched 10 electronic databases, 1980 to July 2013, and hand-searched reference lists and key journals for RCTs that evaluated health system outcomes of CNS transitional care. Study quality was assessed using the Cochrane Risk of Bias and Quality of Health Economic Studies tools. The quality of evidence for individual outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. We pooled data for similar outcomes. Thirteen RCTs of CNS transitional care were identified (n = 2463 participants). The studies had low (n = 3), moderate (n = 8) and high (n = 2) risk of bias and weak economic analyses. Post-cancer surgery, CNS care was superior in reducing patient mortality. For patients with heart failure, CNS care delayed time to and reduced death or re-hospitalization, improved treatment adherence and patient satisfaction, and reduced costs and length of re-hospitalization stay. For elderly patients and caregivers, CNS care improved caregiver depression and reduced re-hospitalization, re-hospitalization length of stay and costs. For high-risk pregnant women and very low birthweight infants, CNS care improved infant immunization rates and maternal satisfaction with care and reduced maternal and infant length of hospital stay and costs. There is low-quality evidence that CNS transitional care improves patient health outcomes, delays re-hospitalization and reduces hospital length of stay, re-hospitalization rates and costs. Further research incorporating robust economic evaluation is needed.


Experimental strategies for studying transcription factor-DNA binding specificities.
Specific binding of transcription factors (TFs) determines in a large part the connectivity of gene regulatory networks as well as the quantitative level of gene expression. A multiplicity of both experimental and computational methods is currently used to discover and characterize the underlying TF-DNA interactions. Experimental methods can be further subdivided into in vitro- and in vivo-based approaches, each accenting different aspects of TF-binding events. In this review we summarize the flexibility and performance of a selection of both types of experimental methods. In conclusion, we argue that a serial combination of methods with different throughput and data type constitutes an optimal experimental strategy.


Inflammatory bowel disease readmissions are associated with utilization and comorbidity.
Hospital care accounts for up to one-third of the cost of inflammatory bowel disease (IBD) management. A select group of patients with IBD is responsible for a large proportion of this utilization, demonstrating the burden of frequent hospitalizations. We aim to better understand the burden of 30-day readmissions among patients with IBD using a national hospital database. Retrospective cohort study of state-specific inpatient databases. The State Inpatient Databases for New York and Florida were used to identify patients with IBD hospitalized between 2009 and 2013. The prevalence of 30-day IBD-specific readmission was determined. The association between 30-day readmission and visit outcomes, specifically length of stay and a composite of comorbid conditions (venous thromboembolism, pneumonia, sepsis, Clostridium difficile infection, enteral and parenteral nutrition, and blood transfusion), was analyzed using multivariable logistic regression. Patients with IBD accounted for 35,514 and 39,506 inpatient stays in New York and Florida, respectively. Of these stays, 13.7% to 16.2% resulted in a 30-day readmission. On multivariable analysis, 30-day readmissions were associated with a longer length of stay than index hospitalizations by 1.00 day (adjusted regression coefficient, 1.00; 95% CI, 0.73-1.26) and a higher likelihood of having a comorbid condition (adjusted odds ratio, 1.83; 95% CI, 1.68-1.99) in New York. Similar associations were confirmed in Florida. Nearly 1 in 7 hospitalizations of patients with IBD lead to a 30-day readmission. These IBD-specific readmissions are associated with increased utilization and comorbidity. Patients at risk for readmission need to be targeted to improve outcomes and IBD care quality.


Utility-value intervention with parents increases students' STEM preparation and career pursuit.
During high school, developing competence in science, technology, engineering, and mathematics (STEM) is critically important as preparation to pursue STEM careers, yet students in the United States lag behind other countries, ranking 35th in mathematics and 27th in science achievement internationally. Given the importance of STEM careers as drivers of modern economies, this deficiency in preparation for STEM careers threatens the United States' continued economic progress. In the present study, we evaluated the long-term effects of a theory-based intervention designed to help parents convey the importance of mathematics and science courses to their high-school-aged children. A prior report on this intervention showed that it promoted STEM course-taking in high school; in the current follow-up study, we found that the intervention improved mathematics and science standardized test scores on a college preparatory examination (ACT) for adolescents by 12 percentile points. Greater high-school STEM preparation (STEM course-taking and ACT scores) was associated with increased STEM career pursuit (i.e., STEM career interest, the number of college STEM courses, and students' attitudes toward STEM) 5 y after the intervention. These results suggest that the intervention can affect STEM career pursuit indirectly by increasing high-school STEM preparation. This finding underscores the importance of targeting high-school STEM preparation to increase STEM career pursuit. Overall, these findings demonstrate that a motivational intervention with parents can have important effects on STEM preparation in high school, as well as downstream effects on STEM career pursuit 5 y later.


Genetic determinants of genus-level glycan diversity in a bacterial protein glycosylation system.
The human pathogens N. gonorrhoeae and N. meningitidis display robust intra- and interstrain glycan diversity associated with their O-linked protein glycosylation (pgl) systems. In an effort to better understand the evolution and function of protein glycosylation operating there, we aimed to determine if other human-restricted, Neisseria species similarly glycosylate proteins and if so, to assess the levels of glycoform diversity. Comparative genomics revealed the conservation of a subset of genes minimally required for O-linked protein glycosylation glycan and established those pgl genes as core genome constituents of the genus. In conjunction with mass spectrometric-based glycan phenotyping, we found that extant glycoform repertoires in N. gonorrhoeae, N. meningitidis and the closely related species N. polysaccharea and N. lactamica reflect the functional replacement of a progenitor glycan biosynthetic pathway. This replacement involved loss of pgl gene components of the primordial pathway coincident with the acquisition of two exogenous glycosyltransferase genes. Critical to this discovery was the identification of a ubiquitous but previously unrecognized glycosyltransferase gene (pglP) that has uniquely undergone parallel but independent pseudogenization in N. gonorrhoeae and N. meningitidis. We suggest that the pseudogenization events are driven by processes of compositional epistasis leading to gene decay. Additionally, we documented instances where inter-species recombination influences pgl gene status and creates discordant genetic interactions due ostensibly to the multi-locus nature of pgl gene networks. In summary, these findings provide a novel perspective on the evolution of protein glycosylation systems and identify phylogenetically informative, genetic differences associated with Neisseria species.


What Could Total Worker Health® Look Like in Small Enterprises?
Small enterprises have fewer resources, are more financially precarious, and have higher rates of occupational injury and illness compared with larger enterprises. Interventions that address the promotion of health and well-being in addition to traditional occupational safety and health hazards, a Total Worker Health® (TWH) approach, may be effective in reducing injuries and preventing illness. However, little research has examined the impact of TWH interventions in small enterprises. The aim of this research was to explore and characterize health and safety practices, policies, and programs in small Midwestern enterprises from a TWH perspective. Utilizing a case studies approach, site visits were conducted with small business, between 10 and 250 employees, from 2014 through 2016 and included workplace audits and interviews with multiple employees in varying roles within each organization. Both open and closed coding were used to identify specific themes. Eight themes emerged from the site visits: value and return on investment, organizational factors, program design, engaging employees, low-cost strategies, evaluation, and integration. These themes overlapped with both the National Institute for Occupational Safety and Health's (NIOSH) Essential Elements of TWH and the NIOSH Fundamentals. Industry sector and enterprise size also affect resources and integration of these resources. As TWH expands to organizations of all sizes, it is necessary to address the unique needs of smaller enterprises.


Schizophrenia and visual backward masking: a general deficit of target enhancement.
The obvious symptoms of schizophrenia are of cognitive and psychopathological nature. However, schizophrenia affects also visual processing which becomes particularly evident when stimuli are presented for short durations and are followed by a masking stimulus. Visual deficits are of great interest because they might be related to the genetic variations underlying the disease (endophenotype concept). Visual masking deficits are usually attributed to specific dysfunctions of the visual system such as a hypo- or hyper-active magnocellular system. Here, we propose that visual deficits are a manifestation of a general deficit related to the enhancement of weak neural signals as occurring in all other sorts of information processing. We summarize previous findings with the shine-through masking paradigm where a shortly presented vernier target is followed by a masking grating. The mask deteriorates visual processing of schizophrenic patients by almost an order of magnitude compared to healthy controls. We propose that these deficits are caused by dysfunctions of attention and the cholinergic system leading to weak neural activity corresponding to the vernier. High density electrophysiological recordings (EEG) show that indeed neural activity is strongly reduced in schizophrenic patients which we attribute to the lack of vernier enhancement. When only the masking grating is presented, EEG responses are roughly comparable between patients and control. Our hypothesis is supported by findings relating visual masking to genetic deviants of the nicotinic α7 receptor (CHRNA7).


Feedback modulation of ligand-engaged alpha L/beta 2 leukocyte integrin (LFA-1) by cyclic AMP-dependent protein kinase.
Rapid interconversion between a firmly adherent and a nonadherent, circulating phenotype is a distinctive feature of mature leukocytes and is thought to be essential for efficient immune surveillance. Leukocyte adhesion is a finely regulated process controlled in part by reversible, activation-dependent up-regulation of beta 1- and beta 2- integrin function. To investigate the molecular basis of such reversibility in human T lymphocytes, we developed a model of alpha L/beta 2 (LFA-1)-dependent adhesion that uses a heterologous cell line expressing human intercellular adhesion molecule-1 as a selected ligand. We show here that intracellular cAMP elevation, followed by cAMP-dependent kinase activation, promotes T cell deadhesion by disassembling the actin-based cytoskeleton, thus dissociating LFA-1 from cytoskeletal anchoring proteins that normally connect the adhesion receptor to F-actin in lymphocytes engaged in intercellular adhesion. Cells costimulated via the CD3 and LFA-1 receptors by specific Abs or by binding to intercellular adhesion molecule-1 display gradual and persistent intracellular cAMP elevations due to the synergistic induction of a protein kinase C-dependent adenylyl cyclase isoform. On the basis of these findings, we propose a feedback model for short term regulation of leukocyte integrins, involving sequential, integrin-dependent activation of the protein kinase C and adenylyl cyclase/cAMP-dependent kinase enzymatic pathways and leading to disengagement of the adhesion receptor from its specific ligand.


Persistent hemispheric differences in the perceptual selection of spatial frequencies.
Previous research has shown that the right hemisphere processes low spatial frequencies more efficiently than the left hemisphere, which preferentially processes high spatial frequencies. These studies have typically measured RTs to single, briefly flashed gratings and/or have directed observers to attend to a particular spatial frequency immediately before making a judgment about a subsequently presented stimulus. Thus, it is unclear whether the hemispheres differ in perceptual selection from multiple spatial frequencies that are simultaneously present in the environment, without bias from selective attention. Moreover, the time course of hemispheric asymmetry in spatial frequency processing is unknown. We addressed both of these questions with binocular rivalry, a measure of perceptual selection from competing alternatives over time. Participants viewed a pair of rivalrous orthogonal gratings with different spatial frequencies, presented either to the left or right of central fixation, and continuously reported which grating they perceived. At the beginning of a trial, the low spatial frequency grating was perceptually selected more often when presented in the left hemifield (right hemisphere) than in the right hemifield (left hemisphere), whereas the high spatial frequency grating showed the opposite pattern of results. This hemispheric asymmetry in perceptual selection persisted for the entire 30-sec stimulus presentation, continuing long after stimulus onset. These results indicate stable differences in the resolution of ambiguity across spatial locations and demonstrate the importance of considering sustained differences in perceptual selection across space when characterizing conscious representations of complex scenes.


Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia.
A line of dopamine-deficient (DD) mice was generated to allow selective restoration of normal dopamine signaling to specific brain regions. These DD floxed stop (DDfs) mice have a nonfunctional Tyrosine hydroxylase (Th) gene because of insertion of a NeoR gene flanked by lox P sites targeted to the first intron of the Th gene. DDfs mice have trace brain dopamine content, severe hypoactivity, and aphagia, and they die without intervention. However, they can be maintained by daily treatment with l-3,4-dihydroxyphenylalanine (L-dopa). Injection of a canine adenovirus (CAV-2) engineered to express Cre recombinase into the central caudate putamen restores normal Th gene expression to the midbrain dopamine neurons that project there because CAV-2 efficiently transduces axon terminals and is retrogradely transported to neuronal cell bodies. Bilateral injection of Cre recombinase into the central caudate putamen restores feeding and normalizes locomotion in DDfs mice. Analysis of feeding behavior by using lickometer cages revealed that virally rescued DDfs mice are hyperphagic and have modified meal structures compared with control mice. The virally rescued DDfs mice are also hyperactive at night, have reduced motor coordination, and are thigmotactic compared with controls. These results highlight the critical role for dopamine signaling in the dorsal striatum for most dopamine-dependent behaviors but suggest that dopamine signaling in other brain regions is important to fine-tune these behaviors. This approach offers numerous advantages compared with previous models aimed at examining dopamine signaling in discrete dopaminergic circuits.


Three-year outcomes after Aquablation therapy compared to TURP: results from a blinded randomized trial.
To compare 3-year efficacy and safety after prostate resection with Aquablation therapy or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostate hyperplasia (BPH). One hundred and eighty-one patients assigned to either Aquablation therapy or TURP were followed for 3 years postoperatively. Patients and follow up assessors were blinded to treatment. Assessments included International Prostate Symptom Score (IPSS), Male Sexual Health Questionnaire (MSHQ-EjD), International Index of Erectile Function (IIEF) and uroflow. Over 3 years of treatment, improvements in IPSS scores were statistically similar across groups. Mean 3-year improvements were 14.4 and 13.9 points in the Aquablation and TURP groups, respectively (difference of 0.6 points, 95% CI -3.3-2.2, p = .6848). Similarly, 3-year improvements in Qmax were 11.6 and 8.2 cc/sec (difference of 3.3 [95% CI -0.5-7.1] cc/sec, p = .0848). At 3 years, PSA was reduced significantly in both groups by 0.9 and 1.1 ng/mL, respectively; the reduction was similar across groups (p = .5983). There were no surgical retreatments for BPH beyond 20 months for either Aquablation or TURP. Three-year BPH symptom reduction and urinary flow rate improvement were similar after TURP and Aquablation therapy. No subjects required surgical retreatment beyond 20 months postoperatively. (ClinicalTrials.gov number, NCT02505919).


CXCR4-Targeted Nanocarriers for Triple Negative Breast Cancers.
CXCR4 is a cell membrane receptor that is overexpressed in triple-negative breast cancers and implicated in growth and metastasis of this disease. Using electrohydrodynamic cojetting, we prepared multicompartmental drug delivery carriers for CXCR4 targeting. The particles are comprised of a novel poly(lactide-co-glycolide) derivative that allows for straightforward immobilization of 1,1'-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (Plerixafor), a small molecule with affinity for CXCR4. Targeted nanocarriers are selectively taken up by CXCR4-expressing cells and effectively block CXCR4 signaling. This study suggests that CXCR4 may be an effective target for nanocarrier-based therapies.


Effects of dietary fish oil on fatty acids and eicosanoids in metastasizing human breast cancer cells.
We examined the relationships between the suppressive effects of dietary fish oil on growth and metastasis of MDA-MB-435 human breast cancer cells in female nude mice and the primary tumor phospholipid fatty acid concentrations, phospholipase A2 activity, and eicosanoid levels. Mice (n = 120) were fed a 23% (wt/wt) corn oil (CO) linoleic acid (LA)-rich diet for seven days before and after 10(6) tumor cells were injected into a mammary fat pad, and then the mice receive one of three isocaloric diets containing 23% total fat but different proportions of CO and menhaden oil (MO) (18% CO-5% MO, 11.5% CO-11.5% MO, 5% CO-18% MO) or a 23% fat diet containing 18% deodorized fish oil supplemented with tocopherol and tert-butylhydroquinone antioxidants (FAO). Primary tumor growth rate was significantly greater in mice fed the 18% CO diet than in the three diets containing higher levels of fish oil (all p < 0.05). The 18% MO diet, but not the 11.5% MO or the 18% FAO diet, suppressed the development of lung metastases compared with the 18% CO diet. Increasing the proportion of MO relative to CO in the diets produced corresponding increases in the primary tumor phospholipid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations and reductions in LA and arachidonic acid. There was a significant positive correlation between the LA concentration in these tumors and the extent of lung metastasis (r = 0.504). Tumor phospholipase A2 activity was unaffected by dietary MO intake. Prostaglandin E2 concentration was inversely correlated with phospholipid EPA (r = -0.484) and DHA (r = -0.439), but there was no relationship with lung metastasis. Tumor leukotriene B4 and 5-hydroxyeicosatetraenoic acid levels were not reduced by dietary MO. The 18% FAO- and the 18% MO-fed mice showed similar relationships for the phospholipid fatty acids and prostaglandin E2, despite the lack of effect on metastasis. The strong correlation between phospholipid LA levels and metastasis and the lack of an association with tumor eicosanoids suggest that the 18% MO diet inhibited metastasis because dietary LA was replaced by other fatty acids.


Follicular Dendritic Cell Sarcoma of the Tonsil: A Multimodality Approach.
Follicular dendritic cell sarcoma (FDCS) accounts for < 0.4% of soft tissue sarcomas. Only 35 cases of tonsillar FDCS have been reported, and majority had localized presentation. We present a case of FDCS of the tonsil, wherein a well-coordinated trimodality approach provided good disease control in advanced disease. A 53-year-old man presented with a painless and enlarging neck mass of 11-month duration, with no other symptoms. Close examination revealed a 10 × 5 cm mass at the left carotid triangle, and a 3.2 × 2.2 cm mass at the left tonsillar fossa. Imaging revealed the tumor to be unresectable due to its attachment to the great vessels. There were no distant metastases. Biopsy and immunohistochemistry were initially deemed consistent with an undifferentiated sarcoma. Palliative chemotherapy was given using single agent doxorubicin and subsequent dacarbazine, resulting in partial response and stable disease, respectively. Pathological re-evaluation was pursued because of the uncharacteristic slow progression of the tumor, revealing diffuse positivity for CD21 and negative for CD1A and CD34, consistent with FDCS. The patient underwent three cycles of gemcitabine plus docetaxel resulting in 50% regression. This allowed dissection of level IB-V lymph nodes and subsequent radiotherapy for the neck and tonsillar mass, with weekly gemcitabine as a radiosensitizer. Evaluation 8 months post-treatment showed no signs of disease progression. Treatment-related complications included radiation dermatitis and swallowing dysfunction, which both resolved on follow-up. This case highlights the multidisciplinary management of a rare type of sarcoma in an uncommon anatomic location. Precise pathologic diagnosis is important in soft tissue sarcoma because of its therapeutic implications. For FDCS, effective response may still be achieved in the third-line setting.


Relationship between community prevalence of obesity and associated behavioral factors and community rates of influenza-related hospitalizations in the United States.
Findings from studies examining the association between obesity and acute respiratory infection are inconsistent. Few studies have assessed the relationship between obesity-related behavioral factors, such as diet and exercise, and risk of acute respiratory infection. To determine whether community prevalence of obesity, low fruit/vegetable consumption, and physical inactivity are associated with influenza-related hospitalization rates. Using data from 274 US counties, from 2002 to 2008, we regressed county influenza-related hospitalization rates on county prevalence of obesity (BMI ≥ 30), low fruit/vegetable consumption (<5 servings/day), and physical inactivity (<30 minutes/month recreational exercise), while adjusting for community-level confounders such as insurance coverage and the number of primary care physicians per 100,000 population. A 5% increase in obesity prevalence was associated with a 12% increase in influenza-related hospitalization rates [adjusted rate ratio (ARR) 1.12, 95% confidence interval (CI) 1.07, 1.17]. Similarly, a 5% increase in the prevalence of low fruit/vegetable consumption and physical inactivity was associated with an increase of 12% (ARR 1.12, 95% CI 1.08, 1.17) and 11% (ARR 1.11, 95% CI 1.07, 1.16), respectively. When all three variables were included in the same model, a 5% increase in prevalence of obesity, low fruit/vegetable consumption, and physical inactivity was associated with 6%, 8%, and 7% increases in influenza-related hospitalization rates, respectively. Communities with a greater prevalence of obesity were more likely to have high influenza-related hospitalization rates. Similarly, less physically active populations, with lower fruit/vegetable consumption, tended to have higher influenza-related hospitalization rates, even after accounting for obesity.


Mice that produce ApoB100 lipoproteins in the RPE do not develop drusen yet are still a valuable experimental system.
Mice typically produce apolipoprotein B (apoB)-48 and not apoB100. Apolipoprotein B100 accumulates in Bruch's membrane prior to basal deposit and drusen formation during the onset of AMD, raising the possibility that they are a trigger for these Bruch's membrane alterations. The purpose herein, was to determine whether mice that predominantly produce apoB100 develop features of AMD. The eyes of mice that produce apoB100 were examined for apoB100 synthesis, cholesteryl esterase/filipin labeling for cholesteryl esters, and transmission electron microscopy for lipid particles and phenotype. Apolipoprotein B100 was abundant in the RPE-choroid of apoB100, but not wild-type mice by Western blot analysis. The apolipoprotein B100,(35)S-radiolabeled and immunoprecipitated from RPE explants, confirmed that apoB100 was synthesized by RPE. Apolipoprotein B100, but not control mice, had cholesteryl esters and lipid particles in Bruch's membrane. Immunoreactivity of ApoB100 was present in the RPE and Bruch's membrane, but not choroidal endothelium of apoB100 mice. Ultrastructural changes were consistent with aging, but not AMD when aged up to 18 months. The induction of advanced glycation end products to alter Bruch's membrane, did not promote basal linear deposit or drusen formation. Mice that produce apoB100 in the RPE and liver secrete lipoproteins into Bruch's membrane, but not to the extent that distinct features of AMD develop, which suggests that either additional lipoprotein accumulation or additional factors are necessary to initiate their formation.


Impact of handgun types on gun assault outcomes: a comparison of gun assaults involving semiautomatic pistols and revolvers.
To examine whether gun assaults committed with semiautomatic pistols are more injurious and lethal than those committed with revolvers. Jersey City, New Jersey from 1992 through 1996. Using police records on fatal and non-fatal handgun assaults, t tests and chi(2) tests were employed to determine if attacks with pistols result in more shots fired than those with revolvers, leading to more gunshot victims and more severely wounded victims. More shots were fired in attacks with pistols (average = 3.2 to 3.7) than in attacks with revolvers (average = 2.3 to 2.6). Although pistol use was unrelated to the probability that an incident resulted in any injury or death, it was associated with a 15% increase in the number of wounded victims in those cases in which people were shot (1.15 per pistol case, 1.0 per revolver case), implying that the total number of gunshot victims may have been 9.4% lower had pistols not been used in any attacks. Pistol use was not related to the number of wounds per gunshot victim. The findings provide limited evidence that recent growth in the production and use of pistols has contributed to higher levels of gunshot victimizations. However, available data did not permit an assessment of whether the associations between gun types and assault outcomes are mediated by characteristics of incidents and actors.


Renin angiotensin system inhibition attenuates adipocyte-breast cancer cell interactions.
Obesity is a significant breast cancer (BC) risk factor and is associated with 20-40% increased risk in obese post-menopausal women compared to their lean counterparts. Several obesity-related metabolic dysregulations have been linked to BC risk, including overactivation of the renin-angiotensin system (RAS). Currently, RAS inhibitors including angiotensin converting enzyme inhibitor (ACEi) and AT1 receptor blockers (ARBs), are used as safe and effective anti-hypertensive therapies in BC patients. However, it is uncertain how inhibition of RAS in adipose tissue impacts obesity-BC crosstalk. We hypothesized that adipose RAS inhibition will reduce BC cell motility and inflammation. We determined (1) the direct effects of Ang II, ACEi (captopril; Cap) or ARB (telmisartan; Tel) on receptor positive MCF-7 and receptor triple negative MDA-MB-231 cells; and (2) the effects of conditioned media (CM) from human mesenchymal stem cells differentiated into adipocytes, which were pretreated with RAS inhibitors, on BC cells. We demonstrated that direct treatments of BC cells with Ang II, Cap or Tel did not alter inflammatory cytokines in either BC cell line. However, CM from Ang II-pretreated adipocytes significantly increased secretion of pro-inflammatory markers at protein level. RAS inhibitors reduced their secretion in MDA-MB-231, but not in MCF-7 cells. Additionally, CM from adipocytes treated with RAS inhibitors significantly reduced markers of inflammation, fat synthesis, and angiogenesis in both BC cell lines. Furthermore, CM from ACEi pretreated adipocytes reduced cell motility in both BC cell lines. Findings from our study indicate an important role of adipose RAS inhibition in adipocyte and BC cell crosstalk.


Hair removal with a non-coherent filtered flashlamp intense pulsed light source.
To evaluate the effects on disruption of hair growth of the non-coherent filtered flashlamp intense pulsed light (IPL) source. Twenty-eight sites on 23 patients with Fitzpatrick type I-III were enrolled using a single treatment IPL followed for three months post-treatment. Another 56 on 48 patients with Fitzpatrick skin types I-V randomly enrolled for two treatments one month apart and followed for six months. Prior to beginning treatment and at each follow-up visit hair counts were obtained by averaging three 1-cm2 areas on a clear acetate template placed over the skin. Repeat hair counts and photographs were obtained at 2, 4, 8, and 12 weeks for the single treatment protocol and at additional 4, 5, and 6 months for the double treatment protocol. Parameters utilized were a 2.8-3.2 millisecond pulse duration typically for three pulses with thermal relaxation intervals of 20-30 milliseconds with a total fluence of 40-42 J/cm2. For the double treatment protocol hair clearance of 64% was achieved immediately following the second treatment. By week 8 reduction of hair counts was 42%. At 6 months, hair counts were reduced by 33%. Non-coherent IPL is an effective modality for long-term hair removal. IPL is safe with minimal side effects of epidermal injury or pigmentation change.


Successful combat of an outbreak due to Clostridium difficile PCR ribotype 027 and recognition of specific risk factors.
In the period April-September 2005, an outbreak of Clostridium difficile infection (CDI) due to PCR ribotype 027 occurred among 50 patients in a 341-bed community hospital in Harderwijk, The Netherlands. A retrospective case-control study was performed to identify risk factors specific for CDI, using a group of patients with CDI (n = 45), a group of randomly selected control patients without diarrhoea (n = 90), and a group of patients with non-infectious diarrhoea (n = 109). Risk factors for CDI and for non-CDI diarrhoea were identified using multiple logistic regression analysis. Independent risk factors for CDI were: age above 65 years (OR 2.6; 95% CI 1.0-5.7), duration of hospitalization (OR 1.04 per additional day; 95% CI 1.0-1.1), and antibiotic use (OR 12.5; 95% CI 3.2-48.1). Of the antibiotics used, cephalosporins and fluoroquinolones were identified as the major risk factors for development of CDI. The risk of developing CDI was particularly high in people receiving a combination of a cephalosporin and a fluoroquinolone (OR 57.5; 95% CI 6.8-483.6). The main factors affecting the risk of non-CDI diarrhoea were proton-pump inhibitors, immunosuppressive drugs, underlying digestive system disease, previous surgery, and gastric tube feeding. The outbreak ended only after implementation of restricted use of cephalosporins and a complete ban on fluoroquinolones, in addition to general hygienic measures, cohorting of patients in a separate ward, education of staff, and intensified environmental cleaning. The results of this study support the importance of appropriate antimicrobial stewardship in the control of hospital outbreaks with C. difficile PCR ribotype 027.


Microbial Community Structure and Associations During a Marine Dinoflagellate Bloom.
Interactions between microorganisms and algae during bloom events significantly impacts their physiology, alters ambient chemistry, and shapes ecosystem diversity. The potential role these interactions have in bloom development and decline are also of particular interest given the ecosystem impacts of algal blooms. We hypothesized that microbial community structure and succession is linked to specific bloom stages, and reflects complex interactions among taxa comprising the phycosphere environment. This investigation used pyrosequencing and correlation approaches to assess patterns and associations among bacteria, archaea, and microeukaryotes during a spring bloom of the dinoflagellate Alexandrium catenella. Within the bacterial community, Gammaproteobacteria and Bacteroidetes were predominant during the initial bloom stage, while Alphaproteobacteria, Cyanobacteria, and Actinobacteria were the most abundant taxa present during bloom onset and termination. In the archaea biosphere, methanogenic members were present during the early bloom period while the majority of species identified in the late bloom stage were ammonia-oxidizing archaea and Halobacteriales. Dinoflagellates were the major eukaryotic group present during most stages of the bloom, whereas a mixed assemblage comprising diatoms, green-algae, rotifera, and other microzooplankton were present during bloom termination. Temperature and salinity were key environmental factors associated with changes in bacterial and archaeal community structure, respectively, whereas inorganic nitrogen and inorganic phosphate were associated with eukaryotic variation. The relative contribution of environmental parameters measured during the bloom to variability among samples was 35.3%. Interaction analysis showed that Maxillopoda, Spirotrichea, Dinoflagellata, and Halobacteria were keystone taxa within the positive-correlation network, while Halobacteria, Dictyochophyceae, Mamiellophyceae, and Gammaproteobacteria were the main contributors to the negative-correlation network. The positive and negative relationships were the primary drivers of mutualist and competitive interactions that impacted algal bloom fate, respectively. Functional predictions showed that blooms enhance microbial carbohydrate and energy metabolism, and alter the sulfur cycle. Our results suggest that microbial community structure is strongly linked to bloom progression, although specific drivers of community interactions and responses are not well understood. The importance of considering biotic interactions (e.g., competition, symbiosis, and predation) when investigating the link between microbial ecological behavior and an algal bloom's trajectory is also highlighted.


Neuroanatomical profiles of treatment-resistance in patients with schizophrenia spectrum disorders.
Widespread structrual abnormalities in subcortical brain regions have been identified in patients with schizophrenia. However, only a few studies have examined the neuroanatomical profiles of patients with treatment-resistant schizophrenia. The aim of this study was to compare differences in subcortical and hippocampal volumes between: (i) treatment-resistant patients who are non-responders to both first-line antipsychotics and clozapine (URS), (ii) treatment-resistant patients who are non-responders to first-line antipsychotics but are responders to clozapine (CLZ-Resp), (iii) responders to first-line antipsychotics (FL-Resp), and (iv) healthy controls. T1-weighted images of 103 participants (27 URS, 29 CLZ-Resp, 21 FL-Resp, and 26 healthy controls) were obtained. Group differences in striatal, thalamic, globus pallidus, amygdala, and hippocampus volumes were examined. Multiple regression analyses were performed to examine the associations between subcortical and hippocampal volumes and participant characteristics. The FL-Resp group showed larger striatal and globus pallidus volumes compared to the URS group and larger post-commissural putamen and globus pallidus volumes compared to healthy controls. The URS group showed smaller thalamic volume compared to healthy controls. There were no subcortical or hippocampal volume differences between the URS and CLZ-Resp groups. Differences in subcortical and hippocampal structural volumes were not related to symptom severity or chlorpromazine antipsychotic dose equivalents. Our findings suggest different structural volume alterations in subcortical brain regions between treatment-resistant schizophrenia and responders to first-line antipsychotics. Whether subcortical structure compromise is a distinct pathophysiological marker of treatment-resistant schizophrenia, or a result of antipsychotic exposure, remains to be explored.


A continuous wave technique for the measurement of the elastic properties of cortical bone.
A continuous wave technique is described for measuring the nine independent orthotropic elastic coefficients from a single cubic specimen. The side dimensions of this cubic specimen are on the order of 5 mm. Because of the small size of the specimen, the spatial resolution of material inhomogeneity using this technique is quite good. Although it is possible to apply this technique to any elastic material such as woods or metals, the elastic properties of human and canine cortical femora are presented here. The orthotropic elastic coefficients and the variation of these coefficients are presented as a function of anatomical position.


Seasonal and spatial variability in Lake Michigan sediment small-subunit rRNA concentrations.
We have used molecular biological methods to study the distribution of microbial small-subunit rRNAs (SSU rRNAs), in relation to chemical profiles, in offshore Lake Michigan sediments. The sampling site is at a depth of 100 m, with temperatures of 2 to 4 degrees C year-round. RNA extracted from sediment was probed with radiolabeled oligonucleotides targeting bacterial, archaeal, and eukaryotic SSU rRNAs, as well as with a universal probe. The coverage of these probes in relation to the present sequence database is discussed. Because ribosome production is growth rate regulated, rRNA concentrations are an indicator of the microbial populations active in situ. Over a 1-year period, changes in sedimentary SSU rRNA concentrations followed seasonal changes in surface water temperature and SSU rRNA concentration. Sedimentary depth profiles of oxygen, reduced manganese and iron, and sulfate changed relatively little from season to season, but the nitrate concentration was approximately fivefold higher in April and June 1997 than at the other times sampling was done. We propose that sediment microbial SSU rRNA concentrations at our sampling site are influenced by seasonal inputs from the water column, particularly the settling of the spring diatom bloom, and that the timing of this input may be modulated by grazers, such that ammonia becomes available to sediment microbes sooner than fresh organic carbon. Nitrate production from ammonia by autotrophic nitrifying bacteria, combined with low activity of heterotrophic denitrifying bacteria in the absence of readily degradable organic carbon, could account for the cooccurrence of high nitrate and low SSU rRNA concentrations.


Anastomotic Sinus That Developed From Leakage After a Rectal Cancer Resection: Should We Wait for Closure of the Stoma Until the Complete Resolution of the Sinus?
The aims of this study were to identify the clinical characteristics of an anastomotic sinus and to assess the validity of delaying stoma closure in patients until the complete resolution of an anastomotic sinus. The subject patients are those who had undergone a resection of rectal cancer from 2011 to 2017, who had a diversion ileostomy protectively or therapeutically and who developed a sinus as a sequelae of anastomotic leakage. The primary outcomes that were measured were the incidence, management and outcomes of an anastomotic sinus. Of the 876 patients who had undergone a low anterior resection, 14 (1.6%) were found to have had an anastomotic sinus on sigmoidoscopy or a gastrografin enema before their ileostomy closure. In the 14 patients with a sinus, 7 underwent ileostomy closure as scheduled, with a mean closure time of 4.1 months. The remaining 7 patients underwent ileostomy repair, but it was delayed until after the follow-up for the widening of the sinus opening by using digital dilation, with a mean closure time of 6.9 months. Four of those remaining seven patients underwent stoma closure even though their sinus condition had not yet been completely resolved. No pelvic septic complications occurred after closure in any of the 14 patients with an anastomotic sinus, but 2 of the 14 needed a rediversion due to a severe anastomotic stricture. Patients with an anastomotic sinus who had been carefully selected underwent successful ileostomy closure without delay.


Directed Functional Connectivity in Fronto-Centroparietal Circuit Correlates With Motor Adaptation in Gait Training.
Lower-extremity robotic exoskeletons are used in gait rehabilitation to achieve functional motor recovery. To date, little is known about how gait training and post-training are characterized in brain signals and their causal connectivity. In this work, we used time-domain partial Granger causality (PGC) analysis to elucidate the directed functional connectivity of electroencephalogram (EEG) signals of healthy adults in robot-assisted gait training (RAGT). Our results confirm the presence of EEG rhythms and corticomuscular relationships during standing and walking using spectral and coherence analyses. The PGC analysis revealed enhanced connectivity close to sensorimotor areas ( C3 and CP3 ) during standing, whereas additional connectivities involve the centroparietal ( CP z) and frontal ( F z ) areas during walking with respect to standing. In addition, significant fronto-centroparietal causal effects were found during both training and post-training. Strong correlations were also found between kinematic errors and fronto-centroparietal connectivity during training and post-training. This study suggests fronto-centroparietal connectivity as a potential neuromarker for motor learning and adaptation in RAGT.


Alignment-free clustering of transcription factor binding motifs using a genetic-k-medoids approach.
Familial binding profiles (FBPs) represent the average binding specificity for a group of structurally related DNA-binding proteins. The construction of such profiles allows the classification of novel motifs based on similarity to known families, can help to reduce redundancy in motif databases and de novo prediction algorithms, and can provide valuable insights into the evolution of binding sites. Many current approaches to automated motif clustering rely on progressive tree-based techniques, and can suffer from so-called frozen sub-alignments, where motifs which are clustered early on in the process remain 'locked' in place despite the potential for better placement at a later stage. In order to avoid this scenario, we have developed a genetic-k-medoids approach which allows motifs to move freely between clusters at any point in the clustering process. We demonstrate the performance of our algorithm, GMACS, on multiple benchmark motif datasets, comparing results obtained with current leading approaches. The first dataset includes 355 position weight matrices from the TRANSFAC database and indicates that the k-mer frequency vector approach used in GMACS outperforms other motif comparison techniques. We then cluster a set of 79 motifs from the JASPAR database previously used in several motif clustering studies and demonstrate that GMACS can produce a higher number of structurally homogeneous clusters than other methods without the need for a large number of singletons. Finally, we show the robustness of our algorithm to noise on multiple synthetic datasets consisting of known motifs convolved with varying degrees of noise. Our proposed algorithm is generally applicable to any DNA or protein motifs, can produce highly stable and biologically meaningful clusters, and, by avoiding the problem of frozen sub-alignments, can provide improved results when compared with existing techniques on benchmark datasets.


Liquid phase exfoliation and crumpling of inorganic nanosheets.
Here we demonstrate through experiment and simulation the polymer-assisted dispersion of inorganic 2D layered nanomaterials such as boron nitride nanosheets (BNNSs), molybdenum disulfide nanosheets (MoS2), and tungsten disulfide nanosheets (WS2), and we show that spray drying can be used to alter such nanosheets into a crumpled morphology. Our data indicate that polyvinylpyrrolidone (PVP) can act as a dispersant for the inorganic 2D layered nanomaterials in water and a range of organic solvents; the effectiveness of our dispersion process was characterized by UV-vis spectroscopy, microscopy and dynamic light scattering. Molecular dynamics simulations confirm that PVP readily physisorbs to BNNS surfaces. Collectively, these results indicate that PVP acts as a general dispersant for nanosheets. Finally, a rapid spray drying technique was utilized to convert these 2D dispersed nanosheets into 3D crumpled nanosheets; this is the first report of 3D crumpled inorganic nanosheets of any kind. Electron microscopy images confirm that the crumpled nanosheets (1-2 μm in diameter) show a distinctive morphology with dimples on the surface as opposed to a wrinkled, compressed surface, which matches earlier simulation results. These results demonstrate the possibility of scalable production of inorganic nanosheets with tailored morphology.


GPR55 - a putative "type 3" cannabinoid receptor in inflammation.
G protein-coupled receptor 55 (GPR55) shares numerous cannabinoid ligands with CB1 and CB2 receptors despite low homology with those classical cannabinoid receptors. The pharmacology of GPR55 is not yet fully elucidated; however, GPR55 utilizes a different signaling system and downstream cascade associated with the receptor. Therefore, GPR55 has emerged as a putative "type 3" cannabinoid receptor, establishing a novel class of cannabinoid receptor. Furthermore, the recent evidence of GPR55-CB1 and GPR55-CB2 heteromerization along with its broad distribution from central nervous system to peripheries suggests the importance of GPR55 in various cellular processes and pathologies and as a potential therapeutic target in inflammation.