Release of dopamine in both caudate nuclei and both substantia nigrae in response to unilateral stimulation of cerebellar nuclei in the cat.
The effects of unilateral focal electrical stimulation of the deep cerebellar nuclei on the activity of the nigrostriatal dopaminergic neurons on both sides of the brain were examined in halothane anaesthetized cats. For this purpose, push-pull cannulae were inserted into both caudate nuclei and both substantia nigrae, and the release of [3H] dopamine ([3H]DA) continuously formed from [3,5-3H]L-tyrosine was estimated in superfusates. The unilateral electrical stimulation of the right cerebellar dentate nucleus induced a long-lasting increase in the release of [3H]DA in the left caudate nucleus and a simultaneous decrease in the release of [3H]transmitter in the right caudate nucleus. These changes were associated with opposite fluctuations in the release of [3H]DA from the corresponding substantia nigrae. Thus, the electrical stimulation of the right dentate nucleus induced a pronounced decrease in the release of the [3H]-amine in the [3H]transmitter in the corresponding substantia nigra, whereas the activity of the contralateral substantia nigra, whereas the release in the ipsilateral substantia nigra was simultaneously increased. In contrast, the unilateral electrical stimulation of the right cerebellar fastigial nucleus resulted only in an increased release of [3H]DA in the ipsilateral (right) caudate nucleus, associated with a decreased release of the [3H]transmitter in the corresponding substantia nigra, whereas the activity of the contralateral (left) dopaminergic system was not significantly affected. These results support a direct functional interaction between the cerebellum and the basal ganglia. They also suggest that the release of DA from dopaminergic axonal terminals is inversely correlated to the extent of the transmitter release from dendrites.


Lethal cardiomyopathy in epidermolysis bullosa associated with amitriptyline.
There are previous reports of dilated cardiomyopathy (DCM) in recessive dystrophic epidermolysis bullosa (RDEB), a debilitating blistering skin disorder. The pathogenesis of DCM in RDEB remains uncertain, although dietary deficiency of selenium and carnitine have been implicated. A 6 year old girl with RDEB who died of DCM is reported; attention is drawn to the possible role of two potentially cardiotoxic drugs, amitriptyline and cisapride.


Responses of motor cortex neurons to visual stimulation in the alert monkey.
Evidence for visually evoked activity in single neurons of area 4 is presented. These neurons modulated their activity in relation to stimuli moving across the visual field of the monkey, without showing habituation. Some of them even had direction sensitivity. Their activity was independent of eye movements and unrelated to muscle contractions. The visually activated neurons were distributed throughout the depth of motor cortex.


Comparison of Gd-Bz-TTDA, Gd-EOB-DTPA, and Gd-BOPTA for dynamic MR imaging of the liver in rat models.
To evaluate the competitive potential of a new lipophilic paramagnetic complex, Gd-Bz-TTDA [4-benzyl-3,6,10-tri (carboxymethyl)-3,6,10-triazado-decanedioic acid] compared with two other commercially available MR hepatobiliary contrast agents, gadobenate dimeglumine (Gd-BOPTA) and gadoxetic acid (Gd-EOB-DTPA), dynamic MR imaging studies were performed on normal and hepatocellular carcinoma (HCC) rat models using a 1.5-Tesla MR scanner. The results indicate that normal rats that were injected with 0.1 mmol/kg Gd-Bz-TTDA showed significantly more intense and persistent liver enhancement than those that were injected with the same dose of Gd-EOB-DTPA or Gd-BOPTA. All of these agents showed similar enhancement patterns in the implanted HCC. The liver-lesion contrast-to-noise ratios were higher and more persistent in rats that were injected with Gd-Bz-TTDA. These results indicate that Gd-Bz-TTDA is comparable with the commercially available hepatobiliary agents, Gd-EOB-DTPA and Gd-BOPTA, and can result in more intense and prolonged liver enhancement while still providing better liver-lesion discrimination. These results warrant further large-scale studies.


An insight into the interaction between malachite green oxalate with human serum albumin: Molecular dynamic simulation and spectroscopic approaches.
Cationic triarylmethane dyes such as malachite green are aromatic xenobiotic compounds causing environmental pollution. The affinity between hazardous materials and biomolecules makes it important to understand the properties of such compounds. Accordingly, in this study, the possible molecular interaction between this pollutant and the human serum albumin (HSA) was investigated using a combination of molecular docking, molecular dynamic simulation and multi-spectroscopic approaches. The docking results illustrated that malachite green oxalate (MGO) could bind to some of the HSA amino acids with the estimated free energy = -32.93 kJ/mol. Further, the results of the dynamic simulation revealed that MGO had a steady interaction with the protein though increasing flexibility and decreasing the HSA compactness. These results were, therefore, in agreement with those obtained by spectroscopic techniques. The MGO concentration of 0.0005 mM could quench the HSA's intrinsic fluorescence by %16.88. The protein structural changes also revealed that the binding interaction of MGO-HSA was accompanied by an increase in the α-helix and a decrease in the β-sheet of the protein. Overall, this study indicated the suitable molecular modeling interaction of MGO and HSA.


Gaucher disease.
Gaucher disease is a glycolipid storage disorder characterized by accumulation of glucocerebroside in the liver, spleen, and bones, and caused by a deficiency of glucocerebrosidase. Glucocerebrosidase cDNA has been cloned and sequenced, and much has been learned about the synthesis and processing of this enzyme. Inherited as an autosomal recessive disorder, Gaucher Disease is relatively common among Ashkenazi Jews. In its most common form, designated Type 1 or adult type of Gaucher disease, the central nervous system is spared. Several organ systems may be involved, including not only the hematopoietic tissues and bones, but also the lungs. Diagnosis can be achieved without marrow examination by estimating the glucocerebrosidase (beta-glucosidase) activity of the peripheral blood leukocytes. Currently available conventional therapy is purely symptomatic in nature, including orthopedic procedures and splenectomy. On an experimental basis, splenectomy may be partial instead of total. Because the disease is due to an abnormality of the monocyte-macrophage system, cells that arise from the hematopoietic stem cell, and because the central nervous system is spared it has been considered a very suitable candidate for experimental therapeutic intervention. Bone marrow transplantation has been attended with limited success, enzyme therapy has not yet been successful, and studies utilizing gene transfer are underway.


Pharmacogenomics, lipid disorders, and treatment options.
Statins form the backbone of lipid-lowering therapy in the prevention of cardiovascular disease. Numerous studies have evaluated the effect of genomics on the clinical efficacy and adverse effects of statins. Several gene variants that can be linked to either the pharmacokinetics or pharmacodynamics of statins have been identified as potentially important, although there are some discrepant findings among studies. Effect sizes are modest for lipid-lowering efficacy and perhaps somewhat larger for risk of myopathy, although results are inconsistent. Pharmacogenomics of nonstatin lipid-lowering agents have not been evaluated to the same extent, given their relatively limited use, although there are some promising candidate genes for further study. Finally, with several new classes of lipid-lowering therapies soon becoming available, there may be a potential application for pharmacogenomics to identify patients ideally suited to receive-or those who should avoid-specific medications.


Early warning signals for critical transitions in cardiopulmonary health, related to air pollution in an urban Chinese population.
Respiratory, and cardio-cerebrovascular health-related diseases significantly threaten human health and together with air pollution form a complex pathophysiological system. Other complex biological systems show that increased variance and autocorrelations in time series may act as valid early warning signals for critical transitions. On population level, we determined the likelihood that increased variance and autocorrelation of hospital visit on cardiopulmonary disease preceded critical transitions in population health by human-pollution interactions. We investigated long-term hospital visits from a hospital in Nanjing City, China during 2006-2016 for the most important cardiopulmonary diseases likely to be influenced by air pollution: cerebrovascular accident disease (CVAD), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), lung cancer disease (LCD), and the grouped categories of respiratory system disease (RESD) and cardio-cerebrovascular system disease (CCD). The time series of standard deviations (SDs) and autocorrelation at-lag-1 (AR-1) were studied as potential Early-Warning Indicators (EWIs) of transitions in population health. Elevated SDs provided an early warning for critical transitions in visit for LCD and overall CCD and CVAD, for the period of 2012-2013, after which a real transition of increased visit occurred for these disease categories. Statistical testing showed that these SDs were significantly increased (p < 0.1). The long-term air pollution together with intermittent pollution episodes may have triggered critical transitions in population health for cardiopulmonary disease. It is recommended to consider significant increases in variability in time series of relevant system parameters, such as visit, as early warning signs for future transitions in populations' health states.


Ultrasensitive pathogen detection with a rolling circle amplification-empowered multiplex electrochemical DNA sensor.
We report a highly sensitive and selective multiplex assay by empowering an electrochemical DNA sensor with isothermal rolling circle amplification. The assay could simultaneously detect and discriminate three common entero-pathogens in a single reaction, with femtomolar sensitivity. It is useful for field- or resource-limited settings.


U.S. alcohol affordability and real tax rates, 1950-2011.
The affordability of alcoholic beverages, determined by the relationship of prices to incomes, may be an important factor in relation to heavy drinking, but little is known about how affordability has changed over time. To calculate real prices and affordability measures for alcoholic beverages in the U.S. over the period from 1950 to 2011. Affordability is calculated as the percentage of mean disposable income required to purchase 1 drink per day of the cheapest spirits, as well as popular brands of spirits, beer, and wine. Alternative income and price measures also are considered. Analyses were conducted in 2012. One drink per day of the cheapest brand of spirits required 0.29% of U.S. mean per capita disposable income in 2011 as compared to 1.02% in 1980, 2.24% in 1970, 3.61% in 1960, and 4.46% in 1950. One drink per day of a popular beer required 0.96% of income in 2010 compared to 4.87% in 1950, whereas a low-priced wine in 2011 required 0.36% of income compared to 1.05% in 1978. Reduced real federal and state tax rates were an important source of the declines in real prices. Alcoholic beverages sold for off-premises consumption are more affordable today than at any time in the past 60 years; dramatic increases in affordability occurred particularly in the 1960s and 1970s. Declines in real prices are a major component of this change. Increases in alcoholic beverage tax rates and/or implementing minimum prices, together with indexing these to inflation could be used to mitigate further declines in real prices.


Study of the gastrointestinal parasitic fauna of captive non-human primates (Macaca fascicularis).
The aim of this study was to examine helminths and protozoans in cynomolgus macaques (Macaca fascicularis) imported from registered breeding facilities in China and their relation to health risks for non-human primate handlers in biomedical research centers and in breeding facilities. Fresh fecal samples were collected from a total of 443 M. fascicularis and analyzed by copromicroscopical analysis, immunoenzymatic, or molecular assays. As to helminths, whose eggs were shed in 2.03% of the samples, Trichuris and Oesophagostomum were the only two taxa found, with low prevalence and low eggs per gram (EPG) values. Protozoans were more frequently detected (87.40%), with Entamoeba coli (85.19%) and Endolimax nana (79.26%) as the most prevalent species shed. Other parasites found by fecal smear examination were uninucleated-cyst-producing Entamoebas (78.52%), Iodamoeba bütschlii (42.96%), and Chilomastix mesnili (24.44%), while cysts of Balantidium coli (22.2%) were only observed by sedimentation. No coproantigens of Giardia duodenalis, Cryptosporidium spp., and Entamoeba histolytica complex were detected. Blastocystis sp. infection was noticed in 87.63% of macaques by PCR. These cynomolgus monkeys were infected with many subtypes (ST1, ST2, ST3, ST5, and ST7), where the predominant Blastocystis sp. subtypes were ST2 (77.5%), followed by ST1 (63.5%). Data collected confirmed the presence of potentially zoonotic parasites and a high parasite diversity, suggesting the need for appropriate and sensitive techniques to adequately control them and related health risks for handlers of non-human primates in biomedical research centers and in breeding facilities.


The incomplete denaturation of DNA in N,N-dimethyl formamide.
In this paper we show that the extent of DNA denaturation achieved by dialysis against N,N-dimethyl formamide depends on both the source of DNA and the buffer used. The stability against denaturation increases with the guanine plus cytosine content. The base sequence also plays a minor role. This behavior is due to differences in the solubility of DNA in the denaturing solvent. The DNAs with a high guanine-cytosine content have a lower solubility in dimethyl formamide and this fact results in a higher stability against denaturation. As a practical consequence, in order to achieve complete denaturation of DNA by dialysis against dimethyl formamide, it is necessary to start with DNA dissolved in a buffer of low ionic strength, preferably below 10(-3) M.


Drinking water treatment residual as a ballast to sink Microcystis cyanobacteria and inactivate phosphorus in tropical lake water.
The combination of a low dose of coagulant with a ballast that can inactive phosphorus (P) in lake sediment-a technique known as "flock and lock"-is one method for restoration of eutrophic lakes. The effectiveness of a drinking water treatment residual (DWTR) as a ballast in flock and lock was assessed using assays of eutrophic lake water from Thailand dominated by Microcystis aeruginosa cyanobacteria colonies by measuring changes in chlorophyll-a, pH, and zeta potential. P sorption isotherms were developed from long-term batch equilibrium experiments; desorption of nutrients and metals was assessed via leaching experiments; and morphological changes to cellular structure were assessed using scanning electron microscopy. Results showed that combining DWTR with a low dose of aluminum sulfate (0.6-4.0 mg Al/L) effectively sank 74-96% of Microcystis, with DWTR dose (50-400 mg/L), initial chlorophyll-a concentration (92-976 µg/L), pH (7.4-9.3), and alkalinity (99-108 ppm CaCO3) identified as factors significantly associated with sinking efficacy. P sorption capacity of the DWTR (7.12 mg/g) was significantly higher than a local soil (0.33 mg/g), enabling the DWTR to inactivate P in lake sediment. Desorption of Al, Fe, Ca and N from the DWTR was estimated to contribute to a marginal increase in concentrations of those compounds in the water column of a small shallow lake (1.2, 0.66, 53.4, and 0.07 µg/L, respectively) following a simulated application. Therefore, pre-treated DWTRs may be a viable alternative ballast in the flock and lock approach to lake restoration, supplementing or replacing modified local soils or lanthanum modified clays.


Oligonucleotide-modulated photocurrent enhancement of a tetracationic porphyrin for label-free homogeneous photoelectrochemical biosensing.
This work reports the first demonstration of an oligonucleotide-modulated label-free homogeneous photoelectrochemical (PEC) biosensing platform based on the adsorption of tetracationic porphyrin (denoted as TMPyP here) onto 1-naphthalenesulfonate anion (NS-)-grafted indium tin oxide electrode (denoted as TMPyP-NS--ITO), which generates a stable and rapid photocurrent response. We found that when NS--ITO electrode was subjected to single-stranded oligonucleotide (ssON) before TMPyP adsorption, a remarkable enhancement of photocurrent intensity was observed from the resulted TMPyP-ssON-NS--ITO electrode with high specificity towards oligonucleotide. A series of investigations were carried out to understand the mechanism of this oligonucleotide-modulated photocurrent enhancement phenomenon. Moreover, the studies of this robust photocurrent enhancement mechanism was successfully extended to develop a signal-on homogeneous PEC biosensing platform for, as a proof-of-concept, label-free M.SssI methyltransferase activity analysis through a judiciously and compatibly engineered signal transduction strategy consisted of hairpin-shaped oligonucleotide probe, restriction endonuclease HpaII, and Exonuclease I. The rationally designed homogeneous PEC biosensor exhibit sensitive PEC response toward M.SssI methyltransferase with a low detection limit of 3.5 mU/mL and a wide linear range from 0.01 to 120 U/mL. Additionally, we show that our homogeneous PEC biosensing platform can be also utilized to screen methyltransferase inhibitors. Therefore, this work will provide a distinctive paradigm for versatile homogeneous PEC biosensing platform that can be used as potential powerful tool toward innovative label-free bioanalytical purposes.


Race-related differences in peripheral blood and in bone marrow cell populations of American black and American white infants.
The present study confirms that in healthy infants, a racial difference exists in peripheral blood hemoglobin levels, total leukocyte, and total neutrophil counts. Racial differences in the composition of the bone marrow are negligible. The only demonstrable difference is confined to the erythroid cell population. No significant difference exists in the incidence of myeloid cells or small lymphocytes.


Induction of tryptophan oxygenase by dexamethasone in isolated hepatocytes. Dependence on composition of medium and pH.
Hepatocytes were isolated from perfused rat livers. 4 x 10-6 cells/ml were incubated at at 37 degrees C in different media in the absence and presence of a steroid hormone, dexamethasone phosphate (2 x 10-5 M). 1. Hormonal enzyme induction occurred in cells suspended in a simple salt medium, devoid of amino acids and macromolecules. This induction was completely blocked by addition of either actinomycin D (2 mu-g/ml) or cycloheximide (50 mu-g/ml). 2. Incubation of cells in media containing defatted albumin did not enhance hormonal enzyme induction, although disintegration of cells during incubation was reduced. Addition of a crude albumin fraction reduced tryptophan oxygenase induction and dextran completely blocked enzyme induction by dexamethasone. 3. An increase of dexamethasone concentration in the presence of albumin to 9 x 10-5 M was unable to raise enzyme induction further, and a still higher concentration of hormone, 3 x 10-4 M, resulted in reduced enzyme induction. 4. The hormonal induction of tryptophan oxygenase was most pronounced when the pH of the medium was between 7.0 and 7.6, with an optium at 7.3. No induction was found when the pH of the medium was either 6.6 or 7.8. The basal tryptophan oxygenase activity was much less influenced by similar pH variations. It is concluded that hepatocytes in suspension are able to carry out hormone-stimulated enzyme synthesis and that factors influencing this process may be studied under controlled conditions in such systems.


Laboratory and clinical effects of the infusion of ACD solution during plateletpheresis.
Transfusion of massive amounts of citrate anticoagulated blood during plateletpheresis with the intermittent flow centrifuge can produce symptoms and electrocardiographic changes suggestive of hypocalcemia. Following 15 procedures the ionized calcium decreased by an average of 32.4%, the average postpheresis serum citrate was 26.7 mg/dl and the QT interval was prolonged by 0.08 sec. Twelve plateletphereses performed with half-strength ACD solution caused an average decrease in ionized calcium of 16%, serum citrate levels of 12.5 mg/dl and QT prolongation of 0.04 sec. No donors experienced significant clinical symptoms with citrate infusion rates of less than 65 mg/kg/h. Solutions with citrate concentrations lower than ACD-A should be developed for use in plateletpheresis procedures involving citrate infusion rates greater than this.


Bilateral condylar atrophy after combined osteotomy for correction of mandibular retrusion. A case report.
Bilateral atrophy of the mandibular condyles after maxillo-mandibular surgery for correction of a Class II open-bite is reported. Although a definite cause could not be ascertained, it is postulated that a biomechanical phenomenon based on increased muscle tension was the most likely causative mechanism.


Plant growth regulation of Bt-cotton through Bacillus species.
Deccan plateau in India periodically experiences droughts due to irregular rain fall and the soil in many parts of the region is considered to be poor for farming. Plant growth promoting rhizobacteria are originally defined as root-colonizing bacteria, i.e., Bacillus that cause either plant growth promotion or biological control of plant diseases. The study aims at the isolation of novel Bacillus species and to assess the biotechnological potential of the novel species as a biofertilizer, with respect to their plant growth promoting properties as efficient phosphate-solubilizing bacteria. Seven different strains of Bacillus were isolated from cotton rhizosphere soil near boys' hostel of Palamuru University which belongs to Deccan plateau. Among seven isolated strains, Bacillus strain-7 has shown maximum support for good growth of eight cotton cultivars. This bacterial species is named Bacillus sp. PU-7 based on the phenotypic and phylogenetic analysis. Among eight cotton cultivars, Mahyco has shown high levels of IAA, proteins, chlorophyll, sugars and low level of proline. Efficacy of novel Bacillus sp. PU-7 with Mahyco cultivar has been checked experimentally at field level in four different cotton grown agricultural soils. The strains supported plant growth in almost all the cases, especially in the deep black soil, with a clear evidence of maximum plant growth by increased levels of phytohormone production and biochemical analysis, followed by shallow black soil. Hence, it is inferred that the novel isolate can be used as bioinoculant in the cotton fields.


Bone mineral content of women receiving tamoxifen for mastalgia.
Dual photon absorptiometry (DPA) has been used to measure the effect of short and medium-term administration of tamoxifen on bone density in the axial skeleton of women with mastalgia. This provided a unique opportunity to monitor the effect of this 'anti-oestrogenic' agent in predominantly premenopausal women, not suffering from malignancy. In addition, plasma levels of calcium, phosphate, alkaline phosphatase and serum levels of oesteocalcin (GLA) have been assayed, both before and after 3 months of starting either tamoxifen or placebo treatment. No significant alterations in bone density were seen. Osteocalcin, alkaline phosphatase and electrolytes were unchanged and there was no dose response observed in women receiving either 10 mg or 20 mg of tamoxifen. Although possessing anti-oestrogenic properties, tamoxifen is also a partial agonist. Administration for the short periods does not measurably influence spinal or femoral bone density and thus the agent can probably be given safely for the short-term treatment of mastalgia.


Two new species of ground crickets (Orthoptera: Trigonidiidae; Nemobiinae) from China.
Here we describe two new species of ground crickets from Yunnan Province, China (Homonemobius brevipennis sp. nov. and Pteronemobius osuviridis sp. nov.). Descriptions, illustrations, and distributions of these new species are provided.


Early treatment responses to peginterferon beta-1a are associated with longer-term clinical outcomes in patients with relapsing-remitting multiple sclerosis: Subgroup analyses of ADVANCE and ATTAIN.
Early intervention with well-tolerated disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is recommended in order to delay disease progression, reduce neurologic damage, preserve brain volume, and optimize long-term patient outcomes. Lack of conversion of new/newly enlarging T2 (NET2) or gadolinium-enhancing (Gd+) lesions to chronic hypointensities (black hole conversion) and achievement of no evidence of disease activity (NEDA) early in the course of treatment are considered potential indicators of treatment effect and predictors of longer-term clinical outcomes. Patients with RRMS who were treated with peginterferon beta-1a in the 2-year ADVANCE phase 3 clinical trial (NCT0090639) and its 2-year open-label extension study, ATTAIN (NCT01332019), were grouped as newly diagnosed (diagnosed ≤1 year prior to enrollment and DMT naive) or non-newly diagnosed. For analyses of the impact of early treatment and disease activity control, the newly diagnosed and non-newly diagnosed subgroups were further divided based on whether they initiated peginterferon beta-1a every 2 weeks (Q2W) starting in study year 1 (continuously treated) or peginterferon beta-1a Q2W or every 4 weeks in study year 2 (delayed treatment). Patient subgroups were evaluated for conversion of NET2 or Gd+ lesions to persistent black holes (PBHs), brain atrophy (percentage change in whole brain volume [WBV]), achievement of NEDA composite outcomes, and the association of these disease activity measures with longer-term clinical outcomes (annualized relapse rate [ARR] and confirmed disability worsening [CDW]). At 2 years, significantly fewer PBHs developed from NET2 lesions or Gd+ lesions in newly diagnosed and non-newly diagnosed patients continuously treated with peginterferon beta-1a than in the corresponding delayed-treatment groups (all p<0.0001). Percentage decrease in WBV from 6 months (rebaselined) to 2 years was significantly lower for newly diagnosed and non-newly diagnosed patients who received continuous peginterferon beta-1a treatment than for patients who received delayed treatment (both p ≤ 0.0442). In study year 1, a higher proportion of newly diagnosed and non-newly diagnosed patients treated with peginterferon beta-1a than those treated with placebo achieved NEDA (newly diagnosed: 28.3% vs 13.5% [p = 0.0010]; non-newly diagnosed: 40.8% vs 15.8% [p<0.0001]). NEDA rates remained stable over study years 2-4 for the newly diagnosed (range: 50.0%-53.9%) and non-newly diagnosed (range: 54.4%-57.0%) subgroups. Patients without PBH conversion had significantly lower ARR at 2 years (newly diagnosed: p = 0.0109; non-newly diagnosed: p = 0.0044) and a lower proportion of patients with 12-week CDW at 2 years (newly diagnosed: p = 0.2787; non-newly diagnosed: p = 0.0045) than the corresponding patient subgroups with PBH conversion. Patients who achieved NEDA in ADVANCE (study years 1-2) had a significantly lower ARR in ATTAIN (study years 3-4) than patients who did not achieve NEDA (newly diagnosed, p = 0.0003; non-newly diagnosed, p = 0.0001). Over 4 years, safety outcomes did not differ for the newly diagnosed and non-newly diagnosed patient subgroups. These results indicate that newly diagnosed and non-newly diagnosed patients treated continuously with peginterferon beta-1a Q2W experienced better disease control over time than those who received delayed treatment. Patients with NEDA or evidence of less radiological disease activity in the first 2 years of treatment had better longer-term clinical outcomes than those with evidence of greater disease activity.


Alcohol and the methylome: design and analysis considerations for research using human samples.
A growing number of studies in human samples have sought to determine whether chronic alcohol use and alcohol use disorders (AUDs) may be associated with epigenetic factors, such as DNA methylation. We review the extant literature in light of some of the challenges that currently affect the design and interpretation of epigenetic research in human samples. A literature search was used to identify studies that have examined DNA methylation in relation to alcohol use or AUDs in human samples (through July 2013). A total of 22 studies were identified. Associations with quantitative or diagnostic phenotypes of alcohol use or AUDs have been reported for several genes. However, all studies to date have relied on relatively small samples and cross-sectional study designs. Additionally, attempts to replicate results have been rare. More generally, research progress is hampered by several issues, including limitations of the technologies used to assess DNA methylation, tissue- and cell-specificity of methylation patterns, the difficulties of relating observed methylation differences at a given locus to a functional effect, and limited knowledge about the molecular mechanisms underlying the effects of alcohol on DNA methylation. Although we share the optimism that epigenetics may lead to new insights into the etiology and pathophysiology of AUDs, the methodological and scientific challenges associated with conducting methylomic research in human samples need to be carefully considered when designing and evaluating such studies.


Comparative efficacy of Zataria multiflora Boiss., Origanum compactum and Eugenia caryophyllus essential oils against E. coli O157:H7, feline calicivirus and endogenous microbiota in commercial baby-leaf salads.
Ready-to-eat salads using baby-leaf and multi-leaf mixes are one of the most promising developments in the fresh-cut food industry. There is great interest in developing novel decontamination treatments, which are both safe for consumers and more efficient against foodborne pathogens. In this study, emulsions of essential oils (EOs) from Origanum compactum (oregano), Eugenia caryophyllus (clove), and Zataria multiflora Boiss (zataria) were applied by spray (0.8 ml) after the sanitizing washing step. The aim was to investigate their ability to control the growth of potentially cross-contaminating pathogens and endogenous microbiota in commercial baby leaves, processed in a fresh-cut produce company. Zataria EO emulsions of 3%, 5% and 10% reduced Escherichia coli O157:H7 by 1.7, 2.2 and 3.5 log cfu/g in baby-leaf salads after 5 days of storage at 7°C. By contrast, reductions in E. coli O157:H7 counts remained the same when clove was applied at concentrations of 5% and 10% (2.5 log cfu/g reduction). Oregano (10%) reduced inoculated E. coli O157:H7 counts in baby-leaf salads by a maximum of 0.5 log cfu/g after 5 days of storage. Zataria showed strong antimicrobial efficacy against E. coli O157:H7 and also against the endogenous microbiota of baby-leaf salads stored for 9 days. Feline calicivirus (FCV), a norovirus surrogate, survived on inoculated baby-leaf salads during refrigerated storage (9 days at 7°C) regardless of treatment. Refrigeration temperatures completely annulled the effectiveness of the EOs against FCV inoculated in baby-leaf salads as occurred in FCV cultures. This study shows that EOs, and zataria in particular, have great potential use as an additional barrier to reduce contamination-related risks in baby-leaf salads. However, further research should be done into foodborne viruses in order to improve food safety.


There is no association between vitamin D status and characteristics of central precocious puberty in girls.
Vitamin D deficiency has been associated with several pathologies in humans and has recently been linked to idiopathic central precocious puberty in girls. We evaluated this potential link in a retrospective study. Among 493 girls with idiopathic central precocious puberty previously described, we selected 145 girls for whom a plasma sample at the initial evaluation was available to determine the concentration of 25OHD and 1,25(OH)2D. We analyzed the correlation between different puberty characteristics (BMI, growth rate the year before the onset of puberty, bone age, LH and FSH peaks, LH/FSH peak ratio, and estradiol concentration) and the concentration of 25OHD and 1,25(OH)2D. The mean 25OHD serum concentration was 27.6±17.3 ng/mL. Eleven percent of the patients had a severe vitamin D deficiency, 18.6% had a moderate deficiency, 39.4% had an optimal vitamin D status, and 31% had a 25OHD concentration above 30 ng/mL. Season was the only factor that appeared to influence the 25OHD concentration. No correlation was found between 25OHD serum concentration and different puberty characteristics. Overall, our patients had a satisfactory vitamin D status. We did not find any correlation between vitamin D status and the characteristics of central precocious puberty. Further studies are required to confirm this hypothesis. What is known: • Vitamin D status seems to affect gonadal hormones and fertility. • Vitamin D deficiency may contribute to earlier puberty and was associated with earlier menarche. What is new: • 25OHD of 145 girls with precocious puberty was similar to or higher than that of healthy French children or adolescents. • We did not find any correlation between vitamin D status and puberty characteristics.


Supporting living well with hearing loss: A Delphi review of self-management support.
To assess consensus amongst stakeholders in adult auditory rehabilitation on what processes might support self-management. A three-round Delphi review was conducted online. Participants responded to five questions relating to living well with a hearing loss and the clinical processes that might support living well. Responses were analysed using thematic analysis. In further rounds, statements arising from the analysis were scored using a nine-point Likert scale, independently and then in the light of the collated panel responses. Statements reaching pre-defined criteria for consensus were identified. A panel of 26 stakeholders in adult auditory rehabilitation were consulted, including people with hearing loss and researchers and professionals who design and implement process change. There was consensus on clinical skills and behaviours that might help individuals live well, including processes that inform and involve the individual with the hearing loss (e.g. providing information about hearing and collaborative goal setting, respectively). The panel identified potential emotional, cognitive, and behavioural markers for living well with a hearing loss. The results of this review provide a rationale for the development and evaluation of interventions that include collaborative clinical behaviours as part of self-management support.


Saccharomyces boulardii inhibits secretagogue-mediated adenosine 3',5'-cyclic monophosphate induction in intestinal cells.
The yeast Saccharomyces boulardii inhibits the secretion induced by cholera toxin (CT) in rat jejunum. The present study was aimed at unraveling the mechanism by which S. boulardii protects intestinal cells against CT. CT-induced adenosine 3',5'-cyclic monophosphate (cAMP) levels were measured by radioimmunoassay in intestinal epithelial cells IEC-6 or HT29-D4 cells exposed to whole yeast or to culture medium conditioned by S. boulardii (Sb-conditioned medium). Sb-conditioned medium significantly reduced CT-induced cAMP levels in IEC-6 cells. This effect was eliminated by heat treatment, trypsin hydrolysis, and trichloroacetic acid precipitation of Sb-conditioned medium. When conditioned medium was fractionated on polyacrylamide gel under nondenaturing conditions, neutralizing activity was shown to be associated with a 120-kilodalton protein. The neutralizing activity was not attributable to proteolytic activity against CT. Sb-conditioned medium reduced the amount of cAMP induced by CT as well as Escherichia coli thermolabile toxin or forskolin in HT29-D4 cells. The modulation of secretagogue-induced cAMP by Sb-conditioned medium did not occur in the presence of pertussis toxin. These results suggest that the neutralization of CT by S. boulardii is mediated by a specific yeast protein and involves a receptor that is negatively coupled to adenylate cyclase.


Oxidation of methylamine by a Paracoccus denitrificans mutant impaired in the synthesis of the bc1 complex and the aa3-type oxidase. Evidence for the existence of an alternative cytochrome c oxidase in this bacterium.
A Paracoccus denitrificans fbcC-ctaDII double mutant strain impaired in the synthesis of both the bc1 complex and the aa3-type oxidase has been constructed. This mutant strain, which is still able to grow on methylamine as sole carbon and energy source, exhibits unimpaired oxygen consumption with succinate, methylamine and endogenous substrates as electron donors. From kinetic studies of the oxidation and reduction rates of cytochromes c, it can be concluded that P. denitrificans contains a second cytochrome c oxidase, different from the aa3-type.


Impact of bone geometry on effective properties of bone scaffolds.
The characterization of bone/scaffold composite mechanical properties is essential for translation to the clinic, but in vivo studies require resources and personnel not available to many investigators. Therefore, the ability to predict composite properties could facilitate scaffold evaluation and reduce the number of in vivo studies required. To date, there have been no studies that have used experimental data to formulate a model of bone morphology or that have examined morphology as a variable in composite properties. In this study, a simple model was developed to predict the effective elastic properties of hydroxyapatite (HA) scaffold/bone composites using representative volume elements (RVE) and finite element analysis. While the RVE for the scaffold is clear, the choice of RVE for bone is not. Two bone geometries were generated for the RVE based on data from an in vivo study: a uniform coating and bridges in pores. Three scaffolds were evaluated in order to consider the effects of scaffold material modulus and porosity. Results showed that the bone geometry had little influence on composite elastic properties when compared to experimental error from the in vivo study. The implication is that such properties can be estimated by measuring the volume fraction of bone using a non-destructive method like microcomputerized tomography and the simple RVE model.


Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells.
To investigate the in vitro effect of drospirenone on human eutopic endometrial (EuSC) and ectopic endometriotic stromal cells (EcSC). Comparative and laboratory study. The experimental procedures were approved by the Institutional Review Board of the University of Tokyo (registration no. 0324-4). University research laboratory. Eight patients undergoing hysterectomy for benign gynecologic disease and 19 patients undergoing cystectomy or adnectomy for endometriosis. EuSC and EcSC were treated with drospirenone. For the analysis of decidualization of EuSC, cells were observed using microscopy, and the production of PRL was measured using enzyme immunoassay. For the analysis of DNA synthesis of EcSC, 5-bromo-2'-deoxyuridine incorporation was measured by ELISA. Cells in apoptosis were detected and measured by flow cytometry. Drospirenone induced decidualization in EuSC, and the induction was negated by RU486. Drospirenone reduced DNA synthesis on EcSC, and this reduction was negated by RU486 or P receptor silencing, but not by aldosterone or mineralocorticoid receptor silencing. Drospirenone did not cause EcSC to undergo apoptosis. Our study demonstrates the direct effects of drospirenone: decidualization of EuSC and reduced DNA synthesis of EcSC, but it does not cause EsSC apoptosis.


Spontaneous splenic rupture after a left-side thoracotomy: report of a case.
We herein describe the case of a 59-year-old man who experienced a spontaneous splenic rupture 12 h after undergoing a left-side thoracotomy for a wedge resection of an unknown pulmonary nodular tumor following a history of malignant melanoma. He demonstrated no special abdominal diseases or traumas, except an uneventful cholecystectomy 12 years previously. Preoperatively, he was not on anticoagulation, aspirin, or nonsteroidal anti-inflammatory medication, and all coagulation tests were inconspicuous. At 12 h after lung surgery the patient showed signs of progredient hypovolemic shock. After ultrasonography, which showed a moderate amount of free intra-abdominal liquid, the patient was urgently taken to the operation room. Bleeding resulted from a rupture of an encapsulated hematoma from the spleen. No signs of adhesion around the spleen or of an injury of the left diaphragm were observed. A pathological analysis of the spleen revealed a normal dimension and a normal histological structure without any evidence of a hematological or neoplastic disease. The patient was discharged on the 12th day after surgery. A review on the literature and the differential diagnosis of this unusual case is presented and discussed.


The "weekend effect" does not impact on outcome of trauma laparotomy - Experience from a level 1 trauma centre in New Zealand.
Trauma centres have been proven to provide better outcomes in developed countries for overall trauma, but there is limited literature on the systematic factors that describe any discrepancies in outcomes for trauma laparotomies in these centres. This study was conducted to examine and interrogate the effect of systematic factors on patients undergoing a trauma laparotomy in a developed country, intending to identify potential discrepancies in the outcome. This was a retrospective study of all laparotomies performed for trauma at a level 1 trauma centre in New Zealand. All adult patients who had undergone an index laparotomy for trauma between February 2012 and November 2020 were identified and laparotomies for both blunt and penetrating trauma were included. Repeat laparotomies and trauma laparotomies in children were excluded. The primary clinical outcomes reviewed included morbidity, length of hospital stay, and mortality. All statistical analysis was performed using R v.4.0.3. During the 9-year study period, 204 trauma laparotomies were performed at Waikato hospital. The majority (83.3%) were performed during office hours (170/204), and the remaining 16.7% were performed after hours (34/204). And 61.3% were performed on a weekday (125/204), whilst 38.7% were performed on the weekend/public holiday (79/204). Most of the parameters in office hours and after hours groups had no statistically significant difference, except lactate (p = 0.026). Most of the variables in weekday and weekend groups had no statistically significant difference, except pH, lactate, length of stay, and gastrointestinal complications (p = 0.012, p < 0.001, p = 0.003, p = 0.020, respectively). The current trauma system at Waikato hospital is capable of delivering care for trauma laparotomy patients with the same outcome regardless of working hours or after hours, weekday or weekend. This confirms the importance of a robust trauma system capable of responding to the sudden demands placed on it.


Effects of Tianmagouteng particles on brain cognitive function in spontaneously hypertensive rats with hyperactivity of liver-yang: A [F-18] FDG micro-PET imaging study.
To collect visualized proof of Tianmagouteng particles (TMGTP) in alleviating cognitive dysfunction and to explore its effects on brain activity in spontaneously hypertensive rats (SHRs) with hyperactivity of liver-yang (Gan Yang Shang Kang, GYSK). Sixteen SHRs were randomized into treatment group and non-treatment. The SHR with GYSK was induced by gavaging aconite decoction (10mL/kg at 0.2g/mL). After the SHR models were prepared, the rats in the treatment group were administered TMGTP (10mL/kg) once a day for 14days.The rats in the non-treatment group or normal rats (control group) received an equivalent volume of saline. Morris water maze test was conducted before and after the treatment to observe cognitive function. Fluorine 18-deoxy glucose [F-18]FDG micro-PET brain imaging scans was performed after treatment. Data were analyzed with two-sample t-test (P<0. 001) using SPM2 image analysis software. Compared with the non-treatment group, the escape latency significantly decreased but the frequency of entrance into the target zone significantly increased in the treatment group. Consistent with the alteration of cognitive functions, TMGTP induced strong brain activity in the following sites: right dorsolateral nucleus and ventrolateral nucleus of thalamus, amygdala, left met thalamus, cerebellum leaflets, original crack, front cone crack, loop-shaped leaflets; but deactivation of right medial frontal gyrus, bilateral corpus callosum, hippocampus, and left dentate gyrus. TMGTP could alleviate cognitive dysfunction in SHRs with GYSK, which was possibly by inducing alteration of glucose metabolism in different brain regions with corresponding functions.


[Resistance to penicillin G and Streptococcus pneumoniae infection at the Hôpital Foch, Paris, France, in 1995].
Decreased susceptibility to penicillin G of pneumococcal strains is continuously increasing in France. We assessed effect of resistance to penicillin on therapeutic management and mortality in adults with pneumococcal pneumonia in our hospital. This one-year retrospective study (1995) included patients with proven pneumococcal infection (positive blood culture, pleural fluid, or specimens from the lower respiratory tract). Strains of Streptococcus pneumoniae were screened for susceptibility to antimicrobial agents. Resistance to penicillin G was defined as a minimal inhibitory concentration > or = 0.12 microgram/ml. Age immune and nosocomial status, first and second line antibiotherapy and death were compared according to the strains susceptibility to penicillin G. A p value below 0.05 was statistically significant. In 15 cases a pneumococcal strain susceptible to penicillin G was isolated while 23 patients were infected with a strain with a decreased susceptibility to penicillin G. Age was significantly higher in the latest group (61.6 versus 54.7 years) while no difference was noted between the 2 groups according to immune and nosocomial status, therapeutic management and death. Resistance to penicillin did neither appear to increase mortality nor to influence therapeutic management in patients with pneumococcal infection.


A new derivative detected in accelerated ageing of artesunate-amodiaquine fixed dose combination tablets.
An unknown impurity detected in small amounts during the heat treatment of artesunate-amodiaquine bilayer tablets was purified by semipreparative HPLC and identified by MS and NMR as the tetrahydrofuranyl acetate-rearranged derivative of anhydrodihydroartemisinin. When anhydrodihydroartemisinin was treated with a Fe(II) salt in acetonitrile-water solution, the same product was generated, together with an isomeric 2-deoxy-4α-hydroxy-anhydrodihydroartemisinin derivative, as expected from the usual homolytic radical opening of the endoperoxide bond previously described for other artemisinin derivatives.


Career resilience of the tourism and hospitality workforce in the COVID-19: The protection motivation theory perspective.
By applying the protection motivation theory, the study aims to investigate factors influencing tourism and hospitality (T&H) workers' career resilience when faced with health-related risks at work during a pandemic. Data were collected from 495 part-time and full-time employees in the Vietnamese tourism and hospitality sector. The study found that workers' perceived vulnerability and perceived severity of the pandemic were positively associated with career resilience. Perceived severity was positively related to self-efficacy and response efficacy, while perceived vulnerability was positively associated with self-efficacy only. Both self-efficacy and response efficacy positively influenced career resilience through the mediating role of health risk preventative behavior. Theoretically, the study advances the stream of research in resilience in general and career resilience in particular among T&H workers when faced with a health-related crisis. Practical implications are provided with recommendations on how to facilitate career resilience among T&H employees working in the current high-risk environment.


Genome-centric metagenomics provides new insights into metabolic pathways of polyhydroxyalkanoates biosynthesis and functional microorganisms subsisting on municipal organic wastes.
The microbial community of a sequencing batch reactor operated under feast and famine conditions for production of polyhydroxyalkanoates (PHAs) was characterized through high-throughput sequencing and metagenomic analysis. The fermented food waste and chemically-enhanced primary sludge was fed in this bioreactor. After acclimation, the PHA yield achieved as high as 0.60-0.69 g CODPHA/g CODS. The complete changes of microbial community structure were found during shifts of feedstock. A synthesis of SCL/MCL-PHAs pathway was established for PHA-producing bioreactor in this mixed-culture system. The structure-performance relationship of PHA-producing microbial community and feedstock composition was investigated. The results showed that microbial community tends to be decentralized and prefer team work for PHA synthesis to consume the multiple substrates and digest inevitable non-VFA contents in fermented liquor. This study also discovered unreported potential PHA producers (e.g., genera Tabrizicola, Nannocystis, Ga0077539, Ga0077559, JOSHI-001, SNC69-320 and UBA2334) subsisting on municipal organic wastes and expands the current knowledge about mixed-culture system that the PHA synthesis pathway is widely existed in activated sludge.


A double-blind multi-centre trial of fluoxetine and dothiepin in major depressive illness. South Wales Antidepressant Drug Trial Group.
The response of patients with major depressive illness to fluoxetine or dothiepin was compared in a double-blind multi-centre trial. No differences in efficacy were observed, but the profile of side-effects differed with tremor, rash, nausea and headache occurring with fluoxetine, and drowsiness, dizziness and visual disturbance with dothiepin. It is likely that fluoxetine will be marketed with a proposed dose range lower than the one used here.


Terminal adenylation in the synthesis of RNA by Q beta replicase.
We investigated the apparent requirement that Q beta replicase must add a nontemplated adenosine to the 3' end of newly synthesized RNA strands. We used abbreviated MDV-1 (+)-RNA templates that lacked either 62 or 63 nucleotides at their 5' end in Q beta replicase reactions. The MDV-1 (-)-RNA strands synthesized from these abbreviated (+)-strand templates were released from the replication complex, yet they did not possess a nontemplated 3'-terminal adenosine. These results imply that, despite observations that all naturally occurring RNAs synthesized by Q beta replicase possess a nontemplated 3'-adenosine, the addition of an extra adenosine is not an obligate step for the release of completed strands. Since the abbreviated templates lacked a normal 5' end, it is probable that a particular sequence at the 5' end of the template is required for terminal adenylation to occur.


Distinct functional states of astrocytes during sleep and wakefulness: Is norepinephrine the master regulator?
Astrocytes are the chief supportive cells in the central nervous system, but work over the past 20 years have documented that astrocytes also contribute to complex neural processes, such as working memory. Recent discoveries of norepinephrine-mediated astrocytic Ca2+ responses have raised the possibility that astrocytic activity in the adult brain is driven by global responses to changes in behavioral state. Moreover, analysis of the interstitial space volume suggests that astrocytes may undergo changes in cell volume in response to activation of norepinephrine receptors. This review will focus on what is known about astrocytic functions within the nervous system, and how these functions interrelate with rapid changes in behavioral state mediated by norepinephrine signaling.


Ejection of a rear facing, golf cart passenger.
The following report details the findings of a series of experiments and simulations performed on a commercially available, shuttle style golf cart during several maneuvers involving rapid accelerations of the vehicle. It is determined that the current set of passive restraints on these types of golf carts are not adequate in preventing ejection of a rear facing passenger during rapid accelerations in the forward and lateral directions. Experimental data and simulations show that a hip restraint must be a minimum of 13 in. above the seat in order to secure a rear facing passenger during sharp turns, compared to the current restraint height of 5 in. Furthermore, it is determined that a restraint directly in front of the rear facing passenger is necessary to prevent ejection. In addressing these issues, golf cart manufacturers could greatly reduce the likelihood of injury due to ejection of a rear facing, golf cart passenger.


A Thieno[3,4-b]thiophene-Based Non-fullerene Electron Acceptor for High-Performance Bulk-Heterojunction Organic Solar Cells.
A thieno[3,4-b]thiophene-based electron acceptor, ATT-1, is designed and synthesized. ATT-1 exhibits a planar conjugated framework, broad absorption with a large absorption coefficient, and a slightly high LUMO energy level. Bulk-heterojunction (BHJ) solar cells based on PTB7-Th electron donor and ATT-1 electron acceptor delivered power conversion efficiencies of up to 10.07%, which is among the best performances reported for non-fullerene BHJ solar cells using PTB7-Th as the electron donor.


New insights into atomic layer BiOBr quantum dot/ZnAl-LDH composites in photocatalytic water treatment: Performance and mechanism.
Insufficient absorption sites and low charge separation notably limit the activation of photocatalytic molecular oxygen. In this study, atomic-layer BiOBr (BiOBr-QDs)/ZnAl-LDH composites with a considerable number of edges were developed to address the above-mentioned problems. The result of this study indicated the spatial separation of atomic-layer BiOBr-QDs/ZnAl-LDH's conduction band maximum (CBM) and valence band minimum (VBM). As a result, holes were produced on the substrate surface based on irradiation, and electrons were generated at the sites of the edge, such that ultra-fast charge separation can be carried out. The edges exposed massive adsorption sites in terms of oxygen molecules. Thus, electrons at the sites of the edge led to the reduction of absorbed oxygen molecules, thus exhibiting stronger photocatalytic •O2- production. Furthermore, the result confirmed that the atomic layer BiOBr-QDs/ZnAl-LDH are promising in environmental catalytic degradation for its increased activity of •O2- production. In this study, a novel insight into advanced photocatalyst design based on edge unsaturated ligand engineering at an atomic level is provided.


Assessment of the hybridization between rhesus (Macaca mulatta) and long-tailed macaques (M. fascicularis) based on morphological characters.
Hybridization between rhesus (Macaca mulatta) and long-tailed (M. fascicularis) macaques has become a focal point of interest. The majority of such studies have evaluated their genetics, but not their morphological characters. We analyzed morphological characters of eight free-ranging populations of Indochinese rhesus and long-tailed macaques distributed at the proposed hybrid zone (15.75-21.58° N) in comparison with one population each of Chinese and Indian-derived rhesus macaques and three populations of Sundaic long-tailed macaques. Chinese and Indian rhesus macaques had a heavier body mass, longer crown-rump length, shorter relative facial length and relative tail length, and a greater contrast of reddish and yellowish dorsal pelage color than the Sundaic long-tailed macaques for which the latter three parameters could be used to visually discriminate between the two species. Although the morphological characters of Indochinese rhesus and long-tailed macaques were intermediate between the Chinese/Indian rhesus and Sundaic long-tailed macaques, they were more similar to their respective conspecifics. The species-specific characters of a shorter tail (<70%) and a bipartite pelage color pattern were retained in the Indochinese rhesus macaques while the longer tail (>90%) and no bipartite pattern was found in the Indochinese long-tailed macaques. No morphological cline was observed across the species and the variations were abrupt to some extent. The hybridization between rhesus and long-tailed macaques may be results of multiple contacts and isolations over a long period of time, thus their evolutionary history should not be drawn solely by genetic or morphological analysis.


Experience with vincristine--associated neurotoxicity.
To evaluate the frequency and severity of occurrence of vincristine-associated neurotoxicity. A retrospective case series study. Hurlingham Oncology Clinic, Nairobi. Thirty-eight patients treated for various neoplasms with vincristine containing chemotherapeutic regimens. The frequency and degree of neurotoxicity when vincristine was given at the standard dose of 1.4 mg/m2. Five patients (13.2%) developed peripheral neuropathy, one having had it even before vincristine was started. Therefore only four (10.5%) had it attributed to vincristine. Four of the patients who developed neuropathy (80%) were HIV-positive. Neuropathy grade 2 (severe) occurred in only two patients leading to discontinuation of the drug. All the neurotoxicity resolved after discontinuation of vincristine. Vincristine induced neuropathy occurred but was rarely severe at a dose of 1.4 mg/m2. It appeared to be more frequent in HIV infected individuals, but controlled studies with bigger sample sizes are required to determine whether this may warrant routine capping of the dose at a maximum of 2 mg.


Spinal drop metastases in recurrent glioblastoma multiforme.
Multifocal dissemination of glioblastomas is very rare but is increasing as patients live longer. Between April 1994 and December 1997 one hundred and fifty one patients with a histologically proven glioblastoma multiforme were operated on in the Neurosurgical Department of the University of Kiel, Germany. Recurrent tumours of these patients were removed in 36 patients. Two patients developed multifocal spread of glioblastoma multiforme including spinal drop metastases. Both patients died 10 and 7 months after the primary operation. On histological examination both tumours showed wide perivascular tumour-cell cuffings in the surrounding brain tissue, so that this perivascular growth might be another explanation for the dissemination in these glioblastomas.


Prognostic and clinicopathological significance of MACC1 expression in hepatocellular carcinoma patients: a meta-analysis.
Metastasis-associated in colon cancer-1 (MACC1) has been reported to be overexpressed in diverse human malignancies. However, the prognostic and clinicopathological value of MACC1 in hepatocellular carcinoma (HCC) remains inconclusive. Therefore, we conducted this meta-analysis to investigate the association between MACC1 expression and the outcomes of HCC. Relevant articles were searched in PubMed, Embase, Sciencedirect, CNKI, and Wanfang databases updated to October 2014. The pooled hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were assessed using STATA 10.0, and then the correlations of MACC1 expression with overall survival (OS), disease-free survival (DFS), and clinicopathological features were analyzed. 9 studies with a total of 1293 HCC patients were included in this meta-analysis. Our results showed that MACC1 over-expression was significantly associated with poor OS (HR = 2.30, 95% CI 1.47-3.59, univariate analysis; HR = 2.39, 95% CI 1.49-3.82, multivariate analysis), poor DFS (HR = 1.73, 95% CI 1.40-2.13, univariate analysis). Moreover, MACC1 over-expression was significantly associated with AFP level (OR = 1.31, 95% CI 1.03-1.68), tumor number (OR = 1.37, 95% CI 1.07-1.75), differentiation (OR = 2.37, 95% CI 1.46-3.83), TNM stage (OR = 2.89, 95% CI 2.18-3.82), vascular invasion (OR = 1.89, 95% CI 1.43-2.50), capsule invasion (OR = 2.89, 95% CI 1.40-5.94), and metastasis (OR = 2.66, 95% CI 1.16-6.10). MACC1 over-expression indicated poor survival rate, high recurrence rate, and aggressive biological behaviors. MACC1 can serve as an indicator of prognosis and a potential novel target for treatment in HCC patients.


Protective effects of Cordyceps sinensis exopolysaccharide‑selenium nanoparticles on H2O2-induced oxidative stress in HepG2 cells.
This work investigated the protective effects of Cordyceps sinensis exopolysaccharide‑selenium nanoparticles (EPS-SeNPs) at different Se/EPS ratios (1/20, 1/3, 1/1, and 4/3) against 0.4 mM H2O2-induced oxidative stress in human hepatoma (HepG2) cells. Results revealed that EPS-SeNPs (0.1-4.0 μg/mL) promoted the proliferation of HepG2 cells with a cell viability of over 90% during H2O2 stress. Different Se/EPS ratios of EPS-SeNPs provided protective effects against H2O2-induced oxidative stress in HepG2 cells by increasing cell viability, restoring cell and nucleus morphology, as well as reducing lactate dehydrogenase (LDH) levels. Particularly, EPS-SeNPs (Se/EPS = 1/1) with the smallest particle size showed the highest cell viability and the greatest inhibitory effect on LDH level. Besides, EPS-SeNPs also inhibited nitric oxide and reactive oxygen species (ROS) production, and increased mitochondrial membrane potential, superoxide dismutase (SOD), and catalase levels while reducing glutathione (GSH) content. Specially, EPS-SeNPs at Se/EPS ratio of 1/3 with smaller size showed the lowest ROS level and the highest antioxidant activities (SOD and GSH), implying that the ROS generation was inhibited by increasing enzymatic and non-enzymatic antioxidants. The enhanced protective effect of EPS-SeNPs (Se/EPS = 1/1 and 1/3) might be attributed to its smaller particle size.


Mindfulness and Metta-based Trauma Therapy (MMTT): Initial Development and Proof-of-Concept of an Internet Resource.
Trauma and stressor-related disorders, including post-traumatic stress disorder (PTSD) and related comorbid disorders such as anxiety, depression, and dissociative disorders, are difficult to treat. Mindfulness-based clinical interventions have proven efficacy for mental health treatment in face-to-face individual and group modalities, although the feasibility and efficacy of delivering these interventions via the internet has not been evaluated. The present research developed mindfulness and metta-based trauma therapy (MMTT) as an internet resource to support the practice of mindfulness and metta (lovingkindness) meditations for self-regulation and healing from trauma and stressor-related disorders. In the present "proof-of-concept" study, research participants (n = 177) recruited online practiced mindfulness and metta meditations and related therapeutic exercises available via the website and rated their perceived credibility as interventions for improving self-regulation and well-being and reducing PTSD symptoms, anxiety, depressive, and dissociative experiences, as well as their experienced ease, helpfulness, and informational value. Results suggest that, independent of level of self-reported current and past psychiatric history and PTSD symptoms, participants considered the MMTT website as a credible and helpful therapeutic intervention for improving self-regulation and well-being and reducing PTSD, anxiety, depression, and dissociation. Overall, participants considered guided and non-guided meditation practices more helpful than a journaling exercise, and participants with increased PTSD symptoms preferred metta (lovingkindness) meditations less than other participants. We conclude that MMTT should be piloted in clinical trials as an adjunctive intervention to evidence-based treatments for persons with mood, anxiety, and trauma and stressor-related disorders, as well as more generally as an online resource to support self-regulation and well-being practices.


Atypical absorption of morphine sulphate through oral mucosa: an unusual case of acute opioid poisoning.
An unusual case of probable opioid poisoning due to atypical absorption of morphine sulphate through the oral mucosa is reported. A patient with advanced laryngeal cancer, who was unable to swallow, became stuporous, bradypneic, and cyanotic and had pinpoint pupils 1 hour after taking a controlled-release tablet of morphine sulphate 30 mg. Intravenous naloxone 0.4 mg induced prompt reversal of the clinical picture. The tablet of morphine, in advanced stage of decomposition, was found in the patient's mouth, the mucosa of which was inflamed and extensively ulcerated because of the long-standing stagnation of food residuals. Usually morphine is not amenable to transmucosal absorption, because of its low lipid solubility. In this case, the retention of the tablet of morphine in the mouth and the breakdown of oral mucosa integrity could have provoked a quick transmucosal absorption of the drug, with by-pass of hepatic first-pass metabolism. This may have induced a peak in drug concentration much higher than that usually resulting from the enteric absorption of controlled-release tablets of morphine.


Daily associations between affect and alcohol use among adults: The importance of affective arousal.
Little is known about whether level of affective arousal (i.e., high vs. low) is associated with alcohol use and whether this relationship differs by valence (i.e., positive vs. negative affect) among adults. Participants were n = 93 self-reported current drinkers (ages 25-65) who reported positive (PA) and negative affect (NA) seven times a day and alcohol use once a day for seven consecutive days. For each individual, mean levels of high arousal PA (e.g., excited), low arousal PA (e.g., satisfied), high arousal NA (e.g., frustrated), and low arousal NA (e.g., sad) were computed for each day. Alcohol use was reported on 30% of person-days, with an average of 2.3 drinks consumed on drinking days. Heavy episodic drinking (4+/5+ drinks for women/men) occurred on 4% of days. After covarying for age, gender, and weekday, days with higher-than-usual levels of high arousal PA were associated with a 52% increase in the odds of consuming any alcohol and a 105% increase in the odds of engaging in heavy episodic drinking. Individuals reporting more low arousal PA on average had a 77% increase in the odds of heavy episodic drinking. No significant associations between high or low arousal NA and alcohol use were found. Greater PA, but not NA, was associated with heavy alcohol use at both the within- and between-person levels, perhaps attributable to social and enhancement drinking motives. Results differed by arousal, highlighting the importance of considering a wide range of affective states when examining alcohol use behavior.


ShRNA targeting Notch1 sensitizes breast cancer stem cell to paclitaxel.
Breast cancer is currently the most lethal gynecologic malignancy in many countries, and paclitaxel is a cornerstone in the treatment of this malignancy. Unfortunately, the efficacy of paclitaxel is limited due to the development of drug resistance. Evidence has suggested that cancer stem cells (CSCs) are involved in resistance to various forms of therapies, including chemotherapy. However, the interaction between paclitaxel resistance and CSCs and its underlying mechanisms have not been previously explored. In this study, we confirmed that paclitaxel enriched breast CSCs (CD44+/CD24-) in a dose-dependent manner in MCF-7 human breast cancer cell line. We then demonstrated that Notch1 was overexpressed in breast CSCs isolated from paclitaxel-treated MCF-7 cells compared to non-CSCs. The short hairpin RNA (shRNA) mediated knock-down of Notch1 inhibited MCF-7 cell proliferation and induced cell apoptosis. The anti-apoptosis protein NF-κB was decreased significantly when treated with shRNA-Notch1, and this effect was sharply improved by combination with paclitaxel. Paclitaxel decreased CD44+/CD24- cell population in MCF-7 cells and reduced the size and number of primary mammospheres after down-regulating the Notch1. Furthermore, shRNA-Notch1 inhibited the growth of tumor xenografts in nude mice noticeably. RT-PCR and Western blotting analysis showed that the expressions of ALDH1, NICD, Hes-1 and the drug transporter ABCG2 were decreased both in vitro and in vivo. These results suggest that Notch1 might play a critical role in the resistance to paclitaxel, and targeting Notch1 may have important clinical applications in cancer therapy.


Cholinergic regulation of female sexual behavior in rats demonstrated by manipulation of endogenous acetylcholine.
Infusions of the cholinesterase inhibitor, eserine, into the lateral ventricle of the brain facilitated lordosis in ovariectomized, estrogen primed female rats. Lordosis was also facilitated by infusions of 5 or 10 micrograms acetylcholine when this was accompanied by a low dose of eserine. Systemic treatment with the muscarinic antagonist, atropine (2 mg), completely blocked the facilitative effects of eserine and acetylcholine. In female rats made highly receptive by treatment with estrogen and progesterone, lordosis was inhibited by infusion of scopolamine into the lateral ventricles. These results agree with previous findings that sexual receptivity is regulated in part by endogenous cholinergic activity.


A validation study of the Qiagen Investigator DIPplex® kit; an INDEL-based assay for human identification.
Marker sets that are based on small insertion/deletion (INDEL) alleles can serve as useful supplementary or stand-alone assays for human identification. A validation study has been performed on a human identification assay based on a panel of 30 INDELs and amelogenin using the Investigator DIPplex® kit (Qiagen). The assay was able to type DNA from a number of forensically relevant sample types and obtain full profiles with 62 pg of template DNA and partial profiles with as little as 16 pg of template DNA. The assay is reproducible, precise, and non-overlapping alleles from minor contributors were detectable in mixture analysis ranging from 6:1 to 19:1 mixtures. Population studies were performed on the 30 indels, and there were no significant departures from Hardy-Weinberg equilibrium or significant linkage disequilibrium between the markers (after correction for sampling). In all populations, the random match probability was 1.43 × 10(-11) or less, and the power of exclusion was greater than .999999999. We also discovered several microvariant alleles in our population samples. The data support that the Investigator DIPplex® kit provides a powerful supplement or stand-alone capability for human identity testing.


Pyrolytic mechanisms of typical organic components of sewage sludge in the presence of CaO: Polysaccharides, proteins, and lipids.
The addition of CaO could facilitate the conversion of sewage sludge (SS) from waste to high-purity syngas. The pyrolytic characteristics of SS are a comprehensive manifestation of polysaccharides, proteins, and lipids, while the influence of CaO on their pyrolytic characteristics is rarely reported. This study conducted a thorough investigation into the pyrolytic mechanism of starch, protein, and lipid in the presence of CaO by analysing their thermal behavior, gaseous products, liquid tar, and residual char. The findings from TGA, GC, GC-MS, and FT-IR analysis indicate that the addition of CaO catalytically lowers the pyrolysis temperature of starch, protein, and lipid components and promotes their conversion into small molecules, resulting in increased syngas production. Moreover, the combination of char with the carbonation and calcination cycle of CaO leads to a significant boost in syngas (H2 and CO) yield, with up to 3 and 10 times increase from starch and protein, respectively, and a higher syngas selectivity of up to 65 %. The study also identifies those polysaccharides and proteins are the primary sources of syngas. This study can provide further insight into SS pyrolysis for syngas production in the presence of CaO and the necessary parameters to predict the pyrolysis behavior of SS in industrial applications.


Information theory-based algorithm for in silico prediction of PCR products with whole genomic sequences as templates.
A new algorithm for assessing similarity between primer and template has been developed based on the hypothesis that annealing of primer to template is an information transfer process. Primer sequence is converted to a vector of the full potential hydrogen numbers (3 for G or C, 2 for A or T), while template sequence is converted to a vector of the actual hydrogen bond numbers formed after primer annealing. The former is considered as source information and the latter destination information. An information coefficient is calculated as a measure for fidelity of this information transfer process and thus a measure of similarity between primer and potential annealing site on template. Successful prediction of PCR products from whole genomic sequences with a computer program based on the algorithm demonstrated the potential of this new algorithm in areas like in silico PCR and gene finding.


Digoxin-verapamil interaction: in vitro studies in rat tissue.
Recent studies have shown a significant increase in plasma digoxin concentration during verapamil treatment. This phenomenon has been attributed in part to reduced renal clearance of digoxin owing to inhibition of the digoxin tubular secretory process. We studied the influence of digoxin-verapamil interaction on [125I]digoxin uptake by various rat tissues in vitro, employing the tissue slice technique. Slice/medium digoxin ratios (mean +/- SD) were: kidney, 4.09 +/- 0.60; heart, 3.63 +/- 0.41; liver, 3.93 +/- 0.39; and muscle, 3.55 +/- 0.55. Addition of verapamil to the incubation medium resulted in a 15.6% reduction of digoxin uptake by kidney tissue, to 3.38 +/- 0.49 (p less than 0.0005). Verapamil failed to reduce digoxin uptake in liver, heart, or striated muscle. We conclude that the renal cortical transport mechanism of digoxin may be inhibited by verapamil. In contrast, the unaffected uptake of digoxin in heart or muscle indicates that the increase in serum digoxin concentration in the presence of verapamil is not caused or accompanied by redistribution of digoxin from the heart or striated muscle.


Dust from Zambian smelters: mineralogy and contaminant bioaccessibility.
Metal smelting is often responsible for local contamination of environmental compartments. Dust materials escaping from the smelting facilities not only settle in the soil, but can also have direct effects on populations living close to these operations (by ingestion or inhalation). In this particular study, we investigate dusts from Cu-Co metal smelters in the Zambian Copperbelt, using a combination of mineralogical techniques (XRD, SEM/EDS, and TEM/EDS), in order to understand the solid speciation of the contaminants, as well as their bioaccessibility using in vitro tests in simulated gastric and lung fluids to assess the exposure risk for humans. The leaching of metals was mainly dependent on the contaminant mineralogy. Based on our results, a potential risk can be recognized, particularly from ingestion of the dust, with bioaccessible fractions ranging from 21 to 89% of the total contaminant concentrations. In contrast, relatively low bioaccessible fractions were observed for simulated lung fluid extracts, with values ranging from 0.01% (Pb) up to 16.5% (Co) of total contaminant concentrations. Daily intakes via oral exposure, calculated for an adult (70 kg, ingestion rate 50 mg dust per day), slightly exceeded the tolerable daily intake limits for Co (1.66× for fly ash and 1.19× for slag dust) and occasionally also for Pb (1.49×, fly ash) and As (1.64×, electrostatic precipitator dust). Cobalt has been suggested as the most important pollutant, and the direct pathways of the population's exposures to dust particles in the industrial parts of the Zambian Copperbelt should be further studied in interdisciplinary investigations.


Application of an iterative Bayesian variable selection method in a genome-wide association study of rheumatoid arthritis.
Genome-wide association studies usually involve several hundred thousand of single-nucleotide polymorphisms (SNPs). Conventional approaches face challenges when there are enormous number of SNPs but a relatively small number of samples and, in some cases, are not feasible. We introduce here an iterative Bayesian variable selection method that provides a unique tool for association studies with a large number of SNPs (p) but a relatively small sample size (n). We applied this method to the simulated case-control sample provided by the Genetic Analysis Workshop 15 and compared its performance with stepwise variable selection method. We demonstrated that the results of iterative Bayesian variable selection applied to when p t n are as comparable as those of stepwise variable selection implemented to when n t p. When n > p, the iterative Bayesian variable selection performs better than stepwise variable selection does.


Microtubule-neurofilament segregation produced by beta, beta'-iminodipropionitrile: evidence for the association of fast axonal transport with microtubules.
The subperineurial injection of beta,beta'-iminodipropionitrile (IDPN) into rat sciatic nerves resulted in focal disorganization of the axonal cytoskeleton characterized by segregation of neurofilaments and microtubules. Shortly after injection, microtubules clustered together to form a central channel, while neurofilaments became chaotically arrayed between the microtubule channel and axolemma. Electron microscopic autoradiography disclosed that rapidly transported organelles were preferentially associated with the microtubule-enriched central channels. These studies indicate that IDPN acts at the level of the axon to disrupt interactions between cytoskeletal elements and show that rapidly transported constituents are preferentially conveyed in association with microtubules. The model provides an opportunity to dissect the interactions of the cytoskeletal elements and other organelles.


Implementing a Serious Illness Risk Prediction Model: Impact on Goals of Care Documentation.
Goals of care conversations can promote high value care for patients with serious illness, yet documented discussions infrequently occur in hospital settings. We sought to develop a quality improvement initiative to improve goals of care documentation for hospitalized patients. Implementation occurred at an academic medical center in Pittsburgh, Pennsylvania. Intervention included integration of a 90-day mortality prediction model grouping patients into low, intermediate, and high risk; a centralized goals of care note; and automated notifications and targeted palliative consults. We compared documented goals of care discussions by risk score before and after implementation. Of the 12,571 patients hospitalized preimplementation and 10,761 postimplementation, 1% were designated high risk and 11% intermediate risk of mortality. Postimplementation, goals of care documentation increased for high (17.6%-70.8%, P< 0.0001) and intermediate risk patients (9.6%-28.0%, P < 0.0001). For intermediate risk patients, the percentage of goals of care documentation performed by palliative medicine specialists increased from pre- to postimplementation (52.3%-71.2%, P = 0.0002). For high-risk patients, the percentage of goals of care documentation completed by the primary service increased from pre-to postimplementation (36.8%-47.1%, P = 0.5898, with documentation performed by palliative medicine specialists slightly decreasing from pre- to postimplementation (63.2%-52.9%, P = 0.5898). Implementation of a goals of care initiative using a mortality prediction model significantly increased goals of care documentation especially among high-risk patients. Further study to assess strategies to increase goals of care documentation for intermediate risk patients is needed especially by nonspecialty palliative care.


[Safety evaluation of mass inoculation of 23 valent pneumococcal polysaccharide vaccine among elderly people aged 60 and above in Shanghai from 2013 to 2017].
Objective: To evaluate the safety of 23 Valent Pneumococcal Polysaccharide Vaccine (PPV23) among eldly people aged 60 and above in Shanghai. Methods: A total of 1 310 660 monitoring data of adverse events following immunization (AEFI) of PPV23 among people aged 60 and above were collected through the National AEFI Surveillance System from September 14, 2013 to December 31, 2017 in Shanghai. And the descriptive epidemiological methods were used for analysis. Results: 433 cases of AEFI were reported from September 14, 2013 to December 31, 2017, with the incidence rate of AEFI was 33.04/100 000 doses. The general reactions were reported as 392 cases (90.53%), with 17 cases of abnormal reactions (3.93%), 23 cases of coincidences (5.31%) and 1 case of psychogenic reactions (0.23%). The reported incidence rates of general reactions and abnormal reactions of free PPV23 inoculation among elderly people in urban areas were 41.31 per 100 000 doses and 1.91/100 000 doses, respectively, which were higher than those in suburban areas (24.18/100 000 doses, 1.32/100 000 doses) and exurban areas (27.84/100 000 doses, 0.59/100 000 doses). The reported incidence rate of general reaction in females (35.38/100 000 doses) was higher than that in males (24.06/100 000 doses), and the reported incidence rate of abnormal reaction in males (1.58/100 000 doses) was higher than that in females (1.03/100 000 doses). The reported incidence rates of general and abnormal reactions were the highest in 60-64 years old group (62.65/100 000 doses and 4.87/100 000 doses, respectively). In addition, all patients with general reactions or abnormal reactions were better or cured. Conclusion: PPV23 vaccination is safe among people aged 60 and above in Shanghai.


Mapping of Perfusion During Full-Thickness Blepharotomy Using Laser Speckle Contrast Imaging.
The aim of this study was to monitor how the blood perfusion in human upper eyelids is affected during full-thickness blepharotomy. Seven eyelids in 5 patients with upper eyelid retraction due to Graves' disease underwent full-thickness blepharotomy. Perfusion was measured using laser speckle contrast imaging in the eyelid margin and in the conjunctival pedicle. Immediately following the procedure, a nonsignificant reduction in perfusion was observed in the skin of the pretarsal eyelid margin, being 66% of the initial value ( p = n.s.). However, a statistically significant decrease in perfusion, to 53% of the initial value ( p < 0.01), was seen in the central pedicle of the conjunctiva. There were no surgical complications such as infection, signs of ischemia, or bleeding. In this study, eyelid perfusion was mapped during full-thickness blepharotomy for the first time using laser speckle contrast imaging. The results showed that perfusion is sufficiently preserved during surgery, probably due to the rich vascular supply in the periocular region, which may explain the low risk of postoperative complications such as ischemia and infection.


Essential amino acid ingestion as an efficient nutritional strategy for the preservation of muscle mass following gastric bypass surgery.
Loss of skeletal muscle in patients who have undergone gastric bypass is a consistent observation. Skeletal muscle constitutes the largest protein/amino acid pool in the body, and loss of skeletal muscle has important implications in health and disease. Sustaining a given level of muscle protein requires a balance between the rates of muscle protein synthesis and breakdown. Current evidence suggests that reduced rate of protein synthesis is implicated in the loss of muscle after gastric bypass. This is not surprising given a less than optimal dietary protein intake after the procedure and because, unlike other macronutrients, protein/amino acids are not stored in the body. Ingesting essential amino acids (EAAs), which cannot be synthesized de novo and have the primary role in the regulation of muscle protein synthesis, can potentially ameliorate loss of muscle protein after gastric bypass. At the same time, ingestion of EAAs provides a more efficient nutritional approach (i.e., greater stimulation of protein synthesis relative to the amount of amino acids ingested) to enhance muscle protein synthesis compared with the ingestion of intact protein. Changing current dietary practices toward increasing ingestion of EAAs provides an approach that can potentially prevent loss of lean body tissue and ultimately achieve a more sustained level of health in patients who have undergone gastric bypass.


Power and optimal study design in iPSC-based brain disease modelling.
Studies using induced pluripotent stem cells (iPSCs) are gaining momentum in brain disorder modelling, but optimal study designs are poorly defined. Here, we compare commonly used designs and statistical analysis for different research aims. Furthermore, we generated immunocytochemical, electrophysiological, and proteomic data from iPSC-derived neurons of five healthy subjects, analysed data variation and conducted power simulations. These analyses show that published case-control iPSC studies are generally underpowered. Designs using isogenic iPSC lines typically have higher power than case-control designs, but generalization of conclusions is limited. We show that, for the realistic settings used in this study, a multiple isogenic pair design increases absolute power up to 60% or requires up to 5-fold fewer lines. A free web tool is presented to explore the power of different study designs, using any (pilot) data.


Outcome following local injection of a liquid amnion allograft for treatment of equine tendonitis or desmitis - 100 cases.
Tendon and ligament injuries are significant causes of loss of use and early retirement in performance horses. Amniotic fluid and tissue are excellent sources of growth factors and cytokines important in tendon and ligament healing. Thus, an equine-origin liquid amnion allograft (ELAA) may be beneficial in the treatment of equine tendonitis and desmitis. Objectives of this study were to report the outcome achieved (i.e. ability to return to work) for horses diagnosed with tendonitis or desmitis lesions treated with local injection of ELAA and to compare these outcomes to those reported for other regenerative medicine modalities. A prospective, multi-center, non-blinded clinical trial was conducted. Equine veterinarians at 14 sites were selected to participate in the data collection for the trial. Criterion for inclusion was a horse presenting with lameness which was attributed to tendonitis or desmitis by diagnostic anesthesia and/or imaging. These horses were subsequently treated by local injection of the lesion with ELAA by the attending veterinarian. Standardized questionnaires describing each horse's signalment, discipline, ability to return to work, and any adverse events were completed and submitted by the attending veterinarian following a minimum of six months of follow-up. The current literature was reviewed to identify clinical studies reporting outcomes of equine tendonitis/desmitis lesions treated with other regenerative therapies. Contingency table analyses were performed comparing outcomes. Questionnaires for 100 horses with 128 tendonitis and desmitis lesions met the inclusion criteria. Of these, 72 horses with 94 lesions returned to or exceeded their original level of work, 10 horses with 13 lesions returned to work but could not perform to previous standards, and 18 horses with 20 lesions did not return to work as a result of the injury. No differences were observed when outcome of horses treated with ELAA were compared to those of similar studies using other regenerative therapies. Treatment of tendonitis and desmitis lesions by local injection of ELAA resulted in similar outcomes for horses returning to previous level of performance as other regenerative modalities such as mesenchymal stem cells, platelet-rich plasma, and autologous conditioned serum; however, blinded placebo-controlled studies are indicated.


RNA FISH for detecting expanded repeats in human diseases.
RNA fluorescence in situ hybridization (FISH) is a widely used technique for detecting transcripts in fixed cells and tissues. Many variants of RNA FISH have been proposed to increase signal strength, resolution and target specificity. The current variants of this technique facilitate the detection of the subcellular localization of transcripts at a single molecule level. Among the applications of RNA FISH are studies on nuclear RNA foci in diseases resulting from the expansion of tri-, tetra-, penta- and hexanucleotide repeats present in different single genes. The partial or complete retention of mutant transcripts forming RNA aggregates within the nucleoplasm has been shown in multiple cellular disease models and in the tissues of patients affected with these atypical mutations. Relevant diseases include, among others, myotonic dystrophy type 1 (DM1) with CUG repeats, Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) with CAG repeats, fragile X-associated tremor/ataxia syndrome (FXTAS) with CGG repeats, myotonic dystrophy type 2 (DM2) with CCUG repeats, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) with GGGGCC repeats and spinocerebellar ataxia type 32 (SCA32) with GGCCUG. In this article, we summarize the results obtained with FISH to examine RNA nuclear inclusions. We provide a detailed protocol for detecting RNAs containing expanded CAG and CUG repeats in different cellular models, including fibroblasts, lymphoblasts, induced pluripotent stem cells and murine and human neuronal progenitors. We also present the results of the first single-molecule FISH application in a cellular model of polyglutamine disease.


Atrial Cardiomyopathy: A Useful Notion in Cardiac Disease Management or a Passing Fad?
The term atrial cardiomyopathy, which has been used sporadically in the medical literature, was recently the subject of a detailed Consensus Document prepared by representatives of the European Heart Rhythm Association, Heart Rhythm Society, Asia-Pacific Heart Rhythm Society, and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiología. They discussed aspects of the definition, histopathology, atrial-specific physiology, atrial pathology, impact on arrhythmia occurrence, imaging, mapping, and ablation. Here, the authors consider critically the added clinical value of this concept and its meaningfulness. They review evidence implicating atrial cardiomyopathy as an independent contributor to the risk of stroke associated with atrial fibrillation and as a determinant of arrhythmia progression. The issue of classification is considered and the authors discuss how atrial cardiomyopathic properties might guide stroke prevention, rhythm maintenance, and rate control in atrial fibrillation. Carefully designed clinical trials are needed to evaluate these potential applications, and will ultimately define the value of this terminology.


Sleep in women undergoing in vitro fertilization: a pilot study.
Sleep disturbances are thought to be frequent in women undergoing IVF despite minimal research of this hypothesis. Our goal was to longitudinally assess sleep duration and disturbances in women undergoing IVF and assess impact of habitual sleep duration on oocytes retrieved, an important outcome in IVF. Actigraphy and questionnaire batteries containing sleep and psychometric instruments were performed prior to and throughout 24 IVF cycles. TST <7 h was present in 46%, 57%, 69%, and 42% of baseline, stimulation, post-oocyte retrieval, and post-embryo transfer recordings. ESS >10 was noted in 24%, 33%, and 36% of cycles during baseline, stimulation, and post-embryo transfer. PSQI >5 was noted in 57%, 43%, and 29% of cycles during baseline, stimulation, and post-embryo transfer. TST (F = 2.95, p = 0.04) and ESS (F = 4.36, p = 0.02) were the only sleep metrics in which a significant main effect of time was found by mixed models analysis. The final linear regression model chosen by stepwise selection to best explain the variability in oocytes retrieved included anti-mullerian hormone, day three follicle stimulating hormone, and baseline TST and explained 40% of the variance in oocytes retrieved (adjusted R2 = 0.40, p = 0.03). Although not statistically significant, a trend towards a linear association between baseline TST and oocytes retrieved was seen with an increase of oocytes retrieved by 1.5 for every hour increase in TST (p = 0.09). This is the first study to describe, with subjective and objective measures, sleep disturbances present throughout the IVF cycle. Importantly, a trend towards a linear relationship between TST and oocytes retrieved was found in this pilot study. Sleep may be a modifiable target to improve outcomes in women undergoing IVF and further investigations are needed.


Spatial heterogeneity of bacterial colonization across different gut segments following inter-species microbiota transplantation.
The microbiota presents a compartmentalized distribution across different gut segments. Hence, the exogenous microbiota from a particular gut segment might only invade its homologous gut location during microbiota transplantation. Feces as the excreted residue contain most of the large-intestinal microbes but lack small-intestinal microbes. We speculated that whole-intestinal microbiota transplantation (WIMT), comprising jejunal, ileal, cecal, and colonic microbiota, would be more effective for reshaping the entire intestinal microbiota than conventional fecal microbiota transplantation fecal microbiota transplantation (FMT). We modeled the compartmentalized colonization of the gut microbiota via transplanting the microbiota from jejunum, ileum, cecum, and colon, respectively, into the germ-free mice. Transplanting jejunal or ileal microbiota induced more exogenous microbes' colonization in the small intestine (SI) of germ-free mice rather than the large intestine (LI), primarily containing Proteobacteria, Lactobacillaceae, and Cyanobacteria. Conversely, more saccharolytic anaerobes from exogenous cecal or colonic microbiota, such as Bacteroidetes, Prevotellaceae, Lachnospiraceae, and Ruminococcaceae, established in the LI of germ-free mice that received corresponding intestinal segmented microbiota transplantation. Consistent compartmentalized colonization patterns of microbial functions in the intestine of germ-free mice were also observed. Genes related to nucleotide metabolism, genetic information processing, and replication and repair were primarily enriched in small-intestinal communities, whereas genes associated with the metabolism of essential nutrients such as carbohydrates, amino acids, cofactors, and vitamins were mainly enriched in large-intestinal communities of germ-free mice. Subsequently, we compared the difference in reshaping the community structure of germ-free mice between FMT and WIMT. FMT mainly transferred LI-derived microorganisms and gene functions into the recipient intestine with sparse SI-derived microbes successfully transplanted. However, WIMT introduced more SI-derived microbes and associated microbial functions to the recipient intestine than FMT. Besides, WIMT also improved intestinal morphological development as well as reduced systematic inflammation responses of recipients compared with FMT. Segmented exogenous microbiota transplantation proved the spatial heterogeneity of bacterial colonization along the gastrointestinal tract, i.e., the microbiota from one specific location selectively colonizes its homologous gut region. Given the lack of exogenous small-intestinal microbes during FMT, WIMT may be a promising alternative for conventional FMT to reconstitute the microbiota across the entire intestinal tract. Video Abstract.


The Incidence of Child Maltreatment Resulting in Hospitalizations for Children Under Age 3 Years.
To assess the incidence of child maltreatment-related hospitalizations for children under 3 years for the population of Washington State. A population-based study using retrospective linked administrative data for all children born in Washington State from 2000 through 2013 (n = 1 191 802). The dataset was composed of linked birth and hospitalization records for the entire state. Child maltreatment-related hospitalizations were identified using diagnostic codes, both specifically attributed to and suggestive of maltreatment. Incidence were calculated for the population, by birth year, by sex, and by maltreatment subtype. A total of 3885 hospitalizations related to child maltreatment were identified for an incidence of 10.87 per 10 000 person-years. Hospitalizations related to child maltreatment accounted for 2.1% of all hospitalizations for children under the age of 3 years. This percentage doubled over time, reaching a high in 2012 (3.6%). More than one-half of all hospitalizations were related to neglect. Maltreatment-related hospitalizations occurred most frequently in the first year of life for all subtypes except for neglect, which occurred the most between 1 and 2 years of age. Male children had higher incidence than female children in general (11.97 vs 9.70 per 10 000 person-years) and across all subtypes. Hospitalizations can be a useful source of population-based child maltreatment surveillance. The identification of neglect-related hospitalizations, likely the result of supervisory neglect, because the most common subtype is an important finding for the development of prevention programming.