Management of dry and transition cows to improve energy balance and reproduction.
Fertility of dairy cows has decreased for the past several decades. Measures of energy balance (EB; e.g., change in EB, EB nadir, cumulative negative EB, or duration of negative EB) are related to reproductive performance. Our research group has concluded that modification of diets fed during the dry or transition period are unlikely to have significant effects on postpartum EB and fertility. Rather, more radical alterations in dairy management are needed if energy status of postpartum cows is to be improved. We have examined the potential to alter EB by shortening or eliminating the dry period. In an initial study, the effects of a 56, 28, and 0 d dry period on ovarian dynamics and reproductive performance of dairy cows were examined. Postpartum EB was improved by reducing the dry period; however, only significantly for the 0 d dry period. Cows on the 0 d dry period did not experience negative EB. Improvements in EB were a reflection of lower milk production and greater feed intake. Consistent with the improvements in EB, time to first ovulation and first service, first service conception rate, services per conception, and days open were all improved by reduction of dry period length. Because small animal numbers were used in the study, a second study was conducted on a commercial dairy with many more animals to determine if results from the initial trial could be duplicated. A comparison was made between a 55 and 34 d dry period. Shortening the dry period resulted in fewer days to first ovulation, fewer days open, and a greater percentage of cows pregnant at 150 days in milk, although the improvements in the latter two variables were only significant for cows in their third or greater lactation. A current study is being performed in a large commercial dairy to examine the effects of eliminating the dry period on reproduction utilizing a large commercial dairy.


Pseudomelanosis duodeni in a postrenal transplant patient.
Pseudomelanosis duodeni is a rare entity characterised by dark pigmented intracellular granules seen within macrophages that lie within the lamina propria of the duodenal villi. There is no known treatment, and the clinical significance and long-term sequelae of this entity are unclear. We present a case of pseudomelanosis duodeni in a 54-year-old woman who presented with a 1-month history of nausea, vomiting and non-bloody diarrhoea. The medical history was significant for diabetes mellitus type 2, end-stage renal disease status postkidney transplant, hypertension, anaemia of chronic disease and hypothyroidism. A gastroduodenal endoscopy revealed pigmented dark lesions in the duodenal mucosa. Biopsies from the second part of the duodenum and duodenal bulb showed pigmented macrophages in the lamina propria. The findings were consistent with duodenal melanosis. In spite of renal transplant with normalisation of renal function, the duodenal melanosis persists, which raises questions on the role of renal impairment in this entity.


How does increasingly plainer cigarette packaging influence adult smokers' perceptions about brand image? An experimental study.
Cigarette packaging is a key marketing strategy for promoting brand image. Plain packaging has been proposed to limit brand image, but tobacco companies would resist removal of branding design elements. A 3 (brand types) x 4 (degree of plain packaging) between-subject experimental design was used, using an internet online method, to expose 813 adult Australian smokers to one randomly selected cigarette pack, after which respondents completed ratings of the pack. Compared with current cigarette packs with full branding, cigarette packs that displayed progressively fewer branding design elements were perceived increasingly unfavourably in terms of smokers' appraisals of the packs, the smokers who might smoke such packs, and the inferred experience of smoking a cigarette from these packs. For example, cardboard brown packs with the number of enclosed cigarettes displayed on the front of the pack and featuring only the brand name in small standard font at the bottom of the pack face were rated as significantly less attractive and popular than original branded packs. Smokers of these plain packs were rated as significantly less trendy/stylish, less sociable/outgoing and less mature than smokers of the original pack. Compared with original packs, smokers inferred that cigarettes from these plain packs would be less rich in tobacco, less satisfying and of lower quality tobacco. Plain packaging policies that remove most brand design elements are likely to be most successful in removing cigarette brand image associations.


Correction: Harnessing the power of AI: Advanced deep learning models optimization for accurate SARS-CoV-2 forecasting.
[This corrects the article DOI: 10.1371/journal.pone.0287755.].


Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney.
Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. We investigated the role of the NAD(P)H oxidase Nox4 in generation of reactive oxygen species (ROS), hypertrophy, and fibronectin expression in a rat model of type 1 diabetes induced by streptozotocin. Phosphorothioated antisense (AS) or sense oligonucleotides for Nox4 were administered for 2 weeks with an osmotic minipump 72 h after streptozotocin treatment. Nox4 protein expression was increased in diabetic kidney cortex compared with non-diabetic controls and was down-regulated in AS-treated animals. AS oligonucleotides inhibited NADPH-dependent ROS generation in renal cortical and glomerular homogenates. ROS generation by intact isolated glomeruli from diabetic animals was increased compared with glomeruli isolated from AS-treated animals. AS treatment reduced whole kidney and glomerular hypertrophy. Moreover, the increased expression of fibronectin protein was markedly reduced in renal cortex including glomeruli of AS-treated diabetic rats. Akt/protein kinase B and ERK1/2, two protein kinases critical for cell growth and hypertrophy, were activated in diabetes, and AS treatment almost abolished their activation. In cultured mesangial cells, high glucose increased NADPH oxidase activity and fibronectin expression, effects that were prevented in cells transfected with AS oligonucleotides. These data establish a role for Nox4 as the major source of ROS in the kidneys during early stages of diabetes and establish that Nox4-derived ROS mediate renal hypertrophy and increased fibronectin expression.


Indoor/outdoor relationships for PM2.5 and associated carbonaceous pollutants at residential homes in Hong Kong - case study.
Six residences were selected (two roadside, two urban, and two rural) to evaluate the indoor-outdoor characteristics of PM(2.5) (aerodynamic diameter <2.5 microm) carbonaceous species in Hong Kong during March and April 2004. Twenty-minute-averaged indoor and outdoor PM(2.5) concentrations were recorded by DustTrak samplers simultaneously at each site for 3 days to examine diurnal variability of PM(2.5) mass concentrations and their indoor-to-outdoor (I/O) ratios. Daily (24-h average) indoor/outdoor PM(2.5) samples were collected on pre-fired quartz-fiber filters with battery-powered portable mini-volume samplers and analyzed for organic and elemental carbon (OC, EC) by thermal/optical reflectance (TOR) following the Interagency Monitoring of Protected Visual Environments (IMPROVE) protocol. The average indoor and outdoor concentrations of 24 h PM(2.5) were 56.7 and 43.8 microg/m(3), respectively. The short-term PM(2.5) profiles indicated that the penetration of outdoor particles was an important contributor to indoor PM(2.5), and a household survey indicated that daily activities were also sources of episodic peaks in indoor PM(2.5). The average indoor OC and EC concentrations of 17.1 and 2.8 microg/m(3), respectively, accounted for an average of 29.5 and 5.2%, respectively, of indoor PM(2.5) mass. The average indoor OC/EC ratios were 5.8, 9.1, and 5.0 in roadside, urban, and rural areas, respectively; while average outdoor OC/EC ratios were 4.0, 4.3, and 4.0, respectively. The average I/O ratios of 24 h PM(2.5), OC, and EC were 1.4, 1.8, and 1.2, respectively. High indoor-outdoor correlations (r(2)) were found for PM(2.5) EC (0.96) and mass (0.81), and low correlations were found for OC (0.55), indicative of different organic carbon sources indoors. A simple model implied that about two-thirds of carbonaceous particles in indoor air are originated from outdoor sources. Indoor particulate pollution has received more attentions in Asia. This study presents a case study regarding the fine particulate matter and its carbonaceous compositions at six residential homes in Hong Kong. The characteristics and relationship of atmospheric organic and elemental carbon were discussed indoors and outdoors. The distribution of eight carbon fractions was first reported in indoor samples to interpret potential sources of indoor carbonaceous particles. The data set can provide significant scientific basis for indoor air quality and epidemiology study in Hong Kong and China.


From heart to muscle: pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection.
The long-term sequelae of the coronavirus disease 2019 (COVID-19) are multifaceted and, besides the lungs, impact other organs and tissues, even in cases of mild infection. Along with commonly reported symptoms such as fatigue and dyspnea, a significant proportion of those with prior COVID-19 infection also exhibit signs of cardiac damage, muscle weakness, and ultimately, poor exercise tolerance. This review provides an overview of evidence indicating cardiac impairments and persistent endothelial dysfunction in the peripheral vasculature of those previously infected with COVID-19, irrespective of the severity of the acute phase of illness. In addition, V̇o2peak appears to be lower in convalescent patients, which may stem, in part, from alterations in O2 transport such as impaired diffusional O2 conductance. Together, the persistent multi-organ dysfunction induced by COVID-19 may set previously healthy individuals on a trajectory towards frailty and disease. Given the large proportion of individuals recovering from COVID-19, it is critically important to better understand the physical sequelae of COVID-19, the underlying biological mechanisms contributing to these outcomes, and the long-term effects on future disease risk. This review highlights relevant literature on the pathophysiology post-COVID-19 infection, gaps in the literature, and emphasizes the need for the development of evidence-based rehabilitation guidelines.


Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase.
We had previously shown that high gene expressions (mRNA levels) of thymidylate synthase (TS; Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997) and thymidine phosphorylase (TP; Metzger et al., Clin. Cancer Res., 4: 2371-2376, 1998) in pretreatment tumor biopsies could identify tumors that would be nonresponsive to 5-fluorouracil (5-FU)-based therapy. In this study, we investigated the association between intratumoral gene expression of the pyrimidine catabolism enzyme dihydropyrimidine dehydrogenase (DPD) and the response of colorectal tumors to the same 5-FU-based protocol. DPD expressions were measured by quantitative reverse transcription-PCR in 33 pretreatment biopsies of colorectal tumors from patients who went on to receive treatment with 5-FU and leucovorin (LV). The range of DPD gene expression in those tumors that were nonresponsive to 5-FU was much broader than that of the responding tumors. None of the tumors with basal-level DPD expressions above a DPD:beta-actin ratio of 2.5 x 10(-3) (14 of 33) were responders to 5-FU/LV therapy, whereas those tumors with DPD gene expressions below DPD: beta-actin ratio of 2.5 x 10(-3) had a response rate of 50%. There was no correlation among DPD, TS, and TP expression values in this set of colorectal tumors, which indicated that these gene expressions are independent variables. All of the tumors that responded to 5-FU therapy (11 of 33) had expression values of all three of the genes, TS, TP, and DPD, below their respective nonresponse cutoff values, whereas, in each of the nonresponding tumors, at least one of these gene expressions was high. The patients with low expression of all three of the genes had significantly longer survival than patients with a high value of any one of the gene expressions. The results of this study show that intratumoral gene expression level of DPD is associated with tumor response to 5-FU and that the use of more than one independent determinant of response permits the identification of a high percentage of responding patients.


Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury.
In vitro studies have shown LY203647 to be a selective antagonist of contractile responses to leukotriene (LT) D4 and LTE4 in guinea pig ileum, trachea and lung parenchyma. In pithed rat, i.v. injection of LTD4 produced pressor responses that were selectively antagonized by LY203647 in a dose-dependent manner [ED50 7.5 (6.0-9.5) mg/kg, i.v.]. In normal anesthetized rats and dogs, LTD4 reduced aortic blood flow and stroke volume in association with systemic vasoconstriction, variable blood pressure responses and no change in cardiac rate. LTD4 did not alter myocardial contractility corrected for alterations in afterload. Pretreatment of rats and dogs with LY203647 (1-10 mg/kg, i.v.) produced dose-related inhibition of the myocardial and systemic hemodynamic effects of LTD4, whereas coadministration of LY203647 reversed established myocardial depression and systemic and pulmonary vasoconstriction during continuous infusion of LTD4 in dogs. LY203647 (10 mg/kg over 90 min, i.v.) infusion in normal dogs abolished or greatly antagonized hemodynamic responses to LTD4 for 6 hr. In subsequent experiments, myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion. LY203647 (10 mg/kg over 90 min, i.v.) treatment did not alter cardiovascular parameters when compared to time-related alterations observed in control dogs. ST segment deviation and the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion also were similar between groups. Resultant infarct sizes were 46 +/- 1 and 45 +/- 1% of the left ventricular mass placed at risk in control and LY203647-treated dogs, respectively. Present data illustrate the prominent cardiac and systemic hemodynamic effects of LTD4 and indicate that LY203647 produces selective and sustained antagonism of cardiovascular LTD4 receptors. Lack of containment of infarction by LY203647 suggests that endogenous cysteinyl-LT do not contribute to reperfusion injury of ischemic myocardium.


The treatment of hyponatremia.
Virtually all investigators now agree that self-induced water intoxication, symptomatic hospital-acquired hyponatremia, and hyponatremia associated with intracranial pathology are true emergencies that demand prompt and definitive intervention with hypertonic saline. A 4- to 6-mmol/L increase in serum sodium concentration is adequate in the most seriously ill patients and this is best achieved with bolus infusions of 3% saline. Virtually all investigators now agree that overcorrection of hyponatremia (which we define as 10 mmol/L in 24 hours, 18 mmol/L in 48 hours, and 20 mmol/L in 72 hours) risks iatrogenic brain damage. Appropriate therapy should keep the patient safe from serious complications of hyponatremia while staying well clear of correction rates that risk iatrogenic injury. Accordingly, we suggest therapeutic goals of 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours. Inadvertent overcorrection owing to a water diuresis may complicate any form of therapy, including the newly available vasopressin antagonists. Frequent monitoring of the serum sodium concentration and urine output are mandatory. Administration of desmopressin to terminate an unwanted water diuresis is an effective strategy to avoid or reverse overcorrection.


Local passive immunization by monoclonal antibodies against streptococcal antigen I/II in the prevention of dental caries.
Local passive immunization with monoclonal antibodies (Mc Ab) to Streptococcus mutans was attempted as an alternative approach to active systemic immunization. We prepared an immunoglobulin G class Mc Ab to the cell surface protein determinant of streptococcal antigen I/II and applied it repeatedly to the teeth of rhesus monkeys. This resulted in decreased colonization by S. mutans in fissures and smooth surfaces of teeth and no dental caries, unlike the results in control animals, which developed caries and showed a high proportion of S. mutans on their teeth. There was no significant difference in serum, salivary, or gingival fluid antibodies to S. mutans between the two groups of animals. Any objections raised over systemic immunization inducing cross-reactive antibodies are therefore overcome by local passive immunization. The mechanism of prevention of colonization has not been established, but we postulate that the Mc Ab which is directed against an important cell surface antigenic determinant of S. mutans (streptococcal antigen I/II) prevents adherence of S. mutans to the acquired pellicle on the tooth surface. S. mutans reacts with the Mc Ab and becomes opsonized, phagocytosed, and killed by the local gingival traffic of neutrophils.


Efficacy of layer treatment with methoprene for control of Rhyzopertha dominica (Coleoptera: Bostrychidae) on wheat, rice and maize.
Insect growth regulators are promising alternatives to traditional pesticides in stored grain. The efficacy of the juvenile hormone analogue methoprene was evaluated as a layer treatment in a laboratory experiment for control of Rhyzopertha dominica (F.) (Coleoptera: Bostrychidae) in wheat, rice and maize. Adults of R. dominica were placed in vials containing 33, 26 and 29 g (to a depth of 6.5 cm) of wheat, rice and maize, respectively, that was entirely or partially treated with 1, 5 or 10 mg kg(-1) methoprene. In wheat and rice, the layer treatments were not as effective as the whole-grain treatment, but there was decreased progeny production as the application rate increased. However, on maize the partial treatments were as effective as the whole-grain treatment at 5 and 10 mg kg(-1) . The results suggest that partial layer treatments with methoprene can be used to control R. dominica on maize but may not be effective for control of this species on wheat and rice.


Mitochondrial DNA and the evolutionary genetics of higher animals.
Mitochondrial DNA (mtDNA) in higher animals is rapidly becoming a well characterized genetic system at the molecular level. In this paper, I shift the focus to consider questions in organismal evolution that can be addressed by mtDNA assay. For the first time, it is possible to estimate empirically matriarchal phylogeny; to determine directionality in crosses producing hybrids; and to study the population genetic consequences of varying female demographies and life histories. The data obtainable from mtDNA may be especially well suited for studies of population genetic structure, dispersal, and historical zoogeography. The female-mediated, clonal transmission of mtDNA is also stimulating new ways of thinking about times to common ancestry of asexual lineages within otherwise sexually reproducing populations; about the possible relevance of mtDNA-nuclear DNA interactions to reproductive isolation; and about the very meaning of the phylogenetic status of related species with respect to particular kinds of genetic characters. These and other topics are reviewed.


Efficacy and Efficiency of Nutritional Support Teams.
Malnutrition is frequent in patients during a hospital admission and may further worsen during the hospital stay without appropriate nutritional support. Malnutrition causes greater complication rates, morbidity, and mortality rates, which increases the length of hospital stay and prolongs rehabilitation. Early recognition of individual nutritional risk and timely initiation of a tailored nutritional therapy are crucial. Recent evidence from large-scale trials suggests that efficient nutritional management not only improves the nutritional status, but also prevents negative clinical outcomes and increases patients' quality of life. Multifaceted clinical knowledge is required to ensure optimal nutritional support, according to a patient's individual situation and to avoid potential complications. Furthermore, clear definition of responsibilities and structuring of patient, and work processes are indispensable. Interdisciplinary and multiprofessional nutritional support teams have been built up to ensure and improve the quality and safety of nutritional treatments. These teams continuously check and optimize the quality of procedures in the core areas of nutritional management by implementing nutritional screening processes using a validated tool, nutritional status assessment, an adequate nutritional care plan development, prompt and targeted nutritional treatment delivery, and provision of accurate monitoring to oversee all aspects of care, from catering to artificial nutrition. The foundation of any nutritional care plan is the identification of patients at risk. The aim of this narrative review is to provide an overview about composition, tasks, and challenges of nutritional support teams, and to discuss the current evidence regarding their efficiency and efficacy in terms of clinical outcome and cost effectiveness.


Advances in the Remote Sensing of Terrestrial Evaporation.
Characterizing the terrestrial carbon, water and energy cycles depends strongly on a capacity to accurately reproduce the spatial and temporal dynamics of land surface evaporation. For this, and many other reasons, monitoring terrestrial evaporation across multiple space and time scales has been an area of focused research for many decades. Much of this activity has been supported by developments in satellite remote sensing, which have been leveraged to deliver new process insights, model development and methodological improvements. In this Special Issue, published contributions explored a range of research topics directed towards the enhanced estimation of terrestrial evaporation. Here we summarize these cutting-edge efforts and provide an overview of some of the state-of-the-art approaches for retrieving this key variable. Some perspectives on outstanding challenges, issues, and opportunities are also presented.


Meiotic origin of triploidy in the frog detected by genetic analysis of enzyme polymorphisms.
A female frog heterozygous at two unlinked loci, specifying electrophoretic forms of mannosephosphate isomerase (MPI) and malate dehydrogenase (MDH) was crossed to male frogs homozygous for different alleles at each locus. In the offspring approximately ten percent proved to be triploid according to nucleolar and chromosome counts of tail tip cells. Most of these triploids had both maternal alleles at the MDH and MPI loci suggesting that the first meiotic division was repressed. Others seemed to represent a repressed second meiotic division and one animal, a pentaploid, could only have resulted from inhibition of both meiotic divisions of the egg. Densitometer tracings of starch gels stained for 6 phosphogluconate and isocitrate dehydrogenases, expected to be heterozygous in a particular cross, demonstrated that the triploids had twice as much maternal as paternal gene product for each locus, similar to patterns found in triploids produced by nuclear transplantation.


EINCR1 is an EGF inducible lincRNA overexpressed in lung adenocarcinomas.
Long non-coding RNAs are being increasingly recognised as important molecules involved in regulating a diverse array of biological functions. For example, many long non-coding RNAs have been associated with tumourigenesis and in this context their molecular functions often involves impacting on chromatin and transcriptional control processes. One important cellular control system that is often deregulated in cancer cells is the ERK MAP kinase pathway. Here we have investigated whether ERK pathway signaling in response to EGF stimulation, leads to changes in the production of long non-coding RNAs. We identify several different classes of EGF pathway-regulated lncRNAs. We focus on one of the inducible lincRNAs, EGF inducible long intergenic non-coding RNA 1 (EINCR1). EINCR1 is predominantly nuclear and shows delayed activation kinetics compared to other immediate-early EGF-inducible genes. In humans it is expressed in a tissue-specific manner and is mainly confined to the heart but it exhibits little evolutionary conservation. Importantly, in several cancers EINCR1 shows elevated expression levels which correlate with poor survival in lung adenocarcinoma patients. In the context of lung adenocarcinomas, EINCR1 expression is anti-correlated with the expression of several protein coding EGF-regulated genes. A potential functional connection is demonstrated as EINCR1 overexpression is shown to reduce the expression of EGF-regulated protein coding genes including FOS and FOSB.


The serotonin 5-Hydroxytryptaphan1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, stimulates sympathetic-dependent increases in venous tone during hypovolemic shock.
Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT)(1A) receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of alpha(2)-adrenergic receptors, we hypothesized that the 5-HT(1A) receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of alpha(2)-adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (+44 +/- 3 mm Hg 35 min after injection, P < 0.01 versus saline) and mean circulatory filling pressure (+4.2 +/- 0.7 mm Hg, P < 0.01 versus saline) in conscious rats subjected to hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, alpha(1)-, or peripheral alpha(2)-adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only alpha(1)-adrenergic receptor blockade diminished the pressor effect of the drug (P < 0.01). 8-OH-DPAT raises blood pressure in rats in hypovolemic shock through both direct vascular activation and sympathetic activation of alpha(1)-adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both alpha(1)- and alpha(2)-adrenergic receptors. The data suggest that 5-HT(1A) receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.


Characterization in humans of 18F-MNI-444, a PET radiotracer for brain adenosine 2A receptors.
PET with selective adenosine 2A receptor (A2A) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A2A. The aim of this study was to describe the first in vivo evaluation of (18)F-MNI-444, a novel PET radiotracer for imaging A2A, in healthy human subjects. Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test-retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. After intravenous bolus injection, (18)F-MNI-444 rapidly entered the brain and displayed a distribution consistent with known A2A densities in the brain. Binding potentials ranging from 2.6 to 4.9 were measured in A2A-rich regions, with an average test-retest variability of less than 10%. The estimated whole-body radiation effective dose was approximately 0.023 mSv/MBq. (18)F-MNI-444 is a useful PET radiotracer for imaging A2A in the human brain. The superior in vivo brain kinetic properties of (18)F-MNI-444, compared with previously developed A2A radiotracers, provide the opportunity to foster global use of in vivo A2A PET imaging in neuroscience research.


Endoscopic mucosal resection and endoscopic submucosal dissection for early gastric cancer: Current and original devices.
Compared with endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR) is easier to perform and requires less time for treatment. However, EMR has been replaced by ESD, because achieving en bloc resection of specimens > 20 mm in diameter is difficult with EMR. The technique of ESD was introduced to resect large specimens of early gastric cancer in a single piece. ESD can provide precise histological diagnosis and can also reduce the rate of recurrence, but has a high level of technical difficulty, and is consequently associated with a high rate of complications, a need for advanced endoscopic techniques, and a lengthy procedure time. To overcome disadvantages in both EMR and ESD, various advances have been made in submucosal injections, knives, other accessories, and in electrocoagulation systems.


Androgen-deprivation therapy alone versus combined with radiation therapy or chemotherapy for nonlocalized prostate cancer: a systematic review and meta-analysis.
In this paper, we reviewed the long-term survival outcomes, safety, and quality-of-life of androgen-deprivation therapy (ADT) alone versus combined with radiation therapy (RT) or chemotherapy for locally advanced and metastatic prostate cancer (PCa). A literature search was performed using OvidSP. Randomized controlled trials (RCTs) that met the following criteria were included: including locally advanced or metastatic PCa, comparing ADT alone versus combined with any treatment method and reporting quantitative data of disease control or survival outcomes. Finally, eight RCTs met the inclusion criteria. Among these, three compared ADT versus ADT plus RT (n = 2344) and one compared ADT versus ADT plus docetaxel-estramustine (n = 413) in locally advanced PCa; two compared ADT versus ADT plus docetaxel (n = 1175) and two compared ADT versus ADT plus estramustine (n = 114) in metastatic PCa. For locally advanced PCa, the addition of RT to long-term ADT can improve the outcomes of survival and tumor control with fully acceptable adverse effects. Specially, the pooled odds ratio (OR) of overall survival (OS) was 1.43 (95% confidence interval 1.20-1.71) when compared ADT plus RT with ADT alone (P < 0.0001). For metastatic hormonally sensitive PCa, the concurrent use of docetaxel plus ADT was effective and safe (pooled OR of OS: 1.29 [1.01-1.65]: P = 0.04). In all, long-term ADT plus RT and long-term ADT plus docetaxel should be considered as proper treatment option in locally advanced and metastatic hormonally sensitive PCa, respectively. The major limitation for the paper was that only eight RCTs were available.


Interaction of very late antigen-4 with VCAM-1 supports transendothelial chemotaxis of monocytes by facilitating lateral migration.
The transient regulation of very late antigen (VLA)-4 avidity by CC chemokines may promote chemotaxis of monocytes across VCAM-1-bearing barriers, whereas late and prolonged activation of VLA-5 may mediate subsequent localization in the extracellular matrix. We demonstrate that interactions of VLA-4 with VCAM-1, fibronectin, or a 40-kDa fragment but not a 120-kDa fragment of fibronectin supported the lateral random migration of isolated blood monocytes induced by CC chemokines, termed chemokinesis. This effect was optimal at intermediate substrate concentrations. Moreover, coimmobilization of VCAM-1 with ICAM-1 allowed better migration than ICAM-1 alone. Chemokinesis on VCAM-1 appeared to be associated with transient regulation of VLA-4 avidity by CC chemokines, given that locking VLA-4 in a high avidity state markedly inhibited migration and the locomotion rate was inversely correlated with the adhesive strength of VLA-4 to VCAM-1 following stimulation with monocyte chemoattractant protein-1. Induction of VCAM-1 expression by endothelial activation with IL-4 improved chemokinesis and lateral migration toward a monocyte chemoattractant protein-1 or a monocyte inflammatory protein-1alpha gradient on endothelium and increased transendothelial chemotaxis of monocytes by a VLA-4-dependent mechanism. In contrast, endothelial activation with IL-4 did not affect the time required for diapedesis of monocytes itself. Hence, VCAM-1 may facilitate transendothelial chemotaxis by supporting lateral migration of attached monocytes along endothelium.


Genetic epidemiology and preventive healthcare in multiethnic societies: the hemoglobinopathies.
Healthy carriers of severe Hemoglobinopathies are usually asymptomatic and only efficiently detected through screening campaigns. Based upon epidemiological data, screenings have been offered for decades to populations of endemic Southern Europe for primary prevention of Thalassemia Major, while for many populations of the highly endemic African and Asian countries prevention for Sickle Cell Disease and Thalassemia Major is mainly unavailable. The massive migrations of the last decades have brought many healthy carriers of these diseases to live and reproduce in non-endemic immigration areas changing the epidemiological pattern of the local recessive diseases and bringing an urgent need for treatment and primary prevention in welfare countries. Nonetheless, no screening for an informed reproductive choice is actively offered by the healthcare systems of most of these welfare countries. As a consequence more children affected with severe Hemoglobinopathies are born today in the immigration countries of Northern Europe than in the endemic Southern European area. Following the Mediterranean example, some countries like the UK and The Netherlands have been offering early pregnancy carrier screening at different levels and/or in specific areas but more accessible measures need to be taken at the national level in all immigration countries. Identification of carriers using simple and inexpensive methods should be included in the Rhesus and infectious diseases screening which is offered early in pregnancy in most developed countries. This would allow identification of couples at risk in time for an informed choice and for prenatal diagnosis if required before the first affected child is born.


Establishing a new service role in tuberculosis care: the tuberculosis link worker.
This paper is a report of a study to develop a social outreach model of care, including the role of a link worker in developing collaborative care pathways, for marginalized groups with tuberculosis. Social risk factors such as homelessness and substance misuse are associated with poor treatment outcomes. Models of interprofessional practice to address the health and social care of patients are needed to improve outcomes. A process evaluation involving a prospective cohort study of 100 patients and interviews with eight agencies involved in their care was conducted in London between January 2003 and April 2005. Outcome measures included a profile of patient need to guide service development; referrals to care providers; goal attainment; social improvement and treatment outcomes; and agencies' views on the benefits of link working. The median age of the sample was 32.4 years and 62% were males. Reasons for referral to the link worker included housing need (56%); welfare benefits (42%); immigration (29%) and clinical management issues (28%). One-third of the patients were referred to other agencies. Goals, as agreed in the care plan, were attained totally or partially for 88% (59/67) of patients and 78% of patients successfully completed treatment. Barriers to attaining goals included service criteria which excluded some groups of patients and, in some cases, a patient's inability to follow a course of action. Link workers can mitigate some of the social risk factors that complicate the treatment of tuberculosis by enabling integrated health and social care.


Brief antecedent ischemia attenuates platelet-mediated thrombosis in damaged and stenotic canine coronary arteries: role of adenosine.
Recent studies suggest that patients with angina before myocardial infarction exhibit improved recovery of coronary perfusion after thrombolysis by an as-yet-unknown mechanism. We therefore proposed that brief antecedent ischemia/reperfusion may, via release of adenosine, improve vessel patency in damaged and stenotic coronary arteries. Anesthetized dogs underwent coronary injury + stenosis, resulting in repeated cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgment of platelet-rich thrombi. Vessel patency was assessed for 3 hours after stenosis by quantification of the nadir of the CFVs, duration of total thrombotic occlusion (flow=0), and area of the flow-time profile (expressed as percent of baseline flow x 180 minutes). In protocol 1, dogs received 10 minutes of coronary occlusion + 10 minutes of reflow or a comparable 20-minute control period before injury + stenosis. The median nadir of the CFVs was higher (4.0 versus 0.3 mL/min), median zero flow duration per 30-minute time interval was shorter (0.4 versus 15.1 minutes), and mean percent flow-time area was greater (54+/-8% versus 28+/-9%) in dogs that received antecedent ischemia versus controls (P<.05). These benefits of antecedent ischemia/reperfusion were largely mimicked by a 10-minute intracoronary adenosine infusion (400 microg/min) in lieu of brief ischemia (protocol 2) and were abolished by administration of the adenosine A1/A2 receptor antagonist PD 115,199 (3 mg/kg i.v.) before brief antecedent coronary occlusion (protocol 3). Brief antecedent ischemia attenuates subsequent platelet-mediated thrombosis in damaged and stenotic canine coronary arteries, due, in large part, to an adenosine-mediated mechanism.


Base of tongue carcinoma: patterns of failure and predictors of recurrence after surgery alone.
Between January 1971 and December 1986, 55 patients with squamous cell carcinoma of the tongue base underwent complete surgical resection with curative intent. No preoperative or postoperative adjuvant therapy was administered. The study group consisted of 41 men and 14 women (median age 61 years). All patients were followed until death (39 patients) or for a median of 9.4 years. Local control at 5 years was 74%. No predictors of local recurrence were discovered. Control in the dissected neck at 5 years was 68%. Control of cancer above the clavicles at 5 years was 48%. Distant metastases developed in 14% of the patients by 5 years. Cause-specific survival at 5 years was 65%. A Cox multivariate regression analysis revealed that pathologic N stage was the only significant independent predictor of recurrence in the dissected neck, recurrence above the clavicles, and cause-specific survival. The 5-year overall survival was 55%. Surgical mortality was 4%.


Can the fetal fibronectin test be used by remote dwelling pregnant women to predict the onset of labour at term and delay transfer for birth in regional settings?
The closure of rural maternity units in Australia means an increasing number of women are transferred into major centres to await birth. Accurately excluding the onset of labour could delay relocation. The fetal fibronectin (fFN) test is used to predict preterm birth; however, the accuracy of this test for determining impending term birth is unclear. 75 women were recruited to this study from<strong> </strong>two remote maternity units. Eligibility criteria were: aged &#8805;18 years, singleton pregnancy, 37+0-40+3 weeks (37 weeks to 40 weeks and 3 days gestation) and no indication for induction of labour or caesarean section in next 7 days. The Quikcheck fFN® test was performed at 37 weeks and then repeated at 7 day intervals. Time-to-birth from test date was modelled using linear regression. Logistic regression models estimated odds of birth within 7 days. Separate models considered first and last test results and those at 38 weeks; adjusted for use of lubricant and gestational age. A shorter time-to-birth was found in women with positive compared with negative fFN tests; significant at first fFN test (adjusted mean difference [AMD] 5.4 days, 95% CI 2.0-8.8) and 38 weeks (AMD 5.7 days, 95% CI 2.2-9.2 days). A positive test was also associated with a significant increase in the odds of birthing within 7 days: first fFN test adjusted odds ratio (AOR) 11.0 (95% CI 2.5-48.7), 38 weeks test AOR 14.4 (95% CI 3.4-60.2), last fFN test AOR 8.1 (95% CI 1.6-39.8). However, of women who gave birth within 7 days of testing a significant proportion had a negative fFN result; first fFN test 8/17(47.1%), 38 weeks test 4/14(28.6%) and last fFN test 29/58(50.0%). The presence of fFN in cervical secretions was associated with impending term birth but its absence did not reliably exclude the onset of birth. Delaying transfer based on these findings would result in some women birthing in their home communities.


Acquisition of imitative speech by schizophrenic children.
Two mute schizophrenic children were taught imitative speech within an operant conditioning framework. The training procedure consisted of a series of increasingly fine verbal discriminations; the children were rewarded for closer and closer reproductions of the attending adults' speech. We found that reward delivered contingent upon imitation was necessary for development of imitation. Furthermore, the newly established imitation was shown to have acquired rewarding properties for the children.


[Homeopathic therapy of chronic prostatitis in participants of the Chernobyl AES accident clean-up].
An accident on the Chernobyl Atomic Power Station (CHAPS) caused unprecedented ecological catastrophe and the problems of studying of the ionizing radiation action on human organism appeared. Irradiation causes occurrence of local reactions in prostatic gland. The efficacy of complex homeopathic remedies produced by firm "Heel" is established in the treatment of chronic prostatitis in participants of an accident liquidation on the CHAPS.


Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays.
Meningiomas are common intracranial tumors, but relatively little is known about the genetic events responsible for their clinical diversity. Although recent genomic studies have provided clues, the genes identified often differ among publications. We used microarray expression profiling to identify genes that are differentially expressed, with at least a 4-fold change, between grade I and grade III meningiomas. We filtered this initial set of potential biomarkers through a second cohort of meningiomas and then verified the remaining genes by quantitative polymerase chain reaction followed by examination using a third microarray expression cohort. Using this approach, we identified 9 overexpressed (TPX2, RRM2, TOP2A, PI3, BIRC5, CDC2, NUSAP1, DLG7, SOX11) and 2 underexpressed (TIMP3, KCNMA1) genes in grade III versus grade I meningiomas. As a further validation step, we analyzed these genes in a fourth cohort and found that patients with grade II meningiomas with high topoisomerase 2-α protein expressions (>5% labeling index) had shorter times to death than patients with low expressions. We believe that this multistep multi-cohort approach provides a robust method for reducing false-positives while generating a list of reproducible candidate genes that are associated with clinically aggressive meningiomas and are suitable for analysis for their potential prognostic value.


AtPIG-S, a predicted Glycosylphosphatidylinositol Transamidase subunit, is critical for pollen tube growth in Arabidopsis.
Glycosylphosphatidylinositol (GPI) addition is one of the several post-translational modifications to proteins that increase their affinity for membranes. In eukaryotes, the GPI transamidase complex (GPI-T) catalyzes the attachment of pre-assembled GPI anchors to GPI-anchored proteins (GAPs) through a transamidation reaction. A mutation in AtGPI8 (gpi8-2), the putative catalytic subunit of GPI-T in Arabidopsis, is transmitted normally through the female gametophyte (FG), indicating the FG tolerates loss of GPI transamidation. In contrast, gpi8-2 almost completely abolishes male gametophyte (MG) function. Still, the unexpected finding that gpi8-2 FGs function normally requires further investigation. Additionally, specific developmental defects in the MG caused by loss of GPI transamidation remain poorly characterized. Here we investigated the effect of loss of AtPIG-S, another GPI-T subunit, in both gametophytes. Like gpi8-2, we showed that a mutation in AtPIG-S (pigs-1) disrupted synergid localization of LORELEI (LRE), a putative GAP critical for pollen tube reception by the FG. Still, pigs-1 is transmitted normally through the FG. Conversely, pigs-1 severely impaired male gametophyte (MG) function during pollen tube emergence and growth in the pistil. A pPIGS:GFP-PIGS transgene complemented these MG defects and enabled generation of pigs-1/pigs-1 seedlings. However, the pPIGS:GFP-PIGS transgene seemingly failed to rescue the function of AtPIG-S in the sporophyte, as pigs-1/pigs-1, pPIGS:GFP-PIGS seedlings died soon after germination. Characterization of pigs-1 provided further evidence that the FG tolerates loss of GPI transamidation more than the MG and that the MG compared to the FG may be a better haploid system to study the role of GPI-anchoring. Pigs-1 pollen develops normally and thus represent a tool in which GPI anchor biosynthesis and transamidation of GAPs have been uncoupled, offering a potential way to study free GPI in plant development. While previously reported male fertility defects of GPI biosynthesis mutants could have been due either to loss of GPI or GAPs lacking the GPI anchor, our results clarified that the loss of mature GAPs underlie male fertility defects of GPI-deficient pollen grains, as pigs-1 is defective only in the downstream transamidation step.


Fluticasone propionate and pentamidine isethionate reduce airway hyperreactivity, pulmonary eosinophilia and pulmonary dendritic cell response in a guinea pig model of asthma.
In this study, we examined the effects of fluticasone propionate (FP) and pentamidine isethionate (PI) on antigen-induced lung inflammation and airway hyperreactivity in guinea pigs. Male guinea pigs were sensitized on days 0 and 14 with 10 micrograms of ovalbumin (OVA) plus 1 mg of Al(OH)3. On day 21, animals were challenged with a 2% OVA aerosol inhalation until they developed pulmonary obstruction. Animals were treated with aerosol inhalation of FP (2 ml of 0.5 mg/ml, five consecutive doses at 12-hr intervals with the last dose given 6 hr before OVA challenge) or PI (30 mg/ml for 30 min 1 hr before OVA challenge), and control animals received no drug before OVA challenge. Airway reactivity to methacholine (MCh) was assessed before sensitization and 18 hr after OVA challenge. At 18 hr after challenge, histological sections of trachea and lung were examined for eosinophil, dendritic cell (DC) and macrophage cell densities in the airways. In control animals, OVA evoked airway hyperreactivity to MCh in conjunction with pulmonary eosinophilia and increases in DC prevalence in the trachea and bronchi. Treatment with FP or PI abolished the OVA-induced hyperresponsiveness and significantly reduced the OVA-induced increases in eosinophils and DCs in the airways. FP and PI had no effect on saline-treated animals. Our study indicates that both inhaled FP and inhaled PI reduce antigen-induced airway hyperreactivity and pulmonary inflammation in guinea pigs. The results also suggest that the DC is a target of the anti-inflammatory effects of these drugs in the airways.


Cafeteria diet-induced insulin resistance is not associated with decreased insulin signaling or AMPK activity and is alleviated by physical training in rats.
Excess energy intake via a palatable low-fat diet (cafeteria diet) is known to induce obesity and glucose intolerance in rats. However, the molecular mechanisms behind this adaptation are not known, and it is also not known whether exercise training can reverse it. Male Wistar rats were assigned to 12-wk intervention groups: chow-fed controls (CON), cafeteria diet (CAF), and cafeteria diet plus swimming exercise during the last 4 wk (CAF(TR)). CAF feeding led to increased body weight (16%, P < 0.01) and increased plasma glucose (P < 0.05) and insulin levels (P < 0.01) during an IVGTT, which was counteracted by training. In the perfused hindlimb, insulin-stimulated glucose transport in red gastrocnemius muscle was completely abolished in CAF and rescued by exercise training. Apart from a tendency toward an approximately 20% reduction in both basal and insulin-stimulated Akt Ser(473) phosphorylation (P = 0.051) in the CAF group, there were no differences in insulin signaling (IR Tyr(1150/1151), PI 3-kinase activity, Akt Thr(308), TBC1D4 Thr(642), GSK3-alpha/beta Ser(21/9)) or changes in AMPKalpha1 or -alpha2, GLUT4, Munc18c, or syntaxin 4 protein expression or in phosphorylation of AMPK Thr(172) among the groups. In conclusion, surplus energy intake of a palatable but low-fat cafeteria diet resulted in obesity and insulin resistance that was rescued by exercise training. Interestingly, insulin resistance was not accompanied by major defects in the insulin-signaling cascade or in altered AMPK expression or phosphorylation. Thus, compared with previous studies of high-fat feeding, where insulin signaling is significantly impaired, the mechanism by which CAF diet induces insulin resistance seems different.


Monitoring the Viral Transmission of SARS-CoV-2 in Still Waterbodies Using a Lanthanide-Doped Carbon Nanoparticle-Based Sensor Array.
The latest epidemic of extremely infectious coronavirus disease 2019 (COVID-19) has created a significant public health concern. Despite substantial efforts to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within a specific location, shortcomings in the surveillance of predominantly asymptomatic infections constrain attempts to identify the epidemiological spread of the virus. Continuous surveillance of wastewater streams, including sewage, offers opportunities to track the spread of SARS-CoV-2, which is believed to be found in fecal waste. To demonstrate the feasibility of SARS-CoV-2 detection in wastewater systems, we herein present a novel facilely constructed fluorescence sensing array based on a panel of three different lanthanide-doped carbon nanoparticles (LnCNPs). The differential fluorescence response pattern due to the counterion-ligand interactions allowed us to employ powerful pattern recognition to effectively detect SARS-CoV-2 and differentiate it from other viruses or bacteria. The sensor results were benchmarked to the gold standard RT-qPCR, and the sensor showed excellent sensitivity (1.5 copies/μL) and a short sample-to-results time of 15 min. This differential response of the sensor array was also explained from the differential mode of binding of the LnCNPs with the surface proteins of the studied bacteria and viruses. Therefore, the developed sensor array provides a cost-effective, community diagnostic tool that could be potentially used as a novel epidemiologic surveillance approach to mitigate the spread of COVID-19.


Innate immune responses in RNA viral infection.
RNA viruses cause a multitude of human diseases, including several pandemic events in the past century. Upon viral invasion, the innate immune system responds rapidly and plays a key role in activating the adaptive immune system. In the innate immune system, the interactions between pathogen-associated molecular patterns and host pattern recognition receptors activate multiple signaling pathways in immune cells and induce the production of pro-inflammatory cytokines and interferons to elicit antiviral responses. Macrophages, dendritic cells, and natural killer cells are the principal innate immune components that exert antiviral activities. In this review, the current understanding of innate immunity contributing to the restriction of RNA viral infections was briefly summarized. Besides the main role of immune cells in combating viral infection, the intercellular transfer of pathogen and host-derived materials and their epigenetic and metabolic interactions associated with innate immunity was discussed. This knowledge provides an enhanced understanding of the innate immune response to RNA viral infections in general and aids in the preparation for the existing and next emerging viral infections.


Cost-effectiveness of direct acting oral anticoagulants in the prevention of thromboembolic complications: limits and concerns of economic evaluations.
: Economic evaluations have a widespread application in many areas of clinical research and play a key role in the clinical decision-making process. However, economic analyses have been sometimes used to produce new 'evidence' that is not adequately tested in the target population. This is the case of data arising from a systematic review of clinical trials evaluating the use of direct acting oral anticoagulants for the prevention of stroke in patients with atrial fibrillation. Taking into account this example, here we discuss the concerns raised by the improper interpretation of the results. Our conclusions are three-fold. Data from economic analyses should not be shifted to a clinical recommendation. Simulation models should not be used to generate new 'evidence' that is not supported by experimental data and is misleading. Clinical judgment is therefore pivotal to interpret results emerging from economic analyses.


What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis.
To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.


Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement.
Purpose The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention's benefit-risk profile. Methods ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community. Results Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low. Conclusion To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.


Ganglion-specific patterns of diabetes-modulated gene expression are established in prevertebral and paravertebral sympathetic ganglia prior to the development of neuroaxonal dystrophy.
In both humans and animal models, diabetic sympathetic autonomic neuropathy is associated with the selective development of markedly enlarged distal axons and nerve terminals (neuroaxonal dystrophy, NAD). NAD occurs in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), but not in the paravertebral superior cervical ganglion (SCG). To identify molecular differences between these ganglia that may explain their selective vulnerability to NAD, we have examined global gene expression patterns in control and diabetic rat sympathetic ganglia before and after the onset of structural evidence of NAD. As predicted, major differences in transcriptional profiles exist between SCG and SMG-CG in normal young adult animals including, but not limited to, known differences in neurotransmitter-related gene expression. Gene expression patterns of diabetic SMG-CG and SCG, prior to the development of NAD lesions, also differ from their age-matched non-diabetic counterparts. However, diabetes has ganglion-specific effects on gene expression; of approximately 110 transcripts that were differentially expressed between diabetic and control sympathetic ganglia, only 5 were differentially expressed as a result of diabetes in both SCG and SMG-CG. Genes involving synapse and mitochondrial structure and function, oxidative stress, and glycolysis were highly represented in the differentially expressed gene set. Differences in the number of synapse-related gene alterations in diabetic SMG-CG (18 genes) versus SCG (2 genes) prior to the onset of NAD may also well explain the selective development of NAD in the SMG-CG. These results provide support for the specificity of diabetes-modulated gene expression for selected neuronal subpopulations of sympathetic noradrenergic neurons.


Effect of monomeric and polymeric co-solutes on cetyltrimethylammonium bromide wormlike micelles: rheology, Cryo-TEM and small-angle neutron scattering.
The effect of hydrophobic and hydrophilic co-solutes on the rheological properties of wormlike micelles of cetyltrimethylammonium bromide (CTAB) and sodium salicylate (NaSal) or sodium bromide (NaBr) was investigated. Monomeric (ethanol, 2-propanol, benzene and benzylic alcohol) and polymeric species (poly(ethylene oxide), poly(vinyl alcohol) and poly(propylene oxide), respectively PEO, PVA and PPO) of varying molecular weight were studied in order to assess the effect of co-solute 'length' on the interactions with the wormlike micelles. Rheological properties were characterised by the plateau modulus G(0) and the relaxation time τ(R) obtained from fits to the Maxwell model, and by the zero-shear viscosity η(0). The rheological properties were unaltered by the addition of all hydrophilic solutes (up to 20 mM). With hydrophobic co-solutes instead, both η(0) and τ(R) decreased considerably, while G(0) was unaffected. The effects were particularly remarkable with PPO for concentrations as low as 5 mM (ca. 0.3 g L(-1)), and τ(R) was seen to follow an exponential decrease with polymer M(w). The effect of the aromatic solutes (benzene and benzyl alcohol) on the rheology was highly dependent on the counterions used to induce micellar growth (Sal(-) or Br(-)), revealing a different type of interaction. Surprisingly, small-angle neutron scattering and Cryo-TEM measurements showed that the drastic changes observed in the rheology were not correlated to any visible structural change. Therefore the strong decrease in viscosity and relaxation time are to be attributed to other mechanisms than micellar break-up or rod-to-sphere transition.


Interleukin-7 production by B lymphocytes affects the T cell-dependent osteoclast formation in an in vitro model derived from human periodontitis patients.
Periodontitis is characterized by irreversible destruction of alveolar bone and connective tissue attachment in the periodontium. We recently reported that T cells support the osteoclastogenesis by the overproduction of nuclear factor-kappa-B-ligand (RANKL) and Tumor Necrosis Factor-alpha (TNF-alpha) in an in vitro osteoclastogenesis model from periodontitis patients (Pp). It is known that IL-7 stimulates the production of osteoclastogenic factors by T cells and IL-6 potentiates IL-7 expression. Thus, we studied the involvement of IL-6 and IL-7 in the T cell regulation of osteoclast (OC) formation, in an in vitro osteoclastogenesis model from Pp. We demonstrated high levels of IL-7 in both the media collected from PBMC cultures of Pp and the sera of the same patients. We also demonstrated that freshly isolated B cells from PBMCs of Pp were the source of IL-7 in our model. B cells, in fact, overexpressed IL-7 at mRNA and protein levels, and this production was up-regulated by IL-6. Moreover, the OC formation decreased in the presence of anti-IL-6 and IL-7 functional antibodies in PBMC cultures from Pp. These data suggest that B cells could be responsible for the T cell-dependent osteoclastogenesis in periodontitis through the involvement of IL-6 and IL-7.


Mild Traumatic Brain Injury Induces Transient, Sequential Increases in Proliferation, Neuroblasts/Immature Neurons, and Cell Survival: A Time Course Study in the Male Mouse Dentate Gyrus.
Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes the process of DG neurogenesis. Here we utilized a clinically relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data show this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which is suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.


Aeolian transport of viable microbial life across the Atacama Desert, Chile: Implications for Mars.
Here we inspect whether microbial life may disperse using dust transported by wind in the Atacama Desert in northern Chile, a well-known Mars analog model. By setting a simple experiment across the hyperarid core of the Atacama we found that a number of viable bacteria and fungi are in fact able to traverse the driest and most UV irradiated desert on Earth unscathed using wind-transported dust, particularly in the later afternoon hours. This finding suggests that microbial life on Mars, extant or past, may have similarly benefited from aeolian transport to move across the planet and find suitable habitats to thrive and evolve.


Metagenomics of antimicrobial and heavy metal resistance in the cecal microbiome of fattening pigs raised without antibiotics.
This study aimed to detect the cecal microbiome, antimicrobial resistance (AMR) and heavy metal resistance genes (MRGs) in fattening pigs raised under antibiotic-free (ABF) conditions compared with ordinary industrial pigs (control, C) using whole-genome shotgun sequencing. ABF pigs showed the enrichment of Prevotella (33%) and Lactobacillus (13%), whereas Escherichia coli (40%), Fusobacterium and Bacteroides (each at 4%) were notably observed in the C group. Distinct clusters of cecal microbiota of ABF and C pigs were revealed; however, microbiota of some C pigs (C1) appeared in the same cluster as ABF and were totally separated from the remaining C pigs (C2). For AMR genes, the highest abundance tet(Q) (35.7%) and mef(A) (12.7%) were markedly observed in the ABF group whereas tet(Q) (26.2%) and tet(W) (10.4%) were shown in the C group. tet(Q) was positively correlated to Prevotella in ABF and C1 samples. In the C2 group, the prominent tet(W) was positively correlated to Fusobacterium and Bacteroides Pigs have never received tetracycline but pregnant sows used chlortetracycline once 7 d before parturition. Chromosomal Cu and Zn resistance genes were also shown in both groups regardless the received Cu and Zn feed additives. A higher abundance of multi-metal resistance genes was observed in the C group (44%) compared with the ABF group (41%). In conclusion, the microbiome clusters in some C pigs were similar to that in ABF pigs. High abundant tetracycline resistance genes interrelated to major bacteria were observed in both ABF and C pigs. MRGs were also observed.IMPORTANCE: Owing to the increased problem of AMR in farm animals, raising farm animals without antibiotics is one method that could solve this problem. Our study showed that only some tetracycline and macrolide resistance genes, tet(Q), tet(W) and mef(A), were markedly abundant in ABF and C groups. The tet(Q) and tet(W) genes interrelated to different predominant bacteria in each group, showing the potential role of major bacteria as reservoirs of AMR genes. In addition, chromosomal Cu and Zn resistance genes were also observed in both pig groups, not depending on the use of Cu and Zn additives in both farms. The association of MRGs and AMR genotypes and phenotypes together with the method to re-sensitize bacteria to antibiotics should be studied further to unveil the cause of high resistance genes and solve the problems.


Maritime accident investigation methodologies.
Whenever a naval disaster occurs, a public outcry is heard to a full investigation into the causes of the event. Although the maritime industry has an outstanding reputation in accident investigation, such investigations are hardly conducted in inland shipping or leisure craft sailing. Due to a number of serious accidents in the maritime sector and increasing interest by public and media, the philosophy of independent investigations has gained interest at a policy making level in the European Union and with international NGO's, such as the International Maritime Organization IMO. The purpose of this paper is to discuss the application of this methodology in all segments of shipping. The paper elaborates a conceptual model, principle processes and available techniques as a common orientation to safety-focused investigations. Accident investigation reports of Dutch investigative agencies are benchmarked to this model assessing the potential of the approach to all segments of shipping. It shows the applicability to minor as well as major accidents and the importance of independence. Systemic deficiencies at all levels in safety of shipping are identified and a generic applicability is demonstrated. It is concluded that independent accident investigation provides a powerful diagnostic tool for reducing the peril of drowning.


Prognostic role of preoperative D-dimer, fibrinogen and platelet levels in patients with oral squamous cell carcinoma.
The relationship between cancer and coagulation has been intensively studied in recent years; however, the effects of coagulation factors on oral squamous cell carcinoma (OSCC) have rarely been reported. This study aimed to investigate the relationship between preoperative D-dimer (DD), fibrinogen (FIB), platelets (PLT) and OSCC, as well as the prognostic value of DD, FIB and PLT in OSCC. We retrospectively investigated a total of 202 patients with OSCC treated at Guanghua Hospital of Stomatology, Sun Yat-sen University. Baseline demographic and clinicopathological information as well as both preoperative and postoperative DD, FIB and PLT results were collected from each patient, and patients with primary OSCC were followed up for disease progression, death or the end of the study. The correlations between preoperative DD, FIB, PLT and other clinical features, as well as the therapeutic effect and PFS were analysed statistically, and postoperative DD and surgical parameters were also analysed. Preoperative DD was significantly correlated with T stage, N stage, clinical stage and relapse of OSCC (P = 0.000, 0.001, 0.000 and 0.000, respectively). Univariate Cox regression analyses showed that high preoperative DD predicted poor prognosis in patients with OSCC (HR = 2.1, P = 0.033), while FIB and PLT showed no prognostic values. Postoperative DD was significantly correlated with preoperative DD and surgical type but not the duration of surgery (P = 0.005, 0.001 and 0.244, respectively). In this study, we suggested that high preoperative DD level may serve as an indicator for synchronous neck dissection in patients with T1, 2 OSCC, and the elevated DD level might be the marker of disease progression in patient follow up.


No evidence of sperm selection by female common shrews.
There is currently much interest in the suggestion that females are capable of post-copulatory (or cryptic) choice for male genetic compatibility. Here, I investigate this idea using data from mixed-paternity litters of the common shrew (Sorex araneus). Females of this species are highly promiscuous and, in natural populations, regularly incur costs of inbreeding by mating with close relatives. Selection should therefore favour female ability for sperm selection on the basis of male relatedness. No evidence was found in support of this idea. Relative number of offspring sired within mixed paternity litters was not significantly correlated with genetic similarity of males to the female mated. Relative fertilization success was, however, significantly related to male epididymal sperm counts. I conclude that most variation in relative fertilization success of male common shrews can be explained in terms of sperm competition, and that females of this species may not be capable of sperm selection.


Maternal mortality in Bahrain 1987-2004: an audit of causes of avoidable death.
The aim of this report was to establish the national maternal mortality rate in Bahrain over the period 1987-2004, to identify preventable factors in maternal deaths and to make recommendations for safe motherhood. There were 60 maternal deaths out of 243 232 deliveries giving an average maternal mortality rate of 24.7 per 100 000 total births. The main causes of death were sickle-cell disease (25.0%), hypertension (18.3%), embolism (13.3%), haemorrhage (13.3%), heart disease (11.7%), infection (8.3%) and other (10.0%). In an audit of care, 17 (28.3%) out of 60 deaths were judged to be avoidable, nearly half of which were due to a shortage of intensive care beds. We recommend that a confidential enquiry of maternal deaths be conducted at the national level every 3 to 5 years.


Minimum-mean-square-error filters for detecting a noisy target in background noise.
A minimum-mean-square-error filter is proposed to detect a noisy target in spatially nonoverlapping background noise. In this model, both the background noise that is spatially nonoverlapping with the target and the noise that is additive to the target and the input image are considered. The criterion used to design the filter is to minimize the mean-square-error between the filter output and a delta function located at the target position in the presence of the noise. Computer-simulation results for a number of noisy input images are presented, and the performance of the filter is determined. We also test the filter discrimination against undesired objects and tolerance to target distortions, such as rotation and scaling.


Postnatal blood pressure in the preterm small for gestational age neonate.
Determine how blood pressure differs in premature infants born small for gestational age (SGA). A retrospective study was conducted on inborn infants 24-32 weeks gestation. Mean arterial blood pressure (MAP) was collected and averaged every 12 h for the first 96 h of life. For each time point, the difference MAP in SGA vs. AGA infants was evaluated with t-testing. Linear mixed-effects modeling was performed to model MAP over time accounting for GA, BW, gender, and SGA status. 356 subjects were evaluated. 52 (14.6%) were SGA. SGA infants were smaller, more likely male, exposed to maternal hypertension, born via caesarian section, and have chronic lung disease and retinopathy of prematurity. MAP in the SGA group more closely matched the MAP of AGA babies of similar GA for the first 24 h of life. Subsequently, SGA infants had lower MAPs more closely resembling their weight-matched counterparts. Mixed modeling showed GA to be significant, p < 0.0001 while BW though still marginally significant had less of an effect, p = 0.049. SGA infants have blood pressure that is strongly associated with GA in the first 24 hours of life, but then fails to increase at the same rate as their AGA counterparts.


Antidepressive Effects of Taraxacum Officinale in a Mouse Model of Depression Are Due to Inhibition of Corticosterone Levels and Modulation of Mitogen-Activated Protein Kinase Phosphatase-1 (Mkp-1) and Brain-Derived Neurotrophic Factor (Bdnf) Expression.
BACKGROUND Depression is a common disorder linked with high levels of chronicity, psycho-social and physical problems, and suicide. Here, we assessed the antidepressant effects of the hydromethanolic extract of Taraxacum officinale and investigated the underlying mechanism. MATERIAL AND METHODS Antidepressant effects were examined by use of the tail suspension test (TST). Concentrations of corticosterone, dopamine, noradrenaline, and adrenaline were examined by biochemical assays. The mRNA expression was assessed by quantitative RT-PCR. Phytochemical analysis was performed by LC/MS. RESULTS The results showed that the extract at the dosage of 50 and 100 mg/kg significantly (p<0.01) alleviated the TST-induced immobility in the mice, and the effects were comparable to the antidepressant drug Bupropion, which was used as the positive control. Investigation of the underlying mechanism revealed that the T. officinale extract exerts it effects by significantly (p<0.05) decreasing the levels of corticosterone and increasing the concentrations of dopamine, noradrenaline, and adrenaline. Further, the extract also increased the expression of brain-derived neurotrophic factor (Bdnf), which was associated with significant (p<0.05) decrease in the expression of mitogen-activated protein kinase phosphatase-1 (Mkp-1), indicative of the antidepressant potential of T. officinale. Finally, the active constituents of the extract, which include isoetin, hesperidin, naringenin, Kaempferol, sinapinic, and gallic acid, were also identified, which could potentially be responsible for its antidepressant effects. CONCLUSIONS In conclusion, T. officinale exerts significant antidepressant effects in a mouse model of depression by inhibition of corticosterone levels and modulation of Mkp-1 and Bdnf expression.


Mediterranean diet and upper aerodigestive tract cancer: the Greek segment of the Alcohol-Related Cancers and Genetic Susceptibility in Europe study.
Several dietary factors have been associated with the occurrence of cancers of the oral cavity and oropharynx, larynx and oesophagus, collectively called upper aerodigestive tract (UADT) cancers, but the evidence is considered as inconclusive. We hypothesised that the traditional Mediterranean dietary pattern may be more strongly inversely associated with UADT cancer risk than individual dietary components, and may explain the unexpectedly low incidence of these cancers in Greece. In the context of the European alcohol-related cancers and genetic susceptibility in Europe project, we have conducted a hospital-based case-control study in Athens, Greece, comparing 239 incident UADT cases and 194 hospital controls with admission diagnoses unrelated to tobacco, alcohol or diet. Adherence to Mediterranean diet was assessed through a widely used score, which ranges from 0 (minimal adherence) to 9 (maximal adherence) and increases with high consumption of plant foods and olive oil and low consumption of meat, dairy products and saturated lipids. Stricter adherence to the Mediterranean diet was associated with a substantial and significant decrease in UADT cancer risk (30 % for a two-unit increase in score), whereas after mutual adjustment, no individual dietary component of this diet was significantly associated with this risk. Adherence to the traditional Mediterranean diet is associated with reduced risk of UADT cancers, and may explain the lower incidence of UADT cancers in Greece, in spite of the smoking and drinking habits of this population.


Effect of Time on MRI Appearance of Graft After ACL Reconstruction: A Comparison of Autologous Hamstring and Quadriceps Tendon Grafts.
After anterior cruciate ligament (ACL) reconstruction (ACLR), changes in the appearance of the ACL graft can be monitored using magnetic resonance imaging (MRI). The purpose of this study was to evaluate and compare the MRI signal intensity (SI) of hamstring and quadriceps tendon grafts during the first postoperative year after ACLR. As a secondary aim, the relationship of SI to clinical and anatomic measurements was analyzed. Cohort study; Level of evidence, 2. A total of 78 patients who underwent ACLR with an autologous graft were reviewed; 55 received hamstring grafts and 23 received quadriceps tendon grafts. At 3 and 9 months postoperatively, 3-T MRI was performed using a dedicated knee coil, and the median SI of the intra-articular ACL graft was measured on sagittal-plane images. Postoperative lateral radiographs were analyzed to determine medial and lateral posterior tibial slope (PTS). Side-to-side difference in anterior knee laxity between injured and uninjured limbs was measured at 6 and 12 months postoperatively. The median SI of quadriceps grafts was significantly greater than hamstring grafts at 3 months after ACLR (P = .02). Between 3 and 9 months, the median SI of quadriceps grafts decreased (P < .001), while that of hamstring grafts did not significantly change (P = .55). The lateral PTS was significantly correlated with median SI measurements at 3 and 9 months such that greater lateral PTS values were associated with greater median SI. The side-to-side difference in anterior knee laxity decreased for the quadriceps group (P = .04) between 6 and 12 months but did not change for the hamstring group (P = .88). The median SI of quadriceps grafts significantly decreased on MRI between 3 and 9 months after ACLR, while the median SI of hamstring grafts did not significantly change. The change in MRI appearance of the quadriceps grafts was paralleled by a reduction in anterior knee laxity between 6 and 12 months after surgery. In the absence of standardized imaging techniques and imaging analysis methods, the role of MRI in determining graft maturation, and the implications for progression through rehabilitation to return to sport, remain uncertain.


Nonreciprocity in the dynamics of coupled oscillators with nonlinearity, asymmetry, and scale hierarchy.
In linear time-invariant dynamical and acoustical systems, reciprocity holds by the Onsager-Casimir principle of microscopic reversibility, and this can be broken only by odd external biases, nonlinearities, or time-dependent properties. A concept is proposed in this work for breaking dynamic reciprocity based on irreversible nonlinear energy transfers from large to small scales in a system with nonlinear hierarchical internal structure, asymmetry, and intentional strong stiffness nonlinearity. The resulting nonreciprocal large-to-small scale energy transfers mimic analogous nonlinear energy transfer cascades that occur in nature (e.g., in turbulent flows), and are caused by the strong frequency-energy dependence of the essentially nonlinear small-scale components of the system considered. The theoretical part of this work is mainly based on action-angle transformations, followed by direct numerical simulations of the resulting system of nonlinear coupled oscillators. The experimental part considers a system with two scales-a linear large-scale oscillator coupled to a small scale by a nonlinear spring-and validates the theoretical findings demonstrating nonreciprocal large-to-small scale energy transfer. The proposed study promotes a paradigm for designing nonreciprocal acoustic materials harnessing strong nonlinearity, which in a future application will be implemented in designing lattices incorporating nonlinear hierarchical internal structures, asymmetry, and scale mixing.


An update review on Commiphora molmol and related species.
The origins of myrrh and frankincense are traced to the Arabian Peninsula. According to Herodotus (5th century BC): "Arabia is the only country which produces frankincense, myrrh, cassia, and cinnamon.., the trees bearing the frankincense are guarded by winged serpents of small size and various colors." Diodorus Siculus wrote, in the second half of the first century BC, that "all of Arabia exudes a most delicate fragrance; even the seamen passing by Arabia can smell the strong fragrance that gives health and vigor." He also mentioned gold mines so pure that no smelting was necessary. The Magi, carrying myrrh, frankincense, and gold, came from the East: Arabia. The frankincense trade route, with transport by donkeys and later by camel caravans, reached Jerusalem and Egypt from the Dhofar region of what is today Oman, through Yemen, turning north to follow the Red Sea coast. It is likely that the same or similar species of the resin-bearing plants grew across the Red Sea in the area that is now Somalia and Ethiopia, while the collection of the gum resins was initiated in Arabia. Myrrh contributed much in the human welfare. Schistosomiasis was known in ancient Egypt since remote times. Haematuria with urinary bladder disturbances was mentioned in four Papyrus papers dated back to 1950-1900 BC, and Schistosoma ova was detected in a cirrhotic liver of a mummy from 1200 BC (Ruffer, 1910). Also, Fasciola eggs were detected in a mummy (Looss, 1896). Fascioliasis infected over 17 million people worldwide causing marked morbidity and mortality (Haseeb et al., 2002). Schistosomiasis affected over 200 million people in 74 countries and territories worldwide (WHO, 1999) causing several chronic complications. Both were incriminated to predispose or accompanied human hepatitis and predisposed to HCV (Wahib et al., 2006). Most zoonotic helminthes induced immune response (Nutman, 2001) characterized by producing of type 2 cytokines, Ig G1, IgG2, IgE antibodies and eosinophil and mast cell activation (Hoffman et al., 2002). Treatment of fascioliasis required high or drug multiple doses with side effect (Farid et al., 1990). In schistosomiasis, praziquantel (PZQ) in use for > 20 years was faced with low efficacy (Leishout et al., 1998), or with increased resistance (Coles et al., 1986; Watt et al., 1988; Herrera et al., 1994; Ismail et al., 1994; 1999; Tonelli et al., 1995; Stelma et al., 1995; Fallon et al., 1997; Bennett et al., 1997; Boisier et al., 1998; Periera et al., 1998; Kusel and Hagan, 1999; Liang et al., 2000; King et al., 2000; N'Goran et al., 2003; Raso et al., 2004), potentiality of carcinogenicity, genotoxicity (Rosenkranz et al., 1995), mutagenicity (Montero et al., 1993), big dose lethality and enhanced clastogenicity of environmental pollutants (Anwar, 1994). On the other hand, Nomicos (2007) in USA reported that since antiquity, the genus Commiphora is composed of more than 200 species, and exploited as a natural drug to treat pain, skin infections, inflammatory conditions, diarrhea, and periodontal diseases. He added that in more recent history, products derived from C. myrrha and various other species of Commiphora are becoming recognized to possess significant antiseptic, anesthetic, and antitumor properties. Traditional practice and evidence-based research have supported that these properties are directly attributable to terpenoids (especially furanoses-quiterpenes), the active compounds present in myrrh essential oil. Very recently, current studies have focused on applying clinical trial methodologies to validate its use as an antineoplastic, an antiparasitic agent, and as an adjunct in healing wounds. Weeks and Simpson (2007) in USA presented the molecular phylogeny of Commiphora, a predominantly tropical African, arid-adapted tree genus to test the monophyly of its taxonomic sections and to identify clades to help direct future study of this species-rich and geographically widespread taxon. The multiple fossil calibrations of Commiphora phylogeny proved that it is sister to Vietnamese Bursera tonkinensis and that its crown group radiation corresponds with the onset of the Miocene. Auffray (2007) in France studied the impact of two types of antioxidant on sebum squalene peroxidation by UV irradiation. The first type was free radical scavenger (Butyl hydroxyl toluene and an olive extract rich in hydroxytyrosol). The second type was the essential oil of C. myrrha, a singlet oxygen quencher. These properties were confirmed using the 2,2-diphenyl-1-picrylhydrazyl test for anti-radical capacity and 1,3-diphenylisobenzofuran test for the capacity to quench singlet oxygen. Also, the author extended an ex vivo method to classify the efficacy of cosmetics to protect squalene by collecting sebum in vivo and irradiating it in a controlled way. The squalene monohydroperoxide formation was monitored by high performance liquid chromatography. This method compared the efficiency of 3 antioxidants at 0.6% in a cosmetic formulation to protect squalene from photo oxidation. The data showed that essential oil of C. myrrha gave the best protection against squalene peroxidation, and that squalene peroxidation during solar exposure was mainly because of singlet oxygen and not due to free radical attack, and that sun care cosmetics should make use not only of free radical scavengers but also of singlet oxygen quenchers. This study aimed to review more than 70 out of hundreds papers (Pub-med-indexed for Medline) on the medical importance and safety of Commiphora molmol and other Commiphora species.


Naproxen sodium in dysmenorrhea. Its influence in allowing continuation of work/school activities.
Sixty-four women with primary dysmenorrhea participated in a double-blind, parallel trial of maproxen sodium versus placebo during three menstrual cycles. Comparative measures employed to assess the efficacy of the medications included changes in pain intensity during each dysmenorrheic episode, the degree of pain relief afforded, the necessity of using a supplementary analgesic, and the extent to which medication enabled the patients to continue their daily activities unimpeded. By these measures, naproxen sodium was significantly superior as compared to the placebo. Particularly striking was the fact that of 22 naproxen sodium treated women who historically had to stay at home from work and/or in bed, only 5 remained incapacitated compared with 21 of 26 patients of the placebo group. Only 1 patient experienced side effects (nausea and hypomenorrhea) from naproxen sodium.


Bot1p is required for mitochondrial translation, respiratory function, and normal cell morphology in the fission yeast Schizosaccharomyces pombe.
Maintenance of cell morphology is essential for normal cell function. For eukaryotic cells, a growing body of recent evidence highlights a close interdependence between mitochondrial function, the cytoskeleton, and cell cycle control mechanisms; however, the molecular details of this interconnection are still not completely understood. We have identified a novel protein, Bot1p, in the fission yeast Schizosaccharomyces pombe. The bot1 gene is essential for cell viability. bot1Delta mutant cells expressing lower levels of Bot1p display altered cell size and cell morphology and a disrupted actin cytoskeleton. Bot1p localizes to the mitochondria in live cells and cofractionates with purified mitochondrial ribosomes. Reduced levels of Bot1p lead to mitochondrial fragmentation, decreased mitochondrial protein translation, and a corresponding decrease in cell respiration. Overexpression of Bot1p results in cell cycle delay, with increased cell size and cell length and enhanced cell respiration rate. Our results show that Bot1p has a novel function in the control of cell respiration by acting on the mitochondrial protein synthesis machinery. Our observations also indicate that in fission yeast, alterations of mitochondrial function are linked to changes in cell cycle and cell morphology control mechanisms.


Effects of coffee on ambulatory blood pressure in older men and women: A randomized controlled trial.
This study assessed the effects of regular coffee drinking on 24-hour ambulatory blood pressure (ABP) in normotensive and hypertensive older men and women. Twenty-two normotensive and 26 hypertensive, nonsmoking men and women, with a mean age of 72.1 years (range, 54 to 89 years), took part in the study. After 2 weeks of a caffeine-free diet, subjects were randomized to continue with the caffeine-free diet and abstain from caffeine-containing drinks or drink instant coffee (5 cups per day, equivalent to 300 mg caffeine per day) in addition to the caffeine-free diet for a further 2 weeks. Change in systolic and diastolic blood pressures (SBP, DBP) determined by 24-hour ambulatory BP monitoring showed significant interactions between coffee drinking and hypertension status. In the hypertensive group, rise in mean 24-hour SBP was greater by 4.8 (SEM, 1.3) mm Hg (P=0.031) and increase in mean 24-hour DBP was higher by 3.0 (1.0) mm Hg (P=0.010) in coffee drinkers than in abstainers. There were no significant differences between abstainers and coffee drinkers in the normotensive group for 24-hour, daytime, or nighttime SBP or DBP. In older men and women with treated or untreated hypertension, ABP increased in coffee drinkers and decreased in abstainers. Restriction of coffee intake may be beneficial in older hypertensive individuals.


Secretion of insulin-like growth factor-I and binding proteins by rat liver fat-storing cells: regulatory role of platelet-derived growth factor.
Insulin-like growth factor (IGF-I) is synthesized in multiple organs, including the liver, and may play a role in tissue growth and repair. We report that liver fat-storing cells (FSC) secrete IGF-I immunoreactivity in the culture medium. Secretion of IGF-I immunoreactivity was blocked in the presence of cycloheximide, suggesting de novo synthesis. Culture medium conditioned by FSC was concentrated and applied to a Sephadex G100 column equilibrated in a denaturing buffer. Two major species with apparent mol wts of 7.5 and greater than 25 k were identified by IGF-I RIA. Reverse phase HPLC of the 7.5 kilodalton species (the size of IGF-I) showed that it eluted in a single peak. To determine whether the higher mol wt species possessed IGF-I binding activity, appropriate fractions were desalted, incubated with [125I]IGF-I for 2 h at 30 C and applied to a Sephadex G100 column equilibrated in a nondissociating buffer. The major peak of radioactivity was confined to a high mol wt region. Western blot ligand analysis revealed the presence of two insulin-like growth factor binding proteins of approximately 28 and 31 kilodaltons. Platelet-derived growth factor, a potent mitogen for FSC, resulted in a 230% increase in release of IGF-I immunoreactivity that could be accounted for by an increase in IGF-I binding activity. In addition IGF-I increased DNA synthesis in FSC and this effect was additive to that of platelet-derived growth factor. IGF-I treatment also resulted in an increase in cell number. IGF-I and insulin-like growth factor binding proteins secreted by FSC may play a role in the hepatic tissue response to injury via autocrine and/or paracrine mechanisms.


AMPA receptor desensitization is the determinant of AMPA receptor mediated excitotoxicity in purified retinal ganglion cells.
The ionotropic glutamate receptors (iGLuR) have been hypothesized to play a role in neuronal pathogenesis by mediating excitotoxic death. Previous studies on iGluR in the retina have focused on two broad classes of receptors: NMDA and non-NMDA receptors including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and kainate receptor. In this study, we examined the role of receptor desensitization on the specific excitotoxic effects of AMPAR activation on primary retinal ganglion cells (RGCs). Purified rat RGCs were isolated from postnatal day 4-7 Sprague-Dawley rats. Calcium imaging was used to identify the functionality of the AMPARs and selectivity of the s-AMPA agonist. Phosphorylated CREB and ERK1/2 expression were performed following s-AMPA treatment. s-AMPA excitotoxicity was determined by JC-1 mitochondrial membrane depolarization assay, caspase 3/7 luciferase activity assay, immunoblot analysis for α-fodrin, and Live (calcein AM)/Dead (ethidium homodimer-1) assay. RGC cultures of 98% purity, lacking Iba1 and GFAP expression were used for the present studies. Isolated prenatal RGCs expressed calcium permeable AMPAR and s-AMPA (100 μM) treatment of cultured RGCs significantly increased phosphorylation of CREB but not that of ERK1/2. A prolonged (6 h) AMPAR activation in purified RGCs using s-AMPA (100 μM) did not depolarize the RGC mitochondrial membrane potential. In addition, treatment of cultured RGCs with s-AMPA, both in the presence and absence of trophic factors (BDNF and CNTF), did not increase caspase 3/7 activities or the cleavage of α-fodrin (neuronal apoptosis marker), as compared to untreated controls. Lastly, a significant increase in cell survival of RGCs was observed after s-AMPA treatment as compared to control untreated RGCs. However, preventing the desensitization of AMPAR with the treatment with either kainic acid (100 μM) or the combination of s-AMPA and cyclothiazide (50 μM) significantly reduced cell survivability. Activation of the AMPAR in RGCs does not appear to activate a signaling cascade to apoptosis, suggesting that RGCs in vitro are not susceptible to AMPA excitotoxicity as previously hypothesized. Conversely, preventing AMPAR desensitization through differential agonist activation caused AMPAR mediated excitotoxicity. Activation of the AMPAR in increasing CREB phosphorylation was dependent on the presence of calcium, which may help explain this action in increasing RGC survival.


Synthesis of silver nanorods by low energy excitation of spherical plasmonic seeds.
Plasmon excitation of Ag seed particles with 600-750 nm light in the presence of Ag(+) and trisodium citrate was used to synthesize penta-twinned nanorods. Importantly, the excitation wavelength can be used to control the reaction rate and, consequently, the aspect ratio of the nanorods. When the excitation wavelength is red-shifted from the surface plasmon resonance of the spherical seed particles, the rate of Ag(+) reduction becomes slower and more kinetically controlled. Such conditions favor the deposition of silver onto the tips of the growing nanorods as compared to their sides, resulting in the generation of higher aspect ratio rods. However, control experiments reveal that there is only a range of low energy excitation wavelengths (between 600 and 750 nm) that yields monodisperse nanorods. This study further highlights the utility of using wavelength to control the size and shape of growing nanoparticles using plasmon-mediated methods.