Effects of diethylnitrosamine on hepatic receptor binding and autophosphorylation of epidermal growth factor and insulin in rats.
Carcinogen-mediated alterations in hepatic membrane growth factor receptor activity were investigated with the use of the hepatocarcinogen diethylnitrosamine [(DENA) CAS: 55-18-5]. For the separate assessment of carcinogen-induced acute membrane receptor changes from changes associated with carcinogen-mediated alterations in growth, the receptor activity was measured both acutely after, and several months after, a single ip dose of DENA in male F344 rats. An acute dose-dependent decrease was observed in ligand binding and autophosphorylation of the epidermal growth factor (EGF) and insulin receptor. Binding decreased sharply by 36 hours and recovered by 30 days in Golgi fractions and more slowly in plasma membranes. Scatchard analysis revealed a decrease in receptor number but not affinity. Chronic DENA administration also decreased insulin and EGF binding. Hepatocellular carcinomas, induced by single DENA injections 1 year previously, had decreased EGF receptor binding and autophosphorylation compared to those seen in age-matched controls and also less extensive insulin receptor changes. Single DENA doses thus have two effects: an acute reversible receptor change and a delayed, apparently permanent change associated with altered growth.


Accumulation of soil-borne aluminium, iron, manganese and zinc in plants cultivated in the region of Moanda (Gabon) and nutritional characteristics of the edible parts harvested.
In central Africa, studies on the transfer of metals from soil to food crops, the composition of foods and the dietary intake of cultivated vegetables are scarce. In this study, aluminium (Al), iron (Fe), manganese (Mn) and zinc (Zn) transfer from naturally (pedogeochemically) contaminated soils into ten edible plants and human exposure to these metals via edible parts of the plants were investigated. The fertility of the soils studied was still satisfactory. Soil Al (33,029-40,031 mg kg(-1)), Fe (20,869 ± 1124 mg kg(-1)) and Zn (248.3 ± 37.9 mg kg(-1)) concentrations were consistent with those found in agricultural soils, but Mn concentrations were above those normally encountered in arable fields (10,000 mg kg(-1)). The results indicated a substantial accumulation of Fe in red roselle leaves and of Al, Mn and Zn in some leafy plants and okra (fruits). The present study highlights that adults consuming vegetables grown on naturally Mn-rich soils ingest significant amounts of Al, Mn and Zn. However, Zn amounts were below the recommended maximum tolerable levels for hazard risk. The study indicated that Al and Mn accumulation in food crops cultivated in the Moanda area of Gabon may represent a health hazard. However, the high levels of Zn in vegetables could be a pathway for Zn supplementation in human nutrition to reduce Zn deficiency in developing countries.


Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1.
A gene signature was previously found to be correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus and simian-human immunodeficiency virus challenge models in non-human primates. In this report, we investigated the presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy (VE). Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with VE represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate the development of new vaccine candidates.


Ages at different reproductive events, numbers of menstrual cycles in between and breast cancer risk.
One hundred and seventy-five pathologically confirmed new cases of female breast cancer in National Taiwan University Hospital were selected as the case group. Four hundred and fifty-seven inpatient controls were individually matched for each case by age and date of admission. Information of reproductive factors and potential confounders were collected from questionnaire interview and medical records. Menstrual cycles before and after first fuIl-term pregnancy were estimated from the questionnaire. Conditional logistic regression was used to estimate the effects of reproductive risk factors and numbers of menstrual cycles before and after first full-term pregnancy. After adjusting for educational level, body mass index, family history of breast cancer and oral contraceptive use, age at menarche and menopause only showed borderline significance. Age at first full-term birth predicted breast cancer risk better. Parity was the most important protective factor. Number of menstrual cycles before first full-term pregnancy was also positively associated with breast cancer risk with linear trends.


Do Wolbachia infections play a role in unidirectional incompatibilities in a field cricket hybrid zone?
Two closely related field crickets, Gryllus firmus and G. pennsylvanicus, hybridize along an extensive north-south zone in the eastern United States. Crosses between G. firmus males and G. pennsylvanicus females produce viable and fertile F1, but the reciprocal cross consistently fails to produce offspring. Wolbachia, a bacterial parasite of arthropods that causes unidirectional incompatibilities in a variety of insect species, has been suggested as the cause of the observed incompatibility between G. pennsylvanicus and G. firmus. We examine the presence/absence of Wolbachia strains, defined by sequencing the ftsZ gene, in four cricket populations from the north-eastern United States. Most G. firmus individuals are infected (100% in Guilford, Connecticut; 65% in Seaside Park, New Jersey) and > 95% of those infected harbour a single strain of Wolbachia. All individuals in G. pennsylvanicus populations (Ithaca, New York; Sharon, Connecticut) are infected; the majority of individuals carry a second strain of Wolbachia, but a significant fraction carry the same strain found commonly in G. firmus. The presence of an apparently identical Wolbachia strain in crickets of both species means that some crosses between G. pennsylvanicus males and G. firmus females should be compatible. We have no evidence of such compatibility. Furthermore, if Wolbachia infections are responsible for the observed incompatibility between species, then incompatibilities must also exist within G. pennsylvanicus, because this species harbours both Wolbachia strains. Although some single pair crosses within G. pennsylvanicus do fail to produce offspring, the proportion is lower than expected if Wolbachia were responsible. Therefore, Wolbachia is unlikely to be involved in reproductive isolation between the two cricket species.


Naringenin improves mitochondrial function and reduces cardiac damage following ischemia-reperfusion injury: the role of the AMPK-SIRT3 signaling pathway.
Mitochondrial dysfunction contributed greatly to myocardial ischemia-reperfusion (MI/R)-induced cardiomyocyte apoptosis. Naringenin is a flavonoid exhibiting potential protective effects on myocardial mitochondria under stress conditions. However, the detailed down-stream signaling pathway involved remains uncovered. This study was designed to elucidate naringenin's mitochondrial protective actions during MI/R with a focus on AMPK-SIRT3 signaling. Sprague-Dawley rats were administered with naringenin (50 mg kg-1 d-1) and subjected to MI/R surgery in the presence or absence of compound C (0.25 mg kg-1, Com.C, an AMPK inhibitor) co-treatment. An in vitro study was performed on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were administered with naringenin (80 μmol L-1) with or without SIRT3 siRNA/AMPK1α siRNA transfection. Naringenin improved post-reperfusion left ventricular systolic pressure and the instantaneous first derivative of left ventricular pressure, and reduced the infarction size and myocardial apoptosis index by suppressing mitochondrial oxidative stress damage (as evidenced by decreased mitochondrial cytochrome c release and oxidative markers) and enhancing mitochondrial biogenesis [as evidenced by increased NRF1, TFAM and oxidative phosphorylation subunit complexes (II, III and IV)]. These protective actions were abolished by Com.C (in vivo) or SIRT3 siRNA (in vitro) administration. Further investigation revealed that Com.C (in vivo) or AMPK1α siRNA (in vitro) markedly suppressed PGC-1α and SIRT3 levels while SIRT3 siRNA (in vitro) inhibited SIRT3 expression without significantly changing AMPK phosphorylation and PGC-1α levels. Taken together, we found that naringenin directly inhibits mitochondrial oxidative stress damage and preserves mitochondrial biogenesis, thus attenuating MI/R injury. Importantly, AMPK-SIRT3 signaling played a key role in this process.


Inflammation and endometriosis.
Endometriosis is defined by presence of endometrial glands and stroma outside the uterine cavity and it affects approximately 5%-10% of women of reproductive age. Although endometriosis is usually considered to be due to retrograde menstruation, the true pathogenesis of this disease remains poorly understood. Endometriosis is associated with an inflammatory response and this inflammation leads to endothelial dysfunction and might even lead to carcinogenesis. Here, we review our current understanding of the role of inflammatory processes in the pathogenesis of endometriosis.


Avian predators are less abundant during periodical cicada emergences, but why?
Despite a substantial resource pulse, numerous avian insectivores known to depredate periodical cicadas (Magicicada spp.) are detected less commonly during emergence years than in either the previous or following years. We used data on periodical cicada calls collected by volunteers conducting North American Breeding Bird Surveys within the range of cicada Brood X to test three hypotheses for this observation: lower detection rates could be caused by bird calls being obscured by cicada calls ("detectability" hypothesis), by birds avoiding areas with cicadas ("repel" hypothesis), or because bird abundances are generally lower during emergence years for some reason unrelated to the current emergence event ("true decline" hypothesis). We tested these hypotheses by comparing bird detections at stations coincident with calling cicadas vs. those without calling cicadas in the year prior to and during cicada emergences. At four distinct levels (stop, route, range, and season), parallel declines of birds in groups exposed and not exposed to cicada calls supported the true decline hypothesis. We discuss several potential mechanisms for this pattern, including the possibility that it is a consequence of the ecological and evolutionary interactions between predators of this extraordinary group of insects.


The level of organization of the motor schema.
The interpretations of Piaget and Schmidt on the level on which the motor schema is supposedly effective were evaluated in pre-school children of different ages in a throwing task. In an analysis of variance on the accuracy scores, significant main effects for age, sex, and throwing arm were found. Further, the results showed no relationship between accuracy scores with the preferred and non-preferred arm in the younger group, while in the older group a moderate relationship was found. This result was interpreted in terms of structural development and as a warning for studies where Schmidt's variability-of-practice hypothesis is tested.


Lisinopril and nifedipine administration inhibits the ex vivo uptake of [45Ca2+] by platelets from hypertensive diabetic patients.
1. The effect of administration of the angiotensin converting enzyme inhibitor (ACEI), lisinopril (Carace; 10-40 mg twice daily) and the calcium channel blocker, nifedipine (Adalat Retard; 20-40 mg twice daily) on ex vivo [45Ca2+] uptake by platelets from hypertensive diabetic (type 1 and 2) patients was investigated. 2. At the end of at least 3 months treatment, blood was collected prior to the patient taking the morning dose of medication and washed platelets prepared. [45Ca2+] uptake was monitored following the addition of adrenaline, isoprenaline and dibutyryl cAMP (dbcAMP), as well as in unstimulated (zero) platelets. 3. Both nifedipine and lisinopril significantly inhibited the ex vivo uptake of [45Ca2+] by platelets when this process was stimulated by adrenaline, isoprenaline and dibutyryl cAMP. Basal uptake was also inhibited in both groups. 4. These data consolidate the hypothesis that ACE inhibitors may possess calcium channel/calcium mobilisation blocking properties. Apart from its hypertensive action, lisinopril may also reduce platelet activity via modulation of calcium dynamics, thereby reducing the incidence of vascular complications associated with diabetes mellitus.


Reducing Stigma Toward Individuals With Schizophrenia Using a Brief Video: A Randomized Controlled Trial of Young Adults.
Stigma decreases healthcare seeking and treatment adherence and increases the duration of untreated psychosis among people with first-episode psychosis (FEP). This study evaluated the efficacy of a brief video-based intervention in reducing stigma among youth toward individuals with FEP and schizophrenia. We hypothesized that the social-contact-based video intervention group would reduce stigma more than written vignette and control groups, and the vignette more than the control group. Using Amazon Mechanical Turk, we recruited and assigned 1203 individuals aged 18-30 to either (a) video intervention, (b) written description of the same content ("vignette"), or (c) nonintervention control arm. In the 90-second video intervention, an empowered young woman with schizophrenia described her FEP and the aspects of successful coping with her everyday life difficulties, exposing the viewer to schizophrenia in the context of her personal narrative. Web-based self-report questionnaires assessed stigma domains, including social distance, stereotyping, separateness, social restriction, and perceived recovery. A MANOVA showed a significant between-group effects for all 5 stigma-related subscales (P < .001). Post hoc pairwise tests showed significant differences between video and vignette vs control for all 5 stigma domains. Video and vignette groups differed significantly on social distance, stereotyping, and social restriction. Secondary analyses revealed gender differences across stigma domains in the video group only, with women reporting lower stigma. A very brief social contact-based video intervention efficaciously reduced stigma toward individuals with FEP. This is the first study to demonstrate such an effect. Further research should examine its long-term sustainability.


Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms.
Both the period of total circulatory arrest to the brain and postischemic-anoxic encephalopathy (cerebral postresuscitation syndrome or disease), after normothermic cardiac arrests of between 5 and 20 mins (no-flow), contribute to complex physiologic and chemical derangements. The best documented derangements include the delayed protracted inhomogeneous cerebral hypoperfusion (despite controlled normotension), excitotoxicity as an explanation for selectively vulnerable brain regions and neurons, and free radical-triggered chemical cascades to lipid peroxidation of membranes. Protracted hypoxemia without cardiac arrest (e.g., very high altitude) can cause angiogenesis; the trigger of it, which lyses basement membranes, might be a factor in post-cardiac arrest encephalopathy. Questions to be explored include: What are the changes and effects on outcome of neurotransmitters (other than glutamate), of catecholamines, of vascular changes (microinfarcts seen after asphyxia), osmotic gradients, free-radical reactions, DNA cleavage, and transient extracerebral organ malfunction? For future mechanism-oriented studies of the brain after cardiac arrest and innovative cardiopulmonary-cerebral resuscitation, increasingly reproducible outcome models of temporary global brain ischemia in rats and dogs are now available. Disagreements exist between experienced investigative groups on the most informative method for quantitative evaluation of morphologic brain damage. There is agreement on the desirability of using not only functional deficit and chemical changes, but also morphologic damage as end points.


[Complications of radical nephrectomy in the treatment of kidney adenocarcinoma].
To evaluate the peri- and post-surgical complications in Renal Adenocarcinoma (RAC) treated with Radical Nephrectomy (RN). Revision of 109 patients with RAC who underwent transperitoneal anterior abdominal RN. Patients were locally staged post-surgically as: T1 + T2 61.5%, T3a 22.9%, T3ab 11% and T3b 4.6%. Approach and conservation of homolateral suprarenal gland were decided based on the preferences of the performing urologist. Hilar lymphadenectomy was performed in all cases. RN was done by a staff member in 77% cases and by a training resident assisted by a staff member in the remaining 23%. Peri-operative complications occurred in 10% patients, most commonly with left RN (13% vs. 7%) (p = 0.1), and further within this group the most frequent ones occurred in those using midpoint laparotomy (17.8% vs. 4%) (p = 0.1). Blood transfusion during surgery was required in 23% patients, this being more frequent when tumours had extended into the venous system (47%) and in left RN by midpoint laparotomy (39% vs. 12.5%) (p = 0.02). There were 32 post-surgical complications in 27 (24.8%) patients, the most common being sepsis of the surgical wound (6.4%); complications were more usual in patients undergoing right RN (31% vs. 20%) (p = 0.08) and in patients with blood transfusions (40% vs. 20%) (p = 0.4). There were no deaths. In our series, RN showed low intraoperative morbidity (10%), non-insignificant post-operative morbidity (24.8%) and no mortality. We consider subcostal laparotomy to be the best surgical approach in left RAC, with low morbidity and low peri-operative blood requirements.


Regulation of the concentration of adenosine 3',5'-cyclic monophosphate and the activity of tyrosine hydroxylase in the rat superior cervical ganglion by three neuropeptides of the secretin family.
Preganglionic nerve stimulation leads to an acute elevation of tyrosine hydroxylase (TH) activity in the rat superior cervical ganglion. This effect is mediated in part by acetylcholine, acting via nicotinic receptors, and in part by a noncholinergic neurotransmitter. As a first step in an attempt to identify this noncholinergic transmitter, we have examined a number of biogenic amines, purine nucleotides, neuropeptides, and other compounds for their ability to increase TH activity. Secretin, vasoactive intestinal peptide (VIP), and PHI (a 27-amino acid peptide with an NH2-terminal histidine and a COOH-terminal isoleucine amide), all members of the secretin family of peptides, increased TH activity acutely. Human pancreatic growth hormone-releasing factor, glucagon, and gastric inhibitory peptide (three other members of this peptide family) and all other transmitter candidates tested had no effect on this enzyme activity. We have examined the possibility that this peptidergic regulation of TH activity is mediated via changes in adenosine 3',5'-cyclic monophosphate (cAMP) levels. When the six members of the secretin family were tested for their ability to increase cAMP levels in the ganglion, secretin, VIP, and PHI significantly increased this cyclic nucleotide, whereas growth hormone-releasing factor, glucagon, and gastric inhibitory peptide produced no significant effects. The rank orders of potency and of efficacy of secretin, VIP, and PHI in altering TH activity and cAMP levels were identical. Furthermore, a strong correlation was found between the cAMP level and the TH activity in individual ganglia exposed to these peptides. Finally, 8-bromoadenosine 3',5'-cyclic monophosphate and forskolin also increased TH activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacotherapeutic considerations in anxiety disorders.
Anxiety disorders comprise a variety of syndromes that require varied pharmacotherapeutic, psychotherapeutic, and behavioral interventions. Benzodiazepines have now replaced older sedatives and hypnotics as the preferred drug treatment for generalized anxiety. For panic disorder and agoraphobia with panic, the tricyclic antidepressants, the monoamine oxidase inhibitors, and the atypical benzodiazepine alprazolam have proved effective. When a simple phobia is severe enough to require treatment, behavioral approaches, with the possible adjunctive use of benzodiazepines, are recommended. Careful diagnostic inquiry, individual titration of doses, and use of conservative dosage schedules (with interrupted periods of treatment) will permit pharmacotherapy with maximum benefit and a minimum of adverse consequences.


Thyrotropin-releasing hormone mobilizes Ca2+ from endoplasmic reticulum and mitochondria of GH3 pituitary cells: characterization of cellular Ca2+ pools by a method based on digitonin permeabilization.
Treatment of 45Ca2+-loaded GH3 pituitary cells with various concentrations of digitonin revealed discrete pools (I and II) of cellular 45Ca2+ defined by differing detergent sensitivities. Markers for cytosol and intracellular organelles indicated that the two 45Ca2+ pools were correlated with the two major cellular Ca2+-sequestering organelles, endoplasmic reticulum (I) and mitochondria (II). Studies with various inhibitors were consistent with these assignments. Mitochondrial uncouplers preferentially depleted 45Ca2+ pool II while trifluoperazine selectively depleted 45Ca2+ pool I. Control experiments indicated that translocation of in situ organellar 45Ca2+ during and after permeabilization was negligible. We used the digitonin-permeabilization method to examine the effect of thyrotropin-releasing hormone (TRH) treatment on intracellular Ca2+ pools of GH3 pituitary cells. TRH was found to rapidly deplete both endoplasmic reticulum and mitochondrial exchangeable Ca2+ by 25-30%. The 45Ca2+ loss from both pools was maximal by 1 min after TRH addition and was followed by a recovery phase; mitochondrial 45Ca2+ content returned to control levels by 30 min. Previous treatment of cells with the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxy-phenylhydrazone blocked TRH-induced 45Ca2+ efflux from mitochondria, while previous treatment with valinomycin, an agent that depleted both 45Ca2+ pools, blocked any additional effect of TRH on these pools. We conclude that TRH rapidly promotes a net loss of exchangeable Ca2+ from GH3 cells as a result of hormone-induced mobilization of Ca2+ from endoplasmic reticulum and mitochondria.


ChIA-PET2: a versatile and flexible pipeline for ChIA-PET data analysis.
ChIA-PET2 is a versatile and flexible pipeline for analyzing different types of ChIA-PET data from raw sequencing reads to chromatin loops. ChIA-PET2 integrates all steps required for ChIA-PET data analysis, including linker trimming, read alignment, duplicate removal, peak calling and chromatin loop calling. It supports different kinds of ChIA-PET data generated from different ChIA-PET protocols and also provides quality controls for different steps of ChIA-PET analysis. In addition, ChIA-PET2 can use phased genotype data to call allele-specific chromatin interactions. We applied ChIA-PET2 to different ChIA-PET datasets, demonstrating its significantly improved performance as well as its ability to easily process ChIA-PET raw data. ChIA-PET2 is available at https://github.com/GuipengLi/ChIA-PET2.


Trace element levels in drinking water and cognitive function among elderly Chinese.
The relation between trace element levels in drinking water and cognitive function was investigated in a population-based study of elderly residents (n = 1,016) in rural China in 1996-1997. Cognitive function was measured using a Chinese translation of the Community Screening Interview for Dementia. A mixed effects model was used to evaluate the effect of each of the elements on cognitive function while adjusting for age, sex, and educational level. Several of the elements examined had a significant effect on cognitive function when they were assessed in a univariate context. However, after adjustment for other elements, many of these results were not significant. There was a significant quadratic effect for calcium and a significant zinc-cadmium interaction. Cognitive function increased with calcium level up to a certain point and then decreased as calcium continued to increase. Zinc showed a positive relation with cognitive function at low cadmium levels but a negative relation at high levels.


[Regional analysis of human and animal hydatidosis in Chile, 1989-1993].
A descriptive study of hydatidosis, a still very prevalent zoonosis in Chile, was carried out with information up to 1993. Both human and animal data were included, the last one based on more reliable information. Regional human distribution up to 1991 shows persistent high notification rates in the extreme south of the country, Aysen and Magallanes hospital discharges, more reliable than notified cases, adds the IX Region of Araucania to the high risk areas, join with more than 30 hospitalizations per 100,000 people in 1989. Mortality case rate suggests strongly a very high subnotification in all the regions, mainly in O'Higgins. This zoonosis affects predominantly, young and middle aged adults, with a similar sex distribution. Cattle infection has decreased in the last 20 years, particularly in sheep. Proportion of infected dogs also tends to show a lowering trend in specific studies. It appears a strong need of a national program for controlling this zoonosis, to be initiated with an epidemiological evaluation by regions and centered in health education, dogs' infection control with treatment and better handling of slaughterhouses.


Bactericidal activity of alveolar macrophages is suppressed by V-ATPase inhibition.
Bafilomycin A(1), a selective inhibitor of V-type H(+)-translocating ATPase (V-ATPase), may be a useful adjunct in cancer chemotherapy (Altan et al. [1998] J Exp Med 187:1583-1598). Therapeutic uses of the enzyme inhibitor need to consider the agent's potential effects on normal (nontumor) cells. This study determined the effects of bafilomycin A(1) on resident alveolar macrophages (mphi). Treatment of alveolar mphi with bafilomycin A(1) (10 microM, 1 h) caused a significant decrement in cytosolic pH. This was accompanied by marked alteration of mphi bactericidal capabilities. The enzyme inhibitor caused a marginal reduction in the phagocytosis of opsonized Staphylococcus aureus and significantly suppressed intracellular killing of the phagocytosed bacteria. In keeping with the effects on intracellular killing, bafilomycin A(1) significantly reduced the production of reactive oxygen species (ROS). On the other hand, cell spreading was enhanced significantly by bafilomycin A(1). Comparable changes in ROS generation and mphi spreading were produced by altering cytosolic pH through changes in extracellular pH (pH(o)) in the absence of bafilomycin A(1). These findings suggest that the agent's effects on ROS production and mphi spreading were related to the accompanying changes in cytosolic pH. The enzyme inhibitor also altered mphi morphology, leading to the shortening of microvilli and focal loss of surface ruffles. These morphologic effects differed from those produced by altering cytosolic pH by changes in pH(o). The results demonstrate that V-ATPase activity is an important determinant of mphi functioning and structure. Therapeutic use of V-ATPase inhibitors might be expected to compromise the bactericidal activity of alveolar mphi.


A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy.
Within the tumour microenvironment (TME), there is a cellular 'tug-of-war' for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between a successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.


QTc Interval Prolongation and Hemorrhagic Stroke: Any Difference Between Acute Spontaneous Intracerebral Hemorrhage and Acute Non-traumatic Subarachnoid Hemorrhage?
A variety of ECG changes occur as an aftermath of stroke. Prolongation of the QTc interval is a well-documented change. We analyzed QTc interval prolongation among patients with acute hemorrhagic strokes. This observational study was conducted at the Emergency Department of Sulaymaniyah General Teaching Hospital and Shar Hospital from September 1st, 2014 to August 31st, 2015. Fifty patients who developed acute spontaneous hypertensive intracerebral hemorrhage (ICH) and 50 patients who developed acute non-traumatic subarachnoid hemorrhage (SAH) were included in the study. All patients underwent resting 12-lead ECG within half an hour of admission. The QTc interval was calculated and analyzed in those 100 patients. Females (62%) outnumbered males (38%) with a female to male ratio of 1.6:1. Forty percent of the patients were between 60-69 years of age. Hypertension was seen in 82% of patients while left ventricular hypertrophy was documented in 40% of patients. The QTc was prolonged in 38 patients (17 patients in the ICH group and 21 patients in the SAH group). In both groups, males demonstrated QTc prolongation more than females. However, there were no statistically significant gender difference between both groups and within the same group. There was a statistically significant association between SAH and QTc prolongation (p-value<0.001); the ICH group did not demonstrate any significant relationship with QTc prolongation. Prolongation in the QTc interval was "statistically" associated with acute SAH only. No gender difference was noted; whether this observation is clinically significant or not, it needs further analytic studies.


Additional cost of hospital-acquired infection to the patient: a case study in Turkey.
Hospital-acquired infections (HAIs) significantly increase both the patient's length of stay and the cost of disease. For this reason, HAIs are one of the most important problems that intensive study is devoted to in many countries around the world. The purpose of this study is to investigate how having a HAI prolongs the length of stay and adds unnecessary cost to the patient. The study compared two matched groups and suggested that a patient with a HAI spent an additional 23 days in the hospital compared with a patient not affected with a HAI. The results also showed that a patient with a HAI had to pay more in almost all cost categories compared with a non-infected patient. The additional cost for an infected patient was calculated as 2026.70 US dollars. As a result of HAIs, the hospital had additional, but avoidable, expenses of 30,754 US dollars for 57 patients over a period of four months.


A salt-regulated peptide derived from the CAP superfamily protein negatively regulates salt-stress tolerance in Arabidopsis.
High salinity has negative impacts on plant growth through altered water uptake and ion-specific toxicities. Plants have therefore evolved an intricate regulatory network in which plant hormones play significant roles in modulating physiological responses to salinity. However, current understanding of the plant peptides involved in this regulatory network remains limited. Here, we identified a salt-regulated peptide in Arabidopsis. The peptide was 11 aa and was derived from the C terminus of a cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily. This peptide was found by searching homologues in Arabidopsis using the precursor of a tomato CAP-derived peptide (CAPE) that was initially identified as an immune signal. In searching for a CAPE involved in salt responses, we screened CAPE precursor genes that showed salt-responsive expression and found that the PROAtCAPE1 (AT4G33730) gene was regulated by salinity. We confirmed the endogenous Arabidopsis CAP-derived peptide 1 (AtCAPE1) by mass spectrometry and found that a key amino acid residue in PROAtCAPE1 is critical for AtCAPE1 production. Moreover, although PROAtCAPE1 was expressed mainly in the roots, AtCAPE1 was discovered to be upregulated systemically upon salt treatment. The salt-induced AtCAPE1 negatively regulated salt tolerance by suppressing several salt-tolerance genes functioning in the production of osmolytes, detoxification, stomatal closure control, and cell membrane protection. This discovery demonstrates that AtCAPE1, a homologue of tomato immune regulator CAPE1, plays an important role in the regulation of salt stress responses. Our discovery thus suggests that the peptide may function in a trade-off between pathogen defence and salt tolerance.


Meta-analysis of prophylactic allopurinol use in post-endoscopic retrograde cholangiopancreatography pancreatitis.
The aim of this study was to evaluate the effectiveness and the safety of allopurinol in the prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. : We used the method recommended by the Cochrane Collaboration to perform a meta-analysis of randomized controlled trials (RCTs) of allopurinol in the prevention of post-ERCP pancreatitis (PEP), including 6 RCTs conducted all over the world. : Six RCTs totaling 1554 patients undergoing ERCP were included. When the RCTs were analyzed, odds ratios of allopurinol were 0.74 (95% confidence interval [CI], 0.37-1.48; P = 0.40) for PEP, 0.87 (95% CI, 0.33-2.28; P = 0.78) for severe PEP, 0.88 (95% CI, 0.37-2.11; P = 0.78) for post-ERCP hyperamylasemia, and 0.19 (95% CI, 0.01-3.91; P = 0.28) for case-fatality ratio of PEP, thus indicating no beneficial effects of allopurinol on acute pancreatitis, PEP death rate, and hyperamylasemia. No evidence of publication bias was found. : Allopurinol cannot prevent the pancreatic injury after ERCP. Allopurinol is not recommended in the prophylaxis of PEP.


New psychological therapies for irritable bowel syndrome: mindfulness, acceptance and commitment therapy (ACT).
The current goal of treatment in irritable bowel syndrome (IBS) focuses primarily on symptom management and attempts to improve quality of life. Several treatments are at the disposal of physicians; lifestyle and dietary management, pharmacological treatments and psychological interventions are the most used and recommended. Psychological treatments have been proposed as viable alternatives or compliments to existing care models. Most forms of psychological therapies studied have been shown to be helpful in reducing symptoms and in improving the psychological component of anxiety/depression and health-related quality of life. According to current NICE/NHS guidelines, physicians should consider referral for psychological treatment in patients who do not respond to pharmacotherapy for a period of 12 months and develop a continuing symptom profile (described as refractory irritable bowel syndrome). Cognitive behavioral therapy (CBT) is the best studied treatment and seems to be the most promising therapeutic approach. However, some studies have challenged the effectiveness of this therapy for irritable bowel syndrome. One study concluded that cognitive behavioral therapy is no more effective than placebo attention control condition and another study showed that the beneficial effects wane after six months of follow-up. A review of mind/body approaches to irritable bowel syndrome has therefore suggested that alternate strategies targeting mechanisms other than thought content change might be helpful, specifically mindfulness and acceptance-based approaches. In this article we review these new psychological treatment approaches in an attempt to raise awareness of alternative treatments to gastroenterologists that treat this clinical syndrome.


3D Imaging of Indentation Damage in Bone.
Bone is a complex material comprising high stiffness, but brittle, crystalline bio-apatite combined with compliant, but tough, collagen fibres. It can accommodate significant deformation, and the bone microstructure inhibits crack propagation such that micro-cracks can be quickly repaired. Catastrophic failure (bone fracture) is a major cause of morbidity, particularly in aging populations, either through a succession of small fractures or because a traumatic event is sufficiently large to overcome the individual crack blunting/shielding mechanisms. Indentation methods provide a convenient way of characterising the mechanical properties of bone. It is important to be able to visualise the interactions between the bone microstructure and the damage events in three dimensions (3D) to better understand the nature of the damage processes that occur in bone and the relevance of indentation tests in evaluating bone resilience and strength. For the first time, time-lapse laboratory X-ray computed tomography (CT) has been used to establish a time-evolving picture of bone deformation/plasticity and cracking. The sites of both crack initiation and termination as well as the interconnectivity of cracks and pores have been visualised and identified in 2D and 3D.


Effect of chemotherapy on urinary volatile biomarkers for lung cancer by HS-SPME-GC-MS and chemometrics.
Volatile organic compounds (VOCs) have been studied as possible biomarkers in several diseases, including lung cancer. Early detection of cancer can improve long-term survival rates and the quality of life, so the study of VOCs in exhaled breath and urine has been increasing in recent years. This study aimed to assess the urinary VOCs that are modified after chemotherapy to identify those with the potential to be lung cancer biomarkers that can be monitored during treatment. Three urine samples from 10 men with stage IV lung adenocarcinoma were collected, as well as urine samples from 14 men with other types of cancer (control group). All samples were analyzed by headspace-solid phase microextraction gas chromatography coupled with mass spectrometry. A total of 21 urinary VOCs were found with different levels after the administration of chemotherapy, with 2-pentanone being one of those that significantly decreased. Furthermore, 2-pentanone and 3-hydroxy-2,4,4-trimethylpentyl-2-methylpropanoate showed statistically significant differences with the control group. Chemotherapy administered to patients with advanced lung adenocarcinoma modified the volatile profile of urine. 2-Pentanone, a final product of the increased rate of fatty acid oxidation and protein hypermetabolism, significantly decreased after chemotherapy. Therefore, monitoring its urinary excretion could be very useful since its decrease over time could indicate an adequate response to chemotherapy and arrest of cancer development. Another VOC that could be a potential lung cancer biomarker is 3 hydroxy-2,4,4-trimethylpentyl-2-methylpropanoate, whose origin may be due to inhibition of the propanoic acid metabolic pathway or increased aldehyde dehydrogenase activity.


Epidemiological Study on Prevalence, Serovar Diversity, Multidrug Resistance, and CTX-M-Type Extended-Spectrum β-Lactamases of Salmonella spp. from Patients with Diarrhea, Food of Animal Origin, and Pets in Several Provinces of China.
A total of 2,283 Salmonella isolates were recovered from 18,334 samples, including samples from patients with diarrhea, food of animal origin, and pets, across 5 provinces of China. The highest prevalence of Salmonella spp. was detected in chicken meats (39.3%, 486/1,237). Fifteen serogroups and 66 serovars were identified, with Salmonella enterica serovars Typhimurium and Enteritidis being the most dominant. Most (85.5%, 1,952/2,283) isolates exhibited resistance to ≥1 antimicrobial, and 56.4% were multidrug resistant (MDR). A total of 222 isolates harbored extended-spectrum β-lactamases (ESBLs), and 200 of these were of the CTX-M type and were mostly detected in isolates from chicken meat and turtle fecal samples. Overall, eight blaCTX-M genes were identified, with blaCTX-M-65, blaCTX-M-123, blaCTX-M-14, blaCTX-M-79, and blaCTX-M-130 being the most prevalent. In total, 166 of the 222 ESBL-producing isolates had amino acid substitutions in GyrA (S83Y, S83F, D87G, D87N, and D87Y) and ParC (S80I), while the plasmid-mediated quinolone resistance (PMQR)-encoding genes oqxA, oqxB, qepA, qnrB, and qnrS were detected in almost all isolates. Of the 15 sequence types (STs) identified in the 222 ESBLs, ST17, ST11, ST34, and ST26 ranked among the top 5 in number of isolates. Our study revealed considerable serovar diversity and a high prevalence of the co-occurrence of MDR determinants, including CTX-M-type ESBLs, quinolone resistance-determining region (QRDR) mutations, and PMQR genes. This is the first report of CTX-M-130 Salmonella spp. from patients with diarrhea and QRDR mutations from turtle fecal samples. Our study emphasizes the importance of actions, both in health care settings and in the veterinary medicine sector, to control the dissemination of MDR, especially the CTX-M-type ESBL-harboring Salmonella isolates.


Active dorsiflexing prostheses may reduce trip-related fall risk in people with transtibial amputation.
People with amputation are at increased risk of falling compared with age-matched, nondisabled individuals. This may partly reflect amputation-related changes to minimum toe clearance (MTC) that could increase the incidence of trips and fall risk. This study determined the contribution of an active dorsiflexing prosthesis to MTC. We hypothesized that regardless of speed or incline the active dorsiflexion qualities of the ProprioFoot would significantly increase MTC and decrease the likelihood of tripping. Eight people with transtibial amputation walked on a treadmill with their current foot at two grades and three velocities, then repeated the protocol after 4 wk of accommodation with the ProprioFoot. A mixed-model, repeated-measures analysis of variance was used to compare MTC. Curves representing the likelihood of tripping were derived from the MTC distributions and a multiple regression was used to determine the relative contributions of hip, knee, and ankle angles to MTC. Regardless of condition, MTC was approximately 70% larger with the ProprioFoot (p < 0.001) and the likelihood of tripping was reduced. Regression analysis revealed that MTC with the ProprioFoot was sensitive to all three angles, with sensitivity of hip and ankle being greater. Overall, the ProprioFoot may increase user safety by decreasing the likelihood of tripping and thus the pursuant likelihood of a fall.


Expression of dopamine transporter and vesicular monoamine transporter 2 mRNAs in rat midbrain after repeated amphetamine administration.
The dopamine transporter (DAT) in pre-synaptic membranes and the vesicular monoamine transporter 2 (VMAT2) in membranes of synaptic vesicles are involved in mediating the acute effects of amphetamine on dopamine transmission. Therefore, using a quantitative method of in situ hybridization and computerized image analysis, the expression of DAT and VMAT2 mRNAs was examined in rats treated for 5 days with amphetamine and killed 3 or 14 days after the last injection. We examined ventral tegmental area (VTA), substantia nigra (SN) and the transitional zone between VTA and SN. Each of these regions was further subdivided into rostral, intermediate and caudal portions. In control rats, autoradiographs revealed a gradient of both DAT and VMAT2 mRNA levels, decreasing gradually from rostral to caudal rat midbrain. After 3 days of withdrawal, a significant increase in DAT mRNA levels was found in rostral portions of VTA (117.9 + 5.8% of control group), SN (116.5 + 4.5%) and the transitional zone (119.6 + 5.6%) and in the intermediate portion of SN (113.5 + 4.3%). VMAT2 mRNA was significantly increased only in rostral and intermediate portions of the transitional zone (120.9 + 4.8 and 113.6 + 4.1%). After 14 days of withdrawal, there was a trend towards increased DAT mRNA levels in intermediate-caudal portions of midbrain, but a statistically significant increase was observed only in the intermediate portion of VTA (120.2 + 7.9%). No changes in VMAT2 mRNA levels were found. Thus, repeated amphetamine administration exerts modest and regionally selective effects on DAT and VMAT2 mRNA expression in subpopulations of midbrain dopamine neurons.


Hypercalcemia in glioblastoma multiforme.
Hypercalcemia is commonly associated with cancer, occurring in around 10-20% of cancer patients. Hypercalcemia is usually related to solid and non-solid malignancies specifically breast cancer, lung cancer and multiple myeloma. Hypercalcemia has been reported to occur in association with astrocytomas, and uncommonly in gliomas. We report a case of a previously healthy man presenting with glioblastoma multiforme . He was found to have persistently elevated serum calcium and calcitriol with normal parathyroid function. This is the first reported case of hypercalcemia associated with glioblastoma multiforme.


Fluorescent acridine-based receptors for H2PO4(-).
Two new pseudopeptidic molecules (one macrocyclic and one open chain) containing an acridine unit have been prepared. The fluorescence response of these receptors to a series of acids was measured in CHCl(3). Receptors are selective to H(2)PO(4)(-) versus HSO(4)(-), and an even higher selectivity is found over other anions such as Cl(-), Br(-), CH(3)COO(-), and CF(3)COO(-). We show that the macrocyclic receptor is more selective for H(2)PO(4)(-) than the related open chain receptor. The supramolecular interactions of triprotonated receptors with different anions have been modeled in silico and have been studied by different experimental techniques. Optimized geometries obtained by computational calculations agree well with experimental data, in particular fluorescence experiments, suggesting that the selective supramolecular interaction takes places through coordination of the anions to the triprotonated form of the receptor.


MRI characteristics of neuromyelitis optica spectrum disorder: an international update.
Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti-aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti-aquaporin-4 antibody are common and some may be relatively unique by virtue of localization and configuration. Some seropositive patients present with brain involvement during their first attack and/or continue to relapse in the same location without optic nerve and spinal cord involvement. Thus, characteristics of brain abnormalities in such patients have become of increased interest. In this regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spectrum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of prime importance because early initiation of effective immunosuppressive therapy is the key to preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multiple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and spinal cord MRI findings of NMOSD.


Exposure to a SARS-CoV-2 infection at work: development of an international job exposure matrix (COVID-19-JEM).
This study aimed to construct a job exposure matrix (JEM) for risk of becoming infected with the SARS-CoV-2 virus in an occupational setting. Experts in occupational epidemiology from three European countries (Denmark, The Netherlands and the United Kingdom) defined the relevant exposure and workplace characteristics with regard to possible exposure to the SARS-CoV-2 virus. In an iterative process, experts rated the different dimensions of the COVID-19-JEM for each job title within the International Standard Classification of Occupations system 2008 (ISCO-08). Agreement scores, weighted kappas, and variances were estimated. The COVID-19-JEM contains four determinants of transmission risk [number of people, nature of contacts, contaminated workspaces and location (indoors or outdoors)], two mitigation measures (social distancing and face covering), and two factors for precarious work (income insecurity and proportion of migrants). Agreement scores ranged from 0.27 [95% confidence interval (CI) 0.25-0.29] for 'migrants' to 0.76 (95% CI 0.74-0.78) for 'nature of contacts'. Weighted kappas indicated moderate-to-good agreement for all dimensions [ranging from 0.60 (95% CI 0.60-0.60) for 'face covering' to 0.80 (95% CI 0.80-0.80) for 'contaminated workspaces'], except for 'migrants' (0.14 (95% CI -0.07-0.36). As country differences remained after several consensus exercises, the COVID-19-JEM also has a country-axis. The COVID-19-JEM assesses the risk at population level using eight dimensions related to SARS-COV-2 infections at work and will improve our ability to investigate work-related risk factors in epidemiological studies. The dimensions of the COVID-19-JEM could also be valuable for other future communicable diseases in the workplace.


Effect of zinc treatment on clinical outcomes in patients with liver cirrhosis: A systematic review and meta-analysis.
Zinc is an essential trace element integral to many cellular and immune functions. Zinc deficiency is highly prevalent in patients with cirrhosis and related to disease severity. To evaluate whether zinc supplementation improves clinical outcomes (disease severity and mortality) in patients with cirrhosis. This prospectively registered systematic review (PROSPERO reference: CRD42018118219) included all studies in Medline, Embase or Cochrane database with inclusion criteria of adult human studies, comparing zinc supplementation of at least 28 d with standard care or placebo in patients with cirrhosis. Mortality and clinical severity score data were extracted. Random effects meta-analyses compared mortality at 6 mo and 2 years. Risk of bias was assessed using the National Institutes of Health quality assessment tool. Seven hundred and twelve articles were identified of which four were eligible. Zinc formulations and doses varied (elemental zinc 3.4-214 mg daily) for different intervention periods in patients with differing etiology and severity of cirrhosis. Two studies were considered to be at high risk of bias. There was no significant difference in 6-mo mortality between patients treated with zinc versus controls [risk ratio 0.98 (0.90-1.05)]. Changes in severity scores were not reported in any study. Zinc supplementation is not associated with reduced mortality in patients with cirrhosis. Findings are limited by the small number of eligible studies and significant heterogeneity in intervention and patient population.


Association between patient activity and long-term cardiac death in patients with implantable cardioverter-defibrillators and cardiac resynchronization therapy defibrillators.
Background Patient activity (PA) has been demonstrated to predict all-cause mortality. However, the association between PA and cardiac death is unclear. Aims The aims of this study were to determine whether PA can predict cardiac death and what is the cut-off of PA to discriminate cardiac death, as well as the mechanism underlying the relationship between PA and survival in patients with home monitoring. Methods This study retrospectively analysed clinical and implantable cardioverter-defibrillator/cardiac resynchronization therapy defibrillator device data in 845 patients. Data regarding PA and PP variability during the first 30-60 days of home monitoring were collected, and mean values were calculated. The primary endpoint was cardiac death, and the secondary endpoint was all-cause mortality. Results The mean PA percentage was 11 ± 5.8%. Based on receiver operating characteristic curve analysis, we determined that a PA cut-off value of 7.84% (113 min) can predict cardiac death. During a mean follow-up period of 31.1 ± 12.9 months (ranging from three to 60 months), PA ≤ 7.84% was associated with increased risks of cardiac death in an unadjusted analysis; after adjusting in a multivariate Cox model, the relationship remained significant between PA≤7.84% and cardiac death (hazard ratio = 3.644, 95% confidence interval = 2.424-5.477, p < 0.001). Moreover, a significant correlation was observed between PA and PP variability ( r = 0.601, p < 0.001). Conclusions A baseline PA ≤ 7.84% was associated with a higher risk of cardiac death in patients who have survived more than three months after implantable cardioverter-defibrillator/cardiac resynchronization therapy defibrillator implantation. PA had a sizable effect on heart rate variability, reflecting autonomic function.


[Non-specific RNA degradation in the presence of magnesium ions].
RNA degradation catalyzed by Mg2+ was studied under the conditions of reverse transcriptase reaction. Agarose gel electrophoresis in 6 M urea was employed to follow the reaction. Natural ribosomal of poly(A)+ RNA as well as synthetic poly(rA) are equally accessible for degradation. Neither an RNAase nor alkali alone is responsible for the degradation. The reaction rate is directly proportional to Mg2+ concentration in the range of 1 to 10 mM, doesn't depend upon RNA concentration and enhances approximately 50 fold upon increasing of pH value from 7.5 to 9.0. It was concluded that the Mg2+ catalyzed degradation reaction is an unspecific one in respect to the primary structure of RNA. The results obtained are useful to optimize the conditions for the reverse transcriptase reaction.


Identification of calreticulin as a nuclear matrix protein associated with human colon cancer.
Colon cancer is one of the most common malignancies among populations in the United States and Western Europe, and one of the leading causes of worldwide morbidity and mortality due to cancer. The early detection of colon cancer is central to the effective treatment of this disease and early detection markers are needed. We have demonstrated that high-resolution two-dimensional gel analysis of nuclear matrix proteins (NMPs) demonstrated a specific oncological fingerprint of colon cancer. Utilizing this approach, four proteins specific for colon cancer was identified. Additionally, one protein was expressed much more strongly in colon cancer compared to adjacent and normal donor tissue. The amino acid composition of this protein revealed sequence similarity with calreticulin. The multi-functional protein, calreticulin, is normally found in the lumen of the endoplasmic reticulum although some reports have described a nuclear localization of the protein. The aim of this study was to confirm the identity of the protein as calreticulin as well as to evaluate the localization of calreticulin in the nuclear matrix of colon cancer tissue.


On the mechanism of action of antipsychotic drugs: a chemical reaction not receptor blockade.
Over forty years ago, biochemist Lauro Galzigna conducted an in-vitro experiment showing that the antipsychotic chlorpromazine reacted with the putative psychotogen adrenochrome to form a polymer resembling melanin. The field of psychopharmacology has essentially ignored that simple but illustrative experiment in the intervening time. The present study reproduces principle elements of Galzigna's experiment and expands the scope to include the antipsychotic medications olanzapine and minocycline. The rate of reaction was slow, with maximal yield of black polymer being achieved by 4, 10 and 7 days with chlorpromazine, olanzapine and minocycline, respectively. Changing the pH was most informative for chlorpromazine and minocycline reactions, where yield increased sharply between pH 6.1 and 6.9, and decreased slightly between pH 6.9 and 7.8, consistent with reaction profiles expected for aromatic substitution. Preincubation of olanzapine with iodine doubled the polymer yield, facilitated by the addition of iodine to the aromatic ring and presumably followed by its departure as a "leaving group". Increasing the salt concentration 1.5-fold depressed yields for all three drugs, most likely via ionic shielding of charged functional groups, diminishing reactivity. The results are discussed in regards to the mechanism of action of antipsychotic medications, casting doubt on commonly held theories. The time course of the chemical reactions presented here and the concentrations required, are much more consistent with clinical results than are models concerning receptor-mediated mechanisms. Furthermore, minocycline was effective in this model, but does not appear to have affinity for the primary receptor families thought by many to mediate antipsychotic efficacy.


Psychopathy and indirect aggression: the roles of cortisol, sex, and type of psychopathy.
Salivary cortisol was examined in relation to indirect aggression and primary psychopathy (i.e., cold affect and interpersonal manipulation) and secondary psychopathy (i.e., criminal tendencies and erratic lifestyle) in a sample of 154 undergraduate students. Results revealed that although psychopathy and indirect aggression were strongly correlated, when statistically controlling for each of type of psychopathy, only primary psychopathy was related to indirect aggression. In women but not in men, lower cortisol was associated with higher levels of primary psychopathy and higher cortisol was associated with higher levels of secondary psychopathy. Cortisol was not related to indirect aggression. Results are discussed from both an evolutionary and developmental perspective.


Sampling considerations for health care improvement.
Sampling in improvement work can pose challenges. How is it different from the sampling strategies many use with research, clinical trials, or regulatory programs? What should improvement teams consider when determining a useful approach to sampling and a useful sample size? The aim of this article is to introduce some of the concepts related to sampling for improvement. We give specific guidance related to determining a useful sample size to a wider health care audience so that it can be applied to improvement projects in hospitals and health systems.


[The academic dossier of Maria de Lourdes Almeida: history and nursing in post-1930s Brazil].
The Special Public Health Service (Serviço Especial de Saúde Pública) reframed both the training and the professional identity of Brazilian nursing when it reopened the doors to black men and women. This is the premise of the present article, which uses the historical method to analyze the results of Brazil's Nursing Program based on the personal experience of one of its actors. Primary sources consist of the documents attached to the academic dossier of Maria de Lourdes Almeida, one of the first beneficiaries of a grant from the Service and head nurse with the Araraquara Special Health Service, part of the Center for Training School of Hygiene and Public Health at the Universidade de São Paulo. It is argued that the Nursing Program, which was implemented in Brazil under the Estado Novo, changed the professional profile of Brazilian nursing after the 1930s and solidified the interventionist policy promoted in the Vargas era.


How many kinases are druggable? A review of our current understanding.
There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases are tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible to discover a drug for each individual kinase? For every human kinase, we gathered data on their citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. Analysis of these factors highlights which kinase groups have a wealth of information available, and which groups still have room for progress. The data suggest a disproportionate focus on the more well characterized kinases while much of the kinome remains comparatively understudied. It is noteworthy that tool compounds for understudied kinases have already been developed, and there is still untapped potential for further development in this chemical space. Finally, this review discusses many of the different strategies employed to generate selectivity between kinases. Given the large volume of information available and the progress made over the past 20 years when it comes to drugging kinases, we believe it is possible to develop a tool compound for every human kinase. We hope this review will prove to be both a useful resource as well as inspire the discovery of a tool for every kinase.


A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life.
Mutations in the cardiac myosin binding protein C (MYBPC3) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis. Mutation screening of MYBPC3 gene was performed in 97 HCM probands. Nineteen (19.5%) resulted to be carriers of the founder p.F305Pfs*27 mutation and other 45 mutation carriers were identified during the evaluation of 14 families. Eleven (38%) mutation carriers were diagnosed between ages 30 years and 40 years. Disease penetrance was incomplete (64.4%), age-related and was greater in men than women (85% vs 48%, p=0.009). Probands carrying the founder mutation exhibited highest prevalence of non-sustained ventricular tachycardia (63% vs 22%, p=0.003; 63% vs 23%, p=0.01) and implantable cardioverter-defibrillator (58% vs 17%, p=0.001; 58% vs 18%, p=0.005) when compared with probands without MYBPC3 mutations or carrying other MYBPC3 mutations. Reduced survival due to sudden cardiac death (SCD) or aborted SCD occurred more frequently after the fourth decade of life in probands carrying p.F305Pfs*27 mutation than those without MYBPC3 mutations (32% vs 15%, p=0.01). p.F305Pfs*27 mutation carriers have a high probability to develop the disease between ages 30 years and 40 years with a significant major risk if they are men. This founder mutation is associated with an increase of SCD/aborted SCD events after the fourth decade of life.These findings are of relevant importance for management and clinical decision-making in patients with HCM.


Proteome regulation during Olea europaea fruit development.
Widespread in the Mediterranean basin, Olea europaea trees are gaining worldwide popularity for the nutritional and cancer-protective properties of the oil, mechanically extracted from ripe fruits. Fruit development is a physiological process with remarkable impact on the modulation of the biosynthesis of compounds affecting the quality of the drupes as well as the final composition of the olive oil. Proteomics offers the possibility to dig deeper into the major changes during fruit development, including the important phase of ripening, and to classify temporal patterns of protein accumulation occurring during these complex physiological processes. In this work, we started monitoring the proteome variations associated with olive fruit development by using comparative proteomics coupled to mass spectrometry. Proteins extracted from drupes at three different developmental stages were separated on 2-DE and subjected to image analysis. 247 protein spots were revealed as differentially accumulated. Proteins were identified from a total of 121 spots and discussed in relation to olive drupe metabolic changes occurring during fruit development. In order to evaluate if changes observed at the protein level were consistent with changes of mRNAs, proteomic data produced in the present work were compared with transcriptomic data elaborated during previous studies. This study identifies a number of proteins responsible for quality traits of cv. Coratina, with particular regard to proteins associated to the metabolism of fatty acids, phenolic and aroma compounds. Proteins involved in fruit photosynthesis have been also identified and their pivotal contribution in oleogenesis has been discussed. To date, this study represents the first characterization of the olive fruit proteome during development, providing new insights into fruit metabolism and oil accumulation process.


Parkinson's disease and occupational exposures: a systematic literature review and meta-analyses.
Objectives We conducted a systematic literature review to identify studies fulfilling good scientific epidemiological standards for use in meta-analyses of relevant risk factors for Parkinson's disease. Methods Our search identified 103 original publications on associations between work and Parkinson's disease. GRADE guidelines were used to ensure high scientific quality, and reliable guidelines were applied to classify the papers. Of the 103 articles, 47 fulfilled good scientific standards while 56 were methodologically deficient and thus excluded from our meta-analyses. Results A total of 23 publications concerned work exposure to pesticides. The weighted relative risk estimate was 1.67 (95% confidence interval 1.42-1.97). A funnel plot and bias test indicated that some publication bias concerning smaller studies might have been present. The risk estimate was not influenced by study design (case-control, cohort, or cross-sectional study) or gender. Higher estimates were found when there was a hereditary taint or onset below age 60. Studies on exposure to metals or electromagnetic fields did not show increased risk. Conclusions Using an elaborated quality protocol, there is now strong evidence that exposure to any pesticide involves a ≥50% increased risk for developing Parkinson's disease.


Adult varicocele.
Adult varicocele presents a challenge for male reproductive specialists. We have yet to fully elucidate the pathophysiology of varicocele. The enigma of the varicocele, although a source of frustration for clinicians, has been a siren call for researchers as attested to by the substantial, if flawed body of literature on the topic. We critically review recent publications on varicocele. Although yielding mixed results, studies this year have explored the potential relationship between oxidative stress and varicocele-associated infertility. In clinically focused research, one group tackled the contentious question of efficacy of surgical varicocele management. Building on the errors of prior meta-analyses, this study takes a fresh view on an old but vital topic. Finally, it is becoming clearer that varicocele affects Leydig cell function as well as seminiferous tubular function, and is a risk factor for androgen deficiency. With exceptions, recent studies support a role for varicocelectomy in the management of infertile couples. In addition, evidence is accumulating that early repair of varicoceles, especially large varicoceles, may be effective in preventing future infertility and may be an effective treatment for androgen deficiency.


Pulsatile pump decreases risk of delayed graft function in kidneys donated after cardiac death.
Organ storage techniques have been under scrutiny to determine the best preservation method, particularly in donation after cardiac death (DCD) kidneys. Conflicting literature on the benefit of pulsatile perfusion (PP) over cold storage (CS) warrants further investigation. We analyzed the risk of developing delayed graft function (DGF) in recipients of DCD and donation after brain death (DBD) kidneys undergoing PP or CS. We stratified on basis of cold ischemic time (CIT) to determine the interaction of preservation techniques, CIT and DCD kidneys on developing DGF. Of 54 136 recipients, 4923 received DCD kidneys of which 3330 (67%) underwent PP. Of 49 213 DBD recipients, 7531 (15%) underwent PP. DCD had a higher risk of DGF versus DBD (adjusted odds ratio, AOR 3.2; 3.0-3.5). PP kidneys had less DGF (AOR 0.59; 0.56-0.63) compared to CS. Interaction models of method by donor type referenced to PP/DBD revealed CS/DBD kidneys had higher DGF (AOR 1.8; 1.7-1.9), whereas CS/DCD kidneys had the highest risk of DGF (AOR 5.01; 4.43-5.67). Even though suggestive for a benefit of PP on DGF, this retrospective analysis cannot address whether this is an intrinsic effect of PP or is associated with the logistics of PP such as discard of DCD kidneys based on pump parameters.


Tai chi mind-body exercise in patients with COPD: study protocol for a randomized controlled trial.
Chronic obstructive pulmonary disease (COPD) is a chronic, progressively debilitating condition that is prevalent in the US and worldwide. Patients suffer from progressive dyspnea and exercise intolerance. Physical exercise is beneficial, but conventional pulmonary rehabilitation programs are underutilized. There remains a need for novel interventions that improve symptoms, quality-of-life, and functional capacity. Tai chi is an increasingly popular mind-body exercise that includes physical exercise, breathing training, mindful awareness, and stress management--components that are essential to the self-management of COPD. There are, however, limited data on the effectiveness of tai chi as a therapeutic intervention in this population. The Primary Aims are to evaluate the efficacy, safety, and feasibility of a 12-week tai chi program for patients with COPD. We utilize a randomized controlled trial design, with participants assigned in a 2:1 ratio to either a group tai chi program (N = 63) or a time/attention-matched education control (N = 31). Our primary outcomes are COPD-specific quality-of-life and exercise capacity. Secondary outcomes include dyspnea, mood, functional status, self-efficacy, and lung function. Cardiopulmonary exercise testing is done in a subset of patients (N = 50). To explore optimal training duration, a subgroup of patients in tai chi are randomly assigned to complete an additional 12 weeks training (total 24 weeks) (Exploratory Aim 1). To explore the impact of a simplified seated intervention including only a subset of tai chi's training components, a third randomly assigned group (N = 31) receives a 12- week mind-body breathing program (N = 31) (Exploratory Aim 2). Results of the BEAM study (Breathing, Education, Awareness, Movement) will provide preliminary evidence regarding the value of tai chi for improving quality of life and exercise capacity in patients with COPD, including information regarding optimal duration. They will also inform the feasibility and potential benefit of an alternative mind-body breathing intervention, and provide insight regarding how isolated mind-body exercise components contribute to the overall effects of tai chi. Should the results be positive, tai chi and related mind-body practices may offer a novel exercise option that is potentially accessible to a large proportion of patients with COPD. This trial is registered in Clinical Trials.gov, ID number NCT01551953. Date of Registration March 1 2012.


Misdiagnosis of persistent asthma of a patient suffering from acute bronchopulmonary aspergillosis (ABPA).
Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by an exaggerated immune response (a hypersensitivity response) to the fungus Aspergillus (most commonly Aspergillus fumigatus).ABPA causes airway inflammation that if left untreated can lead to bronchiectasis (an abnormal dilation of the airways) due to the immune system and fungal spores damaging sensitive lung tissues and ultimately leading to scarring. We present a case of a 32-year-old female patient who was misdiagnosed with persistent asthma and treated accordingly for several months until a reexamination was done and a diagnosis of ABPA was concluded. Treatment was altered which led to the successful recovery of the patient. A reevaluation of the patients' condition was needed to arrive to the correct diagnosis and to put her on the correct treatment as an ABPA patient instead of persistent asthma, concluding that the medical history and physical examination are both of vital significance to stipulate a correct diagnosis.


Prevention of prematurity by single embryo transfer.
The development of assisted reproduction techniques (ART) represents an important advance in the treatment of human infertility. However, their great effectiveness has brought with it an excessive increase in multiple pregnancy rates with the serious medical, financial and social consequences that they entail. Now, the scientific societies, the health professionals, and the infertile couples themselves are aware of these risks and have worked together to implement various strategies to deal with this situation. The result that is being obtained from the strategy of selectively reducing the number of embryos transferred is obvious. The pandemic of multiple pregnancies is being brought under control and so we have effective prevention of the obstetric and neonatal complications arising from it. It is to be hoped that it will also contribute to significantly reducing the rates of prematurity and thus of severe neonatal complications.


Response of quadrant detectors to structured beams via convolution integrals.
We propose a new expression for the response of a quadrant detector using convolution integrals. This expression, exploiting the properties of the convolution, is easier to evaluate by hand. Computationally, it is also practicable to use since a large number of computer programs can evaluate convolutions right away. We use the new expression to obtain an analytical form of the response of a quadrant detector for a Gaussian beam and for Hermite-Gaussian beams in general. We compare this analytic expression for the response for the Gaussian beam with the approximations from previous studies and with the response obtained through simulations. From the response, we also obtained an analytical form for the sensitivity of the quadrant detector to a Gaussian beam. Lastly, we demonstrate the computational ease of using our new expression for the response by calculating the sensitivity of the quadrant detector to the Bessel beam.


Optical properties of vanadium dioxide and vanadium pentoxide thin films.
Several oxides of vanadium undergo a transition from a semiconductor or insulating state to a metal phase at a critical temperature. Vanadium dioxide undergoes this transition near 68 degrees C, while V(2)O(5) undergoes a similar phase transition near 257 degrees C. During the transition a change in oxide crystal structure is accompanied by large changes in electrical and optical behavior. Thin films of vanadium oxides are capable of reversibly switching from the semiconductor to the metallic state at high speeds and with high spatial resolution. Therefore, these oxides have potential use, particularly in thin film form, for a wide variety of applications involving thermally activated electronic or optical switching devices. Such films are of considerable technical interest because of applications in chemical sensors, energy-conserving coatings, transparent conductors, and switching materials. The numerous potential electronic, optical, and optoelectronic device applications which have been suggested have stimulated work on the preparation of thin films by a variety of techniques, including chemical vapor deposition, solgel, evaporation, and sputter deposition. This paper reviews the optical properties of vanadium oxide coatings and stresses the dependence of film properties on sample preparation and resultant film microstructure.


Disadvantageous decision-making on a rodent gambling task is associated with increased motor impulsivity in a population of male rats.
Impulsivity is understood as a range of behaviours, but the association between these behaviours is not well understood. Although high motor impulsivity is a key symptom of disorders like pathological gambling and addiction, in which decision-making on laboratory tasks is compromised, there have been no clear demonstrations that choice and motor impulsivity are associated in the general population. We examined this association in a large population of rodents. We performed a meta-analysis on behavioural data from 211 manipulation-naive male animals that performed a rodent gambling task in our laboratory between 2008 and 2012. The task measures an aspect of both impulsive decision-making and impulsive action, making it possible to evaluate whether these 2 forms of maladaptive behaviour are related. Our meta-analysis revealed that motor impulsivity was positively correlated with poor decision-making under risk. Highly motor impulsive rats were slower to adopt an advantageous choice strategy and quicker to make a choice on individual trials. The data analyzed were limited to that produced by our laboratory and did not include data of other researchers who have used the task. This work may represent the first demonstration of a clear association between choice and motor impulsivity in a nonclinical population. This lends support to the common practice of studying impulsivity in nonclinical populations to gain insight into impulse control disorders and suggests that differences in impulsive behaviours between clinical and nonclinical populations may be ones of magnitude rather than ones of quality.


Properties of phosphofructokinase from the mucosa of rat jejunum and their relation to the lack of Pasteur effect.
1. The properties of phosphofructokinase after its slight purification from the mucosa of rat jejunum were studied. 2. The enzyme is inhibited by almost 100% by an excess of ATP (1.6mm), with 0.2mm-fructose 6-phosphate. AMP, ADP, P(i) and NH(4) (+) at 0.2, 0.76, 1.0 and 2mm respectively do not individually prevent the inhibition of phosphofructokinase activity by 1.6mm-ATP with 0.2mm-fructose 6-phosphate to any great extent, but all of them together completely prevent the inhibition of phosphofructokinase by ATP. 3. One of the effects of high concentrations of ATP on the enzyme was to increase enormously the apparent K(m) value for the other substrate fructose 6-phosphate, and this increase is largely counteracted by the presence of AMP, ADP, P(i) and NH(4) (+). At low concentrations of ATP the above effectors individually decrease the concentration of fructose 6-phosphate required for half-maximum velocity and when present together they decrease it further, in a more than additive way. 4. When fructose 6-phosphate is present at a saturating concentration (5mm), 0.3mm-NH(4) (+) increases the maximum velocity of the reaction 3.3-fold; with 0.5mm-fructose 6-phosphate, 4.5mm-NH(4) (+) is required for maximum effect. The other effectors do not change the maximum reaction velocity. 5. The results presented here suggest that NH(4) (+), AMP, ADP and P(i) synergistically decrease the inhibition of phosphofructokinase activity at high concentrations of ATP by decreasing the concentration of fructose 6-phosphate required for half-maximum velocity. Such synergism among the effectors and an observed, low ;energy charge' [(ATP+(1/2)ADP)/(AMP+ADP+ATP)] in conjunction with the possibility of a relatively high NH(4) (+) and fructose 6-phosphate concentration in this tissue, may keep the mucosal phosphofructokinase active and uninhibited by ATP under aerobic conditions, thus explaining the high rate of aerobic glycolysis and the lack of Pasteur effect in this tissue.


The role of substantia gelatinosa as a gate control.
A gate control exists by which peripheral afferents and descending pathways can modulate sensory transmission. Evidence is presented that the mechanism may exist in the substantia gelatinosa laminae II and III. This area receives all known types of peripheral afferent from skin, from viscera and from high-threshold muscle afferents. The chemistry of the region is unique. Peripheral afferent terminals contain substance P, somatostatin, and fluoride-resistant acid phosphatase. Cells in the region contain enkephalin and GABA. At least three descending systems from the brainstem terminate in the area. The anatomical substrate exists by which cells in laminae II and III can receive afferents and descending axons and intrude onto cells of laminae I, IV, and V. Stimuli limited to the axons of laminae II and III cells in the Lissauer tract produce dorsal root potential and change the excitability of mono- and polysynaptic reflexes. They also change the excitability and receptive fields of cells in laminae IV and V. Recording from single units in laminae II and III reveals cells with many unusual properties not seen in the large dorsal horn cells. These unusual properties include small receptive fields, very prolonged responses to single stimuli, prolonged habituation, and shifting receptive fields. The action of the gate control shows it to be subtle and far beyond a simple control of overall excitability. Excitations and inhibitions are independently controlled. Different types of convergent afferent may be turned on and off. There are signs of both short-and long-lasting actions. It seems that a good case has been made for the cells of substantia gelatinosa taking part in the gate control mechanism.


Association of Early-Phase In-Hospital Glycemic Fluctuation With Mortality in Adult Patients With Coronavirus Disease 2019.
To investigate the association of in-hospital early-phase glycemic control with adverse outcomes among inpatients with coronavirus disease 2019 (COVID-19) in Wuhan, China. The study is a large case series, and data were obtained regarding consecutive patients hospitalized with COVID-19 in the Central Hospital of Wuhan between 2 January and 15 February 2020. All patients with definite outcomes (death or discharge) were included. Demographic, clinical, treatment, and laboratory information were extracted from electronic medical records. We collected daily fasting glucose data from standard morning fasting blood biochemistry to determine glycemic status and fluctuation (calculated as the square root of the variance of daily fasting glucose levels) during the 1st week of hospitalization. A total of 548 patients were included in the study (median age 57 years; 298 [54%] were women, and n = 99 had diabetes [18%]), 215 suffered acute respiratory distress syndrome (ARDS), 489 survived, and 59 died. Patients who had higher mean levels of glucose during their 1st week of hospitalization were older and more likely to have a comorbidity and abnormal laboratory markers, prolonged hospital stays, increased expenses, and greater risks of severe pneumonia, ARDS, and death. Compared with patients with the lowest quartile of glycemic fluctuation, those who had the highest quartile of fluctuation magnitude had an increased risk of ARDS (risk ratio 1.97 [95% CI 1.01, 4.04]) and mortality (hazard ratio 2.73 [95% CI 1.06, 7.73]). These results may have implications for optimizing glycemic control strategies in COVID-19 patients during the early phase of hospitalization.


High glucose exposure promotes activation of protein phosphatase 2A in rodent islets and INS-1 832/13 β-cells by increasing the posttranslational carboxylmethylation of its catalytic subunit.
Existing evidence implicates regulatory roles for protein phosphatase 2A (PP2A) in a variety of cellular functions, including cytoskeletal remodeling, hormone secretion, and apoptosis. We report here activation of PP2A in normal rat islets and insulin-secreting INS-1 832/13 cells under the duress of hyperglycemic (HG) conditions. Small interfering RNA-mediated knockdown of the catalytic subunit of PP2A (PP2Ac) markedly attenuated glucose-induced activation of PP2A. HG, but not nonmetabolizable 3-O-methyl glucose or mannitol (osmotic control), significantly stimulated the methylation of PP2Ac at its C-terminal Leu-309, suggesting a novel role for this posttranslational modification in glucose-induced activation of PP2A. Moreover, knockdown of the cytosolic leucine carboxymethyl transferase 1 (LCMT1), which carboxymethylates PP2Ac, significantly attenuated PP2A activation under HG conditions. In addition, HG conditions, but not 3-O-methyl glucose or mannitol, markedly increased the expression of LCMT1. Furthermore, HG conditions significantly increased the expression of B55α, a regulatory subunit of PP2A, which has been implicated in islet dysfunction under conditions of oxidative stress and diabetes. Thapsigargin, a known inducer of endoplasmic reticulum stress, failed to exert any discernible effects on the carboxymethylation of PP2Ac, expression of LCMT1 and B55α, or PP2A activity, suggesting no clear role for endoplasmic reticulum stress in HG-induced activation of PP2A. Based on these findings, we conclude that exposure of the islet β-cell to HG leads to accelerated PP2A signaling pathway, leading to loss in glucose-induced insulin secretion.


[The value of ultrasonic elastography in diagnosis of salivary gland lesions in patients with Sjogren's syndrome].
The present study was aimed to clinically evaluate transitional treatment of pulpitis during pregnancy. Sixty pregnant women with pulpitis were divided into the first, second and third trimester. They were anesthetized locally using STA system combined with psychological intervention during treatment. The teeth were given one-appointment root canal preparation and filled with vitapex pasta. Normal obturation of the root canal was conducted after delivery. The effects of dental treatment, pregnancy outcomes and neonatal health status were observed. Data of the survey were analyzed by SPSS 20.0 software package, including Student's t test and chi-square test. The symptoms of pulpitis were significantly improved 24h after treatment,and the effective rate was 96.7%. The difference of VAS before and after treatment was statistically significant (P<0.05). Patients had no discomfort till the end of pregnancy,and the success rate was 98.3%. No adverse pregnancy outcomes were observed after treatment during different periods of pregnancy. Neonatal health was good. Significant differences were not found in birth gestational age, body weight, malformations, and neonatal complications between three treatment periods (P>0.05). Transitional treatment of pulpitis during pregnancy is a safe and effective procedure and worthy of wide use clinically.


Muscle glycogen repletion from endogenous carbon sources during recovery from high intensity exercise in the fasted rat.
During recovery from high intensity exercise, substantial and rapid muscle glycogen repletion from endogenous carbon sources is reported in a variety of vertebrate species, the rat being the only reported exception. The major aim of this study was to re-examine the process of glycogen repletion during recovery from high intensity exercise in the rat. In response to 3 min of vigorous swimming, muscle glycogen concentrations decrease markedly from initial levels of 20.2 +/- 1.5 and 21.2 +/- 0.9 mumol g-1 to 6.4 +/- 1.1 and 7.9 +/- 1.4 mumol g-1 in the tibialis anterior and plantaris muscles respectively. The equivalent of 58% of the glycogen carbons mobilized during exercise by the plantaris and 73% of that mobilized by the tibialis anterior muscle is repleted within 1 h following exercise. Using the hepatectomized rat as experimental model, a secondary aim of the study was to evaluate whether the liver is essential for the repletion of muscle glycogen. Although the absence of significant differences in the magnitude of post-exercise muscle glycogen repletion between sham-operated and hepatectomized rats suggests that the resynthesis of muscle glycogen can take place in the absence of hepatic gluconeogenesis, the present study identifies several limitations in the use of acute hepatectomy. Overall, the present study indicates that, in contrast to published views, the rat resembles other vertebrates in that it can support extensive muscle glycogen repletion from endogenous carbon sources during the recovery phase following high intensity exercise.


Determinants of Vaccination Coverage and Consequences for Rabies Control in Bali, Indonesia.
Maintaining high vaccination coverage is key to successful rabies control, but mass dog vaccination can be challenging and population turnover erodes coverage. Declines in rabies incidence following successive island-wide vaccination campaigns in Bali suggest that prospects for controlling and ultimately eliminating rabies are good. Rabies, however, has continued to circulate at low levels. In the push to eliminate rabies from Bali, high coverage needs to be maintained across all areas of the island. We carried out door-to-door (DTD) questionnaire surveys (n = 10,352 dog-owning households) and photographic mark-recapture surveys (536 line transects, 2,597 observations of free-roaming dogs) in 2011-2012 to estimate dog population sizes and assess rabies vaccination coverage and dog demographic characteristics in Bali, Indonesia. The median number of dogs per subvillage unit (banjar) was 43 (range 0-307) for owned dogs estimated from the DTD survey and 17 (range 0-83) for unconfined dogs (including both owned and unowned) from transects. Vaccination coverage of owned dogs was significantly higher in adults (91.4%) compared to juveniles (<1 year, 43.9%), likely due to insufficient targeting of pups and from puppies born subsequent to vaccination campaigns. Juveniles had a 10-70 times greater risk of not being vaccinated in urban, suburban, and rural areas [combined odds ratios (ORs): 9.9-71.1, 95% CI: 8.6-96.0]. Free-roaming owned dogs were also 2-3 times more likely to be not vaccinated compared to those confined (combined Ors: 1.9-3.6, 95% CI: 1.4-5.4), with more dogs being confined in urban (71.2%) than in suburban (16.1%) and rural areas (8.0%). Vaccination coverage estimates from transects were also much lower (30.9%) than household surveys (83.6%), possibly due to loss of collars used to identify the vaccination status of free-roaming dogs, but these unconfined dogs may also include dogs that were unowned or more difficult to vaccinate. Overall, coverage levels were high in the owned dog population, but for future campaigns in Bali to have the highest chance of eliminating rabies, concerted effort should be made to vaccinate free-roaming dogs particularly in suburban and rural areas, with advertising to ensure that owners vaccinate pups. Long-lasting, cheap, and quick methods are needed to mark vaccinated animals and reassure communities of the reach of vaccination campaigns.


Clinical case of the month. Idiopathic pulmonary hemosiderosis presenting as a rare cause of iron deficiency anemia in a toddler--a diagnostic challenge.
Iron deficiency anemia is the most common cause of anemia in all age groups. Idiopathic pulmonary hemosiderosis is an extremely rare etiology of iron deficiency anemia seen predominantly in the pediatric population. Idiopathic pulmonary hemosiderosis is characterized by the triad of symptoms consisting of iron deficiency anemia, diffuse pulmonary infiltrates, and hemoptysis. The clinical presentation is extremely variable, and all three symptoms may not always be seen. Due to the rarity of the disease and the variability in clinical presentation, diagnosis is usually delayed. Early diagnosis and treatment with corticosteroids prevents further episodes of recurrent alveolar hemorrhage and improves the clinical outcome. Hence, a high index of suspicion is required for the diagnosis of this condition in young patients presenting with severe iron deficiency anemia and diffuse pulmonary infiltrates. We report a toddler with idiopathic pulmonary hemosiderosis whose initial clinical presentation was severe iron deficiency anemia.


Deep-Learning Based Quantification of Bovine Oocyte Quality From Microscopy Images.
The success rate of bovine in vitro embryo reproduction is low and highly dependent on the oocyte quality. The selection of the oocyte to be fertilized is done by the embryologists' visual examination of oocytes. It is time-consuming, subjective, and inconsistent between specialists in the area. In this paper, a semi-automatic solution is proposed to score the quality of an immature oocyte. It consists of a deep learning model to classify oocyte competence. The model was trained and tested with real data, composed of images of immature oocytes and their label of whether they developed into blastocysts after fertilization. To the best of our knowledge, automated bovine oocyte classification was not attempted before, but experimental results show that our proposed solution is more robust and objective than specialists' visual assessment and comparable with other works on human oocytes.Clinical relevance- This establishes a semi-automatic real-time method to score bovine immature oocytes, based on stereo-microscopy images. Our method will significantly reduce the time of in vitro embryo production and its success.


Adding once-daily omeprazole 20 mg to metronidazole/amoxicillin treatment for Helicobacter pylori gastritis: a randomized, double-blind trial showing the importance of metronidazole resistance.
We compared the Helicobacter pylori eradication rate after a 14-day treatment with amoxicillin 500 mg t.i.d. and metronidazole 500 mg t.i.d. with or without omeprazole 20 mg once daily. This was a randomized, controlled trial in which omeprazole was given in double-blind fashion. Patients with H. pylori-associated gastritis were enrolled in four centers in Canada from July 1991 to January 1994. Eradication of H. pylori was assessed by histological evaluation and culture of endoscopic biopsies obtained from the antrum and corpus of the stomach. The H. pylori eradication rate was 73% (33 of 45) in the omeprazole-amoxicillin-metronidazole group, compared with 66% (31 of 47) in the amoxicillin-metronidazole group. This 7% difference was not statistically significant (p = 0.43, 95% confidence interval for difference -11% to 26%). Metronidazole primary resistance in the prestudy cultures was found more frequently in the omeprazole-amoxicillin-metronidazole group than in the amoxicillin-metronidazole group. Resistance to metronidazole was an important predictor of treatment failure. The H. pylori eradication rate was 61% (19 of 31) for patients infected with metronidazole-resistant H. pylori strains, compared with 91% (30 of 33) eradication for those infected with metronidazole-sensitive strains (p < 0.01). Vaginal candidiasis was reported in four patients. The H. pylori eradication rate was higher (73%) for omeprazole-amoxicillin-metronidazole than for the dual antibiotic therapy given without omeprazole (66%); however, this difference was not statistically significant. Metronidazole resistance significantly reduces H. pylori eradication rates.


Revision adenoidectomy in children: a meta-analysis.
To estimate the rate of revision surgery after previous adenoidectomy in children and to compare the rate of revision adenoidectomy in children with different conditions and by using different surgical techniques. The study protocol was registered on PROSPERO (CRD42018107877). Two authors independently searched databases, specifically PubMed, MEDLINE, EMBASE, and the Cochrane Review database. The keywords used were "adenoids","adenoidectomy","reoperation","revision"and "regrowth". The revision rate was pooled using a random-effect model. Subgroup analyses were conducted for children based on different settings, countries, risks of bias, and surgical techniques. A total 16 studies with 95 727 children were analyzed (mean age: 4.69 (1.62) years; 60% boys; sample size: 5983 patients). Five studies had a low risk of bias, 10 studies had a moderate risk of bias, and one study had a high risk of bias. The rate of revision adenoidectomy was 1.9%. Ages at initial surgery and follow-up were not significantly associated with revision surgeries. The revision rate was not significantly different in children receiving surgeries in different settings (single center vs multicenter vs population-based, country (non-United States vs United States, and risk of bias. Moreover, surgical techniques, such as curettage, suction cautery, microdebridement, and coblation did not significantly affect revision rates in children who received adenoidectomy. Revision surgery was undertaken with a frequency of 1.9% in children who underwent adenoidectomy. A lack of strong evidence exists to correlate surgical techniques with revision rate in pediatric adenoidectomy.


Atropine-induced ventricular fibrillation: case report and review of the literature.
A bradycardic and mildly hypotensive acute myocardial infarction patient developed sinus tachycardia, ventricular tachycardia, flutter, and fibrillation following intravenous atropine. Previous case reports are reviewed and the literature regarding the advisability of this mode of therapy is discussed. In the light of conflicting opinion as to the necessity of atropine in the mildly hypotensive and bradycardic acute myocardial infarction patient, and in view of its potentially deliterious effects on ischemic myocardium, a cautious and selective application of this drug is advised.