Antioxidant enzyme level in the testes of cirrhotic rats.
An understanding of the tissue and organ level of antioxidant enzymes that scavenge reactive oxygen species may provide an indication of their susceptibility to free radical-related cytotoxic damage. A direct association between testicular production of excessive reactive oxygen species and male infertility has been noted. We measured the activities of superoxide dismutase and glutathione peroxidase in the testes of thioacetamide-induced cirrhotic rats. Antioxidant enzyme activities and trace element levels (copper, zinc, manganese, and selenium) in the testes of thioacetamide-induced cirrhotic and control rats were measured. The statistical difference between the experimental and control groups with regard to the activities of superoxide dismutase and glutathione peroxidase and levels of trace elements was analyzed with Student's t test. Our results showed a significant decrease in the activity of these enzymes in the testes of cirrhotic rats. The testicular levels of copper, zinc, and manganese, which are associated with these antioxidant enzymes, increased, whereas selenium decreased slightly in cirrhotic rats; that decrease was not statistically significant. Our studies showed a drastic decrease in the level of antioxidant enzymes in the testes of cirrhotic rats that could have deleterious effects on sperm function in these animals. Further studies are necessary to understand the exact pathways of trace element metabolism in the testes of cirrhotic rats.


Post-traumatic stress burden in a sample of hospitalized patients with Bipolar Disorder: Which impact on clinical correlates and suicidal risk?
Increasing evidence suggests Bipolar Disorder (BD) to be frequently associated to a history of traumatic experiences and Post-traumatic Stress Disorder (PTSD), with consequent greater symptoms severity, number of hospitalizations and worsening in quality of life. The aim of the present study was to investigate the lifetime exposure to traumatic events and PTSD rates in-patients with BD and to analyze the relationships between PTSD symptoms, clinical characteristics and severity of the mood disorder. A consecutive sample of 212 in-patients with a DSM-5 diagnosis of BD was enrolled at the psychiatric unit of a major University hospital in Italy and assessed by the SCID-5 and MOOD Spectrum-Self Report lifetime version (MOODS-SR). Socio-demographic characteristics, clinical features, substance or alcohol abuse, history of suicide related behaviors were also collected. Lifetime trauma exposure emerged in 72.3% subjects, with a DSM-5 PTSD diagnosis reported by 35.6%. Patients with PTSD showed more frequently a (hypo)manic episode at onset, alcohol or substance abuse, psychotic features, suicide behaviors, higher scores in almost all the MOODS-SR domains, compared to those without PTSD. Cross sectional study. Lack of data about the time since trauma exposure or PTSD onset. Our findings show a history of multiple traumatic experiences in hospitalized patients with BD besides high rates of PTSD, with the co-occurrence of these conditions appearing to be related to a more severe BD. Detailed investigation of post-traumatic stress symptoms is recommended for the relevant implications on the choice of a tailored treatment and the prognosis assessment.


Activation of potassium transport induced by secretagogues in superfused submaxillary gland segments of rat and mouse.
In order to investigate the actions of acetylcholine (ACh), catecholamines and substance P on K transport in the submaxillary gland, measurements of net K flux to and from the gland tissue using flame photometry, Na efflux from the tissue using radioactive 22Na, and membrane potential and input resistance using micro-electrodes were carried out on isolated superfused segments of rat and mouse submaxillary glands. ACh (5.5 X 10(-8) to 5.5 X 10(-4) M), phenylephrine (5 X 10(-7) to 5 X 10(-4) M) or substance P (10(-9) to 10(-5) M) stimulation for 5 min induced a transient K release followed by a small K uptake after the cessation of stimulation. The K release was markedly enhanced by the simultaneous addition of ouabain (10(-3) M). On the other hand, isoprenaline (2.5 X 10(-9) to 2.5 X 10(-5) M) induced a transient K uptake without any preceding K release. The K uptake was completely blocked by the addition of ouabain. Noradrenaline induced only K uptake at a low concentration (3 X 10(-7) M), but induced transient K release followed by marked K uptake at higher concentrations (3 X 10(-6) to 3 X 10(-4) M). The K release induced by noradrenaline was suppressed by the addition of phentolamine (10(-5) M), while the K uptake was suppressed by propranolol (5 X 10(-6) M). The K release induced by ACh, phenylephrine, noradrenaline or substance P was severely reduced by Ca omission from the superfusing solution and restored by the re-admission of Ca. The isoprenaline- or noradrenaline-induced K uptake was, however, little affected by Ca omission. Application of isoprenaline (2.5 X 10(-6) M) induced an increase in 22 Na efflux. The increase in 22Na efflux was completely abolished in the presence of ouabain. Local application to the tissue bath of isoprenaline (4.7 X 10(-13) to 4.7 X 10(-12) mole) or noradrenaline (5.7 X 10(-12) to 5.7 X 10(-11) mole) in the presence of phentolamine (10(-5) M) induced membrane hyperpolarization without any appreciable change in input resistance. The hyperpolarization was abolished in the presence of ouabain (10(-3) M) or propranolol (5 X 10(-6) M) or in a K-free or low Na solution. Higher doses of both agonists, however, induced depolarization or biphasic responses (initial depolarization followed by hyperpolarization). The depolarizations were accompanied by a moderate reduction in input resistance. It is concluded that in the rat and mouse submaxillary gland acinar cells cholinergic, alpha-adrenergic or substance P stimulation causes K release (and perhaps Na uptake) resulting in activation of the Na-K pump, while beta-adrenergic receptor stimulation might directly activate the Na-K pump resulting in K uptake, or might cause Na uptake resulting in activation of the Na-K pump.


[C-reactive protein level and the correlation between lung function and CRP levels in patients with chronic obstructive pulmonary diseases].
To investigate the changes of C-reactive protein (CRP) level in patients with chronic obstructive pulmonary diseases (COPD) and to analyze the correlation between the lung function and CRP levels. Sputum and serum specimens were obtained from 30 COPD patients diagnosed according to the national criteria. The CRP level was measured by enzyme-linked immunosorbent assays. The lung function indexes such as the forced expiratory volume in one second (FEV1) and the forced expiratory volume in one second/forced vital capacity (FEV1/FVC) were also determined. The sputum CRP level in COPD patients was 30-50 times higher than that of the health controls. The sputum CRP level in COPD patients is significantly higher than that of serum in these patients (P < 0.05). The correlation between changes of serum and sputum CRP levels and sputum CRP levels was positive (r = 0.625, P < 0.05). The correlations between changes of serum CRP levels and FEV1 were negative (r = -0.610, -0.725, respectively, P < 0.001). And the correlations between changes of serum and sputum CRP levels and FEV1/FVC were negative (r = -0.639, -0.600, respectively, P < 0.05). The CRP may be secreted from the local respiratory tract. The damage of lung function in COPD patients is associated with the increase of CRP level.


Cross-modal associations between vision, touch, and audition influence visual search through top-down attention, not bottom-up capture.
Recently, Guzman-Martinez, Ortega, Grabowecky, Mossbridge, and Suzuki (Current Biology : CB, 22(5), 383-388, 2012) reported that observers could systematically match auditory amplitude modulations and tactile amplitude modulations to visual spatial frequencies, proposing that these cross-modal matches produced automatic attentional effects. Using a series of visual search tasks, we investigated whether informative auditory, tactile, or bimodal cues can guide attention toward a visual Gabor of matched spatial frequency (among others with different spatial frequencies). These cues improved visual search for some but not all frequencies. Auditory cues improved search only for the lowest and highest spatial frequencies, whereas tactile cues were more effective and frequency specific, although less effective than visual cues. Importantly, although tactile cues could produce efficient search when informative, they had no effect when uninformative. This suggests that cross-modal frequency matching occurs at a cognitive rather than sensory level and, therefore, influences visual search through voluntary, goal-directed behavior, rather than automatic attentional capture.


The current prevalence and diversity of cystic echinococcosis in slaughtered animals in Egypt.
Cystic echinococcosis is a potential zoonotic helminthic disease affect a broad spectrum of mammals including humans worldwide. The economic impact of the disease interestingly requires updated gathering information on the prevalence in slaughtered animals. Accordingly, in the current study, 573 camels, 4300 sheep, and 1235 pigs were surveyed in four Egyptian municipal abattoirs. Among those, 62 (10.82%) camels, 33 (0.77%) sheep and 3 (0.24%) pigs had cystic echinococcosis in lungs, livers and spleen. The diversity of cysts revealed that positive-cystic echinococcosis animals from all species were detected in El-Basatin abattoir. In El-Monieb abattoir, sheep only were infected. In El-Waraa and Beni-Suef abattoirs, cysts were seen in camels only. Infected animals included both sexes. In camels, lungs were the most affected organs, while in sheep, livers were the most abundant. In pigs, hydatid cysts were detected only in lungs. Moreover, camel cysts were mostly large-sized (diameter > 10 cm) with smaller cysts are also recorded. In sheep, small-, moderately- and large-sized cysts were equally present. Cysts in pigs were large-sized. Camels showed a higher percentage of fertile cysts (46.77%; 29/62) followed by sheep (21.21%; 7/33). Calcified/degenerated cysts were less in camels (38.71%; 24/62) than in sheep (75.76%). Non-viable cysts were the less frequent in both species (14.52% in camels and 3.03% in sheep). All cysts recovered from pigs were fertile. In Egypt, governmental agencies and veterinary authorities are asked to potentially eradicate stray dogs (the main definitive host) and towards the proper hygienic disposal of infected offal in abattoirs to minimize the prevalence of cystic echinococcosis.


Expanding phenomenologic heterogeneity of tardive syndromes: Time for an updated assessment tool.
Tardive syndromes (TDS) are a group of hyperkinetic and hypokinetic movement disorders that occurs after exposure to dopamine receptor blocking agents such as antipsychotic and antiemetic drugs. The Abnormal Involuntary Movement Scale (AIMS) is a widely used instrument that has become the standard for assessment of tardive dyskinesia (TDD), the most common form of TDS. However, the AIMS has a number of clinimetric limitations and was designed primarily to assess the anatomic distribution and severity of involuntary movements without regard to phenomenology. To build on recent advances in understanding and treatment of TDS, re-evaluation and revision of the AIMS that could aid both clinical practice and research may be worthwhile. Challenges, such as retaining the efficiency of the current AIMS, incorporating evaluation of impairment in daily activities, and re-training clinicians for a revised examination procedure and rating instrument, are very likely surmountable.


Calmodulin increases Ca-dependent inhibition of the Na,K-ATPase in human red blood cells.
Proteins in human red cell hemolysate were purified to determine which of them increase inhibition of the Na,K-ATPase in the presence of 2 microM free Ca. Samples purified 600,000-fold inhibited the Na,K-ATPase of human red cells in a Ca-dependent manner and stimulated the (Ca+Mg)-ATPase. These samples contained two proteins as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE): calmodulin (18,000 Mr), which comprised most (greater than 90%) of the total protein, and an unidentified protein of approximately 13,000 Mr. Both proteins were a distinctive light yellow when stained with silver. Calmodulin from bovine testes also inhibited the Na,K-ATPase and stimulated the (Ca+Mg)-ATPase. This preparation also contained two proteins as analyzed by SDS-PAGE: calmodulin (95 to 99% of the total protein) and another protein of approximately 13,000 Mr (1 to 5% of the total protein). Both were light yellow when stained with silver. Since the amount of red cell protein was limited, the remainder of the study was carried out with the bovine testes preparation. Heating the testes preparation decreased, but did not abolish, inhibition of the Na,K-ATPase and reduced stimulation of the (Ca+Mg)-ATPase. When corrected for denatured calmodulin, both heated and unheated proteins increased inhibition of the Na,K-ATPase to the same extent. The Na,K-ATPase was inhibited at 2 microM free Ca in a dose-dependent manner over a range of 15 to 100 nM calmodulin. To establish if the inhibition was due to the calmodulin or the 13,000 Mr protein, both were electroeluted after SDS-PAGE. Electroeluted calmodulin stimulated the (Ca+Mg)-ATPase and increased Ca inhibition of the Na,K-ATPase. Electroeluted amounts of the smaller Mr protein slightly stimulated the (Ca+Mg)-ATPase, but had no effect on the Na,K-ATPase. This protein was digested with cyanogen bromide, partially sequenced, and thereby identified as a fragment of calmodulin. We conclude that intact calmodulin increases inhibition of the Na,K-ATPase at 2 microM free Ca. We suggest that calmodulin is part of a mechanism mediating the effects of physiological free Ca on the Na,K-ATPase.


Neonatal cyanosis due to a new (G)γ-globin variant causing low oxygen affinity: Hb F-Sarajevo [(G)γ102(G4)Asn→Thr, AAC>ACC].
A baby girl, born at term, presented with severe cyanosis and received oxygen supplementation. Consecutive arterial blood gas analysis showed a pronounced right shift of the saturation curve, suggesting the presence of a hemoglobin (Hb) variant. A new (G)γ-globin variant was detected, namely HBG2:c.308G, which we have named Hb F-Sarajevo, the city from where the baby's parents originate. This A to C transversion exists in cis to the common (A)γ(T) and the resulting mutant Hb molecule exhibits very low oxygen affinity and cooperativity. Its analogue in the β-globin gene is Hb Kansas [β102(G4)Asn→Thr, AAC>ACC].


Opioid blockade attenuates acquisition and expression of cocaine-induced place preference conditioning in rats.
Endogenous opioid systems have been implicated in experimental cocaine addiction. One aspect of this involvement may be the modulation of the motivational properties of cocaine by endogenous opioids. The present study assessed the effect of opioid blockade with naloxone (NLX) on cocaine's motivational properties using the conditioned place preference procedure. Treatment with doses of NLX that did not induce place aversion (0.01-1.0 mg/kg-1, SC), dose-dependently attenuated place preference induced by cocaine (10 or 20 mg/kg-1, IP). This effect of NLX was present when administered during acquisition of cocaine-induced place preference and when administered before expression of cocaine's motivational effects. These data support the notion that the (conditioned) motivational properties of cocaine are modulated through activation of opioid systems by endogenous opioid peptides. Furthermore, it is suggested that an interaction between endogenous opioid systems and dopaminergic systems in the brain might be of importance in the motivational facilitation of experimental cocaine addiction.


Validation of days alive and out of hospital as a new patient-centered outcome to quantify life impact after heart transplantation.
The number of patients waiting for heart transplantation (HTX) is increasing. Thus, identification of outcome-relevant factors is crucial. This study aimed to identify perioperative factors associated with days alive and out of hospital (DAOH)-a patient-centered outcome to quantify life impact-after HTX. This retrospective cohort study screened 187 patients who underwent HTX at university hospital Duesseldorf, Germany from September 2010 to December 2020. The primary endpoint was DAOH at 1 year. Risk factors for mortality after HTX were assessed in univariate analysis. Variables with significant association were entered into multivariable quantile regression. In total, 175 patients were included into analysis. Median DAOH at 1 year was 295 (223-322) days. In univariate analysis the following variables were associated with reduced DAOH: recipient or donor diabetes pre-HTX, renal replacement therapy (RRT), VA-ECMO therapy, recipient body mass index, recipient estimated glomerular filtration rate (eGFR) and postoperative duration of mechanical ventilation. After adjustment, mechanical ventilation, RRT, eGFR and recipient diabetes showed significant independent association with DAOH. This study identified risk factors associated with reduced DAOH at 1-year after HTX. These findings might complement existing data for outcome of patients undergoing HTX.


Etidocaine in intercostal nerve block for pain relief after thoracotomy; a comparison with bupivacaine.
For pain relief after thoracotomy, intercostal nerve block with etidocaine 1% and bupivacaine 0.5%, both containing adrenaline 5 mug/ml, was used. Duration of skin analgesia for sharp pain was around 11 hours for both solutions. Post-operative pain was noted 6 and 5 hours after injection for etidocaine and bupivacaine respectively. No pathological changes in acid-base balance or ventilation were observed. Peak expiratory flow decreased to 35-40% of the pre-operative values and remained at this level for about 12 hours. Arterial and venous blood levels of the local anaesthetics were low and no signs of toxicity were noted. All patients experienced a certain pain relief from the blocks. Because of shoulder pain in some patients intercostal nerve block alone does not seem to be a perfect post-operative method for pain relief after thoracotomies.


The Genetic Contribution to Type 1 Diabetes.
To provide an updated summary of discoveries made to date resulting from genome-wide association study (GWAS) and sequencing studies, and to discuss the latest loci added to the growing repertoire of genetic signals predisposing to type 1 diabetes (T1D). Genetic studies have identified over 60 loci associated with T1D susceptibility. GWAS alone does not specifically inform on underlying mechanisms, but in combination with other sequencing and omics-data, advances are being made in our understanding of T1D genetic etiology and pathogenesis. Current knowledge indicates that genetic variation operating in both pancreatic β cells and in immune cells is central in mediating T1D risk. One of the main challenges is to determine how these recently discovered GWAS-implicated variants affect the expression and function of gene products. Once we understand the mechanism of action for disease-causing variants, we will be well placed to apply targeted genomic approaches to impede the premature activation of the immune system in an effort to ultimately prevent the onset of T1D.


Kidney disease and psoriasis: novel evidences beyond old concepts.
Psoriasis is an immune-mediated inflammatory disease for a long time considered as a type of pathology characterized by an exclusive skin involvement. Recently it has been shown that patients affected by this disease have a higher risk of developing comorbidities such as cardiovascular diseases, arterial hypertension, diabetes mellitus, and metabolic syndrome. Even the kidneys can be affected by psoriasis through three different mechanisms: immune-mediated renal damage, drug-related renal damage and chronic renal damage. Renal function should be monitored periodically to minimize the risk of renal adverse events.


Validity and reliability of two-dimensional video-based assessment to measure joint angles during running: A systematic review and meta-analysis.
Two-dimensional video analysis systems (2DVAS) are commonly used by clinicians and researchers to determine angles during running. The aim of this systematic review (PROSPERO: CRD42022322798) was to synthesize the literature on the criterion validity and reliability of 2DVAS for measuring angles during running compared to three-dimensional motion analysis systems (3DMAS). We searched for articles on MEDLINE/Pubmed, EMBASE, SciELO, and LILACS up to October/2022. We included studies that evaluated the validity of 2DVAS (when compared to 3DMAS) and/or the reliability of 2DVAS measurements of lower limb and trunk angles during running. Qualitative and quantitative analyses were performed. Seven hundred and five studies were found and 17 were included. Ten studies analysed criterion validity between 2DVAS and 3DMAS and the results ranged from poor to excellent, with most of the parameters assessed presenting poor or moderate validity. Inter-rater reliability of 2DVAS was assessed in nine studies and most of the parameters investigated had good to excellent reliability. Intra-rater reliability (between-day processing) of angular running parameters - investigated in ten studies - was considered excellent for most of the parameters analysed. Inter-session reliability was assessed in three studies and was defined as good or excellent for most of the variables assessed. 2DVAS is a reliable method for measuring joint angles during running. However, the validity of 2DVAS compared to 3DMAS ranges from low to moderate for most running parameters. Therefore, based on the available evidence, caution should be taken when applying 2DVAS, particularly for frontal and transverse plane angles.


A predatory bivalved euarthropod from the Cambrian (Stage 3) Xiaoshiba Lagerstätte, South China.
Bivalved euarthropods represent a conspicuous component of exceptionally-preserved fossil biotas throughout the Lower Palaeozoic. However, most of these taxa are known from isolated valves, and thus there is a limited understanding of their morphological organization and palaeoecology in the context of early animal-dominated communities. The bivalved euarthropod Clypecaris serrata sp. nov., recovered from the Cambrian (Stage 3) Hongjingshao Formation in Kunming, southern China, is characterized by having a robust first pair of raptorial appendages that bear well-developed ventral-facing spines, paired dorsal spines on the trunk, and posteriorly oriented serrations on the anteroventral margins of both valves. The raptorial limbs of C. serrata were adapted for grasping prey employing a descending stroke for transporting it close the mouth, whereas the backwards-facing marginal serrations of the bivalved carapace may have helped to secure the food items during feeding. The new taxon offers novel insights on the morphology of the enigmatic genus Clypecaris, and indicates that the possession of paired dorsal spines is a diagnostic trait of the Family Clypecarididae within upper stem-group Euarthropoda. C. serrata evinces functional adaptations for an active predatory lifestyle within the context of Cambrian bivalved euarthropods, and contributes towards the better understanding of feeding diversity in early ecosystems.


Coagulation abnormalities associated with neoplasia.
Subclinical abnormalities in hemostasis occur commonly in small animal patients with cancer, but the incidence of clinical thrombosis or hemorrhage is unknown. Malignancy can lead to abnormalities in both primary and secondary hemostasis, which in turn can lead to either thrombotic or hemorrhagic tendencies. These coagulation abnormalities can be associated with the tumor itself, with anticancer chemotherapy, or with secondary organ dysfunction. Thrombocytopenia and DIC are probably the most common defects associated with clinical bleeding in small animal patients.


Comparative distribution of bombesin/GRP- and substance-P-like immunoreactivities in rat hypothalamus.
Immunohistochemical localization of bombesin/gastrin-releasing peptide ( GRP )-like immunoreactivity (BN/ GRP -LI) and substance P-like immunoreactivity (SP-LI) in consecutive sections of rat hypothalamus was studied. Bombesin/ GRP -like immunoreactivity in the hypothalamus was partially characterized by gel filtration chromatography followed by radioimmunoassay. In the hypothalamus, SP-LI was more widely distributed than BN/ GRP -LI. Only the anterior and medial parvocellular parts of the nucleus paraventricularis and the nucleus suprachiasmaticus contained numerous cell bodies which exhibited BN/ GRP -LI. Neurons in these areas did not exhibit SP-LI. In contrast, cell bodies exhibiting SP-LI were numerous in the nucleus preopticus medialis and lateralis, nucleus anterior, nucleus ventromedialis and dorsomedialis, nucleus lateralis, nucleus arcuatus, and nucleus premamillaris ventralis and dorsalis. Only occasional cell bodies in these areas exhibited BN/ GRP -LI. It is concluded that the neuronal systems in the hypothalamus containing BN/ GRP -LI and SP-LI are separate, though the terminal fields in many areas overlap. Two peaks of BN/ GRP -LI were detected after gel filtration chromatography from extracts of the rat nucleus paraventricularis. The high molecular weight form coeluted with synthetic GRP (1-27), and the small molecular weight form eluted after synthetic bombesin. Thus, the endogenous BN/ GRP -LI is probably not authentic bombesin.


Prevalence of hepatitis C virus in the Mexican population: a systematic review.
Although hepatitis C virus (HCV) infection is considered a relevant public health problem in Mexico, the prevalence is still under discussion. The objective of this study was to conduct a systematic review to explore the prevalence of HCV infection in the Mexican population. A systematic review of studies reporting prevalence in Mexican population was performed using several free-access databases. Sixty-eight works fulfilled the search criteria. From these, 44 studies involved asymptomatic subjects and 28 involved patients or high-risk subjects. Prevalence of blood donors (6,955,558 persons) ranged from 0.0% to 2.05%, with 7/32 studies reporting values >1%, whereas prevalence of non-donor asymptomatic subjects (28,528 persons) from 0.0% to 2.7%, with 7/11 studies reporting values >1%, and medical personnel from 0.0% to 2.08% (1,227 persons), with 4/11 studies reporting values >1%. Prevalence of patients with chronic hepatic disease ranged from 6.7% to 77%. The most prevalent genotype was 1 (30.0-87.5%), of which subtype 1b is the most frequent (11.9-61.9%). The main risk factors were blood transfusion and unprotected sex or having multiple sex partners. The prevalence in the Mexican population seems to be in accordance with that previously estimated by the World Health Organization (1-2.5%).


Monoclonal antibodies against spermatozoa of the common carp (Cyprinus carpio L.). I. A study germ cell antigens in adult males and females.
Eleven monoclonal antibodies that recognize membrane determinants on spermatozoa of the carp Cyprinus carpio L. have been produced. Indirect immunofluorescence revealed that these determinants are uniformly distributed on the surface of head and midpiece. Most of them are also present on the outer membrane of precursor sperm cells. Although none of the monoclonal antibodies reacted with carp somatic tissue, five monoclonal antibodies were positive for surface membrane determinants of oogonia and early prophase oocytes in carp ovary. Preliminary analysis of the testis and ovary of three other species of fish showed that some carp determinants are shared with germ cells from Barbus conchonius, Clarias lazera, or Salmo gairdneri.


Analytical applications of room-temperature ionic liquids: a review of recent efforts.
Room-temperature ionic liquids (RTILs) are solvents that may have great potential in chemical analysis. Recent surge in the number of publications/reports/books/monographs clearly indicate an increasing interest of scientific and engineering community toward these exciting and unique solvents. Consequently, a variety of analytical applications of RTILs have started to emerge. This review presents an account of some of the recent reports on RTILs in major subdisciplines of analytical chemistry. Specifically, recent literature representing the applications of RTILs in chromatography, extraction, electroanalytical chemistry, sensing, and spectrometry is reviewed. With a rapid growth in the number of publications on analytical applications of RTILs, it appears that in the near future these neoteric solvents are definitely going to be a permanent feature in analytical chemistry.


[High-dose cytarabine treatment with asparaginase (Capizzi schedule) in recurrent or refractory AML in the adult].
4 patients with refractory AML or AML in relapse were treated with high dose Ara-C and L-asparaginase. Although only one patient was resistant against this type of treatment, a durable complete remission could be achieved in only one case. Severe myelosuppression was observed in all 4 cases; non-hematologic toxicity, however, was minimal.


Surgical treatment of superficial esophageal cancer.
The worldwide incidence of superficial esophageal cancer (SEC) is increasing. The aim of this study is to review the systematic surgical outcomes of esophagectomy for SEC. Only manuscripts written in English and written between 1980 and 2003 were selected from MEDLINE. The keywords consisting of superficial esophageal cancer, early esophageal cancer, and early stage or superficial stage or stage I in esophageal cancer were searched. There were no exclusion criteria for published information relevant to the topics. The most representative articles were selected when there were several articles from the same institution. Case reports were excluded. DATA EXTRACTIONS: Thirty-two manuscripts were finally collected from MEDLINE and eight articles were also added from reference lists of the pertinent literatures. In evaluating the statistical analysis of the complications of the reported literature, collective method was used. The collected information was organized. The conclusions drawn from those articles showed that the overall prevalence of SEC accounted around 10% and increased to 25% in the 2000s. The overall incidence of lymph node metastasis of SEC was about 25% and its incidences in mucosal and submucosal cancer were 5 and 35%, respectively. The percentage of the cases of squamous cell carcinoma (SCC) vs adenocarcinoma (AC) widely varied depending on the geographic locations reported; most SCC cases were from the Asian countries and most AC cases were from the European countries. Clinical significance of multimodal treatment for SEC has dramatically developed in the recent era and could provide various potential therapeutic options for SEC. These concepts make it possible to individualize surgical management of SEC as part of various multimodal treatments. The operative approaches for SEC varied from minimally invasive thoracoscopic esophagectomy, limited transabdominal distal esophagectomy, conventional transthoracic esophagectomy, transhiatal esophagectomy without thoracotomy, en bloc esophagectomy, and to extended esophagectomy with a complete three-field lymph node dissection. A 5-year overall survival rate of SEC after esophagectomy was good (46 to 83%) to excellent (71 and 100%) for mucosal SEC, but far from satisfactory (33 and 78%) for submucosal SEC. Early diagnosis, development of multimodal treatment, standardization of the surgical procedure including routine lymph node dissection, and improved perioperative management of patients have led to a better survival for patients with SEC.


Ecological specialisation in habitat selection within a macropodid herbivore guild.
Specialist species show stronger resource selection, narrower niches and lower niche overlap than generalist species. We examined ecological specialisation with respect to habitat selection in a macropodid community comprising the western grey kangaroo Macropus fuliginosus, red-necked wallaby M. rufogriseus and swamp wallaby Wallabia bicolor in the Grampians National Park, Victoria, Australia. We used radio tracking to quantify habitat selection. We predicted that because the fitness benefits of generalisation and specialisation differ, there would be a mix of generalised and specialised species in our community. As all three macropodid species show marked sexual dimorphism, we also expected that they would show sex-based specialisation. Finally, because many large herbivores select different habitats for foraging and resting, we predicted that our species would specialise on a subset of their overall selected habitat based on activity period (diurnal or nocturnal). All three species specialised on the available resources to some degree. Western grey kangaroos were specialists, at least during the active period. Niche data for the two wallaby species were harder to interpret so we could not determine their degree of specialisation. Within species, we found no evidence of sex-based specialisation. However, we found clear evidence of specialisation by activity period in western grey kangaroos and red-necked wallabies, but not in swamp wallabies. The strength of behavioural decisions made during the active period in influencing specialisation points to the likelihood that bottom-up processes regulate this community.


Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2.
Mutations in receptor tyrosine kinase (RTK) genes can confer resistance to receptor-targeted therapies. A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib. We studied the mechanisms of HER2-T798M-induced resistance to identify potential strategies to overcome that resistance. HER2-T798M was stably expressed in BT474 and MCF10A cells. Mutant cells and xenografts were evaluated for effects of the mutation on proliferation, signaling, and tumor growth after treatment with combinations of inhibitors targeting the EGFR/HER2/HER3/PI3K axis. A low 3% allelic frequency of the T798M mutant shifted 10-fold the IC50 of lapatinib. In mutant-expressing cells, lapatinib did not block basal phosphorylation of HER2, HER3, AKT, and ERK1/2. In vitro kinase assays showed increased autocatalytic activity of HER2-T798M. HER3 association with PI3K p85 was increased in mutant-expressing cells. BT474-T798M cells were also resistant to the HER2 antibody trastuzumab. These cells were sensitive to the pan-PI3K inhibitors BKM120 and XL147 and the irreversible HER2/EGFR TKI afatinib but not the MEK1/2 inhibitor CI-1040, suggesting continued dependence of the mutant cells on ErbB receptors and downstream PI3K signaling. BT474-T798M cells showed increased expression of the EGFR ligands EGF, TGFα, amphiregulin, and HB-EGF. Addition of the EGFR neutralizing antibody cetuximab or lapatinib restored trastuzumab sensitivity of BT474-T798M cells and xenografts, suggesting that increased EGFR ligand production was causally associated with drug resistance. Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene-amplified breast cancer cells harboring T798M mutant alleles.


The sweet taste in the calf. I. Chorda tympani proper nerve responses to taste stimulation of the tongue.
Electrophysiological recordings were obtained from the chorda tympani nerve in calves during stimulation with NaCl, quinine hydrochloride, citric acid, acesulfan-K, aspartame, fructose, galactose, glucose, glycine, lactose, maltose, monellin, Na-saccharin, sucrose, thaumatin, and xylitol. In cattle the chorda tympani innervates the posterior third of the tongue as well as the anterior part. It was found that the posterior receptive field generally responded better to sweet substances than the anterior. Glycine and Na-saccharin followed by xylitol were the most effective sweet stimuli. The monosaccharides elicited larger responses than the disaccharides. Aspartame gave a weak nerve response in 5 of 13 calves. Monellin and thaumatin elicited no change in chorda tympani nerve activity and did not crossadapt with any sweetener. No effects on citric acid responses were observed after application of miraculin.


Sequence of retrograde atrial activation of the human heart. Correlation with P wave polarity.
Studies were performed in 6 patients during open heart surgery to correlate the relative sequence of atrial activation with the polarity of the retrograde P wave in electrocardiographic leads II, III, and aVF. Bipolar atrial electrograms were recorded from selected sites during threshold pacing from sites low on the right side of the atrial septum which when paced resulted in the inscription of either negative or positive P waves in electrocardiograph leads II, III, and aVF. When the atria were paced from a site just anterior to the coronary sinus ostium (negative P waves), the posteroinferior left atrium was activated early and Bachmann's bundle late during the inscription of the P wave. When the atria were paced from a site 2 cm anterior to the coronary sinus ostial site (positive P waves), Bachmann's bundle was activated early during the P wave and the posteroinferior left atrium was activated relatively later. These data from man are consistent with previous studies in the canine heart. Therefore, we deduced that in man during the inscription of negative retrograde P waves in leads II, III, and aVF, atrial activation occurs primarily in a retrograde fashion. However, during the inscription of positive retrograde P waves in man, activation occurs rapidly up the interatrial septum (we believe via the anterior internodal pathway) to Bachmann's bundle, from where it then spreads in a manner similar to that which occurs during normal sinus rhythm.


Autoradiographic determination of cerebral glucose content, blood flow, and glucose utilization in focal ischemia of the rat brain: influence of the plasma glucose concentration.
Focal cerebral ischemia was produced by occlusion of the middle cerebral artery in rats. Cerebral blood flow measured with [14C]iodoantipyrine was severely reduced in the lateral portion of neostriatum. This area of dense ischemia was sharply demarcated against the surroundings. The adjacent cortex was perfused at one-third of normal, whereas blood flow in the medial neostriatum was only slightly reduced. This pattern of perfusion was independent of the plasma glucose concentration of the animal. In contrast, the glucose utilization calculated from the 2-[3H]deoxyglucose accumulation depended on the plasma glucose concentration. Enhanced glucose utilization was evident in the border areas surrounding the ischemic focus in normoglycemic animals. Neither acutely nor chronically diabetic animals had such an increase of metabolism in the borderzone. Moderately hyperglycemic rats had a narrow rim of enhanced glucose utilization immediately surrounding the ischemic core, whereas animals with plasma glucose values above 22 mmol/L had no such rim. In mild hypoglycemia (2-4 mmol/L), the glucose utilization was slightly enhanced in the border areas, but during severe hypoglycemia (less than 2.5 mmol/L), the glucose utilization declined gradually toward the ischemic core. Glucose content, and thereby the lumped constant (measured by 3-0-[14C]methylglucose) showed little regional variation, except in the ischemic core. These findings indicate that blood flow alterations after occlusion of the middle cerebral artery in rats are not influenced by the plasma glucose utilizations. In contrast, glucose utilization depends on a combination of plasma glucose concentration and blood flow instead of blood flow per se.


Evaluation of serum vascular endothelial growth factor (VEGF) and microvessel density (MVD) as prognostic indicators in carcinoma breast.
Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide. A great deal of interest has been paid to the predictive value of neoangiogenesis represented by microvessel density (MVD), on clinical progression and prognosis of several types of tumors. Serum VEGF levels may therefore be clinically useful for the prediction of increase in tumor growth, metastasis or recurrence spread in individual patients. A total of 265 cases of breast lesions were studied to note the importance of Serum VEGF as a prognostic marker in cases of breast carcinoma. The expressed serum VEGF levels and microvessel density (MVD) were assessed quantitatively and were correlated with tumor grade, tumor necrosis, stromal reaction and nodal metastasis. Serum VEGF was increased in patients with lesions of breast and the levels of serum VEGF in malignant lesions were significantly increased when compared to benign lesions. It was also noted that the levels of serum VEGF increased with increasing grades of malignancy. MVD showed a significant correlation in the early stages of the malignant tumors, where there was no necrosis, but in tumors associated with necrosis and hemorrhage MVD failed to show significant correlation. Hence, serum vascular endothelial growth factor can be used as a more reliable, non-invasive adjunctive diagnostic criteria in the assessment of the grade and hence, the prognosis of malignant tumors of the breast.


Failure of IGF-I infusion to promote growth in Zn deficient hypophysectomized rats.
The retarded growth of zinc-deficient rats is associated with low plasma insulin-like growth factor-I (IGF-I). To determine whether the low circulating IGF-I concentrations are responsible for the stunted growth, the growth response of zinc-deficient hypophysectomized rats to supplementation with recombinant human IGF-I (hIGF-I) was investigated. There were three dietary groups: zinc-deficient (0.9 mg zinc/kg diet), controls (66 mg zinc/kg diet) and zinc-adequate pair-fed (66 mg zinc/kg diet). All rats in each group received hIGF-I (150 micrograms/day) by subcutaneous infusion for 12 days, except for half of the animals in the control group which were sham-treated and which received vehicle infusion for the same period of time. The magnitude of the change was small, nevertheless infusion of hIGF-I significantly increased (p < 0.05) the body weight, tail length, liver weight and tibial epiphyseal width of control animals. This growth effect of hIGF-I was inhibited by lack of zinc in the diet, as evidenced by continuous weight loss, no increase in tail length and lowered tibial epiphyseal width in zinc-deficient animals. We conclude that systemic supplementation of hIGF-I can promote growth in hypophysectomized rats. The absence of weight gain and bone growth in zinc-deficient animals during the infusion period suggests that the growth promoting effect of circulating IGF-I is impaired by zinc deficiency.


The distance behavior of hospital patients: a disaggregated analysis.
Regional health systems planning implicitly incorporates information about the distance behavior of hospital patients, in specifying hospital catchment areas, service-specific catchment areas and levels of centralization. Distance behavior of patients varies depending on their diagnoses and on the treatment and diagnostic procedure(s). In this study, a variety of procedures, ranging from those which are routine to those which are highly specialized, are analyzed within the framework of distance behavior. Regionalization of selected services will, by definition, affect distance behavior.


Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction.
SOCS-1 (suppressor of cytokine signaling-1) is a representative of a family of negative regulators of cytokine signaling (SOCS-1 to SOCS-7 and CIS) characterized by a highly conserved C-terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS-1 and SOCS-3 inhibited both interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF)-induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts. Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling. The SOCS-1 and SOCS-3 N-terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS-1 and SOCS-3 to inhibit LIF signal transduction. Unlike SOCS-1, SOCS-3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS-1 and SOCS-3 act on the JAK-STAT pathway in different ways. Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different.


The impact of the written request process on drug development in childhood cancer.
The Food and Drug Administration (FDA) Modernization Act, enacted in 1997, created a pediatric exclusivity incentive allowing sponsors to qualify for an additional 6 months of marketing exclusivity after satisfying the requirements outlined in the Written Request (WR). This review evaluates the impact of the WR mechanism on the development of oncology drugs in children. A search of the FDA document archiving, reporting, and regulatory tracking system was performed for January 1, 2000 to December 31, 2010. Drugs were identified and pediatric-specific labeling information was obtained from firstname.lastname@example.com and FDA Pediatric Labeling Changes Table. Fifty WRs have been issued for oncology drugs. Pediatric studies have been submitted for 14 drugs. Thirteen received pediatric exclusivity. As of December 31, 2010, labeling changes have been made for 11 drugs. Three drugs were approved for pediatric use. WRs have provided a mechanism to promote the study of drugs in pediatric malignancies. Information from studies resulting from the WRs regarding safety, pharmacokinetics, and tolerability of oncology drugs has been incorporated into pediatric labeling for 11/14 of the drugs. Earlier communication and collaboration between the FDA, National Cancer Institute, clinical investigators, and commercial sponsors are envisioned to facilitate the identification and prioritization of emerging new drugs of interest for WR consideration. Since this is the only regulatory mechanism, resulting from specific legislative initiatives relevant to cancer drug development for children, efforts to enhance its impact on increasing drug approval for pediatric cancer indications are warranted.


Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder.
To determined the localization of CB(1) and CB(2) receptors in rat bladder and investigate the effect of a mixed CB(1)/CB(2) receptor agonist, ajulemic acid (AJA), on chemically evoked release of the sensory neuropeptide calcitonin gene-related peptide (CGRP). Whole rat bladders were incubated in a series of tissue baths containing physiologic salt solution to measure baseline CGRP release by enzyme immunoassay. Capsaicin (30 nM) and adenosine triphosphate (10 muM) were used to provoke CGRP release in the presence or absence of AJA. Specificity of AJA for CB(1) and CB(2) receptors was determined using antagonists. Localization was determined by immunofluorescence for CB(1) and CB(2) receptors in fixed bladders. Immunofluorescence showed the localization of CB(1) and CB(2) receptors in the bladder. Mean baseline CGRP release was 605 +/- 62 pg/g of bladder weight, and AJA had no effect on CGRP release. The addition of adenosine triphosphate/capsaicin significantly increased the CGRP release over baseline, by 44% (P < .05), and AJA application significantly decreased CGRP release, by 29% compared with controls (P < .05). The CB(1) and CB(2) antagonists AM 251 and AM 630, respectively, reversed the blunting effect of AJA on evoked CGRP release, resulting in an increase of 40% and 38% over baseline, respectively. CB(1) and CB(2) receptors are localized in the urothelium of rat bladder, and application of AJA inhibits the evoked release of CGRP by acting on CB(1) and CB(2) receptors. These findings identify a potential new pathway for study in the evaluation and treatment of painful bladder syndrome/interstitial cystitis.


In Vitro Activities of Five Antifungal Drugs Against Opportunistic Agents of Aspergillus Nigri Complex.
Black aspergilli, particularly Aspergillus niger and A. tubingensis, are the most common etiological agents of otomycosis followed by onychomycosis, pulmonary aspergillosis and aspergilloma. However, so far there is no systematic study on their antifungal susceptibility profiles. A collection of 124 clinical and environmental species of black aspergilli consisted of A. niger, A. tubingensis, A. uvarum. A. acidus and A. sydowii were verified by DNA sequencing of the partial β-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MECs of caspofungin were performed based on CLSI M38-A2. Posaconazole and caspofungin had the lowest MIC range (0.016-0.125 µg/ml and 0.008-0.031 µg/ml, respectively), followed by amphotericin B (0.25-4 µg/ml), voriconazole (0.125-16 µg/ml) and itraconazole (0.25 to >16) in an increasing order. Some strains of A. niger showed high MIC value for itraconazole and voriconazole (>16 µg/ml), in contrast only environmental isolates of A. tubingensis had high itraconazole MICs (>16 µg/ml). These results confirm that posaconazole and caspofungin are potential drugs for treatment of aspergillosis due to opportunistic agents of Aspergillus Nigri complex. However, in vivo efficacy remains to be determined.


DNA Methylation Regulates a Set of Long Non-Coding RNAs Compromising Hepatic Identity during Hepatocarcinogenesis.
Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis. The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis. Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients' prognosis.


Next generation tools for high-throughput promoter and expression analysis employing single-copy knock-ins at the Hprt1 locus.
We have engineered a set of useful tools that facilitate targeted single copy knock-in (KI) at the hypoxanthine guanine phosphoribosyl transferase 1 (Hprt1) locus. We employed fine scale mapping to delineate the precise breakpoint location at the Hprt1(b-m3) locus allowing allele specific PCR assays to be established. Our suite of tools contains four targeting expression vectors and a complementing series of embryonic stem cell lines. Two of these vectors encode enhanced green fluorescent protein (EGFP) driven by the human cytomegalovirus immediate-early enhancer/modified chicken beta-actin (CAG) promoter, whereas the other two permit flexible combinations of a chosen promoter combined with a reporter and/or gene of choice. We have validated our tools as part of the Pleiades Promoter Project (http://www.pleiades.org), with the generation of brain-specific EGFP positive germline mouse strains.


Application of community data to surface complexation modeling framework development: Iron oxide protolysis.
This study presents a comprehensive community data-driven surface complexation modeling framework for simulating potentiometric titration of mineral surfaces. Compiled community data for ferrihydrite, goethite, hematite, and magnetite are fit to produce representative protolysis constants that can reproduce potentiometric titration data collected from multiple literature sources. Using this framework, the impact of surface complexation model type and surface site density (SSD) on the fit quality and protolysis constants can be readily evaluated. For example, the non-electrostatic model yielded a poor data fit compared to diffuse double layer model and constant capacitance models due to the absence of known surface charge effects. Regardless of the choice of iron oxide mineral, pKa1 decreased with increasing SSD while the opposite tendency was observed for pKa2. This newly developed framework demonstrates a method to reconcile community data-wide potentiometric titration data using Findable, Accessible, Interoperable, Reusable data principles to produce mineral protolysis constants that improve robustness of surface complexation models for applications in metal sorption and reactive transport modeling. The framework is readily expandable (as community data increase) and extensible (as the number of minerals increase). The framework provides a path forward for developing self-consistent, comprehensive, and updateable surface complexation databases for surface complexation and reactive transport modeling.


Morbidity and mortality in acute lower limb ischaemia: a 5-year review.
A series of 204 consecutive patients with acute lower limb ischaemia was treated over a 5-year period in a Regional Vascular Unit. The mean age was 70 years, with a range of 41-98 and a female to male ratio of 1:0.94. Eighty-eight percent were treated by operation. Twenty-one had simultaneous vascular reconstructive procedures. Fifty-three patients died within 30 days (mortality rate 26%), and 12 required major amputation. Of these, four died resulting in a limb salvage rate of 95% in the survivors. An analysis of factors affecting outcome has shown increasing age, level of occlusion, recent myocardial infarction, pre-existing peripheral arterial disease and cardiopulmonary functional class to be major determinants of morbidity and mortality.


Early rehabilitative concepts in therapy of the comatose brain injured patients.
To evaluate the changes of vegetative parameters and behavioural assessment in comatose patients after severe brain injury during the Multimodal-Early-Onset-Stimulation (MEOS) in early rehabilitation. We studied 16 predominantly male (3:1) patients, age mean 43.6 (16-77) years. Mean coma duration was 22.2 (8-41) days, therapy duration (MEOS) 9.8 (1-30) days. The initial GCS was 6.6 (3-9), KRS 5.3 (0-15). Including criteria for therapy: Severe head trauma, coma for at least 48 hours (GCS < 8), vegetative stability, normal intracranial pressure, abandon of mechanical ventilation, sedation and severe infections. MEOS was finished in achieving GCS > 9, follow-up investigations were made after 2 years. We identified significant changes in two vegetative parameters (heart/respiratory frequencies), even in deep coma (GCS 3-4). Most significant changes were caused by tactile and acoustic stimulation. Standardized behavioural assessment turned out to be particularly advisable in cases of medium coma (GCS 5-7). Stimulation of tactile and acoustic senses resulted mainly in mimical, head and eye movements. Follow-up was possible in 14 patients: One remained in a vegetative state (GOS 2), two exhibited severe neurologic/neuropsychologic deficits, depending on care (GOS 3), six substained major functional deficits (GOS 4), at though they were able to perform the tasks of daily life on their own, three patients reached GOS 5. Two returned to their former jobs. The present results indicate that stimulation therapy should be based on a close observation of patterns of behaviour, and, at least in deep coma stages, involve the registration of vegetative parameters. It may be sensitive to identify parameters predicting a favourable or unfavourable outcome. Preliminary data seem to support the hypothesis that the absence of any response to external stimuli is indicative of an unfavourable outcome.


Effects of anesthesia upon 18F-FDG uptake in rhesus monkey brains.
The kinetics of 18F-fluorodeoxyglucose (18F-FDG) in the monkey brain were monitored, and comparisons were made between the conscious state and when under ketamine and pentobarbital anesthesia. Rhesus monkeys were intravenously injected with 18F-FDG and followed by 60 min of PET scanning. In the conscious state, the 18F-FDG concentration reached a plateau 5 min after intravenous injection. Under ketamine anesthesia, the 18F-FDG concentration gradually increased with time in all monitored regions. At 60 min after injection, the concentration in the striatum was about 3.2 times greater than that in the conscious state, and about 4.5 times greater in the cerebral cortex. Under pentobarbital anesthesia, the 18F-FDG concentration in the occipital cortex was slightly lower. These findings demonstrate that 18F-FDG concentration in the monkey brain is significantly affected by anesthesia. The results also imply the existence of a short-term regulation mechanism for hexokinase activity in intact monkey brain.


Fate of DNA lesions that elicit sister-chromatid exchanges.
Using 3-way differential staining (TWD) of sister chromatids, the fate of DNA lesions involved in sister-chromatid exchange (SCE) formation was determined in murine bone marrow cells in vivo, after treatment with either mitomycin C (MMC) or cyclophosphamide (CP). Both MMC (2.6 mg/kg b.w.) and CP (7 mg/kg b.w.) induced an SCE frequency near the expected in the 2 subsequent cell divisions, but the frequency of SCE occurring at the same locus in successive cell divisions was substantially lower than expected. The results are compared with previous data obtained after exposure to gamma-rays. A model of SCE induction is proposed.


[The effect of oxytocin and vasopressin on individual behavior and EEG-correlates of narcotic dependent rats in the "open field" test].
A single intracerebral injection of oxytocin activated the behavior, increased the frequency and amount of hippocampal theta-rhythm whereas vasopressin elicited opposite effects during "open field" test in drug-dependent rats with implanted electrodes in different brain structures.


Phylogeny and classification of the trapdoor spider genus Myrmekiaphila: an integrative approach to evaluating taxonomic hypotheses.
Revised by Bond and Platnick in 2007, the trapdoor spider genus Myrmekiaphila comprises 11 species. Species delimitation and placement within one of three species groups was based on modifications of the male copulatory device. Because a phylogeny of the group was not available these species groups might not represent monophyletic lineages; species definitions likewise were untested hypotheses. The purpose of this study is to reconstruct the phylogeny of Myrmekiaphila species using molecular data to formally test the delimitation of species and species-groups. We seek to refine a set of established systematic hypotheses by integrating across molecular and morphological data sets. Phylogenetic analyses comprising Bayesian searches were conducted for a mtDNA matrix composed of contiguous 12S rRNA, tRNA-val, and 16S rRNA genes and a nuclear DNA matrix comprising the glutamyl and prolyl tRNA synthetase gene each consisting of 1348 and 481 bp, respectively. Separate analyses of the mitochondrial and nuclear genome data and a concatenated data set yield M. torreya and M. millerae paraphyletic with respect to M. coreyi and M. howelli and polyphyletic fluviatilis and foliata species groups. Despite the perception that molecular data present a solution to a crisis in taxonomy, studies like this demonstrate the efficacy of an approach that considers data from multiple sources. A DNA barcoding approach during the species discovery process would fail to recognize at least two species (M. coreyi and M. howelli) whereas a combined approach more accurately assesses species diversity and illuminates speciation pattern and process. Concomitantly these data also demonstrate that morphological characters likewise fail in their ability to recover monophyletic species groups and result in an unnatural classification. Optimizations of these characters demonstrate a pattern of "Dollo evolution" wherein a complex character evolves only once but is lost multiple times throughout the group's history.


The role of PERK-eIF2α-ATF4-CHOP pathway in sevoflurane induced neuroapoptosis and cognitive dysfunction in aged mice.
Postoperative cognitive dysfunction (POCD) is a common surgical complication that causes additional pain in patients and affects their quality of life. To address this problem, emerging studies have focused on the POCD. Recent studies have shown that aging and anesthetic exposure are the two major risk factors for developing POCD. However, few reports described the exact molecular mechanisms underlying POCD in elderly patients. In the previous studies, the endoplasmic reticulum (ER) stress and neuroapoptosis in the hippocampus were associated with inducing POCD; however, no further information on the related signaling pathways could be disclosed. The PERK-eIF2α-ATF4-CHOP pathway is identified as the main regulatory pathway involved in ER stress and cell apoptosis. Therefore, we assume that the occurrence of POCD induced by sevoflurane inhalation may potentially result from ER stress and neuroapoptosis in the hippocampus of aged mice mediated by the PERK-eIF2α-ATF4-CHOP pathway. In our study, we found a relationship between sevoflurane inhalation concentration and memory decline in aged mice, with a 'ceiling effect'. We have confirmed that POCD induced by sevoflurane results from ER stress and neuroapoptosis in the hippocampus of aged mice, which is regulated by the over-expression of PERK-eIF2α-ATF4-CHOP pathway. Furthermore, we also showed that the dephosphorylation inhibitor of eIF2α (salubrinal) could down-regulate PERK-eIF2α-ATF4-CHOP pathway expression to inhibit ER stress and enhance the cognitive function of aged mice. In general, our study has elucidated one of the molecular mechanisms of sevoflurane-related cognitive dysfunction in aged groups and provided new strategies for treating sevoflurane-induced POCD.


A new method for preservation of viable leukocytes at near-zero temperatures.
We propose a new effective, available, and economic method for preservation of leukocytes at near-zero temperatures for 6 days using an original protecting solution.


Eco-evolutionary dynamics: An experimental demonstration in nature.
Ecological change drives rapid evolution, which then should feed back to influence ecological change. A new study uses experiments with Timema stick insects to demonstrate such feedbacks in nature, revealing that they can be very rapid, strong, and stabilizing.


Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors.
N-Methyl-D-aspartate receptors (NMDARs) in the brain are influenced by psychoactive drugs such as 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (ketamine) and its analog 2-(ethylamino)-2-(3-methoxyphenyl)-cyclohexanone (methoxetamine). The recreational methoxetamine use can cause several toxicities and methoxetamine-related deaths have also been reported. Therefore, it has been banned in many countries. Since 2020, methoxetamine derivatives, 2-(ethylamino)-2-(m-tolyl)cyclohexan-1-one (deoxymethoxetamine) and 2-(isopropylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxisopropamine), have been sold online as designer drugs. However, how deoxymethoxetamine and methoxisopropamine act on NMDARs remains unknown. In this study, we first performed in silico docking studies of NMDARs, and deoxymethoxetamine and methoxisopropamine in addition to the major methoxetamine metabolites, 2-amino-2-(3-methoxyphenyl)-cyclohexanone (N-desethyl methoxetamine) and 2-(ethylamino)-2-(3-hydroxyphenyl)-cyclohexanone (O-desmethyl methoxetamine). The docking study suggested each compound interacts with NMDARs. We also determined the half-maximal inhibitory concentration (IC50s) of the methoxetamine-related compounds for NMDARs using NMDAR-expressing cartwheel interneurons of mice and patch-clamp recordings. We found that the IC50s of methoxetamine, deoxymethoxetamine, methoxisopropamine, N-desethyl methoxetamine, and O-desmethyl methoxetamine for NMDARs were 0.524, 0.679, 0.661, 1.649, and 0.227 μM, respectively. These results indicate that the methoxetamine-related compounds act as potent NMDAR blockers. Thus, deoxymethoxetamine and methoxisopropamine, both of which may cause damage by blocking NMDARs, are serious concerns. N-Desethyl methoxetamine and O-desmethyl methoxetamine may cause several adverse effects when methoxetamine is metabolized.


Convergence of finger tremor and EEG rhythm at the alpha frequency induced by rhythmical photic stimulation.
The frequencies of EEG alpha rhythm and physiological finger tremor overlap at 9-10 c/sec, suggesting a functional relationship between the two mechanisms. We measured the correlation between the two rhythms when they occurred spontaneously and when rhythmical photic stimulation was applied. Rhythmical physiological finger tremor (9.7 c/sec +/- 1.06 S.D.) was accompanied by an alpha rhythm (10.3 c/sec +/- 0.51 S.D.) spontaneously, showing a one-to-one relationship at times. When photic stimulation was provided at a frequency (11 Hz) close to the subject's spontaneous alpha rhythm, a frequency-convergence occurred between finger tremor (10.3 c/sec +/- 0.68 S.D.) and the EEG (10.6 c/sec +/- 0.35 S.D.). The correlation coefficient between the two rhythms under photic stimulation was significantly higher (0.49 +/- 0.14 S.D.) than under the spontaneous condition (0.13 +/- 0.16; P less than 0.05). Consistent with this, the mean difference between finger tremor and EEG frequencies was significantly lower during photic stimulation (0.83 c/sec +/- 0.46 S.D.) than during the spontaneous condition (1.23 c/sec +/- 0.82 S.D.) (t = 2.54; P less than 0.05, t-test for correlated means). These findings indicate that the EEG and physiological finger tremor tend toward synchrony with each other in an environment of photic stimulation, supporting our hypothesis of a functional relationship between the two mechanisms.


Elemental, fatty acid, and protein composition of appendicoliths.
Appendicoliths are commonly found obstructing the lumen of the appendix at the time of appendectomy. To identify factors that might contribute to their formation we investigated the composition of appendicoliths using laser ablation inductively coupled plasma mass spectroscopy, gas chromatography, polarized light microscopy, X-ray crystallography and protein mass spectroscopy. Forty-eight elements, 32 fatty acids and 109 human proteins were identified within the appendicoliths. The most common elements found in appendicoliths are calcium and phosphorus, 11.0 ± 6.0 and 8.2 ± 4.2% weight, respectively. Palmitic acid (29.7%) and stearate (21.3%) are the most common fatty acids. Some stearate is found in crystalline form-identifiable by polarized light microscopy and confirmable by X-ray crystallography. Appendicoliths have an increased ratio of omega-6 to omega-3 fatty acids (ratio 22:1). Analysis of 16 proteins common to the appendicoliths analyzed showed antioxidant activity and neutrophil functions (e.g. activation and degranulation) to be the most highly enriched pathways. Considered together, these preliminary findings suggest oxidative stress may have a role in appendicolith formation. Further research is needed to determine how dietary factors such as omega-6 fatty acids and food additives, redox-active metals and the intestinal microbiome interact with genetic factors to predispose to appendicolith formation.


Isolation of a putative keratocyte activating factor from the corneal stroma.
Fetal bovine serum has commonly been used to expand the population of keratocytes in culture. Tissue extracts, however, have also been used to grow other cell types. We prepared a DMEM/F12 extract of corneal stroma and compared the growth and morphology of collagenase-isolated keratocytes cultured in DMEM/F12, or DMEM/F12 containing either stromal extract or fetal bovine serum. Cell proliferation was measured by 3H-thymidine and BrdU incorporation as well as by DNA quantitation. The extract was fractionated by gel filtration. Cell morphology was assessed by phase-contrast microscopy. Culture in both extract and serum stimulated keratocytes to proliferate, but keratocytes cultured in the extract grew more slowly due to a longer cell cycle and to a lower final density because of greater sensitivity to contact inhibition. Keratocytes cultured in serum became fibroblastic while those cultured in extract retained the dendritic morphology of quiescent keratocytes. The stimulating factors in the corneal extract were more sensitive to heat inactivation and of higher molecular weight than the stimulating factors in serum. These results indicate that the mitogenic activity in extract and serum are different and that the phenotypes resulting from growth in serum and extract are also different. Keratocytes cultured at low cell densities in the corneal extract may mimic keratocyte activation, an initial and crucial event for keratocytes during the corneal wound healing process.


Experimental study on adsorption of PbCl2 and CdCl2 on kaolin modified by leachates from municipal solid waste incineration power plant.
Six kinds of waste liquids produced in the treatment process of leachate in a waste incineration plant were used to improve the adsorption effect of raw kaolin on heavy metal chloride. The capture performances of these modified kaolin on PbCl2 and CdCl2 vapor were investigated in a two-stage fixed bed combustor. The results indicated that the adsorption effects of raw kaolin on PbCl2 and CdCl2 were improved in some experimental groups, main effective component was Na+ in the leachate, but the influences did not change regularly with the increase in the concentration of Na + introduced into kaolin. The adsorbents formed by modifying 10 g kaolin with 21.25 ml leachate 2 were the best adsorbents for PbCl2 and CdCl2. The capture efficiencies of PbCl2 and CdCl2 can reach 95% and 63.88%, with the increase of 36% and 53%, respectively. Using leachate as modifying agent had the same effect as directly using Na+. Adsorptions of PbCl2 and CdCl2 were still mainly chemical adsorptions. After adsorption of PbCl2, the modified kaolin not only generated PbA12Si2O8, but also produced other chemical compounds. The adsorption of CdCl2 by modified kaolin did not generate CdAl2Si2O8, but other chemical reactions occurred to generate CdAl2O4 and Pb8Cd (Si2O7)3.


Structure of human ACE gives new insights into inhibitor binding and design.
Angiotensin-converting enzyme (ACE) is a primary target of drugs used for controlling hypertension. A new X-ray crystallographic structure of the key catalytic domain of ACE provides detailed information about the structure of its active site, located in a deep channel, and its interactions with an inhibitor. Such information might facilitate the rational design of ACE inhibitors that are more potent and more selective and therefore of clinical use.


Editorial to: Advance in the Treatment of Pediatric Leukemia.
The history of leukemia goes back many years and John Bennet, a Scottish physician, described in 1845 a 28-year old patient with swelling of the spleen who then developed fever, bleeding and increasing swellings in his neck, groin and armpits [...].


Indications, Resource Allocation, and Outcomes Associated with Ex-Utero Intrapartum Treatment Procedures: A North American Fetal Therapy Network Survey.
Neonates with cardiorespiratory compromise at delivery are at substantial risk of hypoxic neurologic injury and death. Though mitigation strategies such as ex-utero intrapartum treatment (EXIT) exist, the competing interests of neonatal beneficence, maternal non-maleficence, and just distribution of resources require consideration. Due to the rarity of these entities, there are few systematic data to guide evidence-based standards. This multi-institutional, interdisciplinary approach aims to elucidate the current scope of diagnoses that might be considered for such treatments and examine if treatment allocation and/or outcomes could be improved. After IRB approval, a survey investigating diagnoses appropriate for EXIT consultation and procedure, variables within each diagnosis, occurrence of maternal and neonatal adverse outcomes, and instances of suboptimal resource allocation in the last decade was sent to all North American Fetal Treatment Network center representatives. One response was recorded per center. We received a 91% response rate and all but one center offer EXIT. Most centers (34/40, 85%) performed 1-5 EXIT consultations per year and 17/40 (42.5%) centers performed 1-5 EXIT procedures in the last 10 years. The diagnoses with the highest degree of agreement between centers surveyed to justify consultation for EXIT are head and neck mass (100%), congenital high airway obstruction (90%), and craniofacial skeletal conditions (82.5%). Maternal adverse outcomes were noted in 7.5% of centers while neonatal adverse outcomes in 27.5%. A large percentage of centers report cases of suboptimal selection for risk mitigation procedures and several centers experienced adverse neonatal and maternal outcomes. This study captures the scope of EXIT indications and is the first to demonstrate the mismatch in resource allocation for this population. Further, it reports on attributable adverse outcomes. Given suboptimal allocation and adverse outcomes, further examination of indications, outcomes, and resource use is justified to drive evidence-based protocols.


Simple formulae for the calculation of RHO, T1 and T2 from a properly designed diagnostic NMR experiment.
The calculation of rho, T1 and T2 images from a minimal set of source images is considerably simplified if proper values for the sequence parameters are chosen. For the spin-echo technique a setup is suggested - a ratio of three between the effective repetition time of the T2- and the T1-weighted acquisitions - which not only produces the desired simplifications but which also is entirely compatible with normal diagnostic practice and close to optimum for two-point measurements.


Effect of Asymmetric Tension on Biomechanics and Metabolism of Vertebral Epiphyseal Plate in a Rodent Model of Scoliosis.
To investigate the effect of asymmetric tension on idiopathic scoliosis (IS) and to understand its pathogenic mechanism. The rodent model of scoliosis was established using Sprague-Dawley rats with left rib-tethering from T6 to T12 , tail and shoulder amputation, and high-cage feeding. Vertebrae epiphyseal cartilage plates were harvested from the convex and concave sides. To analyze differences on the convex and concave sides, finite element analysis was carried out to determine the mechanical stress. Protein expression on epiphyseal cartilage was evaluated by western blot. Micro-CT was taken to evaluate the bone quality of vertebral on both sides. Scoliosis curves presented in X-ray radiographs of the rats. Finite element analysis was carried out on the axial and transverse tension of the spine. Stresses of the convex side were -170.14, -373.18, and -3832.32 MPa (X, Y, and Z axis, respectively), while the concave side showed stresses of 361.99, 605.55, and 3661.95 MPa. Collagen type II, collagen type X, Sox 9, RunX2, VEGF, and aggrecan were expressed significantly more on the convex side (P < 0.05). There was asymmetric expression of protein on the epiphyseal cartilage plate at molecular level. Compared with the convex side, the concave side had significantly lower value in the BV/TV and Tb.N, but higher value in the Tb.Sp (P < 0.05). There was asymmetry of bone quality in micro-architecture. In this study, asymmetric tension contributed to asymmetry in protein expression and bone quality on vertebral epiphyseal plates, ultimately resulting in asymmetry of anatomy. In addition, asymmetry of anatomy aggravated asymmetric tension. It is the first study to show that there is an asymmetrical vicious circle in IS.


Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women With Inflammatory Bowel Disease.
Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child. Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest. Among 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51). Biologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.


Validation of the OPTIMIPARK Questionnaire: A Tool to Optimize Treatment in Parkinson's Disease.
Dopamine replacement therapy reduces most motor and nonmotor features of Parkinson's disease. However, with disease progression, adjustments of dopaminergics and the application of advanced therapies must be considered. To validate the OPTIMIPARK questionnaire as a tool to help clinicians make therapeutic decisions on patients treated with levodopa. We tested a questionnaire including 9 items encompassing motor and nonmotor signs, complications, and disability in a multicenter, observational, cross-sectional study. A neurologist (neurologist 1 [N1]) assessed patients according to regular clinical practice and blinded to the OPTIMIPARK questionnaire score. Therapeutic decisions were classified as "no changes," "adjustment of conventional treatment," and "advanced therapy indicated." External neurologists (neurologist 3 [N3] and neurologist 4 [N4]), who only knew the patient age, years of disease, and current treatment, made their therapeutic decisions based on the OPTIMIPARK score. Concordance between the criterion of the N1 versus the OPTIMIPARK-based N3-N4 consensus was analyzed applying weighted κ. The area under Receiving Operating Characteristic (ROC) curves was calculated for OPTIMIPARK scores. A total of 113 patients with Parkinson's disease were included. The OPTIMIPARK-based decision led to a higher proportion of patients requiring therapeutic modification than N1 assessment (74% vs. 60%; P = 0.002). Concordance between the N1 and N3-N4 decisions was moderate, whereas interobserver agreement among N3 and N4 was high. Area Under the Curve(AUC) values of 0.83 and 0.82 were found for "no changes" and "advanced therapy indicated" decisions by the N1 neurologist. OPTIMIPARK might be more sensitive than regular clinical practice in suggesting the need for a therapeutic change. Furthermore, the low and high scores identify with high accuracy well-adjusted patients and candidates for advanced therapy, respectively.


Role of shear stress on composition, diversity and dynamics of biofilm bacterial communities.
This article evaluates the effect of shear stress on the composition of biofilm bacterial communities. For the first time, a Conical Couette-Taylor Reactor (CCTR) was used to develop biofilms at varying shear stresses (from 0.055 to 0.27 Pa) and provided a useful model for studying the effect of hydrodynamics on biofilms. The composition, diversity and dynamics of biofilm bacterial communities were analysed using the PCR-SSCP fingerprint method. Results clearly demonstrate a link between shear stress and composition of the microbial communities. High shear stresses decrease biofilm diversity and the analysis of biofilm community dynamics suggests that shear stress would slow down biofilm maturation and tend to maintain a young biofilm.


Direct tandem duplication in chromosome 19q characterized by array CGH.
Partial trisomy of the long arm of chromosome 19 is a rare aneusomy. Only six cases of pure duplications have been previously reported, two of which were prenatally detected. Here we describe the clinical manifestations in a 15-month-old girl with a de novo dup(19)(q12q13.2) and the application of array-based comparative genomic hybridization with a resolution of approximately 1 Mb to characterize the duplicated segment. Seven clones were found duplicated, and the size of the fragment was determined to be 10.8 Mb. The scarce number of patients reported and the difficulty of accurately defining the duplicated segment when conventional cytogenetic methods are applied hamper the delineation of a clinical phenotype for duplication of chromosome 19q. To our knowledge this is the fifth live born reported with a pure dup(19), and the first report in which the duplicated segment has been accurately characterized by means of array CGH.


Evaluation of a two-way SMS messaging strategy to reduce neonatal mortality: rationale, design and methods of the Mobile WACh NEO randomised controlled trial in Kenya.
Globally, approximately half of the estimated 6.3 million under-5 deaths occur in the neonatal period (within the first 28 days of life). Kenya ranks among countries with the highest number of neonatal deaths, at 20 per 1000 live births. Improved identification and management of neonates with potentially life-threatening illness is critical to meet the WHO's target of ≤12 neonatal deaths per 1000 live births by 2035. We developed an interactive (two-way) short messaging service (SMS) communication intervention, Mobile Solutions for Neonatal Health (Mobile women's and children's health (WACh) NEO), focused on the perinatal period. Mobile WACh NEO sends automated tailored SMS messages to mothers during pregnancy and up to 6 weeks post partum. Messages employ the Information-Motivation-Behaviour Skills framework to promote (1) maternal implementation of essential newborn care (ENC, including early, exclusive breast feeding, cord care and thermal care), (2) maternal identification of neonatal danger signs and care-seeking, and (3) maternal social support and self-efficacy. Participants can also send SMS to the study nurse, enabling on-demand remote support. We describe a two-arm unblinded randomised controlled trial of the Mobile WACh NEO intervention. We will enrol 5000 pregnant women in the third trimester of pregnancy at 4 facilities in Kenya and randomise them 1:1 to receive interactive SMS or no SMS (control), and conduct follow-up visits at 2 and 6 weeks post partum. Neonatal mortality will be compared between arms as the primary outcome. Secondary outcomes include care-seeking, practice of ENC and psychosocial health. Exploratory analysis will investigate associations between maternal mental health, practice of ENC, care-seeking and SMS engagement. This study received ethical approval from the University of Washington (STUDY00006395), Women and Infants Hospital (1755292-1) and Kenyatta National Hospital/University of Nairobi (P310/04/2019). All participants will provide written informed consent. Findings will be published in peer-reviewed journals and international conferences. NCT04598165.


Emerging targets for combination therapy in melanomas.
Cutaneous melanomas are often difficult to treat when diagnosed in advanced stages. Melanoma cells adapt to survive in extreme environmental conditions and are among the tumors with larger genomic instability. Here we discuss some intrinsic and extrinsic mechanisms of resistance of melanoma cells to both conventional and target therapies, such as autophagy, adaptation to endoplasmic reticulum stress, metabolic reprogramming, mechanisms of tumor repopulation and the role of extracellular vesicles in this later phenomenon. These biological processes are potentially targetable and thus provide a platform for research and discovery of new drugs for combination therapy to manage melanoma patient treatment.


Musculoskeletal oncology and thermal ablation: the current and emerging role of interventional radiology.
The role of interventional radiology (IR) is expanding. With new techniques being developed and tested, this radiology subspecialty is taking a step forward in different clinical scenarios, especially in oncology. Musculoskeletal tumoral diseases would definitely benefit from a low-invasive approach that could reduce mortality and morbidity in particular. Thermal ablation through IR has already become important in the palliation and consolidation of bone metastases, oligometastatic disease, local recurrences, and treating specific benign tumors, with a more tailored approach, considering the characteristics of every patient. As image-guided ablation techniques lower their invasiveness and increase their efficacy while the collateral effects and complications decrease, they become more relevant and need to be considered in patient care pathways and clinical management, to improve outcomes. We present a literature review of the different percutaneous and non-invasive image-guided thermal ablation methods that are currently available and that could in the future become relevant to manage musculoskeletal oncologic diseases.


Behavioral and ecological interactions of foraging mice (Peromyscus melanotis) with overwintering monarch butterflies (Danaus plexippus) in México.
Mice (Peromyscus melanotis) immigrate extensively to overwintering colonies of monarch butterflies (Danaus plexippus) in México. There they feed on both live and dead butterflies that accumulate on the ground and in low vegetation. Through a series of feeding experiments, we examined the potential impact of mouse predation on these colonies, as well as how this predation was influenced by the accessibility and the degree of desiccation of the monarchs. Mice attacked on average 39.9 wet (freshlykilled) butterflies per night. We estimated that a population of mice (75-105 individuals) could kill approximately 0.40-0.57 million butterflies in a 1 ha colony (4-5.7% of the colony) over the 135-day overwintering season. In feeding experiments, mice fed disproportionately on: 1) wet (hydrated) monarchs close to the ground versus those perched higher; 2) wet monarchs, when both wet and dry (desiccated) monarchs were on the ground; and 3) wet monarchs on stakes versus dry monarchs on the ground. Mice commonly ate the entire abdomen of dry monarchs, whereas they fed selectively on the abdomen of wet monarchs by discarding the bitter, cardenolide-laden cuticle and eating the internal tissues. These results suggest that the monarchs' state of desiccation is more important than their accessibility in determining the feeding preferences of these mice. However, the monarchs' strong tendency to crawl up vegetation does appear to reduce their risk to mouse predation.


The structure of apo-calmodulin. A 1H NMR examination of the carboxy-terminal domain.
The structure of the carboxy-terminal domain of bovine calmodulin, TR2C, in the calcium-free form was investigated using two-dimensional 1H NMR. Sequential resonance assignments were made using standard methods. Using information from medium and long range contacts revealed by nuclear Overhauser enhancement, the secondary structure and global fold were determined. The apo protein possesses essentially the same secondary structure as that in the calcium activated form of intact calmodulin. However, the secondary structural elements are rearranged so that the hydrophobic binding pocket is closed in the apo-form.


Acute haemodynamic effects and pharmacokinetics of ramipril in patients with heart failure. A placebo controlled three-dose study.
The aim of the present study was primarily to evaluate the haemodynamic effects of the ACE-inhibitor ramipril which is active via its metabolite ramiprilat. Ramipril 1.25, 2.5 and 5 mg and placebo was administered orally to 4 groups of 12 patients with heart failure (NYHA III) in a double-blind randomised, parallel study. Haemodynamics were monitored for 24 h and blood was sampled and urine collected for up to 96 h. In the placebo-treated group the cardiac index (CI) was significantly increased (15.8%) and right atrial pressure decreased (26.6%). Ramipril 1.25 mg had insignificant haemodynamic effects compared to placebo and the 2.5 mg dose had significant effects on some haemodynamic variables. Ramipril 5 mg had pronounced and sustained effects on pulmonary artery pressure, which fell by 43.7%, and pulmonary capillary wedge pressure (PCWP; -59.1%); systemic vascular resistance was also decreased 21%. A significant effect on CI was only seen after 2.5 mg ramipril (+7.4%). The mean maximal degree of ACE inhibition was 73.2, 90.4 and 98.5%, respectively, after the three doses of ramipril. Complete inhibition of ACE-activity was seen at a mean plasma concentration of ramiprilat of 4.7 ng.ml-1. The degree of inhibition declined with a half life of about 75 h. There was a significant relation between the degree of ACE-inhibition and change in PCWP but not with the change in SVR. Ramipril was mainly eliminated in the form of ramiprilat and inactive metabolites.


Use of therapeutic drug monitoring to characterize cefepime-related neurotoxicity.
Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime-related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN. This was a retrospective study of adult inpatients admitted between 2016 and 2018 who received cefepime therapeutic drug monitoring (TDM). Potential CRN cases were identified utilizing a standard definition. The primary outcomes of the study were to determine the incidence of CRN and evaluate the relationship between cefepime trough concentrations, the average daily AUC, and neurotoxicity. Bayesian posteriors were generated for each patient using a cefepime pharmacokinetic (PK) model, and the mean daily area under the concentration-time curve (AUC) was calculated. Multiple regression was performed to assess the association between CRN, cefepime PK, and clinical predictors of neurotoxicity. Four hundred eighty-one patients with 503 hospital encounters received cefepime TDM and were included in the analysis. The incidence of CRN was 4.4% (22/503). Patients with CRN had a higher incidence of renal dysfunction, hypertension, and diabetes mellitus compared to patients without CRN (non-NT). The mean cefepime trough concentration was significantly greater in the CRN patients than in the non-NT group (61.8 ± 33.7 vs. 30 ± 27.7 mg/L, respectively, p = 0.0002). Cefepime trough concentration and renal dysfunction were independently associated with increased risk of CRN in the adjusted multiple regression model. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CRN. Delaying cefepime TDM greater than 72 h after the initiation of cefepime was associated with a 3-fold increased risk of CRN. Cefepime should be used cautiously in hospitalized patients with renal dysfunction due to the risk of neurotoxicity. Dose optimization utilizing TDM early in cefepime treatment may minimize adverse effects and improve patient safety.


Bioreducible polypeptide containing cell-penetrating sequence for efficient gene delivery.
To design excellent polypeptide-based gene vectors and determine the gene delivery efficiency. Polypeptides (designated as xPolyK6, xPolyK6-R81 and xPolyK6-R82), comprising the DNA condensing and buffering peptide HK6H as well as cell penetrating peptide (CPP) R8 were obtained by the oxidative polymerization of CHK6HC and CR8C at different molar ratios in 4 mL phosphate-buffered saline (PBS) containing 30% (v/v) DMSO at room temperature for 96 h. The cytotoxicity of vectors was studied by MTT assay. Moreover, particle size, zeta potential and morphology along with the in vitro transfection efficiency and cellular uptake of vector/plasmid DNA (pDNA) complexes were characterized at various w/w ratios to determine their potential in gene therapy. All the vectors presented excellent ability of binding and condensing pDNA, additionally with low cytotoxicity. Simultaneously, transfection efficiency of the vectors appeared apparent dependence on the vector composition. The distinct correlation between the content of CR8C with the transfection efficiency demonstrated the effective improvement in transfection efficacy by the oxidative polymerization. Particularly, xPolyK6-R82 possessed the highest transfection efficiency at a w/w ratio of 50. Furthermore, xPolyK6-R82 also presented the best cellular uptake capability demonstrated by confocal microscopy and flow cytometry. Bioreducible polypeptides incorporating with proper amount of CPP are promising as effective non-viral gene vectors in gene therapy.


Impairment of human polymorphonuclear leukocyte chemotaxis by 2,5-hexanedione.
The effect of n-hexane metabolites on human polymorphonuclear leukocyte chemotaxis and luminol-dependent chemiluminescence was investigated. No effect was detected when 2-hexanol, 2-hexanone and gamma-valerolactone were used; 2,5-hexanedione at 75 micrograms/ml inhibited chemotaxis and a direct correlation between increasing the xenobiotic concentration and the degree of inhibition was found. Chemotactic peptide-induced chemiluminescence was not affected by 2,5-hexanedione. In order to clarify the phenomenon, plasma membrane fluidity was investigated by fluorescence polarization of the fluorescent probe trimethylammonium diphenylhexatriene. 2,5-hexanedione increased the membrane fluidity, while the other n-hexane metabolites did not change the degree of fluorescence polarization. Results suggest that the cellular functions modulated by membrane-cytoskeletal organization are affected by 2,5-hexanedione also at the low concentrations.


Hypothermia and cardiopulmonary bypass during resection of extensive arteriovenous malformation followed by microvascular reconstruction.
A patient is presented in whom hypothermic hypoperfusion and cardiopulmonary bypass were used to aid in resection of a mandibular arteriovenous malformation. This was followed by immediate microvascular reconstruction using a fibular osteocutaneous microvascular free tissue transfer. Prior attempted resection after highly selective embolization had proved inadequate. We found that the operative field, using hypothermic hypoperfusion was bloodless and enabled safe, rapid excision of the malformation. After patient rewarming, microvascular reconstruction was readily performed. No neurologic sequelae resulted, and no recurrence of the malformation has been noted.


Detection of Toxoplasma gondii IgG antibodies in juvenile great grey kangaroos, Macropus giganteus giganteus.
Serial IgG antibody titers to Toxoplasma gondii from three juvenile great grey kangaroos (Macropus giganteus giganteus) with clinical signs consistent with toxoplasmosis were compared with titers from three clinically normal juveniles of similar age. The modified agglutination test was used to measure antibodies to T. gondii. Results demonstrated declining antibody titers to T. gondii in five of six animals. Antibody titers were similar in animals with and without clinical signs. This was interpreted as an indication that maternal IgG antibodies to T. gondii were transferred to juveniles, presumably in milk, rather than an indication of clinical disease. Therefore, clinicians should interpret Toxoplasma serology results in juvenile macropods cautiously.


Endothelin and endothelin antagonism: roles in cardiovascular health and disease.
Endothelin is the most potent mammalian vasoconstrictor yet discovered. Its three isoforms play leading roles in regulating vascular tone and causing mitogenesis. The isoforms bind to two major receptor subtypes (ETA and ETB), which mediate a wide variety of physiologic actions in several organ systems. Endothelin may also be a disease marker or an etiologic factor in ischemic heart disease, atherosclerosis, congestive heart failure, renal failure, myocardial and vascular wall hypertrophy, systemic hypertension, pulmonary hypertension, and subarachnoid hemorrhage. Specific and nonspecific receptor antagonists and ECE inhibitors that have been developed interfere with endothelin's function. Many available cardiovascular therapeutic agents, such as angiotensin-converting-enzyme inhibitors, calcium-entry blocking drugs, and nitroglycerin, also may interfere with endothelin release or may modify its activity. The endothelin antagonists have great potential as agents for use in the treatment of a wide spectrum of disease entities and as biologic probes for understanding the actions of endothelin in human beings.