Incidence of severe local anaesthetic toxicity and adoption of lipid rescue in Finnish anaesthesia departments in 2011-2013.
Although the incidence of severe local anaesthetic systemic toxicity (LAST) has been declining, the risk of LAST still remains. There are no national treatment guidelines for LAST in Finland. We performed a national survey of the occurrence of LAST and its treatment in 2011-2013. A structured electronic questionnaire was sent to the anaesthesia department chiefs of all Finnish public hospitals (n = 45) in spring 2014. We collected information about the occurrence and outcome of LASTs and existence of treatment protocols. The questionnaire response rate was 100% covering approximately 95% of all regional anaesthesias managed by anaesthesiologists in Finnish hospitals. The total number of regional anaesthesias, excluding spinal anaesthesia, performed by anaesthesiologists was approximately 211,700 during the survey period. Fifteen cases of LAST were reported (0.7 : 10,000); all patients recovered without negative sequelae. Fourteen patients, in five of whom ultrasound guidance had been applied, developed central nervous system toxicity symptoms and only one cardiac symptoms. Lipid emulsion was given to this latter patient, and to four of the other 14. The relative risk (95% confidence intervals) for occurrence of LAST in non-academic hospital vs. university hospitals was 3.3 (1.0-10.3; P = 0.04). Treatment protocols for LAST included lipid emulsion in 47% of the departments. The incidence of LAST in Finland is very low. Several departments have adopted lipid emulsion treatment for LAST despite lack of national recommendations and knowledge of the possible mechanism of action.


The effects of inorganic lead on the spontaneous and potassium-evoked release of 3H-5-HT from rat cortical synaptosome interaction with calcium.
Interaction of lead with the serotonergic system has been studied in vitro in rat brain synaptosomal fraction prepared from cortical tissue. Synaptosomes were loaded with 3H-5-HT and spontaneous and K+-evoked release of the amine was examined in the presence and the absence of calcium. It was shown that lead itself induced the release of 3H-5-HT (EC50 = 27 microM). This effect decreased (40%) in the presence of calcium without modification of the EC50. Moreover, lead markedly inhibited the K+-evoked release of 3H-5-HT observed in the presence of calcium. This effect was obtained either in the presence of lead or using synaptosomes pretreated with lead and washed. These results indicate that lead interferes with neuronal 5-HT release by mechanism(s) involving calcium.


Cellular composition of a cerebral hemisphere primary culture.
In this overview attention is given to available markers and methods for characterizing cell elements in a culture system. Primary cultures from newborn rat cerebral hemispheres were grown for 14 days. The population of cells was dominated by astrocytic glial cells (60-70%), but cells with properties of macrophages, endothelial-like cells, mesenchymal-like cells, ependymal-like cells, and oligoblasts were also found. Neither mature neurons nor oligodendroglial cells were observed. The enrichment in astroglial-like cells makes the cultures a satisfactory astroglial-cell model, at least for some purposes.


Effects of Temperature and Moisture on Conidia Germination, Infection, and Acervulus Formation of the Apple Marssonina Leaf Blotch Pathogen (Diplocarpon mali) in China.
Apple Marssonina leaf blotch (AMLB; Diplocarpon mali) is a severe disease of apple that mainly causes premature leaf defoliation in many apple growing areas worldwide. AMLB epidemic development is closely related to temperature and rainfall. In this study, the effects of temperature and moisture on conidium germination, infection on leaves, and acervulus production were investigated under controlled environments. The temperature required for conidium germination and infection ranged from 5 to 30°C, with the optimum at approximately 23°C. The temperature required for acervulus formation was slightly higher, with the optimum at 24.6°C. Wetness was needed in order for conidia to germinate and infect; only a few conidia germinated at 100% RH. However, lesions can produce acervuli in dry conditions. The minimum duration of leaf wetness required for conidia to complete the entire infection process was 14, 8, 4, and 6 h at 10, 15, 20, and 25°C, respectively. A model describing the effect of temperature and leaf wetness duration was built. The model estimated that the optimum temperature for conidial infection was 22.6°C and the minimum wetness duration required was 4.8 h. This model can be used to forecast D. mali conidial infection to assist in disease management in commercial apple production.


Pharmacologic intervention of skin vasospasm and ischemic necrosis in pigs.
Ischemic necrosis resulting from vasospasm is a common complication in skin flap surgery, and serotonin released by traumatized platelets is likely to play an important role in the pathogenesis of skin vasospasm in flap surgery. We studied the pathogenic role of serotonin and its pharmacologic intervention thereof in skin flap ischemic necrosis in pigs. We observed that serotonin caused a concentration-dependent (10(-8)-10(-5) M) increase in perfusion pressure in isolated perfused pig skin flaps. This vasoconstrictive effect of serotonin was blocked by S1C/2-serotonergic receptor antagonists LY53857 (10(-5) M) and ketanserin (10(-5) M), but not by an alpha 1-adrenoceptor antagonist (prazosin 10(-5) M), or a thromboxane A2 (TxA2)/endoperoxide receptor antagonist (SQ30741 10(-5) M). The vasoconstrictive effect of serotonin was more pronounced (p < 0.05) in the presence of an endothelium-derived nitric oxide (NO) synthesis inhibitor [N omega-monomethyl-L-arginine (L-NA) or NG-nitro-L-arginine (L-NMMA) 10(-5) M] but not a cyclooxygenase inhibitor (indomethacin 10(-5) M). In in vivo studies, serotonin infusion (5 micrograms/kg/min intravenously, i.v.) significantly (p < 0.05) decreased pig random pattern skin flap capillary blood flow. This in vivo vascular effect was also completely blocked in pigs pretreated with LY53857 (0.4 mg/kg i.v.). In a separate experiment without serotonin infusion, i.v. prazosin (2-8 micrograms/kg), dazmegrel (2-6 mg/kg), or SQ30741 (2-4 mg/kg) had no significant effect on skin flap capillary blood flow as compared with control. On the other hand, i.v. sergolexole or LY53857 significantly (p < 0.05) increased skin flap capillary blood flow in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)


The virulent Wolbachia strain wMelPop increases the frequency of apoptosis in the female germline cells of Drosophila melanogaster.
Wolbachia are bacterial endosymbionts of many arthropod species in which they manipulate reproductive functions. The distribution of these bacteria in the Drosophila ovarian cells at different stages of oogenesis has been amply described. The pathways along which Wolbachia influences Drosophila oogenesis have been, so far, little studied. It is known that Wolbachia are abundant in the somatic stem cell niche of the Drosophila germarium. A checkpoint, where programmed cell death, or apoptosis, can occur, is located in region 2a/2b of the germarium, which comprises niche cells. Here we address the question whether or not the presence of Wolbachia in germarium cells can affect the frequency of cyst apoptosis in the checkpoint. Our current fluorescent microscopic observations showed that the wMel and wMelPop strains had different effects on female germline cells of D. melanogaster. The Wolbachia strain wMel did not affect the frequency of apoptosis in cells of the germarium. The presence of the Wolbachia strain wMelPop in the D. melanogasterw1118 ovaries increased the number of germaria where cells underwent apoptosis in the checkpoint. Based on the appearance in the electron microscope, there was no difference in morphological features of apoptotic cystocytes between Wolbachia-infected and uninfected flies. Bacteria with normal ultrastructure and large numbers of degenerating bacteria were found in the dying cyst cells. Our current study demonstrated that the Wolbachia strain wMelPop affects the egg chamber formation in the D. melanogaster ovaries. This led to an increase in the number of germaria containing apoptotic cells. It is suggested that Wolbachia can adversely interfere either with the cystocyte differentiation into the oocyte or with the division of somatic stem cells giving rise to follicle cells and, as a consequence, to improper ratio of germline cells to follicle cells and, ultimately, to apoptosis of cysts. There was no similar adverse effect in D. melanogaster Canton S infected with the Wolbachia strain wMel. This was taken to mean that the observed increase in frequency of apoptosis was not the general effect of Wolbachia on germline cells of D. melanogaster, it was rather induced by the virulent Wolbachia strain wMelPop.


Three distinct morphological classes of receptors in fish olfactory organs.
Three morphologically distinct classes of receptor-neurons are proposed: (1) type I ciliar cells, (2) microvillar cells and (3) type II ciliar cells. Retrograde transport of horseradish peroxidase by axons in the olfactory nerve to the olfactory organs of goldfish (Carassius auratus) and channel catfish (Ictalurus punctatus) provided evidence that these axon-bearing cells are present in the organs of both species. Goldfish olfactory organs were also studied with scanning electron microscopy, dissociated with papain for isolated cell preparations, and processed for ultrastructural localization of acid phosphatase activity. Type I ciliar cells are similar to ciliar olfactory receptors found in all vertebrate classes. Microvillar cells are present in the olfactory organs of most fishes and in the tetrapod vomeronasal organ. In goldfish and catfish, type I ciliar and microvillar cells are concentrated on the inner third of each lamella, nearest to the median raphe. Type II ciliar cells have often been described as respiratory-type or ciliated nonsensory cells. They are structurally similar to respiratory epithelial cells in the nasal cavities of tetrapods and have motile cilia that beat synchronously, indicative of their role in mediating fluid flow over the olfactory epithelium. In goldfish they occur singly and in aggregates throughout the organ. In catfish they are segregated from type I ciliar and microvillar cells on the outer two-thirds of each lamella. In goldfish and catfish they have axons that pass through the olfactory nerve to the olfactory bulb; hence, they are receptor-neurons as well as analogous to respiratory epithelium. In addition to the three receptor types described above, cells resembling receptors with rodlike distal processes were seen filled with horseradish peroxidase and observed with scanning and transmission electron microscopy. Cells of similar structure have been documented elsewhere, often called "rod cells," and sometimes considered a separate receptor type in fishes. In this study, a number of rodlike processes were found with their ciliar or microvillar components partially fused. High levels of acid phosphatase activity were localized to these processes, and examples were found that corresponded to each of the three receptor types. Olfactory receptor turnover is believed to persist through life. The evidence presented supports the hypothesis that fusion of their dendritic apical processes marks an early stage of receptor cell senescence.


The biosynthesis of prostate-specific antigen in non prostatic cell lines.
The biosynthesis of prostate specific antigen (PSA) was studied in human epidermoid carcinoma, (KB) cells and in normal human embryonic lung (WI-38)cells. The prostate carcinoma cell line, PC-35F12 was used as a control. PSA specific antibodies were used to precipitate the immunologically reactive peptides from cell extracts and conditioned media. The immunoprecipitates were analyzed by electrophoresis followed by fluorgraphy. Human PSA is initially synthesized as 32-kDa secretory glycopeptide containing one N-linked oligosaccharide and then processed to a 34-kDa secretory glycoprotein in KB cells. PSA is also expressed in normal human embryonic lung cells, WI-38. These results confirm that PSA expression is not prostate specific, but is also found in some nonprostatic cells. From these results, we conclude that PSA may play an important physiologic role in several tissues.


Pharmacokinetics of diltiazem in severe renal failure.
The acute effects of a single dose of diltiazem (Tildiem), a calcium antagonist, were studied in 9 patients with severely impaired renal function (GFR between 0.03 and 0.87 ml/s/1.73 m2). Control measurements were made of inulin and PAH clearance, creatinine, blood pressure, heart rate and ECG. Following administration of diltiazem 120 mg, 7 blood samples were collected in the first 12 h and after 24 h, 32 h, 48 h; urine was collected for the first 12 h, 12-24 h and 24-48 h, and blood pressure, heart rate and ECG were recorded after 6 h. Diltiazem and its main metabolite, desacetyldiltiazem, had a pharmacokinetic profile similar to that in patients with normal renal function (peak plasma concentration, half-life and urinary excretion). Diltiazem is normally eliminated in the urine to a small extent, because it is metabolized, and this also applies to desacetyldiltiazem, which is probably further metabolized.


[Adenoma of the papilla of Vater. Diagnostic and therapeutic problems of a rare site for an adenoma].
Intermittent jaundice and recurrent colicky upper abdominal pain in two patients, aged 46 and 48 years, were found by endoscopy to be due to an adenoma of the papilla of Vater. Transduodenal local excision with papilloplasty made both patients free of symptoms.


Novel approach to automatically classify rat social behavior using a video tracking system.
In the past, studies in behavioral neuroscience and drug development have relied on simple and quick readout parameters of animal behavior to assess treatment efficacy or to understand underlying brain mechanisms. The predominant use of classical behavioral tests has been repeatedly criticized during the last decades because of their poor reproducibility, poor translational value and the limited explanatory power in functional terms. We present a new method to monitor social behavior of rats using automated video tracking. The velocity of moving and the distance between two rats were plotted in frequency distributions. In addition, behavior was manually annotated and related to the automatically obtained parameters for a validated interpretation. Inter-individual distance in combination with velocity of movement provided specific behavioral classes, such as moving with high velocity when "in contact" or "in proximity". Human observations showed that these classes coincide with following (chasing) behavior. In addition, when animals are "in contact", but at low velocity, behaviors such as allogrooming and social investigation were observed. Also, low dose treatment with morphine and short isolation increased the time animals spent in contact or in proximity at high velocity. Current methods that involve the investigation of social rat behavior are mostly limited to short and relatively simple manual observations. A new and automated method for analyzing social behavior in a social interaction test is presented here and shows to be sensitive to drug treatment and housing conditions known to influence social behavior in rats.


Immune Infertility Should Be Positively Diagnosed Using an Accurate Method by Monitoring the Level of Anti-ACTL7a Antibody.
Infertility is currently a major public health problem. Anti-sperm antibodies (ASAs) markedly reduce sperm quality, which can subsequently lead to male and/or female infertility. The accurate detection of ASAs derived from specific spermatozoa is, therefore, clinically useful. We have focused on the spermatozoa-specific expression protein ACTL7a for many years and have developed an enzyme-linked immunosorbent assay (ELISA) to detect the concentration of anti-ACTL7a antibodies in fertile sera (n = 267) and infertile sera (n = 193). Infertile sera were collected from the positive sera of tray agglutination tests (TAT), which is a routine ASA screening methodology. We found that the concentration of anti-ACTL7a antibodies was significantly higher in the infertile sera (than in the fertile sera, P < 0.0001) and much higher in the TAT ≥ 16 infertile sera. The ELISA was much better for male sera detection (AUC = 0.9899). If we set the standard at a strongly positive value (calculated by ROC curve), the positive predictive value of the antibody detection reached 100 percent, with a false positive rate of zero. The developed ELISA method for anti-ACTL7a antibody detection is therefore sensitive, accurate, and easy to perform, making it an excellent potential tool for future clinical use.


Intervention cost-effectiveness for pediatric anxiety and OCD: A systematic review and integrated database model.
While multiple treatments for pediatric anxiety and obsessive compulsive disorder (OCD) are efficacious, little is known about their cost-effectiveness. In response, we sought to provide relevant information through systematic review and cost-effectiveness simulation. We evaluated the cost-effectiveness of treatment for pediatric anxiety and OCD in two ways. First, we conducted a systematic review following PRISMA guidelines. Second, we evaluated cost-effectiveness for antidepressant medication, cognitive behavioral therapy, and their combination via a simulation that integrated information from the Truven MarketScan database and the NIMH National Database for Clinical Trials Related to Mental Illness. Both systematic review and simulation found antidepressant medication and cognitive behavioral therapy to be cost-effective for pediatric anxiety and OCD. Antidepressant medication was the least costly approach, and cognitive behavioral therapy provided additional cost-effectiveness, especially for OCD. During systematic review, relatively few articles provided information about both costs and effectiveness. While there was a notable margin of error to support multiple interventions as cost-effective, limited prior research decreased precision of point estimates and comparisons between interventions. Both antidepressant medication and cognitive behavioral therapy were found to be cost-effective for pediatric anxiety and OCD. Results supported investment from third party payers, who serve as critical gatekeepers that can increase treatment dissemination. However, more precise information would better inform the exact amount of investment needed, especially with regard to selection decisions between active interventions. Cost-effectiveness research would benefit from systematic collection of data on treatment costs and quality of life in future clinical trials.


Different roles of hepatic hypothermic ischemia and ischemic preconditioning in chemically induced hepatocarcinogenesis in rats.
Hepatic ischemia-reperfusion (IR) injury, an unfavorable complication of hepatectomy, could be prevented by hypothermic ischemia and ischemic preconditioning (IPC). However, the effects of these two approaches on hepatocarcinogenesis have not been examined. The aim of the study was to investigate roles of hypothermic ischemia and IPC in a chemically induced rat liver tumor model. Twenty-four Sprague-Dawley rats were treated with diethylnitrosamine and phenobarbital to induce hepatocellular carcinoma. Rats underwent hepatic ischemic injury, hypothermic ischemia, and IPC. Twenty-eight-wk-old rats were sacrificed to evaluate the morbidity and growth of liver tumor. Cytokines were measured at the protein and messenger RNA level. IR injury significantly promoted liver tumor development. Intriguingly, hypothermic ischemia, but not IPC, delayed liver carcinogenesis, although both of them suppressed the hepatic IR injury. IPC-treated rats showed elevated interleukin (IL)-6 concentration in the serum and messenger RNA expression in liver. In addition, higher levels of IL-6 activated signal transducer and activator of transcription 3 in the liver of IPC-treated rats. The hepatic expression of target genes of signal transducer and activator of transcription 3 signaling, cyclin D1, c-myc, c-fos, and c-jun, all of which might participate in tumor progression, increased in IPC group, compared with that of IR group. These data indicated hypothermic ischemia could ameliorate both IR injury and liver tumor development. However, IPC, another effective method to prevent hepatic IR injury, might exacerbate liver tumor growth. The elevated level of IL-6 was one of the reasons for the different effects of hypothermic ischemia and IPC on hepatocarcinogenesis in rats.


Variogram-based fault diagnosis in an interconnected tank system.
We consider in this paper the fault diagnosis problem of a three tank system DTS-200 pilot plant. The presented approach is based on the analysis of the variogram, which is a graphical variance representation that characterizes the distribution of a measured dataset, and is used to extract the sensor fault parameters. These parameters are obtained by determining the best mathematical model that fits the empirical data. Nonlinear regression techniques are used to estimate the model coefficients. Experimental study is provided to illustrate the potential applicability of this method in process monitoring.


Awareness training in the treatment of head and facial tics.
The effectiveness of awareness training alone in treating multiple tics in a young adult was assessed using a multiple baseline across behaviors design. The results showed that the awareness training was very effective in suppressing both head and facial tics and that the treatment effects generalized to a nonclinic situation. Follow-up data showed that both tics were still at low levels one, two, four and eight months after treatment. Treatment satisfaction ratings by the subject and social validation ratings by independent observers are also reported.


Bond strength of cements to nickel-chromium and silver-palladium alloys.
The bonding of zinc phosphate, polycarboxylate, and reinforced ZOE cements to nickel-chromium and silver-palladium alloys was measured by cementing flat surfaces of the metals together. Polycarboxylate cement produced higher bond strengths than the other two cements to both metals. Polycarboxylate cement bonded better to nickel-chromium alloys than to a silver-palladium alloy. Zinc phosphate and reinforced ZOE cements had similar bond strengths except for Biobond, to which zinc phosphate cement provided higher bond strength. Polycarboxylate cement failed cohesively to both types of metals, and zinc phosphate and reinforced ZOE cements failed adhesively.


HOXA13 promotes colon cancer progression through β-catenin-dependent WNT pathway.
Human class I homeobox A13 (HOXA13) was initially identified as a transcription factor and has an important role in embryonic development and malignant transformation. However, the clinical significance and the molecular mechanisms of HOXA13 in colon cancer development and progression are still unknown. In this study, we found that HOXA13 was highly expressed in colon cancer tissues, and its expression was associated with histological grade, T stage, N stage and tumour size. In vitro studies showed that HOXA13 promoted colon cancer cell proliferation, migration and invasion. Bioinformatics analysis revealed that HOXA13 expression was positively correlated with the WNT signalling pathway. In vitro studies showed that HOXA13 promoted the malignant phenotype of colon cancer cells by facilitating the nuclear translocation of β-Catenin. Moreover, XAV939, an inhibitor of β-Catenin, reversed the HOXA13-mediated effects on invasion and proliferation of colon cancer cells. In vivo studies further verified that HOXA13 promoted tumour formation through the Wnt/β-Catenin pathway. Collectively, these results suggest that HOXA13 is a potential oncogene that functions by promoting the nuclear translocation of β-Catenin, thereby maintaining the proliferation and metastasis of colon cancer.


Cytotoxic effect of fatty acids in vitro on Ehrlich exudative carcinoma cells and normal exudative cells (leukocytes).
A mixture of pure fatty acids isolated hydrolytically from linseed oil in the form of water-soluble salts with ethanolamine were examined for cytotoxicity for Ehrlich carcinoma and normal exudative cells. Cytotoxicity of the mixture was similar to that of salts of oleic and linolenic acids. On the other hand, the mixture of fatty acids and oleic acids was more toxic for normal exudative cells than linolenic acid.


Parent and Provider Perspectives on Primary Continuity Intensivists and Nurses for Long-Stay Pediatric Intensive Care Unit Patients.
Rationale: Primary continuity intensivists and nurses for long-stay patients (LSPs) in pediatric intensive care units (PICUs) are understudied strategies used to mitigate the fragmented care of typical rotating care models. Objectives: To investigate the advantages and disadvantages of primary continuity intensivists and nurses for LSPs as perceived by their parents and PICU providers. Methods: We conducted a prospective cross-sectional mixed-methods study of the perspectives of parents whose children were admitted to a PICU for >10 days and had one or more complex chronic conditions regarding the care provided by their PICU intensivists and nurses. As part of a trial, patients had been randomized to care provided by a rotating on-service intensivist who changed weekly and by PICU nurses who changed every 12 hours (usual care group) or to care provided by the same on-service intensivist plus a primary continuity intensivist and primary nurses (primary group). In addition, PICU providers (intensivists, fellows, and nurses) were queried for their perspectives on primary intensivists and nurses. Novel questionnaires, assessed for content and face validity and for readability, were used. The parental questionnaire involved indicating their degree of agreement with 16 statements about their children's care. The provider questionnaire involved rating potential advantages of primary continuity intensivists and nurses and estimating the frequency of disadvantages. Descriptive statistics and divergent stack bar charts were used; parents' and providers' responses were compared, stratified by their children's group (usual care or primary) and provider role, respectively. Results: The parental response rate was 71% (120 completed questionnaires). For 10 of 16 statements, parents whose children had primary continuity intensivists and nurses indicated significantly more positive perceptions of care (e.g., communication, listening, decision making, problems due to changing providers). The provider response rate was 61% (117 completed questionnaires); more than 80% believed that primary intensivists and nurses were highly or very highly beneficial for LSPs. Providers perceived more benefits for patients/families (e.g., informational continuity, facilitating and expediting decision making) than for staff/institutions (e.g., staff satisfaction). Providers reported associated stress, expenditure of time and effort, and decreased staffing flexibility with primary practices. Conclusions: Perceived benefits of primary continuity intensivists and nurses by both parents and providers support more widespread adoption and study of these continuity strategies.


Leishmania spp. in Squamata reptiles from the Mediterranean basin.
Leishmania tarentolae is a nonpathogenic trypanosomatid species isolated from geckoes in the Mediterranean basin. In Italy, L. tarentolae and Leishmania infantum occur in sympatry in areas where canine leishmaniosis (CanL) is endemic. Here, we investigated the prevalence and distribution of L. tarentolae in reptilian hosts and the presence of L. infantum in the same animals in southern Italy. From April 2020 to April 2021, lizards and snakes were captured in urban, peri-urban sites, natural parks, and dog shelters. Blood was individually sampled and assessed for the presence of Leishmania spp. by cytology and/or molecular biology. Captured lizards were euthanized and their tissues/organs were tested by duplex real-time-PCR for the detection of L. infantum and L. tarentolae and the positive ones were amplified by conventional PCR to confirm the species identification by sequencing. Samples were also screened by real-time PCR for L. infantum kDNA minicircle. Of the 259 collected Squamata reptiles, 34 (13.1%) specimens scored positive for Leishmania spp., with a prevalence of 10% for L. tarentolae (n = 26) and of 3.1% for L. infantum (n = 8). Positive lizards were mostly Podarcis siculus (n = 26) from dog shelters, with six specimens positive for L. infantum. In addition, L. tarentolae was detected in one Podarcis filfolensis lizard, and in five T. mauritanica geckos (with one gecko and P. filfolensis lizard showing amastigote-like forms in thrombocytes), whereas L. infantum was detected in one T. mauritanica, and one Hemidactylus turcicus. Data herein reported demostrate that saurian reptiles living in CanL endemic areas of the Mediterranean basin may be exposed to both L. tarentolae and L. infantum indicating a sympatric circulation of these species in different vertebrate hosts. Moreover, this study represents the first molecular evidence of L. infantum infection in European reptiles.


[Acute ischemic stroke. New approaches to antithrombotic treatment].
The only recommended therapy in the acute phase of ischemic stroke is thrombolysis within 4.5-(6) h after symptom onset. For secondary stroke prevention platelet inhibitors or, in cases of cardiac embolism, anticoagulants are used. However, these substances bear significant limitations: either they show only moderate efficacy (platelet inhibitors), or they are associated with a considerable bleeding risk (rt-PA, anticoagulants). Although the majority of strokes are caused by embolic or thrombotic vessel occlusion, strikingly little is known about the pathophysiological role of platelets and their local function in the brain vasculature. The recent development of novel transgenic mouse lines paved the way for the in-depth analysis of the different molecular steps of thrombus formation involving platelets and the plasma coagulation cascade in models of acute ischemic stroke. It was demonstrated that prevention of early platelet adhesion to the damaged vessel wall by blocking the platelet surface receptors GPIbα or GPVI dramatically protects against experimental stroke without increasing the frequency of intracranial hemorrhage. Moreover, the critical involvement of the blood coagulation factor XII (FXII)-driven intrinsic coagulation cascade in thrombus formation during the course of ischemic brain damage could be unraveled thereby disproving established concepts of hemostasis. Based on these findings novel pharmacological blockers of GPIbα and FXIIa were designed that likewise proved to be safe and effective in animal stroke studies. Those compounds now lay the groundwork for a novel and intriguing concept in ischemic stroke and other thromboembolic diseases: antithrombosis devoid of any bleeding complications. Further preclinical testing is currently ongoing.


Effectiveness and tolerability of liraglutide in patients with type 2 diabetes mellitus and obesity after bariatric surgery.
Current guidelines do not offer detailed recommendations on antidiabetic drug therapy in type 2 diabetes (T2D) after bariatric surgery (BS), and reported experience is scarce. To evaluate the effectiveness and tolerability of liraglutide at 2 years in patients with morbid obesity after undergoing BS and subsequent relapse, persistence, or new diagnosis of T2D, comparing the results with a cohort of nonsurgical diabetic patients also treated with liraglutide. Obesity clinic at a University Hospital. We conducted a retrospective study of 2 cohorts of patients (with and without previous BS) with T2D and obesity who had started treatment with liraglutide at least 2 years before their inclusion in the study. The main outcome measures were the differences in glycated hemoglobin (A1C) and weight at 104 weeks between both groups. A total of 164 patients were included, 15 with previous BS and 149 without BS. Mean baseline parameters were A1C 6.6% and body mass index 40.3 kg/m2 for the BS group, and A1C 7.5% and body mass index 39.7 kg/m2 for the non-BS group. At 2 years, A1C and weight were significantly decreased in both groups (BS group: ΔA1C -0.39%, Δweight -3.4 kg; non-BS group: ΔA1C -0.67%, Δweight -3.8 kg; all results P<.05), with no significant differences in A1C and weight reduction between both groups. There was a significant lower frequency of withdrawals due to all causes and a nonsignificant lower rate of vomiting and hypoglycemia in patients with BS. Liraglutide achieved a significant reduction in weight and A1C at 2 years in patients with T2D previously treated with BS, showing good gastrointestinal tolerance.


Calibration of forest 137Cs cycling model "FoRothCs" via approximate Bayesian computation based on 6-year observations from plantation forests in Fukushima.
Predicting the environmental fate of 137Cs in forest ecosystems along with the concentrations of 137Cs in tree parts are important for the managements of radioactively contaminated forests. In this study, we calibrate the Forest RothC and Cs model (FoRothCs), a forest ecosystem 137Cs dynamics model, using observational data obtained over six years from four forest sites with different levels of 137Cs contamination from Fukushima Prefecture. To this end, we applied an approximate Bayesian computation (ABC) technique based on the observed 137Cs concentrations (Bq kg-1) of five compartments (leaf, branch, stem, litter, and soil) in a Japanese cedar plantation. The environmental decay (increment) constants of the five compartments were used as the summary statistics (i.e., the metric for model performance) to infer the five parameters related to 137Cs transfer processes in FoRothCs. The ABC technique successfully reconciled the model outputs with the observed trends in 137Cs concentrations at all sites during the study period. Furthermore, the estimated parameters are in agreement with the literature values (e.g., the root uptake rates of 137Cs). Our study demonstrates that model calibration with ABC based on the trends in 137Cs concentrations of multi compartments is useful for reducing the prediction uncertainty of 137Cs dynamics in forest ecosystems.


The effect of repeated umbilical cord occlusions on pulmonary surfactant protein mRNA levels in the ovine fetus.
In this study we sought to determine the effect of brief repeated umbilical cord occlusions (rUCO) on surfactant protein (SP) mRNA levels in the fetal sheep lung at two different gestational ages. Fourteen fetuses at 112 to 115 days' gestation (control n = 7, rUCO n = 7) and 15 fetuses at 130 to 133 days' gestation (control n = 7, rUCO n = 8) were studied over 4 successive days with rUCO of 90 seconds duration performed every 30 minutes for 3 to 5 hours each day in the rUCO animals. Blood samples were collected for corticotrophin (ACTH) and cortisol measurements. Animals were killed within 1 hour of the final cord occlusion. SP-A, -B, -C, and -D mRNA levels were determined in lung tissue using a ribonuclease protection assay. Cord occlusions resulted in temporary increases in circulating ACTH on day 1 with both gestational ages, but the elevations were blunted by day 4. Plasma cortisol levels increased transiently with the larger effect being observed on day 4, in particular with the near-term group. With advancing gestational age there was a significant (P < .05) increase in the level of SP-A (control 112-115 days: 0.01 +/- 0.01 vs control 130-133 days: 0.07 +/- 0.02 fmol/mg RNA), SP -B (control 112-115 days: 0.02 +/- 0.01 vs control 130-133 days: 0.07 +/- 0.01 fmol/mg RNA) and SP-C (control 112-115 days: 0.13 +/- 0.09 vs control 130-133 days: 0.51 +/- 0.10 fmol/mg RNA), but not SP-D mRNA levels (control 112-115 days: 0.002 +/- 0.002 vs control 130-133 days: 0.01 +/- 0.002 fmol/mg RNA). At 112 to 115 days, there was no significant change in any of the SP mRNA levels following rUCO compared to controls. However, the same regime of rUCO at 130 to 133 days resulted in an 85% reduction in SP-A and SP-B mRNA content and a 66% reduction in SP-C mRNA levels compared to controls. The surprising decrease in SP-A and SP-B mRNA levels, which contrasts with other studies, suggests intermittent asphyxial episodes impact differently on surfactant apoprotein mRNA expression than does prolonged hypoxia.


Potential role of embelin in the prevention of Freund's adjuvant induced inflammation and ROS.
Inflammation is a complex biological response involving immune cells to an infection creating injury to the normal tissues. The anti-inflammatory efficacy of embelin, a benzoquinone from the plant Embelia ribes, was screened for antioxidant and anti-inflammatory activity in carrageenan and Freund's adjuvant-induced inflammation models. Embelin exhibited significant dose-dependent antioxidant potential. In carrageenan-induced inflammation, embelin (20 mg/kg) showed an inhibition of oedema by 71.01 ± 0.12% and 81.91 ± 0.67% in Freund's adjuvant-treated chronic inflammation model and resulted in a noticeable increase in adrenal size and restoration of the weight of spleen. Embelin also demonstrated cytoprotective effects on HEK-293 cells under induced oxidative stress. In silico analysis, embelin demonstrated binding energy of - 7.7 kcal/Mol and - 7.0 kcal/Mol with COX1 and COX2 with two hydrogen bonds. These results further prove that embelin could be a promising anti-inflammatory agent and supports the traditional use of Embelia ribes for rheumatism.


Comparative effects of more versus less aggressive treatment with statins on the long-term outcome of patients with acute ischemic stroke.
There are no studies that compared the effects of different intensities of statin treatment on the long-term outcome of patients with recent ischemic stroke. We aimed to evaluate these effects. We prospectively studied 436 consecutive patients who were discharged after acute ischemic stroke (39.2% males, age 78.6 ± 6.7 years). Statin treatment was categorized in equipotent doses of atorvastatin. One year after discharge, the functional status was assessed with the modified Rankin scale (mRS). Adverse outcome was defined as mRS between 2 and 6. The occurrence of ischemic stroke, myocardial infarction and death was recorded. Adverse outcome rates were lower in patients treated with atorvastatin 20 mg/day or more potent doses of statins than in patients treated with atorvastatin 10 mg/day (63.5, 38.2 and 48.2%, respectively; p = 0.004). In binary logistic regression analysis, independent predictors of adverse outcome were the mRS at discharge (relative risk (RR) 2.33, 95% confidence interval (CI) 1.77-3.07, p < 0.001) whereas more aggressive treatment with statins independently predicted favorable outcome (atorvastatin 20 vs. 10 mg/day, RR 0.30, 95% CI 0.11-0.87, p = 0.026; atorvastatin 40 mg/day or more potent dose of statins vs. atorvastatin 10 mg/day, RR 1.66, 95% CI 0.62-4.44, p = NS). The incidence of cardiovascular events and all-cause mortality showed a trend for being lower in patients treated with atorvastatin 40-80 mg/day or rosuvastatin 10-40 mg/day than in those treated with less potent doses of statins. More aggressive statin treatment improves the long-term functional outcome of patients with acute ischemic stroke more than less aggressive treatment.


A Comprehensive Analysis of Benign Vocal Fold Lesions Causing Hoarseness of Voice and Our Experience with Cold Knife Endolaryngeal Surgery in a Tertiary Healthcare Centre.
Benign vocal fold lesions (BVFL) frequently affect the general population and cause significant hoarseness by interfering with daily communication. Healthcare for low income groups in India is all about affordability and availability without giving up on quality and providing maximum satisfaction. (1) To analyse over a period of 4 years, the demographics, clinical profile, diagnostics and management options of BVFL. (2) To assess the diagnostic potential of rigid laryngoscopy in diagnosing these lesions. (3) Cold knife endolaryngeal surgery as a cost effective, satisfactory and efficient treatment modality to tackle majority of these BVFL. A prospective cross sectional study over a period of 4 years from 2013 to 2017. 114 patients presenting with hoarseness of voice were evaluated by indirect laryngoscopy followed by video laryngoscopy and stroboscopy in the department of ENT, MYH Hospital Indore (M.P.). Male:female ratio of 1.59:1 with male predominance (61.4%) and maximum incidence in the third decade (32%). All cases presented with hoarseness (100%) while vocal fatigue (63%) was the most common associated complaint followed by foreign body sensation (60%). Housewives (32%) were most commonly involved non professional group while teachers (13%) constituted the most common group of professionals. Laryngitis (26%) involving bilateral vocal folds diffusely was the most common finding followed by vocal fold sulcus (18%) and vocal fold cysts (14%). The duration of symptom was 6 months to 1 year in 52% patients. The positive predictive value for rigid laryngoscopy was 100% for vocal nodules, arytenoid granulomas and anterior glottis web. Out of 114 patients, 66 patients improved on conservative management while 48 patients underwent cold knife endolaryngeal surgery. As per the GRBAS scale to assess the post therapeutic prognosis, all had good outcome of voice with only two recurrences due to patient non compliance. In this rapidly evolving era of sophisticated lasers which is a costly affair that requires skilled personnel and safety precautions, the prime goal in a government run setup has always been to provide affordable and quality healthcare to the common man. Cold knife endolaryngeal surgery is a simple, cost effective and efficient way to tackle most of these lesions and hence helps in achieving this goal.


Influence of non-uniform flow on toxic elements transport in soil column percolation test.
The influence of flow channels on the leaching behavior of toxic elements in contaminated soil cannot be neglected in a column percolation test. This study presents a visualization of the flow channel formed in the soil and evaluated the relationship between the leaching behavior of soil components and flow. We conducted column percolation tests with two types of filling methods (Compaction and No compaction) and used X-ray computed tomography to visualize the soil structure and non-uniform flow. Additionally, the variations of flow in a cross section of water were evaluated using hydraulic conductivity based on differential pressure. Under No compaction, a flow occurred throughout the soil column at the beginning of the water passage, but a non-uniform flow emerged as the liquid-solid ratio increased; under Compaction, a non-uniform flow was formed from the beginning of water passage. The leaching behavior of the major components and toxic elements from soil with high adsorptive properties was significantly affected by the filling method up to a liquid-solid ratio of 2. These results suggest that the non-uniform flow formed in the column percolation test has a significant impact on the leaching of soil components.


Characterization of calcium transport in the luminal and the basolateral membrane from kidney cortex of hypercalcemic rats bearing the Walker 256 carcinosarcoma.
The Walker 256 (W256) carcinosarcoma did not significantly modify calcium uptake by brush border membrane (BBM) vesicles in the kidney of the host rat, compared with that in membranes isolated from control animals. However, it showed a tendency to increase at near equilibrium in W256 tumor-host rats, associated with a decreased BBM protein content. ATP-dependent calcium influx by basolateral membrane (BLM) vesicles from W256 tumor-bearing rats was also increased compared with that in control BLM. This stimulation was due to a decreased Km for calcium. Passive calcium permeability or the Na+/Ca2+ exchanger were unchanged in BLM from W256 tumor-host rats compared with control BLM. Pre-stimulation of control rat cortical tubules with either 10(-7) M parathyroid hormone-related protein (PTHrP) (1-34) or 10(-4) M N6,2'-O-dibutiryl cyclic AMP before BLM isolation, did not modify the ATP-dependent calcium uptake by BLM vesicles compared with control membranes. However, our results do not rule out that the stimulated ATP-dependent calcium influx in BLM from W256 tumor-host rats could be mediated by the interaction among PTHrP and other humoral factors. Our findings suggest a possible mechanism for the increased renal calcium reabsorption in this animal model for humoral hypercalcemia of malignancy.


Inflammatory Monocytes and Subsets of Macrophages with Distinct Surface Phenotype Correlate with Specific Integrin Expression Profile during Murine Sepsis.
Monocytes and macrophages participate in both pro- and anti-inflammatory responses during sepsis. Integrins are the cell adhesion receptors that mediate leukocyte migration and functions. To date, it is not known whether integrin profiles correlate with their trafficking, differentiation, and polarization during sepsis. In this study, using endotoxemia and cecal ligation and puncture model of murine sepsis, we have analyzed the role of surface integrins in tissue-specific infiltration, distribution of monocytes and macrophages, and their association with inflammation-induced phenotypic and functional alterations postinduction (p.i.) of sepsis. Our data show that Ly-6Chi inflammatory monocytes infiltrated into the peritoneum from blood and bone marrow within a few hours p.i. of sepsis, with differential distribution of small (Ly-6CloCD11bloF4/80lo) and large peritoneal macrophages (Ly-6CloCD11bhiF4/80hi) in both models. The results from flow cytometry studies demonstrated a higher expression of integrin α4β1 on the Ly-6Chi monocytes in different tissues, whereas macrophages in the peritoneum and lungs expressed higher levels of integrin α5β1 and αvβ3 in both models. Additionally, F4/80+ cells with CD206hiMHCIIlo phenotype increased in the lungs of both models by six hours p.i. and expressed higher levels of integrin αvβ3 in both lungs and peritoneum. The presence of such cells correlated with higher levels of IL-10 and lower levels of IL-6 and IL-1β transcripts within six hours p.i. in the lungs compared with the mesentery. Furthermore, bioinformatic analysis with its experimental validation revealed an association of integrin α4 and α5 with inflammatory (e.g., p-SRC) and integrin αv with regulatory molecules (e.g., TGFBR1) in macrophages during sepsis.


Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years.
In Denmark, newborn screening (NBS) for cystic fibrosis (CF) was introduced on 1 May 2016. The implementation and results from the first 2 years of the national newborn CF screening program are presented. The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane conductance regulator gene (CFTR) was performed. Of 126 522 newborn infants 126 338 were tested (99.85%), and 4730 samples (3.7%) were assessed for CFTR mutations. Twenty-six infants were screen-positive and referred for diagnostic follow-up of whom 22 were confirmed to have a CF diagnosis, four had one known and one CFTR allele with unknown pathogenicity, classified as cystic fibrosis screening positive inconclusive diagnosis (CFSPID), PPV 84.6%. One of the four children classified as CFSPID was later found to carry the two identified CFTR variants in cis and was reclassified as a carrier of CF. We found two false negatives; one exhibited an IRT level above the 50 ng/mL cutoff but was below the 145 ng/mL very high cutoff and with no F508del mutation present. The second false-negative fell below the 50 ng/mL IRT cutoff but was diagnosed shortly after birth on the basis of meconium ileus. Screening sensitivity, 91.7%. Two hundred thirty-two children were identified as carriers of CF, which is twofold above the estimated annual number of carriers. All but one carrier were heterozygous for the F508del CFTR mutation. Sixteen percent of the sequenced samples revealed rare CFTR variants, which were classified as nonpathogenic in relation to CF. During the first 2 years of NBS CF screening in Denmark, we identified close to the expected number of infants with CF using an algorithm based on IRT, presence of F508del mutation and comprehensive genetic analysis. CFSPID accounted for only a small minority, despite comprehensive CFTR sequencing, whereas more carriers than initially expected were identified.


Worry about health in smoking behaviour change.
Many smokers and ex-smokers worry about their health. Given that worry keeps attention focused on the threat, it was expected that worrying about health in smokers would motivate them to quit and in ex-smokers may prevent relapse. Furthermore, worry was expected to influence the process of smoking cessation in interaction with self-efficacy, which is a measure of control over smoking, and with disengagement beliefs, which distorts the threatening meaning of potential motivating information. In the present study 380 smokers and 324 ex-smokers were recruited to join a prospective study with a follow-up of eight months. At T1, smoking/quitting behavior, worry and the other psychological constructs were assessed. At T2 quitting activity in smokers and relapse in ex-smokers were assessed. As expected, smokers who worried about the health effects of smoking reported higher quitting activity at T2. The three-way interactions between worry, self-efficacy and disengagement beliefs in the prospective prediction of quitting activity and relapse were significant: Among smokers with high self-efficacy combined with strong disengagement beliefs, worry led to more quitting activity. Among ex-smokers with low self-efficacy combined with strong disengagement beliefs, worry led to more relapse. The present results suggest new ways of approaching the stimulation of quitting and the prevention of relapse.


Effects of Opioid-Limiting Legislation and Increased Provider Awareness on Postoperative Opioid Use and Complications After Hip Arthroscopy.
On August 31, 2017, Ohio passed legislation that regulates how opioids can be prescribed postoperatively. Studies have shown that such legislation is successful in reducing the morphine milligram equivalents (MMEs) prescribed after certain orthopaedic procedures. (1) To determine if the opioid prescription-limiting legislation in Ohio reduced the cumulative MMEs prescribed after hip arthroscopy without significantly affecting the rates of emergency department (ED) visits, hospital readmissions, and reoperations within 90 days postoperatively, and (2) to assess risk factors associated with increased postoperative opioid dosing. Cohort study; Level of evidence, 3. This study included patients who underwent primary and revision hip arthroscopy at a single institution over a 4-year period. The prelegislation (PRE) and postlegislation (POST) groups were defined as patients who underwent surgery before August 31, 2017, and on/after this date, respectively. The Ohio Automated Rx Reporting System was queried for controlled-substance prescriptions from 30 days preoperatively to 90 days postoperatively, and patient medical records were reviewed to collect demographic, medical, surgical, and readmission data. Inverse probability weighting-adjusted mean treatment effect regression models were used to measure the difference in mean outcomes between the PRE and POST cohorts. A total of 546 patients (228 PRE, 318 POST) were identified. There was a 25% reduction in the cumulative MMEs prescribed to the POST group as compared with the PRE group during the first 90 days postoperatively (840 vs 1125 MME, respectively; P < .01). The legislation was associated with a significant decrease in the cumulative MMEs prescribed in the first 90 postoperative days (mean treatment effect = -280.6; P < .01), and there were no significant between-group differences in the frequency of ED encounters (8.8% PRE, 11.6% POST; P = .32), hospital readmissions (1.3% PRE, 0.9% POST; P = .70), or reoperations (0.9% PRE, 0.6% POST; P ≥ .99) during this period. Preoperative opioid use was a significant independent risk factor for increased cumulative MMEs in the first 90 days postoperatively (β = 275; P < .01). Opioid prescription-limiting legislation in Ohio was associated with significant reductions in opioid MMEs dosing in the 90-day period following hip arthroscopy. This legislation had no significant effect on ED utilization, hospital readmissions, or reoperations within the same period. Preoperative opioid use was a significant risk factor for increased MME dosing after hip arthroscopy.


Nephroblastoma and multilocular cyst simulating hydronephrosis. A case report.
An unusual variant of nephroblastoma occurring in association with a multilocular cyst of the kidney is described in a 4-year-old black child.


A Combination of B- and N-Doped π-Systems Enabling Systematic Tuning of Electronic Structures and Properties.
Doping heteroatoms into polycyclic aromatic hydrocarbons (PAHs) may alter their structures and thereby physical properties. This study reports the construction of B/N-codoped PAHs via combining the B- and N-doped π-systems. Two π-extended B/N-codoped PAHs were synthesized through the Mallory photoreaction. Both feature a C48 BN2 π-skeleton, which is assembled by linearly fusing three substructures including B-doped and sp2 -hybridized N-doped π-moieties and one pyrene unit. In comparison to the pristine B-doped analog, their intramolecular charge transfer (ICT) states are distinctly modulated by the fused N-doped π-system and the further incorporated cyano group, leading to their tunable optical properties, as revealed by detailed theoretical and experimental analysis. Furthermore, these three molecules have sufficient Lewis acidity and can coordinate with Lewis base to form Lewis acid-base adducts, and notably, such intermolecular complexation can further dynamically modulate their ICT transitions and thereby photophysical properties, such as producing blue, green and red fluorescence.


Role of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the secretion of tumor necrosis factor-alpha and interleukin-10 by the PPD antigen of Mycobacterium tuberculosis.
Here we investigated the role of the phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase (MAPK) pathways in the secretion of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 in human primary monocytes after stimulation with the PPD antigen of Mycobacterium tuberculosis. MAPK [extracellular signal-regulated kinase (ERK) 1/2 and p38] and Akt are rapidly phosphorylated in human monocytes stimulated with PPD. We found that the PI 3-K-Akt pathway stimulated by PPD is essential for both IL-10 and TNF-alpha production, although the inhibition of IL-10 production was more pronounced. The analysis of cytokine production using specific inhibitors of the MAPK pathway revealed that both p38 and ERK activation are essential for PPD-induced TNF-alpha production, whereas p38, but not ERK, activation is essential for IL-10 secretion. The inhibition of PI 3-K did not significantly activate p38 MAPK or ERK 1/2 in PPD-stimulated human monocytes. Further, the Src inhibitor PP2 inhibited the release of TNF-alpha but enhanced IL-10 release, suggesting the differential regulation of Src kinase in upstream signaling. Collectively, these data suggest that the PI 3-K and MAPK pathways play a central role in the regulation of both pro- and anti-inflammatory cytokines by the PPD antigen of M. tuberculosis.


Potential interactions of drug-natural health products and natural health products-natural health products among children.
To determine the frequency of concurrent use of conventional medications and natural health products (NHP) and their potential interactions in children arriving at an emergency department. A survey of parents and patients 0 to 18 years at a large pediatric ED in Toronto, Ontario, Canada. A total of 1804 families were interviewed in this study. Concurrent drug-NHP use was documented in 355 (20%) of patients and 269 (15%) of NHP users were receiving more than one NHP simultaneously. Theoretically possible NHP-drug or NHP-NHP interactions in the preceding 3 months were identified in 285 (16%) children. There were 35 different NHP-medication interaction pairs and 41 NHP-NHP interaction pairs. NHP-medication interactions were predominantly pharmacokinetic (modified absorption, 35%); potential NHP-NHP interactions were mostly pharmacodynamic (increased risk of bleeding, 47%). Medications are used concurrently with NHP in every fifth pediatric patient in the emergency department and many NHP users are receiving more than 1 NHP simultaneously. One quarter of all paired medication-NHP or NHP-NHP could potentially cause interactions. Although we can not confirm that these were true interactions resulting in clinical symptoms, parents and health care providers need to balance the potential benefit of concurrent NHP-medication use with its potential harms.


Conservation of ribosomal fidelity during ageing.
The function of ribosomes prepared from the liver of young (2--5 months old) and senescent (15--26 months old) mice were compared in vitro. The conclusions that can be drawn from the liver of senescent mice is 10 to 40% lower than that of young mice; (2) the fidelity of translation does not change grossly with age; (3) the thermosensitivity of translational activity of ribosomes and the activity of ribosome-associated ribonuclease do not change with age; (4) there is an age-dependent accumulation of free 40S ribosomal subunits in the cytoplasm of mouse liver. The relation of age-dependent changes in the structure and function of ribosomes is discussed.


Epileptogenesis due to peripheral injury as a cause of focal epilepsy.
To report three patients in whom focal epilepsy developed shortly after painful soft tissue injuries to their hands. Case reports. The attacks started in the injured hand. No evidence was found of an underlying brain lesion by history or from imaging studies. These cases suggest the possibility that the injuries led to a plastic change in the sensory/motor cortex, leading to increased excitability and ultimately to seizures. This suggests that epileptogenesis can occur in response to painful peripheral stimuli in some individuals.


Trace level determination of perfluorinated compounds in water by direct injection.
A new, fast LC-MS/MS method for the determination of perfluorinated surfactants in water samples by direct injection without pre-concentration is reported. The current method requires only 4 min to analyze nine perfluoroalkyl compounds in a single analytical run. Standard addition and internal standard quantification were used to determine the level of some perfluorinated carboxylic and sulfonic acids, including perfluorooctanoic sulfonate (PFOS) and perfluorooctanoic acid (PFOA), in Great Lakes water samples. Statistically significant differences were observed between the results obtained using different quantification methods. A relatively small difference between the PFOS values obtained with the standard addition method, with and without peak area normalization, clearly indicates that standard addition is the best quantification method when mass-labeled standards are not available. Based on the paired t-test statistical analysis, the concentrations calculated using external standardization were the least accurate, with the highest mean difference from the standard addition calculated values. Both PFOS and PFOA were present at less than 10 ng l(-1) in all Great Lake samples. Higher levels were detected in tributaries of Lake Ontario and effluents from sewage treatment plants.


Neuroradiologic evaluation of the subdural pathogenesis in infants with small heads.
A marginal low density area is often revealed by CT scan in infants with microcephalia. However, it is difficult to assess precisely the main pathologic state of the marginal low density area and also whether such a lesion exists in the subdural-epiarachnoid space or in the subarachnoid space. A carotid angiographic evaluation of cortical vessels in the marginal avascular area was made and suggestive results were obtained. When there is acute subdural effusion or subdural hematoma, cortical arteries in the marginal avascular area will have a straightened and attenuated figure. But when such a pathologic state persists for a long period, it induces secondary cortical atrophy and the subarachnoid space becomes enlarged. The cortical artery appears as if it is flying in the enlarged subarachnoid space because it is detached from the gyrus and the sulcus following the cortical atrophy. This is why we named it the 'flying artery.' Angiographic findings allow more precise interpretation of the marginal low density area in the CT scan.


Some patterns of metallic nanoparticles' combined subchronic toxicity as exemplified by a combination of nickel and manganese oxide nanoparticles.
Stable suspensions of NiO and/or Mn3O4 nanoparticles with a mean diameter of 16.7 ± 8.2 nm and 18.4 ± 5.4 nm, respectively, prepared by laser ablation of 99.99% pure metals in de-ionized water were repeatedly injected IP to rats at a dose of 0.50 mg or 0.25 mg 3 times a week up to 18 injections, either separately or in different combinations. Many functional indices as well as histological features of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The accumulation of Ni and Mn in these organs was measured with the help of AES and EPR methods. Both metallic nanoparticles proved adversely bio-active, but those of Mn3O4 were found to be more noxious in most of the non-specific toxicity manifestations. Moreover, they induced a more marked damaging effect in the neurons of the caudate nucleus and hippocampus which may be considered an experimental correlate of manganese-induced parkinsonism. Mathematical analysis based on the Response Surface Methodology (RSM) revealed a diversity of combined toxicity types depending not only on particular effects these types are assessed for but on their level as well. The prognostic power of the RSM model proved satisfactory.


Investigation into the intestinal metabolism of [D-Ala1] peptide T amide: implication for oral drug delivery.
The anti-AIDS drug, [D-Ala1] Peptide T amide (D-ASTTTNYT.NH2) is an octapeptide which competitively inhibits the attachment of HIV to the receptor CD4 molecule on the T-lymphocyte. The objective of the study is to investigate the degradative process of this peptide and its effective enzyme inhibitors. The metabolites of [D-Ala1] Peptide T amide in rabbit brush-border membrane vesicles at pH 6.5 are ASTT, ASTTTN, YT and Y. The sequential time-course study of each metabolite reveals that enkephalinase (EC 18.104.22.168) plays an important role in the hydrolysis of [D-Ala1] Peptide T amide to ASTT. With the addition of an enkephalinase inhibitor, thiorphan, 85% of degradation was inhibited. Aminopeptidase is also involved in its degradative process and 25% of inhibition was observed by amastatin, an aminopeptidase inhibitor. The results show that no significant difference was observed between the in situ and chronical loop perfusion studies and enzyme activities are somewhat inhibited under acidic conditions in both methods. Approx. 90% of the parent peptide remained when rats were perfused with pH 4.0 peptide solution at a flow rate of 0.123 ml/min, while only 60% was recovered when pH 6.5 peptide solution was applied. The addition of amastatin made a quadrupled increase in the amount of parent peptide recovered. A 117-fold increment was observed when thiorphan was added. The dimensionless wall permeability of this peptide was 1.19 +/- 0.16 when pH 4.0 peptide solution was used during chronical loop perfusion study. Therefore, this study suggests that [D-Ala1] Peptide T amide could be absorbed via small intestine where enzymatic degradation s a rate-limiting step for the absorption of this peptide.


Homomorphic inference of deep neural networks for zero-knowledge verification of nuclear warheads.
Disarmament treaties have been the driving force towards reducing the large nuclear stockpile assembled during the Cold War. Further efforts are built around verification protocols capable of authenticating nuclear warheads while preventing the disclosure of confidential information. This type of problem falls under the scope of zero-knowledge protocols, which aim at multiple parties agreeing on a statement without conveying any information beyond the statement itself. A protocol capable of achieving all the authentication and security requirements is still not completely formulated. Here we propose a protocol that leverages the isotopic capabilities of NRF measurements and the classification abilities of neural networks. Two key elements guarantee the security of the protocol, the implementation of the template-based approach in the network's architecture and the use of homomorphic inference. Our results demonstrate the potential of developing zero-knowledge protocols for the verification of nuclear warheads using Siamese networks on encrypted spectral data.


New heterocyclic analogues of 4-(2-chloro-5-methoxyanilino)quinazolines as potent and selective c-Src kinase inhibitors.
A series of 5,7-disubstituted quinazolines, bearing 4-heteroaryl substituents such as 2-pyridinylamine or 2-pyrazinylamine, has been synthetised and evaluated as c-Src kinase inhibitors. Highly potent inhibition, high selectivity and physical properties suitable for oral dosing were achieved within this series: 23d and 42 were identified as sub-0.1muM inhibitors in a c-Src-driven cell proliferation assay and displayed adequate rat pharmacokinetics after oral administration.


Cholinergic neurons of the adult rat striatum are immunoreactive for glutamatergic N-methyl-d-aspartate 2D but not N-methyl-d-aspartate 2C receptor subunits.
Cholinergic neurons of the striatum play a crucial role in controlling output from this region. Their firing is under the control of a relatively limited glutamatergic input, deriving principally from the thalamus. Glutamate transmission is effected via three major subtypes of receptors, including those with affinity for N-methyl-d-aspartate (NMDA) and the properties of individual receptors reflect their precise subunit composition. We examined the distribution of NMDA2C and NMDA2D subunits in the rat striatum using immunocytochemistry and show that a population of large neurons is strongly immunoreactive for NMDA2D subunits. From their morphology and ultrastructure, these neurons were presumed to be cholinergic and this was confirmed with double immunofluorescence. We also show that NMDA2C is present in a small number of septal and olfactory cortical neurons but absent from the striatum. Receptors that include NMDA2D subunits are relatively insensitive to magnesium ion block making neurons more likely to fire at more negative membrane potentials. Their localization to cholinergic neurons may enable very precise regulation of firing of these neurons by relatively small glutamatergic inputs.


MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity.
Metastasis-associated protein 2 (MTA2) is a core subunit of the nucleosome remodeling and deacetylating (NuRD) complex and functions by mediating chromatin remodeling and gene silencing. However, its biological actions and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remain elusive. The aim of this study was to explore the function and regulation mechanism of MTA2 in PDAC. As shown in GEO, ICGC, and TCGA databases, a higher expression of MTA2 was noticed in the PDAC tissues than in the normal pancreatic tissues. Moreover, a higher expression level of MTA2 was associated with a shorter overall survival time in these public PDAC databases. We further investigated the underlying mechanisms of these observations by using a chromatin immunoprecipitation (ChIP)-based deep sequencing, luciferase reporter, and quantitative ChIP assays. We identified the repressive binding of MTA2 to the promoter of phosphatase and tensin homolog (PTEN). We also found that Snail recruited MTA2 and HDAC1 to suppress PTEN expression. Ectopic expression and knockdown of MTA2 were performed to evaluate the effects of this gene on PDAC cell proliferation, migration, and invasion. Using CCK-8, colony formation and transwell assays, and a xenograft tumor model, we revealed that MTA2 promoted PDAC cell proliferation, migration, and invasion in vitro and PDAC tumor growth in vivo by downregulation of PTEN. In benzyl isothiocyanate (BITC)-treated MIA Paca-2 cells and PANC-1 cells, MTA2 level decreased in a dose- and time-dependent manner with concomitant upregulation of PTEN level and downregulation of phosphorylated PI3K and AKT levels, providing evidence of the involvement of MTA2 and PTEN in the regulation of the PI3K/AKT pathway in BITC-mediated PDAC suppression. Collectively, these findings uncover a novel role for MTA2 in the regulation of PDAC progression and help to elucidate the mechanisms involved in this process.


[Changes in the activity of proteases and trypsin inhibitors in wheat leaves in the initial period of cold hardening and subsequent dehardening].
The dynamics of amidase, cysteine protease, and trypsin inhibitor activities were studied in the leaves of wheat (Triticum aestivum L.) seedlings grown under controlled conditions (25 degrees C, illuminance 10 kLx, 14-h photoperiod) and subjected to cold hardening (5 degrees C, 10 kLx, 14-h photoperiod). Changes in the activity of amidases and cysteine proteases proved to precede an increase in cold resistance during cold hardening and a decrease in cold resistance after the end of cold hardening. The activity of trypsin inhibitors changed only during cold hardening. It is suggested that amidases, cysteine proteases, and trypsin inhibitors are involved in the cold adaptation of plants.


Polymorphisms in the 5-hydroxytryptamine 2A receptor and CytochromeP4502D6 genes synergistically predict fluvoxamine-induced side effects in japanese depressed patients.
5-Hydroxytryptamine (5-HT) receptors are thought to be associated with the gastrointestinal side effects induced by selective serotonin reuptake inhibitors. CytochromeP450 (CYP) 2D6 may also be associated with the side effects induced by fluvoxamine, since the plasma fluvoxamine concentration depends on a CYP2D6 gene polymorphism. This study investigated whether 5-HT receptor and CYP2D6 gene polymorphisms could predict the occurrence of the side effects. The effects of 5-HT receptor and CYP2D6 gene polymorphisms on the incidence of gastrointestinal side effects induced by fluvoxamine were investigated in 100 depressed outpatients who gave written consent to participate in the study. The patients visited every 2 weeks until the week 12 end point and the fluvoxamine dose was changed in response to their clinical symptoms. All side effects, including the gastrointestinal side effects, were assessed at each visit. Polymerase chain reaction was used to determine A-1438G of the 5-HT2A receptor, C195T and Pro16Ser of the 5-HT3A receptor, Tyr129Ser of the 5-HT3B receptor, and the *5 and *10 alleles of CYP2D6. Both the A-1438G polymorphism of the 5-HT2A receptor gene and the CYP2D6 gene polymorphism had significant effects on the incidence of gastrointestinal side effects. Cox regression was used to analyze the combination effect of the two polymorphisms on the gastrointestinal side effects. Cox regression analysis showed that lower metabolizers (LMs) of CYP2D6 with the G/G genotype of the 5-HT2A A-1438G polymorphism had a 4.242-fold (P = 0.009) and LMs with the A/G genotype had a 4.147-fold (P = 0.004) higher risk of developing gastrointestinal side effects than normal metabolizers with the A/A genotype. The 5-HT3A and 3B gene polymorphisms had no significant effects on the incidence of gastrointestinal side effects. 5-HT2A receptor and CYP2D6 gene polymorphisms had a synergistic effect for the prediction of fluvoxamine-induced gastrointestinal side effects.


Early onset of nephrotic syndrome after treatment with D-penicillamine in a patient with Wilson's disease.
Wilson's disease responds to a variety of treatments including D-penicillamine and trientene. Nephrotic syndrome is a late complication of D-penicillamine treatment. We report a pediatric patient with Wilson's disease who developed nephrotic syndrome 2 wk after beginning D-penicillamine. His nephrosis resolved and his disease is quiescent with trientene treatment.


Academic goals orientation questionnaire for Colombian nursing students: Validity and reliability study.
Academic motivation guides students toward the achievement of academic objectives and influences their learning. However, there is little research on this subject in nursing education, and validated instruments are not available in Latin America. To determine the validity and reliability of the Academic Goals Orientation Questionnaire in Colombian nursing students. Cross-sectional psychometric study developed in the second semester of 2016. Undergraduate students in nursing at the National University of Colombia (n = 323). The Academic Goals Orientation Questionnaire was administered electronically. In addition, the variables of age, sex and academic year were collected. An analysis of construct validity was carried out by exploratory and confirmatory factor analysis. The reliability of the questionnaire was studied with Cronbach's alpha. The exploratory factor analysis revealed the presence of four factors that explain 53.4% of the total variance and that correspond to the dimensions of the original instrument. The overall reliability was α = 0.714. The confirmatory factor analysis verified a good fit of the model (χ2 = 128, p = .024); its standardized mean square residue (SRMR) was 0.0471; the root mean square error of approximation (RMSEA) was 0.03 (IC95% = 0.011-0.044), and the comparative fit index (CFI) was 0.972. The learning or task goal obtained the highest average score (m = 4.67, 95% CI = 4.629-4.712), and the Work avoidance goal was the worst rated (m = 2.126, 95% CI = 2.055-2.198) by the students. The Academic Goal Orientation Questionnaire has an adequate validity and reliability in the Colombian context that allows it to be applied in nursing students. However, it is recommended to expand the study with larger samples and other countries in the same context.


Scaffold-associated procedures are superior to microfracture in managing focal cartilage defects in the knee: A systematic review & meta-analysis.
Debate continues as to whether surgical treatment with chondral-regeneration devices is superior to microfracture for focal articular cartilage defects in the knee. To evaluate the superiority of scaffold-associated chondral-regeneration procedures over microfracture by assessing: (1) Patient-reported outcomes; (2) Intervention failure; (3) Histological quality of cartilage repair. A three-concept keyword search strategy was designed, in accordance with PRISMA guidelines: (i) knee (ii) microfracture (iii) scaffold. Four databases (Ovid Medline, Embase, CINAHL and Scopus) were searched for comparative clinical trials (Level I-III evidence). Critical appraisal used two Cochrane tools: the Risk of Bias tool (RoB2) for randomized control trials and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I). Study heterogeneity permitted qualitative analysis with the exception of three patient-reported scores, for which a meta-analysis was performed. Twenty-one studies were identified (1699 patients, age range 18-66 years): ten randomized control trials and eleven non-randomized study interventions. Meta-analyses of the International Knee Documentation Committee (IKDC), Knee Injury And Osteoarthritis Outcome Score (KOOS) for pain and activities of daily living, and Lysholm score demonstrated statistically significant improvement in outcomes for scaffold procedures compared to microfracture at two years. No statistical difference was seen at five years. Despite the limitations of study heterogeneity, scaffold-associated procedures appear to be superior to MF in terms of patient-reported outcomes at two years though similar at five years. Future evaluation would benefit from studies using validated clinical scoring systems, reporting failure, adverse events and long-term clinical follow up to determine technique safety and superiority.


Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice.
Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain.


Defecatory symptoms during and after the first pregnancy: prevalences and associated factors.
A prospective cohort study was undertaken to evaluate the impact of pregnancy and the first delivery on the defecatory symptoms and to identify associated factors. Included were 487 nulliparous pregnant women who completed four questionnaires. Flatus and fecal incontinence, constipation, and painful defecation are already present in early pregnancy and are significantly predictive for reporting symptoms after delivery, except for fecal incontinence. A third or fourth degree sphincter tear was significantly associated with fecal incontinence 12 months postpartum and with de novo fecal incontinence, while other factors associated with de novo onset of symptoms were of borderline significance. Defecation symptoms already present in early pregnancy are highly predictive for reported symptoms at 12 months postpartum except for fecal incontinence that is mainly related to anal sphincter lesion. Therefore, investigating the effects of childbirth in general on the anorectal function is not justified without knowledge of this function during pregnancy.


[Structures of endovascular recanalization in Germany : Cross-sectional survey of certified stroke units 2016-2018].
In this cross-sectional study data from 299 certified stroke units (SU) in Germany were analyzed from January 2016 to December 2018 and included comprehensive stroke centers (CSC 34%), local SU (62%), and telemedical SU (4%). In a total of 2487 SU monitor beds, 251,539 cases of stroke treatment were documented. The number of monitor beds (10.8 vs. 7.2) and stroke cases per year (1143 vs. 708) were significantly higher in CSC than in local SU. A total of 9251 endovascular recanalization (ER) procedures were performed annually by 475 interventionalists. The overall rate of ER was 3.7% of all stroke cases, including intracerebral hemorrhage (ICH) and transient ischemic attacks (TIA). A total of 124 of the SUs (41.5%) had a 24/7 ER structure in which 55% of all stroke treatments and 96% of all ERs were carried out. In the vast majority of CSC the ER structure was robust (≥4 interventionalists, 52%) or acceptable (3 interventionalists, 27%). In contrast, the majority of local SU (88%) had to transfer patients for ER over average distances of 40 km (range 1-160 km). Overall, the ER structures in Germany between 2016 and 2018 could be described as good to very good.


Urgent carotid endarterectomy is safe in patients with few comorbid medical conditions.
Recent reports from single institutions have confirmed the efficacy of carotid endarterectomy (CEA) performed in the urgent or emergent setting, although with higher perioperative mortality and morbidity. We determined the results of urgently performed CEA in academic and community hospitals and whether patient or hospital factors affected outcome. The records of patients undergoing CEA in all nonfederal hospitals in the state of Connecticut between 1992 and 2002 were reviewed, and symptomatic patients who presented in an urgent or emergent fashion were compared to patients treated electively. Multivariable logistic regression was used to determine the effect of patient risk factors on perioperative mortality, stroke, and cardiac complications. Patients undergoing urgent CEA (n = 764, 6.3%) had higher perioperative mortality (2.0% vs. 0.3%, p < 0.0001) and stroke (2.9% vs. 1.1%, p < 0.0001) but not cardiac complications (3.0% vs. 2.2%, p = 0.14) compared to patients undergoing elective CEA (n = 11,312). Patients undergoing urgent CEA and with high rates of associated comorbidity had a higher risk of perioperative mortality (7.8% vs. 0.4, p = 0.001), stroke (10.9% vs. 0.8%, p = 0.0002), and cardiac complications (14.1% vs. 0.8%, p < 0.0001) compared to patients presenting urgently but with little comorbidity. Perioperative mortality was associated with performance of the procedure in hospitals with low bed capacity (odds ratio [OR] = 4.6, p = 0.01). Perioperative stroke was associated with renal insufficiency (OR = 5.3, p = 0.04). Perioperative cardiac complications were associated with diabetes (OR = 2.6, p = 0.03) and performance in hospitals with low bed capacity (OR = 5.0, p < 0.01). Urgent admission was associated with age >/=80 (OR = 1.2, p = 0.04), renal disease (OR = 1.8, p = 0.05), and cardiac disease (OR = 1.3, p < 0.01). Urgently performed CEA has higher perioperative mortality and stroke compared with electively performed cases. However, the subset of patients with low rates of associated comorbid medical conditions but urgently needing CEA is associated with low rates of perioperative complications. Patients with severe associated comorbid medical conditions who present urgently for CEA may form a high-risk group of patients to be considered for referral to large treatment centers or possibly alternative therapy.


Temporal relationships between inhibitory effects of glucocorticoids on cells of the CEM-C7 human leukaemic lymphoblast cell line.
Events preceding glucocorticoid-induced growth inhibition and cytolysis were studied in CEM-C7 human leukaemic lymphoblasts. Inhibitory effects on uridine and thymidine incorporation and on RNA polymerase A activity preceded cell killing, and may relate to the arrest of the cells in the G1 phase of the cell cycle. An inhibitory effect on RNA polymerase B activity emerged later than the effect on RNA polymerase A; this action may reflect commitment to cell death. Cell death was not apparent within the first 24 hr of steroid treatment but thereafter was associated with extensive DNA fragmentation. The lethal action of dexamethasone in CEM-C7 cells was potentiated by 3-aminobenzamide, an inhibitor of poly(ADP-ribose)polymerase.


Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.
The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis. An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM. There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic-clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug-resistant epilepsy. This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.


Vasoactive intestinal peptide (VIP) and peptide having N-terminal histidine and C-terminal isoleucine amide (PHI) stimulate adenylate cyclase activity in human heart membranes.
The presence of receptors, recognized by Vasoactive Intestinal Peptide (VIP) and Peptide having N-terminal Histidine and C-terminal Isoleucine amide (PHI), was documented in membranes from human right auricle and left ventricular cardiac muscle by the ability of these peptides to stimulate adenylate cyclase. The capacity of VIP and PHI to activate the enzyme was comparable, in auricle as well as ventricle membranes, the affinity of the system being moderately higher for VIP than for PHI. In auricles, dose-effect curves appeared compatible with the coexistence of high-affinity and low-affinity VIP receptors. PHI could not, however, discriminate these subclasses of VIP receptors.


[Torture survivors in Norway--physician's responsibility].
Many political refugees who seek asylum in Norway have been imprisoned and subjected to torture. This review is based on the author's personal experience since 1976. 44 men (22-45 years of age) and 9 women (23-32 years of age), all of them exposed to physical torture, were included in the study. The methods of torture are described. They were all given a full clinical examination by the author, including photos of possible injuries. The survivors showed physical and sexual sequelae, for instance multiple fractures of bones and teeth, tinnitus, broken testicles. In my opinion, the most important therapist for torture victims is their general practitioner, who should work with nurses, physiotherapists, dentists and psychologists.


Molecular cloning and characterization of a putative proline dehydrogenase gene in the Colorado potato beetle, Leptinotarsa decemlineata.
Leptinotarsa decemlineata adults exhibit a season-dependent activity. In spring, post-diapause beetles often fly a long distance from overwintering sites to potato fields. In summer and autumn, the flight ability is sharply reduced. Proline is the main energy substrate of L. decemlineata during flight and proline dehydrogenase (ProDH) catalyzes the first step in proline catabolism. Here we identified a putative LdProDH gene; it had three cDNA isoforms which shared the same 5'UTR and coding region, but differed in the lengths of 3'UTRs (515, 1 092 and 1 242 bp for isoforms-1, -2 and -3, respectively). LdProDH encoded a 616 amino acid protein that showed high sequence similarity to ProDH-like proteins from other insect species. LdProDH was expressed in the third and fourth instars larvae and adults, but not in pupae. Dietary ingestion of bacterially expressed LdProDH-dsRNA by adults significantly decreased its messenger RNA (mRNA) level, and caused an elevation of free proline content in the hemolymph. Further observation revealed that three canonical polyadenylation signals (AATAAA) were tandemly located in the 3'UTR of isoform-3. The first, second and third polyadenylation sites gave rise to isoforms-1, -2 and -3, respectively. Analysis of the genomic DNA uncovered that the three isoforms resulted from alternative polyadenylation. The mRNA level of isoform-1, which expressed at low levels in pre-diapause adults, became abundant in post-diapause beetles. It is indicated that the LdProDH expression is fine-tuned through 3'UTR to control proline catabolism for the season-dependent activity of L. decemlineata adults.


Aza-Heterocycles via Copper-Catalyzed, Remote C-H Desaturation of Amines.
The majority of medicines contain a nitrogen atom within a five- or six- membered ring. To rapidly access both such aza-heterocycles, we sought to develop a remote C-H desaturation of amines. Inspired by the Hofmann-Löffler-Freytag synthesis of five-membered pyrrolidines, we tackled the century-old challenge of synthesizing six-membered piperidines by H-atom transfer. We present herein a double, vicinal C-H oxidation by dual catalysis, entailing Ir photocatalytic initiation of 1,5-HAT by an N-centered radical and Cu-catalyzed interception of the C-centered radical to facilitate desaturation. By this mechanism, two C-H bonds (δ and ε to N) are regioselectively removed from unbiased, remote positions of an alkyl chain. Over 50 examples illustrate efficiency, selectivity, functional group tolerance, and medicinal utility of this synthesis of both internal and terminal δ vinylic amines and aza-heterocycles. Mechanistic experiments probe the alkylcopper intermediate, as well as kinetics and regioselectivity of the HAT and elimination steps.


In vivo modulation of rat liver acyl-coenzyme A:cholesterol acyltransferase by phosphorylation and substrate supply.
Rats were infused intravenously with a bolus of mevalonolactone or cholesterol-rich chylomicron and microsomes prepared from the livers at times up to 2 h after the infusion. Acyl-CoA cholesterol acyltransferase (ACAT) activity was measured in the microsomes under conditions that define the activity state of the enzyme which recent evidence suggests may depend on the degree of phosphorylation of the enzyme. ACAT activity was increased by both treatments. Some of the observed increase could be attributed to an increase in the supply of substrate cholesterol to the enzyme. The remaining change in activity was consistent with a change in the activity state of ACAT occurring in vivo in response to the influx of cholesterol to the enzyme.


Quantitative analysis of antiviral drug toxicity in proliferating cells.
The toxicity of most antiviral compounds was dependent on the type of cell used to assay toxicity. Ranking of compounds according to toxicity was, however, very similar (p less than 0.01) in the three different cell types used in this study. The difference in toxicity observed for 9-beta-D-arabinofuranosyladenine between Flow 5000 cells and CCRF-SB cells could not be accounted for by differences in the intracellular concentrations. On the other hand, the different toxicities observed for ribavirin and 2'-deoxy-5-trifluorothymidine between Flow 5000 cells and CCRF-SB cells may be caused by the culture conditions (as shown for one cell type, HeLa S3, grown either as monolayer or in suspension) rather than by cell-specific differences. The growth-inhibitory effect of most antiviral compounds increased with treatment time, indicating an additive nature of toxicity. The ability of cells to recover from toxic treatment with drugs varied greatly from compound to compound (from undetectable regrowth to 140% growth compared to control cells). Coaddition of natural nucleosides could, at best, only partly protect cells from the toxic influences of antiviral nucleoside analogs. As a result of comparing antiviral effects and toxicity in vitro, the unselective compounds may be eliminated from further development at the screening level.


Kappa statistics to measure interrater and intrarater agreement for 1790 cervical biopsy specimens among twelve pathologists: qualitative histopathologic analysis and methodologic issues.
As part of a program project to evaluate emerging optical technologies for cervical neoplasia, we performed fluorescence and reflectance spectroscopic examinations of patients with abnormal Papanicolaou smears. Biopsy specimens were taken from each area and measured optically, and study pathologists performed qualitative histopathologic readings. Several methodologic issues arose in this analysis: (1) the interpathologist and intrapathologist agreement between institutions for the 1790 biopsy specimens; (2) the interinstitutional agreement among the two institutions conducting the trials on 117 randomly chosen biopsy specimens; (3) the interinstitutional agreement among the two institutions and a third expert gynecologic pathologist to ensure the expert readings were comparable to those outside both institutions on 117 randomly chosen biopsy specimens; and (4) an additional three reviews of the 106 difficult biopsy specimens by all three institutions. All 1790 specimens from 850 patients were reviewed three times at each institution in blinded fashion; those for which the first and second reviews were identical were not reviewed a third time. A randomly selected sample of 117 specimens was randomly ordered and read by study pathologists at The University of Texas M. D. Anderson Cancer Center, British Columbia Cancer Agency (BCCA), and Brigham and Women's Hospital (BWH). The 106 difficult cases were treated in the same manner as the randomized and random-ordered cases. Generalized, unweighted, and weighted kappas and their 95% confidence intervals were used to assess agreement. Binary comparisons were used to compare diagnostic categories. The kappas for the three readings of the overall data set using eight-category World Health Organization (WHO) criteria were as follows: 0.66 for the generalized, 0.72 for weighted, and ranged from 0.59 to 0.94 unweighted binary categories; those read using four-category Bethesda criteria: 0.70 for generalized, 0.69 for weighted, and 0.56-0.94 for unweighted binary categories. For the pool versus the study pathologist readings, the eight-category kappa was 0.51 for generalized, 0.72 for weighted, and 0.56-0.82 for unweighted binary categories; for those read using Bethesda criteria: 0.70 for generalized, 0.70 for weighted, and 0.59-0.82 for the unweighted binary categories. The interpathologist and intrapathologist readings were fair by Landis standards at the low end of the diagnostic scale (atypia, human papillomavirus, and CIN1) and substantial to almost perfect at the high end (CIN2, CIN3, and CIS). The randomly selected and randomly ordered sample of 117 specimens read with the WHO system yielded a generalized kappa of 0.45; among the three institutions (M. D. Anderson Cancer Center vs. BCCA, M. D. Anderson vs. BWH, and BCCA vs. BWH), the unweighted kappas were 0.46, 0.41, and 0.49 and the weighted were 0.65, 0.66, and 0.68, respectively; for the Bethesda, a generalized kappa of 0.65, unweighted kappas of 0.66, 0.65, and 0.47, and weighted of 0.74, 0.72, and 0.74. The difficult specimens read with the WHO system yielded a generalized kappa of 0.23; among the three institutions the unweighted kappas were 0.20, 0.30, and 0.37, and the weighted were 0.17, 0.34, and 0.31; for the Bethesda, a generalized kappa of 0.25; among the three institutions, the unweighted kappas were 0.21, 0.32, and 0.37, and the weighted were: 0.07, 0.21, and 0.37, respectively. Kappas in this expert group of pathologists were in the moderate, substantial, and almost perfect ranges for the overall and randomized samples. The randomized sample was representative of the larger sample. The kappa of the specimens for which disagreements arose was, predictably, in the slight range. Our findings will aid both the correlations with optical measurements using fluorescence and reflectance spectroscopy and the quantitative histopathologic analysis of these study specimens.