Copy number variations of DNA repair genes and the age-related cataract: Jiangsu Eye Study.
DNA damage is critical in the pathogenesis of age-related cataract (ARC). This study examined the association of copy number variations (CNVs) of DNA repair genes with susceptibility to ARC in the Han Chinese. Study participants were from the population-based Jiangsu Eye Study, which includes 780 ARC patients and 525 controls. DNA was extracted from blood for copy number (CN) assays using RT-PCR. The Comet assay was to assess DNA damage in peripheral lymphocytes. Novel CNV was detected in WRN. Initial analyses found that CN = 3+ for WRN had an increased risk of ARC (odds ratio [OR] = 1.88, P = 0.02); CN = 1 for HSF4 had an increased risk of ARC (OR = 4.09, P = 0.004). CN = 3+ for WRN was associated with nuclear and posterior subcapsular cataract (OR = 2.06, P = 0.02; OR = 3.72, P = 0.02). CN = 1 for HSF4 was associated with nuclear and posterior subcapsular cataract (OR = 5.73, P = 0.001; OR = 6.80, P = 0.01). The combination WRN and HSF4 CNVs markedly increased the risk of ARC; the OR was increased from 2.63 by HSF4 alone to 6.80 by combined WRN and HSF4 CNVs. However, after multiple testing correction, only HSF4 CNV was associated with ARC overall and with nuclear and posterior subcapsular cataract as well. The DNA damage in lymphocytes from ARC patients was significantly higher when compared to normal controls. HSF4 and WRN CNVs might be involved in ARC pathogenesis in the Han Chinese. These findings suggest the importance of DNA repair in ARC susceptibility and distinct risk factors in ARC subtypes.


Transdermal testosterone delivery: testosterone patch and gel.
Testosterone replacement treatment is usually life-long. Fortunately, testosterone administration is relatively safe and until the age of 50 years few side effects are noted with normal doses of testosterone. After the age of 50 years when prostate disease becomes more prevalent, shorter-acting testosterone preparations, allowing a fast reduction of circulating testosterone levels, may be an advantage. Testosterone has an impact on sexual and non-sexual behaviour and short-acting testosterone preparations may be better suited for the initiation of long-term administration allowing the monitoring of behavioural effects. Testosterone can be delivered to the circulation through the intact skin, both genital and non-genital. Transdermal administration delivers testosterone at a controlled rate into the systemic circulation, avoiding hepatic first pass and reproducing the diurnal rhythm of testosterone secretion and without the peak and trough levels observed with the use of the traditional long-acting testosterone injections. In conclusion, both the testosterone patch and testosterone gel are valuable contributions to androgen replacement treatment meeting the requirements specified for testosterone replacement treatment.


A Phytol-Enriched Diet Activates PPAR-α in the Liver and Brown Adipose Tissue to Ameliorate Obesity-Induced Metabolic Abnormalities.
Peroxisome proliferator-activated receptor alpha (PPAR-α) is a ligand-activated transcription factor that regulates lipid and carbohydrate metabolism. We investigate the effects of naturally occurring PPAR-α agonists, phytol, and its metabolite phytanic acid, on obesity-induced metabolic disorders using a mouse model. A luciferase reporter assay shows that phytanic acid potently activates PPAR-α among PPAR subtypes. In high-fat-diet-induced, severely obese mice, a phytol-enriched diet increases phytanic acid levels in the liver and adipose tissue, where PPAR-α is abundantly expressed. A phytol-enriched diet ameliorates severe obesity and the related metabolic abnormalities of white adipose tissue. Moreover, the expression of PPAR-α target genes in the liver and brown adipose tissue is enhanced by a phytol-enriched diet, suggesting that phytol and phytanic acid activate PPAR-α in these organs. We confirm that phytanic acid treatment induced PPAR-α target gene expression in both primary hepatocytes and brown adipocytes from wild-type mice, but not in these cells from PPAR-α-deficient mice. A phytol-enriched diet may increase phytanic acid levels in the liver and brown adipocytes, thereby activating PPAR-α in these organs and ameliorating obesity-induced metabolic diseases.


A new species of the genus Cenocorixa (Hemiptera, Heteroptera, Corixidae) from China.
A new species of the genus Cenocorixa Hungerford (Hemiptera, Heteroptera, Corixidae) is described from China. Cenocorixayuanjiangensis sp. nov. is reported from Yunnan Province. An updated key to the Chinese species of Cenocorixa is presented.


Tranexamic acid may be a useful pharmacotherapy for endoscopically resistant small bowel angiodysplasia.
Small bowel angiodysplasia (SBAD) is reported to account for nearly 50% of cases of small bowel bleeding. When SBAD occurs frequently, it is difficult to treat all the angiodysplasias endoscopically, and gastrointestinal bleeding often recurs. Hormone therapy, somatostatin analogs, thalidomide and vascular endothelial growth factor (VEGF)-neutralizing antibodies have been reported to reduce gastrointestinal angiodysplasia (GIAD) bleeding. However, there is no strong evidence to recommend them. Also, there are no guidelines for their use. Hereditary hemorrhagic telangiectasia (HHT) is a hereditary disease caused by abnormalities in VEGF, resulting in multiple GIADs. A treatment guideline has been created for GIAD in HHT, and the use of tranexamic acid, an antifibrinolytic agent, is the first recommendation pharmacotherapy for GIAD with gastrointestinal bleeding that is difficult to treat endoscopically. It has been reported that fibrinolysis is accelerated in GIAD patients who are not HHT, similar to HHT patients. The use of tranexamic acid for gastric antral vascular ectasia in GIAD has been reported to be useful. However, there are very few reports of its use for SBAD. There are concerns with tranexamic acid use regarding the development of thrombosis/embolism, but there are few reports of such side effects. Future clinical trials including tranexamic acid for SBAD are desired.


Oligosaccharide motion in erythrocyte membranes investigated by picosecond fluorescence polarization and microsecond dichroism of an optical probe.
Oligosaccharide chains on the surfce of human erythrocytes were labeled with the probe eosin 5-thiosemicarbazide. The probe was conjugated to aldehydes produced by oxidation of sialic acid and galactose residues. The probe is associated mostly with glycophorin A after sialic acid labeling, whereas multiple components, including band 3 and lipids, are labeled after galactose oxidation. Fast molecular motion was studied by measuring steady-state and picosecond time-resolved fluorescence depolarization. Slower motions were investigated by observing flash-induced transient dichroism. It was found that both eosin-labeled sialic acid and galactose residues exhibit a rapid motion with correlation time of approximately 3 nsec. This motion is assigned to independent motion of the probe, possibly in conjunction with a short segment of the oligosaccharide chain. The order parameter of the fast motion is 0.8.-0.9, demonstrating that its angular amplitude is highly restricted. For eosin-labeled sialic acid, the order parameter in the microsecond time range is 0.2-0.3. It is deduced that a second, slower rotational motion is present, which is assigned to a cooperative motion of the oligosaccharide chains. The correlation time of this motion is in the range 10(-7)-(10-5) sec. Some eosin-labeled galactose residues may have a similar slow motion, but most appear to be remarkably immobile over the time range 10(-8)-10(-3) sec.


Inferior Hepatic Fissures: Anatomic Variants in Trinidad and Tobago.
Classic descriptions of the visceral surface of the human liver only define three fissures: transverse, sagittal and umbilical fissures. Any additional fissures that are present on the visceral surface of the liver are considered variant inferior hepatic fissures (IHFs). This study was carried out to document the prevalence of IHFs in the Eastern Caribbean. Knowledge of these variants is important to clinicians who treat liver disorders in persons of the Caribbean diaspora. In this study, two independent researchers observed all consecutive autopsies performed at the facility over a period of 10 weeks. They examined the visceral surface of the unfixed liver in situ. Any specimen with variant IHFs was selected for detailed study. We documented the relation of the variant IHFs to nearby viscera and then explanted the livers using a standardized technique. The following details were recorded for each liver: number, location, depth, length, and width of IHFs. All measurements were checked independently by two researchers and the average measurement was used as the final dimension. Each liver was then sectioned in 1 cm sagittal slices to document the relationship of intraparenchymal structures. We observed 60 consecutive autopsies in unselected cadavers. Variant IHFs were present in 21 (35%) cadavers at a mean age of 68.25 years (range: 61 - 83; median 64.5; standard deviation (SD) ± 8.45). The variants included a deep fissure in the coronal plane between segments V and VI in 19 (31.7%) cadavers (related to the right branch of the portal vein in 63.2% of cases), a well-defined segment VI fissure running in a sagittal plane in four (6.7%) cadavers, a well-defined fissure incompletely separating the caudate process from the caudate lobe proper in five (8.3%) cadavers, a consistent fissure that arose from the left side of the transverse fissure and coursed between segments II and III in three (5%) cadavers, and a deep coronal fissure dividing the quadrate to form an accessory quadrate lobe in one (1.7%) cadaver. Almost one in three unselected persons in this population have anatomically variant fissures on the visceral surface of the liver. The variants include Rouvière's sulci (31.7%), caudate notches (8.3%), segment VI fissures (6.7%), left medial segment fissures (5%), and quadrate fissures (1.7%). The clinical relevance of these variants is discussed. Any clinician treating liver diseases in persons of Caribbean extract should be aware of their presence.


aPKC-ι/P-Sp1/Snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma.
Cholangiocarcinoma (CCA) is a highly malignant bile duct cancer that tends to invade and metastasize early. The epithelial-mesenchymal transition (EMT) has been implicated in cancer cell invasion and metastasis, as well as in cancer cell evasion of host immunity. In this study, we investigated the interaction between atypical protein kinase C-iota (aPKC-ι) and Snail in the regulation of EMT and its relationship to CCA immunosuppression. Our results demonstrated that aPKC-ι, Snail, and infiltrated immunosuppressive cells were significantly up-regulated in CCA tumor tissues and linked to poor prognosis. aPKC-ι induced EMT and immunosuppression by regulating Snail in vitro and in vivo, although aPKC-ι did not directly interact with Snail in coimmunoprecipitation experiments. To further clarify the molecular interaction between aPKC-ι and Snail in relation to EMT, quantitative iTRAQ-based phosphoproteomic analysis and liquid chromatography-tandem mass spectrometry were conducted to identify the substrates of aPKC-ι-dependent phosphorylation. Combined with coimmunoprecipitation, we showed that specificity protein 1 (Sp1) was directly phosphorylated by aPKC-ι on Ser59 (P-Sp1). Both Sp1 and P-Sp1 were up-regulated in CCA tumor tissues and associated with clinicopathological features and poor prognosis in CCA patients. Moreover, using chromatin immunoprecipitation assays, we found that P-Sp1 regulated Snail expression by increasing Sp1 binding to the Snail promoter. P-Sp1 also regulated aPKC-ι/Snail-induced EMT-like changes and immunosuppression in CCA cells. Our findings further indicated that CCA cells with EMT-like features appear to generate immunosuppressive natural T regulatory-like cluster of differentiation 4-positive (CD4+ )CD25- cells rather than to increase CD4+ CD25+ natural T regulatory cells, in part by mediating T regulatory-inducible cytokines such as transforming growth factor β1 and interleukin 2. These results demonstrate that aPKC-ι promotes EMT and induces immunosuppression through the aPKC-ι/P-Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA. (Hepatology 2017;66:1165-1182).


Immunodepression, Infections, and Functional Outcome in Ischemic Stroke.
Stroke remains one of the main causes of mortality and morbidity worldwide. Immediately after stroke, a neuroinflammatory process starts in the brain, triggering a systemic immunodepression mainly through excessive activation of the autonomous nervous system. Manifestations of immunodepression include lymphopenia but also dysfunctional innate and adaptive immune cells. The resulting impaired antibacterial defenses render patients with stroke susceptible to infections. In addition, other risk factors like stroke severity, dysphagia, impaired consciousness, mechanical ventilation, catheterization, and older age predispose stroke patients for infections. Most common infections are pneumonia and urinary tract infection, both occur in ≈10% of the patients. Especially pneumonia increases unfavorable outcome and mortality in patients with stroke; systemic effects like hypotension, fever, delay in rehabilitation are thought to play a crucial role. Experimental and clinical data suggest that systemic infections enhance autoreactive immune responses against brain antigens and thus negatively affect outcome but convincing evidence is lacking. Prevention of poststroke infections by preventive antibiotic therapy did not improve functional outcome after stroke. Immunomodulatory approaches counteracting immunodepression to prevent stroke-associated pneumonia need to account for neuroinflammation in the ischemic brain and avoid further tissue damage. Experimental studies discovered interesting targets, but these have not yet been investigated in patients with stroke. A better understanding of the pathobiology may help to develop optimized approaches of preventive antibiotic therapy or immunomodulation to effectively prevent stroke-associated pneumonia while improving long-term outcome after stroke. In this review, we aim to characterize epidemiology, risk factors, cause, diagnosis, clinical presentation, and potential treatment of poststroke immunosuppression and associated infections.


Screening for Anger and Sleep Difficulties.
Mental health screens are designed to detect individuals at risk of psychological disorders. In the military setting of this study, these disorders were post-traumatic stress disorder (PTSD) and alcohol use. This study extends the literature on deployment-related mental health screening by including measures of sleep difficulties and anger as predictors of postdeployment PTSD and alcohol abuse. Evidence that measures of anger and sleep difficulties contribute incremental validity to the prediction of postdeployment mental health problems, including substance abuse, would be helpful in designing interventions to assist the rehabilitation of returning personnel. A test battery containing the PTSD Checklist-Civilian (PCL-C) to screen for PTSD, the Kessler 10 to screen for psychological distress, a Sleep Difficulties scale, an exposure to trauma scale, and an anger scale was administered to 212 personnel nearing completion of a deployment to the Middle East. A second battery containing the PCL-C, the Kessler 10, and a measure of alcohol consumption (Alcohol Use Disorders Identification Test [AUDIT]) was administered to the same personnel 3 to 6 months after return to Australia. Hierarchical regression analyses assessed the predictive validity of measures of psychological distress (anxiety and depression), PTSD symptomatology, sleep disturbance, and anger in relation to postdeployment measures of PTSD symptomatology and alcohol use. Time 1 measures predicted 24.4% of the variance in postdeployment PCL-C scores and 13.1% of the variance in AUDIT scores, with the Sleep Difficulties scale contributing to the prediction of the PCL-C score and the anger scale helping to predict AUDIT scores. On the basis of these findings, we recommend the inclusion of improved measures of both anger and sleep difficulties in end-of-deployment mental health screens. A less behaviorally specific and more wide-ranging anger scale is recommended for future studies that aim to evaluate the role of anger in screening batteries. Our findings suggest that the Sleep Difficulties scale used in this study would be a worthwhile addition to mental health screening because it is moderately correlated with both Time 1 and Time 2 measures of PTSD symptomatology and psychological distress. Furthermore, there is minimal stigma associated with the experience of sleep difficulties.


Downregulation of fibrosis and inflammatory signalling pathways in rats liver via Pulicaria crispa aerial parts ethanol extract.
Liver is a vital organ for the detoxification of toxic substances in the body, where fibrosis is the major cause of liver damage. Pulicaria crispa processes many therapeutic applications such as antioxidant, antimicrobial, anticancer and anti-ulcerative agent. This study aimed to modulate the fibrosis and inflammatory signalling pathways in carbon tetrachloride (CCl4)-induced liver damage in rats via treatment with Pulicaria crispa aerial parts ethanol extract (PCEE). CCl4 was intraperitoneally injected at a dose of 0.5 mL/kg b.wt./twice a week/six consecutive weeks, PCEE was orally allocated at a dose of 250 mg/kg b.wt./day/six weeks and silymarin was orally administrated at a dose of 100 mg/kg, b.wt/day/six weeks. The plant extract evaluation was done through measuring aspartate and alanine aminotransferases (AST& ALT), alkaline phosphatase (ALP), total lipids (TP), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low level glycoprotein-cholesterol (LDL-C), alpha fetoprotein (AFP), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6). The liver architectures were also estimated. The phytochemical analysis of the extract showed the presence of sterols and/or triterpenoids. Treatments with plant extract suppressed significantly (p < 0.0001) the levels of AST, ALT, ALP, TP, TG, TC, LDH-C, MDA, NO, AFP, TNF-α and IL-6, while increased (p < 0.0001) the levels of HDL-C, GSH and SOD. The histopathological features confirmed the therapeutic role of the plant extract. PCEE succeeded to exert anti-fibrotic, anti-inflammatory and anti- oxidants effects in CCl4-induced liver fibrosis.


Flavonoids with antioxidant action (naringin and rutin) and the release of mastocytic and nonmastocytic histamine.
In view of the data about the antioxidant mechanism of the membrane-stabilizing action of the bioflavonoids, the participation of this mechanism in the release of histamine as well is assumed to be possible. Experiments are carried out on 35 male albino rats. The effect of the flavonoids naringin and rutin on the level of mastocytic and nonmastocytic histamine is studied, as well as on its release induced by compound 48/80 (2 mg/kg i. p.). The substances are applied intraperitonealy in doses of 200 mg/kg; corresponding to 10% DL50. The histamine content is determined fluorimetrically by the method of Schore et al. (1959). The results show that naringin and rutin have no effect on the levels of mastocytic and nonmastocytic histamine. They prevent the release of mastocytic histamine, induced by compound 48/80.


Quantitative Proteomic Analysis on the Slightly Acidic Electrolyzed Water Triggered Viable but Non-Culturable Listeria monocytogenes.
This study undertakes a comprehensive exploration of the impact of slightly acidic electrolyzed water (SAEW) on Listeria monocytogenes, a common foodborne pathogen, with a particular focus on understanding the molecular mechanisms leading to the viable but nonculturable (VBNC) state. Given the widespread application of SAEW as an effective disinfectant in the food industry, uncovering these molecular pathways is crucial for improving food safety measures. We employed tandem mass tags (TMT), labeling proteomic techniques and LC-MS/MS to identify differentially expressed proteins under two doses of SAEW conditions. We indicated 203 differential expressed proteins (DEPs), including 78 up-regulated and 125 down-regulated DEPs. The functional enrichment analysis of these proteins indicated that ribosomes, biosynthesis of secondary metabolites, and aminoacyl-tRNA biosynthesis were enriched functions affected by SAEW. Further, we delved into the role of protein chlorination, a potential consequence of reactive chlorine species generated during the SAEW production process, by identifying 31 chlorinated peptides from 22 proteins, with a dominant sequence motif of Rxxxxx[cY] and functionally enriched in translation. Our findings suggest that SAEW might prompt alterations in the protein translation process and trigger compensatory ribosome biosynthesis. However, an imbalance in the levels of elongation factors and AARSs could hinder recovery, leading to the VBNC state. This research carries substantial implications for food safety and sanitation, as it adds to our understanding of the SAEW-induced VBNC state in L. monocytogenes and offers potential strategies for its control.


A new technique of hepatic vein reconstruction in partial liver transplantation.
The shortage of pediatric donor livers has stimulated the development of advanced surgical approaches such as partial liver transplantation, which produces the same results as whole organ replacement. Differences in body weight between donor and recipient of more than four times, however, usually necessitate extended reduction hepatectomy and modified ways of performing vascular reconstruction. Therefore, following ex vivo "trisegmentectomy," a new technique of hepatic venous drainage was developed with an end-to-side anastomosis of the left donor hepatic vein to the preserved recipient inferior vena cava. This operative technique was applied to four children, one of whom had a retransplantation performed in exactly the same fashion. There were no specific complications related to this particular surgical technique. From our preliminary experience we conclude that reduced-size liver transplantation can be safely performed with the described type of hepatic vein reconstruction, especially when large donor organs have to be used for small children.


Earlier Goals of Care Discussions in Hospitalized Terminally Ill Patients and the Quality of End-of-Life Care: A Retrospective Study.
The association between physician-directed goals of care discussions (GOCDs) and the use of aggressive interventions in terminally ill patients has not been well characterized in the literature. We examined the associations between the timing of physician-directed GOCDs in terminally ill patients and the use of aggressive interventions, probability of dying in the inpatient setting, and intensive care unit (ICU) utilization. This retrospective cohort study included patients admitted to our urban community hospital in 2015 who had a terminal diagnosis on admission and either died on an inpatient unit or were discharged to hospice. The primary independent variable was the number of days from admission to GOCD, expressed as a proportion of the patient's length of stay (LOS). We used robust variance Poisson and zero-inflated negative binomial regression, as appropriate, to estimate the associations between goals of care timing and risk of having an intervention, risk of dying in the inpatient setting, odds of ICU admission, and ICU LOS. A total of 197 cases were included. After adjusting for age, language, gender, insurance, dementia, and decision maker (patient versus surrogate decision maker), later GOCD was significantly associated with greater risk of having an aggressive intervention (risk ratio [RR] = 1.04, 95% confidence interval [CI] = 1.02-1.06), greater risk of death as an inpatient (RR = 1.04, 95% CI = 1.02-1.06), and greater odds of ICU admission (odds ratio = 1.19, 95% CI = 1.02-1.39). Later GOCDs were associated with greater risk of aggressive interventions and death as an inpatient and greater odds of ICU admission. Goals of care discussion should be done routinely and early during the hospitalization of terminally ill patients.


Monkeypox virus in relation to the ecological features surrounding human settlements in Bumba zone, Zaire.
Since monkeypox virus was discovered in animals in 1958 and in man in 1971, several efforts have been made to identify the reservoir of the virus in nature. In July 1985 a study on human environments and animals suspected to maintain virus transmission was carried out in northern Zaire. The study revealed three well demarcated areas: the human settlement area, the agricultural area and the primary tropical rain forest. The first two were found inhabited by terrestrial and arboreal rodents and bats, while the larger animals have abandoned them. Data on human morbidity collected in the preceding years suggested that most of the patients were infected either in the settlement or in the agricultural area. Isolation of the virus from a squirrel confirmed this suggestion and proved, on the other hand, that the virus could circulate in an area deprived of the larger wild animals, including primates. The virus isolation and results of serologic testing suggest that out of three groups of animals inhabiting the agricultural area, the squirrels Funisciurus anerythrus should be considered a priority candidate to sustain virus transmission.


Do both timing and duration of screen use affect sleep patterns in adolescents?
Sleep duration has declined in adolescents over the last 30 years and screen use has been identified as a risk factor. Studies have examined the duration of screen use and screen-based activities but have not differentiated between evening and night-time use. Cross sectional questionnaire survey of adolescents recruited in schools. Sleep habits on school nights and weekends, symptoms of insomnia and daytime repercussions were recorded using an online questionnaire administered in the classroom setting. Sleep deprivation (<7 hours in bed /night), school night sleep restriction (≥2 hours difference in sleep duration on school nights vs weekends), excessive sleepiness (score >6 on a visual analogue scale), duration of screen use and timing of screen use (evening vs after bedtime) were determined. 2513 students (53.4% female, median age 15 years) were included. 20% were sleep deprived and 41% sleep restricted. A clear dose effect relationship in a model controlling for age, sex, school level and sociodemographic class was seen with all levels of night-time screen use on sleep deprivation and sleep restriction (>2 hours use sleep deprivation OR 5.23[3.03-9.00]. sleep restriction OR 2.05[1.23-3.42]) and > 2 hours evening use (>2 hours use sleep deprivation OR 2.72[2.15-3.44] sleep restriction OR 1.69[1.36-2.11]) but not moderate evening use. All night-time use and > 2 hours evening use increased the risk of insomnia, non refreshing sleep, and affected daytime function (daytime sleepiness, lack of energy and irritability). Both duration of screen use and timing are associated with adverse effects on sleep and daytime functioning in adolescents. More than 2 hours evening use and all night-time use should be avoided.


Vaginal solitary fibrous tumor: a case report with recurrence after incomplete excision.
Primary solitary fibrous tumors (SFTs) of the female genital tract are exceedingly rare. We report a spindle cell tumor of the vagina with features consistent with a SFT in a 52-year-old woman. The original tumor was studied with the appropriate panel of immunohistochemical stains. The first recurrence of the tumor was 10 months after its original incomplete excision, and a second recurrence occurred 29 months later. Both recurrences were analyzed using the same immunohistochemical panel. After considering several related differential diagnoses, the diagnosis of SFT was made based on the morphological and immunophenotypic features. To the best of our knowledge, this is the third case of vaginal SFT in the English literature, with 2 recurrences after incomplete excision.


[Guidelines based on scientific evidence for the application of platelet transfusion concentrates].
Platelet transfusion concentrates are commonly used to prevent and treat bleeding due to thrombocytopenia and abnormal platelet function. Although these concentrates are indispensable while safely conducting anticancer chemotherapy and surgery, their use may cause certain adverse effects, including fever, urticaria, anaphylaxis, and transfusion-related acute lung injury. In addition, repeated platelet transfusions may induce allogeneic antibodies, possibly resulting in platelet transfusion refractoriness (PTR). Intrinsically, the use of platelet transfusion concentrates should be carefully administered and reserved to a minimum. This chapter introduces the guidelines based on scientific evidence for the therapeutic use of platelet transfusion concentrates, which The Japan Society of Transfusion Medicine and Cell Therapy recently established.


TNF receptor 1-dependent beta cell toxicity as an effector pathway in autoimmune diabetes.
Autoimmune diabetes is characterized by a chronic progressive inflammatory autoimmune reaction that ultimately causes the selective elimination of pancreatic beta cells. To address the question of whether the cell death-inducing cytokines TNF and lymphotoxin alpha are involved in this process, we generated nonobese diabetic (NOD) mice that are deficient for TNF receptor 1 (TNFR1 or TNFRp55). Insulitis developed in these mice similarly to that in normal control NOD mice, but progression to diabetes was completely abrogated. Since this was probably due to the complex immunomodulatory effects of TNF and lymphotoxin alpha signaled via TNFR1 on lymphohemopoietic cells, adoptive transfer experiments with spleen cells from diabetic NOD mice were conducted. It was found that the absence of TNFR1 in recipients delayed diabetes induced by normal control and precluded diabetes induced by perforin-deficient spleen cells. In a CD8+ T cell-mediated model of diabetes, however, diabetes induced by adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus glycoprotein-specific CD8+ T cells was not delayed by the absence of TNFR1 in recipient mice. Together with the described expression patterns of perforin and TNF in the mononuclear islet infiltrates of NOD mice, these results indicate that two diabetogenic effector mechanisms are delivered by distinct cell populations: CD8+ T cells lyse beta cells via perforin-dependent cytotoxicity, whereas CD4+ T cells, macrophages, and dendritic cells contribute to diabetes development via TNFR1-dependent beta cell toxicity.


Anesthetic Implications in a Child with Crouzon Syndrome.
Crouzon syndrome (CS) is an autosomal dominant genetic disorder characterized by craniofacial dysostosis. Premature fusion of skull base leads to midfacial hypoplasia, shallow orbit, mandibular prognathism, overcrowding of upper teeth, high-arched palate, and upper airway obstruction. It is important for anesthesiologists managing such patients to recognize and avoid potential airway complications. Here, we present a case of a 10-year-old child with CS posted for ptosis correction surgery. Use of peripheral nerve blocks to cut down opioid requirement, inhalational induction, and maintenance are key aspects in successful management of such cases.


Outcomes of the Modified Broström Procedure Augmented With Suture-Tape for Ankle Instability in Patients With Generalized Ligamentous Laxity.
Although recent biomechanical studies have reported mechanical superiority of augmented anterior talofibular ligament reconstruction using suture-tape, clinical evidence regarding the efficacy of suture-tape augmentation is still insufficient. This prospective study was performed to evaluate the outcomes of the modified Broström procedure augmented with suture-tape for chronic ankle instability with generalized ligamentous laxity, which has been known to be a poor prognostic factor for anatomic ligament repair. Twenty-eight patients with generalized ligamentous laxity were followed for more than 2 years after the augmented modified Broström procedures for chronic ankle instability. Generalized ligamentous laxity was defined as a Beighton score ≥4 points. The clinical evaluation consisted of the Foot and Ankle Outcome Score (FAOS) and Foot and Ankle Ability Measure (FAAM) score. Measurement of talar tilt angle and anterior talar translation was obtained from stress radiographs to evaluate mechanical ankle stability. FAOS and FAAM scores had significantly improved from preoperative average 63.2 and 54.3 points to 90.6 and 89.5 points at final follow-up, respectively ( P < .001). Talar tilt angle and anterior talar translation had significantly improved from preoperative average 16.2° and 12.1 mm to 3.6° and 4.2 mm at final follow-up, respectively ( P < .001). Preoperative side-to-side comparison with stress radiographs was significantly different, but this returned to within nonstatistical differences at final follow-up, respectively ( P = .105, .532). Although 6 patients sustained an ankle sprain after operation, only 1 patient (3.6%) showed a recurrence of subjective and mechanical instability. Suture-tape augmentation for the modified Broström procedure appears to be an effective operative alternative for chronic ankle instability with generalized ligamentous laxity. As one of the methods to improve the clinical outcomes in patients with relative contraindications of the modified Broström repair, this procedure provided reliable stability with the advantages of anatomic ligament repair through the augmentation using suture-tape. Level IV, prospective case series.


Presenting the direct intercultural effectiveness simulation: an implicit trait policy on intercultural competence.
An implicit trait policy (ITP) represents the interaction between a personal disposition and general domain knowledge on how to effectively handle a specific (intercultural) situation. Such an ITP is a proven construct to create instruments that can predict future effective behavior. Moreover, such a simulation can provide valuable proxies for actual (future) behavior, as measures of (future) real life intercultural interactions are not always available. In a series of three studies (N1 = 224, N2 = 291, N3 = 478), the present research introduces a "Direct Intercultural Effectiveness Simulation" or DIES, an instrument that simulates intercultural effectiveness by directly tapping into an ITP on intercultural competence. First and foremost, the present research demonstrates that the DIES instrument generates reliable and construct-valid measures of intercultural effectiveness. Second, the DIES instrument also shows expected converging and diverging patterns when correlated with a nomological network on intercultural effectiveness. And third, the DIES measure is further validated by integration into an ITP framework of intercultural effectiveness based on theoretical and empirical accounts from literature. The DIES instrument generates a reliable and valid measure of intercultural effectiveness by tapping into an ITP on intercultural competence. Theoretically, the present research integrates the instrument into literature by empirically verifying an ITP framework of intercultural effectiveness. In practice, the DIES instrument can be used as an awareness or training proxy for actual behavior to tackle important problems like ethnic prejudice and discrimination.


Parental desire and acceptability of spermatogonial stem cell cryopreservation in boys with cancer.
In the near future, a substantial proportion of adults will be childhood cancer survivors. The cryopreservation and transplantation of spermatogonial stem cells (SSCs) is currently successful in animals; application in humans seems likely in the near future. Cryopreserving SSCs might become an important issue in childhood cancer. Because this might require testicular biopsies or hemicastration, parental desire/acceptability for SSC collection was enquired for. Three hundred eighteen parents of boys surviving at least 2 years after the diagnosis of cancer were asked about collecting SSCs by biopsy or hemicastration and collecting sperm by masturbation or electrostimulation. Opinions were assessed as if at the time of diagnosis and at the present time. Sixty-three per cent of parents responded. At diagnosis, SSC collection by means of biopsy was approved by 61%, hemicastration by 33% and collecting sperm by 70% (P < 0.013). The acceptability of performing hemicastration was significantly lower than all other forms of SSC/sperm collection. No differences were observed between parents' present opinion and opinion at diagnosis. No differences related to treatment intensity, presumed negative fertility effects and pubertal state were found. Infertility is a major topic for parents. For prepubertal boys, the collection of SSCs might be a great relief in respect of the fertility issue. Collecting SSCs by biopsy is desired and accepted by the majority of parents; hemicastration is accepted by one-third of parents. The translation of SSC cryopreservation and transplantation from animal models to humans is eagerly awaited.


Vitamin A5/X controls stress-adaptation and prevents depressive-like behaviors in a mouse model of chronic stress.
9-cis-13,14-dihydroretinoic acid (9CDHRA), acts as an endogenous ligand of the retinoid X receptors (RXRs), and is an active form of a suggested new vitamin, vitamin A5/X. Nutritional-relevance of this pathway as well as its detailed role in vertebrate physiology, remain largely unknown. Since recent GWAS data and experimental studies associated RXR-mediated signaling with depression, we explored here the relevance of RXR and vitamin A5/X-mediated signaling in the control of stress adaptation and depressive-like behaviors in mice. We found that compromised availability of 9CDHRA in Rbp1-/- mice was associated with increased despair in the forced swim and anhedonia in the sucrose preference test. 9CDHRA similarly to synthetic RXR agonist, BMS649, normalized despair behaviors in Rbp1-/- but not Rxrγ-/- mice, supporting involvement of RXR signaling in anti-despair activity of these ligands. Importantly, similarly to BMS649, the 9CDHRA and its nutritional-precursor, 9-cis-13,14-dihydroretinol (vitamin A5/X alcohol), prevented development of depressive-like behaviors in mice exposed to chronic social defeat stress, revealing the beneficial role of RXRs and its endogenous ligand in stress adaptation process. These data point to the need for relevant nutritional, biochemical and pharmacological studies of this signaling pathway in human, both in physiological conditions and in pathologies of stress-related disorders.


Effect of interfacial bond quality on the direction of polymerization shrinkage flow in resin composite restorations.
Shrinkage in light curing resin composites is assumed to be directed toward the light source. However, the strong bond at the dentin-resin interface achieved by newer generation dentin bonding systems may affect the direction of polymerization shrinkage. In this study, various curing modes of adhesive resin simulating different bond qualities were applied to determine the extent of interfacial gap formation with a scanning electron microscope. We also measured the free surface depression with a profilometer. The direction of polymerization shrinkage was inferred from the ratio of the interfacial gap measurement at the floor to the free surface depression. Various curing modes used in this study include Group 1: light curing of resin composite without the bonding agent as the negative control; Group 2: simultaneous light curing of the bonding agent and resin composite; Group 3: start of the chemical cure of the dual-cured bonding agent before light curing the resin composite; Group 4: curing the light-initiated bonding agent before insertion and light curing of the resin composite. When the bonding agent was light cured prior to inserting the resin composite (Group 4), the free surface depression was the greatest and the interfacial gap smallest among those in all groups. Therefore, if a good bond between dentin and resin composite can be established, the shrinkage flow will be directed toward a center located near the bonded interface rather than toward the incident light, thus reducing detrimental shrinkage stress.


Ultrasound-Induced Tumor Perfusion Changes and Doxorubicin Delivery: A Study on Pulse Length and Pulse Repetition Frequency.
To investigate the appropriate combination of pulse length (PL) and pulse repetition frequency (PRF) when performing ultrasound stimulated microbubble (USMB) to enhance doxorubicin (DOX) delivery to tumors. A total of 48 tumor-bearing mice were divided into four groups, namely groups A-D. The mice in groups B-D were treated with chemotherapy and USMB treatment with different combinations of PL and PRF, and group A was control. Contrast-enhanced ultrasound imaging was conducted to analyze tumor blood perfusion. Fluorescence microscopy and high-performance liquid chromatography were used to qualitatively and quantitatively analyse DOX release. The structural changes of tumors were observed under light microscope and transmission electron microscope. Furthermore, another 24 tumor-bearing mice were treated with sonochemotherapy and some related inflammatory factors were measured to explore the underlying mechanism. With PL of three cycles and PRF of 2 kHz, the tumor perfusion area ratio increased by 26.67%, and the DOX concentration was 4.69 times higher than the control (P < .001). With PL of 34.5 cycles and PRF of 200 Hz, the tumor perfusion area ratio decreased by 12.7% and DOX did not exhibit increased extravasation compared with the control. Microvascular rupture and hemorrhage were observed after long PL and low PRF treatment. While vasodilation and higher levels of some vasodilator inflammatory factors were found after treatment with short PL and high PRF. USMB treatment using short PL and high PRF could enhance tumor blood perfusion and increase DOX delivery, whereas long PL and low PRF could not serve the same purpose.


Leiomyosarcoma of the nasal cavity and paranasal sinuses.
A case of leiomyosarcoma of the nasal cavity and paranasal sinuses is presented along with a review of the medical literature. The clinicopathological aspects of this tumor are discussed. The mode of treatment is complete surgical excision with close follow-up due to its high rate of local recurrence. The long-term survival with recurrent disease in this case is unusual.


Linking brain vascular physiology to hemodynamic response in ultra-high field MRI.
Functional MRI using blood oxygenation level-dependent (BOLD) contrast indirectly probes neuronal activity via evoked cerebral blood volume (CBV) and oxygenation changes. Thus, its spatio-temporal characteristics are determined by vascular physiology and MRI parameters. In this paper, we focus on the spatial distribution and time course of the fMRI signal and their magnetic field strength dependence. Even though much is still unknown, the following consistent picture is emerging: a) For high spatial resolution imaging, fMRI contrast-to-noise increases supra-linearly with field strength. b) The location and spacing of penetrating arteries and ascending veins in the cortical tissue are not correlated to cortical columns, imposing limitations on achievable point-spread function (PSF) in fMRI. c) Baseline CBV distribution may vary over cortical layers biasing fMRI signal to layers with high CBV values. d) The largest CBV change is in the tissue microvasculature, less in surface arteries and even less in pial veins. e) Venous CBV changes are only relevant for longer stimuli, and oxygenation changes are largest in post-capillary blood vessels. f) The balloon effect (i.e. slow recovery of CBV to baseline) is located in the tissue, consistent with the fact that the post-stimulus undershoot has narrower spatial PSF than the positive BOLD response. g) The onset time following stimulation has been found to be shortest in middle/lower layers, both in optical imaging and high-resolution fMRI, but we argue and demonstrate with simulations that varying signal latencies can also be caused by vascular properties and, therefore, may potentially not be interpreted as neural latencies. With simulations, we illustrate the field strength dependency of fMRI signal transients, such as the adaptation during stimulation, initial dip and the post-stimulus undershoot. In sum, vascular structure and function impose limitations on the achievable PSF of fMRI and give rise to complex fMRI transients, which contain time-varying amount of excitatory and inhibitory neuronal information. Nevertheless, non-invasive fMRI at ultra-high magnetic fields not only provides high contrast-to-noise but also an unprecedented detailed view on cognitive processes in the human brain.


Subcutaneous infusion and capillary "finger stick" sampling of stable isotope tracer in metabolic studies.
Metabolic studies utilizing stable isotope tracer in humans have typically used intravenous tracer infusions and venous blood sampling. These studies explore subcutaneous infusion of isotope and "finger stick" capillary blood sampling to measure glucose turnover. Five subjects received simultaneous 8-h infusions of glucose labeled with isotope: [1-(13)C]glucose subcutaneously and [6,6-(2)H(2)]glucose intravenously. At regular intervals, venous and finger stick blood specimens were obtained. Finger stick blood was applied to filter paper. Substrate and isotopic steady state was reached after 7.0 h with both routes of infusion. The isotopic enrichments of finger stick and venous specimens did not differ significantly for the subcutaneously infused [1-(13)C]glucose (p = 0.33 and p = 0.23, respectively) but the finger stick [6,6-(2)H(2)]glucose enrichment was slightly higher (p < 0.03) than that of the venous sample. Using [6,6-(2)H(2)]glucose infusion and venous plasma sampling as the reference method, the [1-(13)C]glucose gave estimates of glucose R(a) that were 13% (plasma) and 17% (finger stick) lower (p < 0.001 and p < 0.02, respectively). This difference could be attributed to recycling of (13)C label. In conclusion, subcutaneous infusion and finger stick specimen collection onto filter paper represent a potential method of conducting in vivo studies of substrate metabolism outside of a hospital-based research unit.


Sedimentation and electrophoretic migration of DNA knots and catenanes.
Various site-specific recombination enzymes produce different types of knots or catenanes while acting on circular DNA in vitro and in vivo. By analysing the types of knots or links produced, it is possible to reconstruct the order of events during the reaction and to deduce the molecular "architecture" of the complexes that different enzymes form with DNA. Until recently it was necessary to use laborious electron microscopy methods to identify the types of knots or catenanes that migrate in different bands on the agarose gels used to analyse the products of the reaction. We reported recently that electrophoretic migration of different knots and catenanes formed on the same size DNA molecules is simply related to the average crossing number of the ideal representations of the corresponding knots and catenanes. Here we explain this relation by demonstrating that the expected sedimentation coefficient of randomly fluctuating knotted or catenated DNA molecules in solution shows approximately linear correlation with the average crossing number of ideal configurations of the corresponding knots or catenanes.


[The worrying rise in the frequency of cesarean section].
The rise in the incidence of Cesarean section over the last thirty years is due to several factors. In particular, maternal age is increasing, parity is declining, and situations potentially requiring Cesarean section are more frequently encountered than before (prematurity, medically assisted procreation, antenatal diagnosis, previous Cesarean section, etc.). Medicolegal pressure is also increasing, and the precautionary principle is leading more and more physicians to propose Cesarean section rather than trial labor. However, although the risks of this form of delivery have decreased, they are still higher than those of vaginal delivery, except in the emergency setting. Moreover, various pathophysiologic studies have demonstrated marked changes in the elevator muscles, nerves and pelvic support after vaginal delivery. The maternal morbidity and mortality of elective caesarean delivery at term, before the onset of labor, appear to be similar to those associated with vaginal birth. However, the maternal risks (particularly placenta praevia, placenta accreta, and uterine rupture) during subsequent pregnancies following Cesarean delivery require careful evaluation. After Cesarean section, the risk of placenta praevia during the next pregnancy is between 1% and 4%. There is subsequently a linear increase, with the risk of placenta praevia reaching nearly 10% after four Cesarean deliveries. The risks and benefits of each form of delivery are extremely difficult to weigh up, and predictors of safe vaginal delivery are lacking.


[The role and place of pathogenetic therapy with glucocorticosteroid hormones in the treatment of patients with novel coronavirus infection (COVID-19)].
In December 2019, in Wuhan (PRC), there was an outbreak of a new coronavirus infection (COVID-19) caused by coronavirus type 2 (SARS-CoV-2), which has a zoonotic origin. The World Health Organization announced the COVID-19 pandemic on March 11, 2020. In most cases, the disease is asymptomatic or mild. However, up to 15% of patients require hospitalization, and 5% develop a critical condition. To date, no effective antiviral drug COVID-19 has been found that can reduce mortality. Pathological changes in the lungs are manifested by diffuse alveolar damage, which is clinically manifested by increasing respiratory failure, accompanied by a decrease in saturation and oxygen concentration in arterial blood. It is assumed that autoimmune reactions play an important role in the development of multiple organ failure. Generalized inflammation is characterized by an increase in the concentration of C-reactive protein, ferritin, interleukin-1 and interleukin-6, and other markers. At the stage of development of infection in the form of a cytokine storm, proinflammatory cytokines can themselves become pathogenetic factors in the development of critical conditions, multiple organ failure and deaths. Therefore, a key challenge in treating hospitalized patients with COVID-19 is to control generalized inflammation. Glucocorticosteroid hormones (GCS) are widely used as anti-inflammatory drugs in the clinic of infectious diseases. However, until recently, there was no convincing data on the effectiveness of GCS in patients with COVID-19. Recently published results of a large randomized clinical trial (RECOVERY) showing the efficacy of GCS (dexamethasone) in the treatment of critically ill patients with COVID-19. At the same time, the feasibility and effectiveness of GCS in patients with COVID-19 outside critical conditions, the pathogenetic mechanisms that determine the effectiveness/ineffectiveness of these drugs and the validity of their use remain insufficiently studied.


Internet-based attentional bias modification training as add-on to regular treatment in alcohol and cannabis dependent outpatients: a study protocol of a randomized control trial.
The automatic tendency to attend to and focus on substance-related cues in the environment (attentional bias), has been found to contribute to the persistence of addiction. Attentional bias modification (ABM) interventions might, therefore, contribute to treatment outcome and the reduction of relapse rates. Based on some promising research findings, we designed a study to test the clinical relevance of ABM as an add-on component of regular intervention for alcohol and cannabis patients. The current protocol describes a study which will investigate the effectiveness and cost-effectiveness of a newly developed home-delivered, multi-session, internet-based ABM (iABM) intervention as an add-on to treatment as usual (TAU). TAU consists of cognitive behavioural therapy-based treatment according to the Dutch guidelines for the treatment of addiction. Participants (N = 213) will be outpatients from specialized addiction care institutions diagnosed with alcohol or cannabis dependency who will be randomly assigned to one of three conditions: TAU + iABM; TAU + placebo condition; TAU-only. Primary outcome measures are substance use, craving, and rates of relapse. Changes in attentional bias will be measured to investigate whether changes in primary outcome measures can be attributed to the modification of attentional bias. Indices of cost-effectiveness and secondary physical and psychological complaints (depression, anxiety, and stress) are assessed as secondary outcome measures. This randomized control trial will be the first to investigate whether a home-delivered, multi-session iABM intervention is (cost-) effective in reducing relapse rates in alcohol and cannabis dependency as an add-on to TAU, compared with an active and a waiting list control group. If proven effective, this ABM intervention could be easily implemented as a home-delivered component of current TAU. Netherlands Trial Register, NTR5497 , registered on 18th September 2015.


External validation of the ROSC after cardiac arrest (RACA) score in a physician staffed emergency medical service system.
The return of spontaneous circulation (ROSC) after cardiac arrest (RACA) score may have implications as a quality indicator for the emergency medical services (EMS) system. We aimed to validate this score externally in a physician staffed urban EMS system. We conducted a retrospective cohort study. Data on resuscitation attempts from the Helsinki EMS cardiac arrest registry from 1.1.2008 to 31.12.2010 were collected and analyzed. For each attempted resuscitation the RACA score variables were collected and the score calculated. The endpoint was ROSC defined as palpable pulse over 30 s. Calibration was assessed by comparing predicted and observed ROSC rates in the whole sample, separately for shockable and non-shockable rhythm, and separately for resuscitations lead by a specialist, registrar or medical supervisor (i.e., senior paramedic). Data are presented as medians and interquartile ranges. Statistical testing included chi-square test, the Mann-Whitney U test, Hosmer-Lemeshow goodness of fit test and calculation of 95% confidence intervals (CI) for proportions. A total of 680 patients were included of whom 340 attained ROSC. The RACA score was higher in patients with ROSC (0.62 [0.46-0.69] than in those without (0.46 [0.36-0.57]) (p < 0.001). Observed against predicted ROSC indicated reasonable calibration overall (p = 0.30), with better calibration in patients with a shockable initial rhythm (p = 0.75) than in patients with a non-shockable rhythm (p = 0.04). There was no statistical difference between observed and predicted ROSC rates in resuscitations attended by a specialist (50% vs 53%, 95% CI 45-55) or registrar (55% vs 53%, 95% CI 48-62), but rates were lower than predicted in resuscitations lead by a medical supervisor (36% vs 49%, 95% CI 25-47). Developing a practical severity-of-illness scoring system for out-of-hospital cardiac arrest patients would allow patient heterogeneity adjustment and measurement of quality of care in analogy to commoly used severity-of-illness- scores developed for the similar purposes for the general intensive care unit population. However, transferring RACA score to another country with different population and EMS system might affect the performance and generalizability of the score. This study found a good overall calibration and moderate discrimination of the RACA score in a physician staffed urban EMS system which suggests external validity of the score. Calibration was suboptimal in patients with a non-shockable rhythm which may due to a local do-not-attempt-resuscitation policy. The lower than expected overall ROSC rate in resuscitations attended by medical supervisors requires further study.


Common and specific amino acid residues in the prokaryotic polypeptide release factors RF1 and RF2: possible functional implications.
Termination of protein synthesis is promoted in ribosomes by proper stop codon discrimination by class 1 polypeptide release factors (RFs). A large set of prokaryotic RFs differing in stop codon specificity, RF1 for UAG and UAA, and RF2 for UGA and UAA, was analyzed by means of a recently developed computational method allowing identification of the specificity-determining positions (SDPs) in families composed of proteins with similar but not identical function. Fifteen SDPs were identified within the RF1/2 superdomain II/IV known to be implicated in stop codon decoding. Three of these SDPs had particularly high scores. Five residues invariant for RF1 and RF2 [invariant amino acid residues (IRs)] were spatially clustered with the highest-scoring SDPs that in turn were located in two zones within the SDP/IR area. Zone 1 (domain II) included PxT and SPF motifs identified earlier by others as 'discriminator tripeptides'. We suggest that IRs in this zone take part in the recognition of U, the first base of all stop codons. Zone 2 (domain IV) possessed two SDPs with the highest scores not identified earlier. Presumably, they also take part in stop codon binding and discrimination. Elucidation of potential functional role(s) of the newly identified SDP/IR zones requires further experiments.


The incidence and significance of elevations of serum and urinary amylase levels following transcystic duct cholangiography.
Transcystic duct cholangiography does not increase the incidence of amylase elevations or clinical pancreatitis postoperatively. Significant rises in serum and two hour urinary amylase following routine cholecystectomy are quite common, regardless of whether or not transcystic duct cholangiography is performed. Many of these elevated amylase levels may arise from sources other than the pancreas.


Spinal learning: central modulation of pain processing and long-term alteration of interneuronal excitability as a result of nociceptive peripheral input.
The influence of nociceptive peripheral input on the response characteristics of spinal interneurons may result in long-term alterations of interneuronal excitability and modify their responses to subsequent stimuli. Such neuromodulation has been found to result in physiological changes including hyperalgesia, lowering of pain thresholds, expansion of receptive fields and changes in response behaviors of muscles. These types of alterations may contribute to clinically significant findings including muscle spasm, hypomobility, edema, chronic pain, recurrences in areas of previous injury and resistance to treatment. This article reviews studies concerning plasticity of response behaviors of interneurons including habituation, spinal learning, spinal fixation, neuromodulation and the effects of substance P. Potential clinical and chiropractic application are discussed and a brief review of clinically relevant studies of chiropractic adjustments are cited.


Postmaxillectomy rhinorrhea: corrected by transposition of parotid duct opening.
Two patients experienced chronic rhinorrhea following maxillary resection for cancer. This annoying symptom had been persistent for 12 and 13 years, respectively. Transposition of the parotid duct orifice on the operated side from a position lying above the maxillary prosthesis to a point below the prosthesis brought relief. Both patients had endured this nuisance for many years thinking it was a normal sequela of their operation. Multiple physicians had failed to identify the problem.


Oral conditions and salivary analysis in HIV-uninfected subjects using preexposure prophylaxis.
New prevention strategies have been advocated to control the progression of HIV/AIDS, such as preexposure prophylaxis (PrEP). The aim of this study is to evaluate the potential changes in the oral and salivary conditions of HIV-uninfected subjects using PrEP. Subjects were evaluated before beginning the medication (T0), at the first follow-up (T1), and at the second follow-up (T2). Xerostomia, presence of untreated cavitated caries, oral hygiene habits, taste, gingival and plaque index, stimulated salivary flow rate (SSFR), and salivary concentrations of calcium, glucose, urea, and total proteins were evaluated. Data obtained were analyzed using statistical tests (p<0.05). Forty-seven participants (41 men; 6 women) were evaluated at T0. Thirty (28 men; 2 women) and 17 men were reassessed at T1 and T2, respectively. There was no difference between the SSFR and oral and salivary conditions between T0, T1, and T2 (p>0.05), except for the salivary calcium concentration, that increased at T2 compared to T1 (p=0.02). There was significant difference between taste and xerostomia at T1 (p=0.017), and the need to drink to swallow at T2 (p=0.015). There was significant correlation between the reported amount of saliva and taste (p=0.039, r=-0.378) at T1. The prolonged use of PrEP seems to be associated with reports of dry mouth and worsening of taste, possibly associated with increased salivary calcium concentration.


Molecular-targeted therapies in head and neck cancer.
The increasing understanding of tumor biology has opened the door to a new class of biological agents directed at specific molecular targets in the treatment of squamous cell carcinomas of the head and neck. These targeted agents present the opportunity to more effectively attack the crucial cellular pathways contributing to tumor growth and survival, while minimizing toxicity. Cetuximab, which targets epidermal growth factor (EGF) receptor signaling, was the first such biological agent to be proven effective in head and neck squamous cell cancers. Currently, there are dozens of targeted agents at various stages of testing for use in the treatment of head and neck cancers. In this article, we review strategies aimed at key pathways, including EGF receptor signaling, the Vascular Endothelial Growth Factor (VEGF) pathway, and PI3K/AKT/mammalian target of rapamycin activation.


Tyrosine phosphate hydrolysis of host proteins by Trypanosoma cruzi is linked to cell invasion.
Invasion of cultured L6E9 myoblasts by Trypanosoma cruzi induced tyrosine dephosphorylation of proteins of 234, 205, and 50 kDa. Invasion was greatly reduced in the presence of the protein tyrosine phosphate inhibitors sodium o-vanadate and zinc chloride, and in the presence of excess phosphotyrosine or p-nitrophenyl phosphate, but not in the presence of excess phosphoserine or phosphothreonine. These results suggest an important role for protein tyrosine dephosphorylation in the invasion of host cells by T. cruzi.


GDF9 modulates the reproductive and tumor phenotype of female inha-null mice.
Intraovarian factors play important roles in coordinating germ cell and somatic cell growth in the ovary. Prior to the onset of gonadotropin stimulation and reproductive cyclicity, follicle development is dependent upon locally produced growth factors, such as the transforming growth factor beta family members inhibin, activin, and GDF9. In the absence of inhibin in prepubertal mice (Inha(-/-)), there are marked alterations in preantral follicle growth, but no evidence of ovarian tumors characteristic of adult Inha-null mice. To ascertain the contribution of GDF9 to the Inha-null phenotype, we analyzed folliculogenesis in postnatal Inha Gdf9 double knockout mice. Deletion of Gdf9 from Inha(-/-) rescues the initial growth defects found at early follicle stages in Inha(-/-) ovaries, but surprisingly enhances the onset of pretumor lesions. The normalization of growth dynamics between granulosa cells and oocytes of Inha Gdf9 double knockout mice is also accompanied by a reduction in levels of the activin/inhibin beta B subunit, Inhbb, which is upregulated in Inha(-/-) ovaries. However, at later ages, Inha Gdf9 double knockout ovaries are similar to Inha(-/-) ovaries, and show upregulation of the activin/inhibin subunits and downregulation of the growth factor, kit ligand, thus resulting in a local environment that is growth-promoting for granulosa cells but growth-inhibitory for oocytes. These data suggest a sequential mechanism of action initiated by GDF9 in the Inha knockout mouse that promotes defective folliculogenesis. These studies thus provide a novel role for GDF9 in causing reproductive defects and suppressing tumor initiation in the Inha(-/-) mouse model.


Disulfide bonds are neither required, present, nor compatible with full activity of human recombinant acidic fibroblast growth factor.
Human acidic fibroblast growth factor (aFGF) is a potent broad-spectrum mitogen that contains three Cys residues within its monomeric structure. We have found that site-directed mutants in which any one of these Cys residues is converted to serine remain highly active, although variably dependent on heparin, so none of the three possible intramolecular disulfide bonds that can be formed are required for mitogenic activity. Furthermore, a dispensable disulfide bond that might stabilize the active conformation is not present since all three Cys residues are accessible to chemical modification in recombinant as well as brain-derived aFGFs. Finally, formation of a disulfide bond between the two Cys residues conserved among all seven known members of the FGF family results in a virtually inactive product that can subsequently be reactivated by reduction. Thus, despite the extracellular function of aFGF, its Cys residues do not form intramolecular disulfide bonds in the active conformation.


Degradation of pentaerythritol tetranitrate (PETN) by granular iron.
Pentaerythritol tetranitrate (PETN), a nitrate ester, is used primarily as an explosive. It is of environmental concern, posing a threat to aquatic organisms with an estimated EC50 five times greater than that of RDX. This study evaluated the kinetics and products of PETN degradation in the presence of granular iron. PETN transformation in columns containing 100% granular iron and 30% iron mixed with 70% silica sand followed pseudo first-order kinetics, with average half-lives of 0.26 and 1.58 min, respectively. The reduction pathway was proposed to be sequential denitration, in which PETN was stepwise reduced to pentaerythritol with the formation of pentaerythritol trinitrate and pentaerythritol dinitrate as intermediates. The intermediate of pentaerythritol mononitrate was not detected; however, the nearly 100% nitrogen mass recovery supported complete denitration. Nitrite was released in each denitration step and was subsequently reduced to ammonium by iron. Nitrate was not detected during the experiment suggesting that hydrolysis was not involved in PETN degradation. Batch experiments showed that when solid-phase PETN is present, dissolution is the rate-limiting factorfor PETN mass removal. Using 50% methanol as a cosolvent PETN solubility was enhanced and thus the removal efficiency was improved. The results demonstrate excellent potential of using iron to remediate PETN-contaminated water.


Biofilm colonization in chronic treatment refractory infections presenting with discharging sinuses: A study in a tertiary care hospital of Eastern India.
Treatment refractory chronic recurrent infections mean those chronic infections which recur by same causal agents with similar drug responsiveness after apparent relief following full course of recommended antimicrobial management. Fifty different samples were collected from patients with chronic surgical site infections, laparoscopic port site infections, anal fistula, mesh hernioplasty, chronic dacryocystitis, chronic osteomyelitis, and chronic burn wounds. Samples were processed for culture, identification, antibiotic sensitivity testing using standard microbiological techniques. Biofilm (BF) forming capacity for aerobic organisms were tested by tissue culture plate method. Those for anaerobes and atypical mycobacteria were studied by a novel method using atomic force microscopy (AFM). In vivo BF colonization in lacrimal mucosae of chronic dacryocystitis, patients were studied from histopathological sections by Gram staining, H and E, and fluorescent in situ hybridization (FISH). Out of fifty different samples, sixty-three isolates were obtained in pure culture as follows: Staphylococcus aureus (25.39%), Escherichia coli (14.28%), Klebsiella pneumonia (14.28%), Mycobacterium abscessus (12.69%), Citrobacter spp. (9.52%), Bacteroides fragilis (6.3%), Pseudomonas aeruginosa (4.7%), Proteus spp. (4.7%), Staphylococcus epidermidis (3.1%), Enterobacter spp. (1.5%), Morganella morganii (1.5%), and Peptostreptococcus spp. (1.5%). Among the isolates, 74% were found to be BF producers in the following frequency: P. aeruginosa 100%, S. epidermidis 100%, B. fragilis 100%, Klebsiella spp. 88.88%, S. aureus 81.25%, M. abscessus 75%, Citrobacter spp. 83.33%, Proteus spp. 66.66%, E. coli spp. 33.33%, and Enterobacter spp. 0%. AFM has been proven to be a useful method for detection of in vitro grown BF including those for anaerobes and atypical Mycobacteria. In vivo BF detection becomes possible by FISH. S. aureus was the most common isolate. Among the aerobic isolates, P. aeruginosa and S. epidermidis were found to be the most common BF producers. Atypical mycobacteria were also found to be BF producers. Diagnosis of BF s in chronic infections significantly changes the management strategy as these infections can no longer be dealt simply with antibiotics alone but require mechanical removal of the foci along with antibiotic coverage for complete cure.


Occupational disease among non-governmental employees in Malaysia: 2002-2006.
In the absence of systematic occupational disease surveillance, other data collected by governmental agencies or industry is useful in the identification of occupational diseases and their control. We examined data on occupational diseases reported by non-governmental employees to the national workers' social security organization in Malaysia, 2002-2006. The overall incidence rate of occupational disease was 2.8 per 100,000 workers. There was an increase in the annual number and rates of occupational disease over time. The most frequently reported conditions were hearing impairment (32%) and musculoskeletal disorders (28%). Workers in the non-metallic manufacturing industry had the highest average incidence rate of hearing impairment (12.7 per 100,000 workers) and musculoskeletal disorders (3.5 per 100,000 workers), compared to all other industries. Preventive measures should focus on safety education, engineering control and workplace ergonomics. Enforcing workplace standards and incorporating an ongoing surveillance system will facilitate the control and reduction of occupational disease.


Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment of asthma.
The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting β2-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion. It is difficult to interpret the data that we have described because the preclinical and clinical development of FF/VI FDC was not really based on solid information on quantitative PK/PD approach. Unfortunately, for both FF and VI we only know concentrations in systemic blood, a compartment that is downstream of both target and non-target respiratory tissue. This lack of information does not allow us to understand the temporal relationship between the delivered dose and the drug concentration at the sites of action within the lungs. In addition, all studies performed with FF and VI did not address the fundamental issue that asthma can significantly alter lung deposition, absorption and also clearance of inhaled medicines.


Prenatal diagnosis of exencephaly.
This paper presents a sonographic diagnosis of exencephaly made during the last trimester of gestation. The sonogram showed the absence of bones in the cranial vault together with the presence of a disorganized cerebral mass, with loss of its normal anatomy. Post-partum examination of the newborn confirmed the findings of the sonogram. We briefly review the characteristics of exencephaly, its aetiology, and its relationship to anencephaly.


Atrial fibrillation, TIAs and completed strokes.
A retrospective survey of 1076 patients with completed strokes and 789 with transient ischemic attacks (TIAs) revealed that 5.6% of those with completed strokes but only 1.6% of those with TIAs were in atrial fibrillation. TIAs in the presence of atrial fibrillation tended to last longer than 60 minutes except in individuals who had coexistent carotid disease that might have been the source of their attacks. It is suggested that emboli from the fibrillating atrium rarely cause brief TIAs, and more usually cause 'long' TIAs or completed strokes.


Unexpected Coelenterazine Degradation Products of Beroe abyssicola Photoprotein Photoinactivation.
Ca2+-regulated photoproteins of ctenophores lose bioluminescence activity when exposed to visible light. Little is known about the chemical nature of chromophore photoinactivation. Using a total synthesis strategy, we have established the structures of two unusual coelenterazine products, isolated from recombinant berovin of the ctenophore Beroe abyssicola, which are Z/E isomers. We propose that during light irradiation, these derivatives are formed from 2-hydroperoxycoelenterazine via the intermediate 8a-peroxide by a mechanism reminiscent of that previously described for the auto-oxidation of green-fluorescent-protein-like chromophores.


[Local recurrence of prostate cancer: hormone therapy].
The majority of patients receive HT after biochemical progression despite primary therapy of prostate cancer with curative intent. It is difficult to differentiate at a low rise in PSA level, e.g., <or=1 ng/ml, between local or systemic recurrence. The PSA doubling time (DT) is the most reliable surrogate parameter to decide if HT should be initiated. In practice, however, the trigger PSA is used instead. The latter is closely related to the timing of HT. A high PSA is a contraindication for local salvage therapy. Intermittent HT is apparently as effective as continuous HT and shortens the time of HT exposure. Traditional HT employs a LHRH agonist, however, the side effect profile is a disadvantage due to the long duration of this treatment, e.g., sarcopenia, osteopenia, or even cognitive impairment. The alternative is nontraditional HT: nonsteroidal antiandrogen (AA) alone such as bicalutamide 150 mg or peripheral androgen blockade (AA plus 5alpha-reductase inhibitor). Even after a long duration of the latter HT the side effects are less pronounced (gynecomastia) and treatable. Particularly in patients with high-risk primary tumors [Gleason score 7(4+3)-10 or an initially high PSA], nontraditional HT may be followed by secondary HT.


Revised stereochemistry of ficifolidione and its biological activities against insects and cells.
Ficifolidione (1), a moderately active insecticidal compound from two species of Myrtaceae, and its derivatives were synthesized to evaluate their insecticidal activity. X-ray crystallographic analyses and specific rotation values of ficifolidione and its C-4 (2) demonstrated that the structure of ficifolidione differs from the reported absolute structure; that is, the C-4 configuration of ficifolidione should have an S configuration. The reported insecticidal activity of ficifolidione (1) and its C-4 epimer (2) against adult houseflies (Musca domestica), mosquito larvae (Culex pipiens), and cutworms (Spodoptera litura) was not observed. The cytotoxicities of ficifolidione and its derivatives (1-4) against four cell lines, Sf9, Colon26, HL60, and Vero, were also measured because ficifolidione has a phloroglucinol-derived moiety, a motif that is often present in the structure of cytotoxic chemicals. Compound 1 exhibited IC50 values of ca. 32, 9, 3, and 12 μM for Sf9, Colon26, HL60, and Vero cells, respectively, indicating that ficifolidione possesses selective cytotoxicity against the four cell lines. In HL60 cells treated with 1, DNA fragmentation and the activation of procaspase 3 were observed, suggesting that the cytotoxicity is induced by apoptosis.


A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin.
A secreted inhibitor of angiogenesis that is controlled by a tumor suppressor gene in hamster cells has been found to be similar to a fragment of the platelet and matrix protein thrombospondin. The two proteins were biochemically similar and immunologically crossreactive and could substitute for one another in two functional assays. Human thrombospondin inhibited neovascularization in vivo and endothelial cell migration in vitro, as does the hamster protein, gp140. gp140 sensitized smooth muscle cells to stimulation by epidermal growth factor, as does human thrombospondin. The thrombospondin gene has been localized on human chromosome 15. These results demonstrate a function for the ubiquitous adhesive glycoprotein thrombospondin that is likely to be important in the normal physiological down-regulation of neovascularization. In addition, they raise the possibility that thrombospondin may be one of a number of target molecules through which a tumor suppressor gene could act to restrain tumor growth.


Homonymous Ganglion Cell Layer Thinning After Isolated Occipital Lesion: Macular OCT Demonstrates Transsynaptic Retrograde Retinal Degeneration.
A 48-year-old man was examined 24 months after medial and surgical treatment of an isolated well-circumscribed right occipital lobe abscess. An asymptomatic residual left homonymous inferior scotoma was present. Fundus examination revealed temporal pallor of both optic discs, and optical coherence tomography (OCT) revealed mild temporal loss of retinal nerve fiber layer in both eyes. No relative afferent pupillary defect was present. Assessment of the retinal ganglion cell layer demonstrated homonymous thinning in a pattern corresponding to the homonymous visual field loss. There were no abnormalities of the lateral geniculate nuclei or optic tracts on review of the initial brain computed tomography and follow-up magnetic resonance imaging. We believe our patient showed evidence of transsynaptic retrograde degeneration after an isolated right occipital lobe lesion, and the homonymous neuronal loss was detected on OCT by assessing the retinal ganglion cell layer.


Evaluation of advocacy projects in undergraduate and graduate dental hygiene leadership courses.
The intent of this investigation was to describe learners' outcomes regarding a Legislative Advocacy Project and Health Policy Advocacy Project in required leadership courses in dental hygiene curricula. The 7-week legislative project was completed by Bachelor of Science (BS) in a traditional classroom setting and Master of Science (MS) degree dental hygiene students in an online course. The course requirement was a written paper all enrolled students completed, which comprised a significant portion of the final grade. Objectives were developed for topics presented and active learning strategies engaged students to extend learning to a higher level. Weekly activities provided a mechanism for formative assessment, and a rubric determined whether the objectives were met for the summative assessment. In 2016, the BS course was revised to include health policy, and the policy project was implemented. The majority of students earned A or B grades on the assignments. The overall mean for the BS legislative projects based on 4 years was 89.1 (n = 104); the MS mean based on 12 years was 92 (n = 81). The mean for the BS policy projects, based on 4 years, was 91.9 (n = 111). The instructional design of both advocacy projects' objectives, active learning strategies, and summative assessment were strategically aligned and created an effective environment for learning. Oral health practitioners who are empowered to engage in advocacy initiatives are needed in the next generation. Administrators and faculty are called to action to become leaders and advocates for advocacy education in all oral healthcare programs.


Changes in Regional Brain Grey-Matter Volume Following Successful Completion of a Sensori-Motor Intervention Targeted at Healthy and Fall-Prone Older Adults.
Previous studies have suggested that discrete cross-sensory events could be incorrectly combined in the brain of older adults with a history of falls, possibly undermining motor and balance control. Based on previous findings that multisensory integration is modifiable with practice, even in an ageing population, we designed a serious game, named CityQuest, to train typical, everyday multisensory processes including sensori-motor control, spatial navigation, obstacle avoidance and balance control. Played over several sessions, this game was shown to improve these functions in older adults with and without a history of falls, depending on the specific condition of the game on which they were trained. Here, using voxel-based morphometry analysis of anatomical magnetic resonance imaging (MRI) data, we investigated structural changes in the brain of a smaller group of older adults from those who successfully completed this five-week intervention. A grey-matter (GM) volume increase in the precentral gyrus, and GM volume reduction in the inferior temporal and orbitofrontal gyri, was found for all participants. Changes in GM volume within regions of the cerebellum were differentially associated with fall-prone and healthy older adults. Furthermore, a greater GM volume increase in the precentral gyrus was observed in participants who performed the full CityQuest intervention relative to those required to avoid obstacles only. Our results support previous evidence that multisensory training can affect structural changes in the older brain and have implications for programmes designed for the successful rehabilitation of perceptual and cognitive functions.


Transmission characteristics of splices in graded-index multimode fibers.
Losses and baseband bandwidth changes caused by a splice in a graded-index multimode fiber have been studied theoretically. Splices are classified into three categories, and their influence on mode conversion coefficients and baseband frequency response has been investigated. Transmission characteristics for splices in cascade are also investigated.


When communities are really in control: ethical issues surrounding community mobilisation for dengue prevention in Mexico and Nicaragua.
We discuss two ethical issues raised by Camino Verde, a 2011-2012 cluster-randomised controlled trial in Mexico and Nicaragua, that reduced dengue risk though community mobilisation. The issues arise from the approach adopted by the intervention, one called Socialisation of Evidence for Participatory Action. Community volunteer teams informed householders of evidence about dengue, its costs and the life-cycle of Aedes aegypti mosquitoes, while showing them the mosquito larvae in their own water receptacles, without prescribing solutions. Each community responded in an informed manner but on its own terms. The approach involves partnerships with communities, presenting evidence in a way that brings conflicting views and interests to the surface and encourages communities themselves to deal with the resulting tensions.One such tension is that between individual and community rights. This tension can be resolved creatively in concrete day-to-day circumstances provided those seeking to persuade their neighbours to join in efforts to benefit community health do so in an atmosphere of dialogue and with respect for personal autonomy.A second tension arises between researchers' responsibilities for ethical conduct of research and community autonomy in the conduct of an intervention. An ethic of respect for individual and community autonomy must infuse community intervention research from its inception, because as researchers succeed in fostering community self-determination their direct influence in ethical matters diminishes. ISRCTN 27581154.


Experience with a new vascular prosthetic device (Sparks mandril) for periodic haemodialysis.
In eighteen months, eleven Sparks mandrils have been implanted in ten patients who presented serious vascular access problems. So far nine mandrils have been anastomosed and six are functioning. In one patient the apparatus, inserted in the right leg, clotted after 108 dialyses and was reinserted in the left arm; after a further forty dialyses the patient died from causes not connected with dialysis. Another patient's Sparks mandril thrombosed from infection on the fourth post-operative day. Using a single needle apparatus, 693 dialyses have been carried out with particular problems either for the patients or the grafts.


[Liver resection and transplantation for hepatic tumors].
Hepatic surgery has made substantial advances in the last two decades due to technical developments and improvements in perioperative management. This has reduced surgery dependent mortality to less than 5%, and provides the possibility of carrying out more substantial hepatic resections and to interpret the indications more liberally, also for tumours localized unfavorably. A widely standardized surgical technique as well as new possibilities for organ conservation and, in particular, immunosuppression mean that given suitable indications, liver transplantation is today regarded as a routine procedure for the treatment of hepatocellular carcinoma. This work provides an overview of the current status of surgical therapy for the most frequent, benign liver tumours, as well as for hepatocellular and cholangiocellular carcinoma.


[Medical history of the province of Yaracuy].
After pinpointing the way in which Yaracuy State was constituted, and the indian origin of its local medicine, medical practice during XVIIth century in this territory is reviewed, with special reference to paramedical staff predominance and the beginning of industrial medicine in Venezuela. The first people from Yaracuy State who studied and graduated in medicine are mentioned, as well as outstanding personalities until present century.


Potential to Detect Hydrogen Concentration Gradients with Palladium Infused Mesoporous-Titania on D-Shaped Optical Fiber.
A distributed sensing capable high temperature D-shaped optical fiber modified with a palladium nanoparticle sensitized mesoporous (∼5 nm) TiO2 film, is demonstrated. The refractive index of the TiO2 film was reduced using block copolymer templating in order to realize a mesoporous matrix, accommodating integration with optical fiber. The constructed sensor was analyzed by performing direct transmission loss measurements, and by analyzing the behavior of an integrated fiber Bragg grating. The inscribed grating should reveal whether the refractive index of the composite film experiences changes upon exposure to hydrogen. In addition, with frequency domain reflectometry the distributed sensing potential of the developed sensor for hydrogen concentrations of up to 10% is examined. The results show the possibility of detecting chemical gradients with sub-cm resolution at temperatures greater than 500 °C.


Long-Term Effects of Moderate Concussive Brain Injury During Adolescence on Synaptic and Tonic GABA Currents in Dentate Granule Cells and Semilunar Granule Cells.
Progressive physiological changes in the hippocampal dentate gyrus circuits following traumatic brain injury (TBI) contribute to temporal evolution of neurological sequelae. Although early posttraumatic changes in dentate synaptic and extrasynaptic GABA currents have been reported, and whether they evolve over time and remain distinct between the two projection neuron classes, granule cells and semilunar granule cells, have not been evaluated. We examined long-term changes in tonic GABA currents and spontaneous inhibitory postsynaptic currents (sIPSCs) and in dentate projection neurons 3 months after moderate concussive fluid percussion injury (FPI) in adolescent rats. Granule cell tonic GABA current amplitude remained elevated up to 1 month after FPI, but decreased to levels comparable with age-matched controls by 3 months postinjury. Granule cell sIPSC frequency, which we previously reported to be increased 1 week after FPI, remained higher than in age-matched controls at 1 month and was significantly reduced 3 months after FPI. In semilunar granule cells, tonic GABA current amplitude and sIPSC frequency were not different from controls 3 months after FPI, which contrast with decreases observed 1 week after injury. The switch in granule cell inhibitory inputs from early increase to subsequent decrease could contribute to the delayed emergence of cognitive deficits and seizure susceptibility after brain injury.


Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice.
Statins have antiinflammatory and antiatherogenic effects that have been attributed to inhibition of RHO protein geranylgeranylation in inflammatory cells. The activity of protein geranylgeranyltransferase type I (GGTase-I) is widely believed to promote membrane association and activation of RHO family proteins. However, we recently showed that knockout of GGTase-I in macrophages activates RHO proteins and proinflammatory signaling pathways, leading to increased cytokine production and rheumatoid arthritis. In this study, we asked whether the increased inflammatory signaling of GGTase-I-deficient macrophages would influence the development of atherosclerosis in low-density lipoprotein receptor-deficient mice. Aortic lesions in mice lacking GGTase-I in macrophages (Pggt1b▵/▵) contained significantly more T lymphocytes than the lesions in controls. Surprisingly, however, mean atherosclerotic lesion area in Pggt1b▵/▵ mice was reduced by ≈60%. GGTase-I deficiency reduced the accumulation of cholesterol esters and phospholipids in macrophages incubated with minimally modified and acetylated low-density lipoprotein. Analyses of GGTase-I-deficient macrophages revealed upregulation of the cyclooxygenase 2-peroxisome proliferator-activated-γ pathway and increased scavenger receptor class B type I- and CD36-mediated basal and high-density lipoprotein-stimulated cholesterol efflux. Lentivirus-mediated knockdown of RHOA, but not RAC1 or CDC42, normalized cholesterol efflux. The increased cholesterol efflux in cultured cells was accompanied by high levels of macrophage reverse cholesterol transport and slightly reduced plasma lipid levels in vivo. Targeting GGTase-I activates RHOA and leads to increased macrophage reverse cholesterol transport and reduced atherosclerosis development despite a significant increase in inflammation.


Intraoperative ultrasound-guided retrieval of an airgun pellet from the tongue: a case report.
Real-time intraoperative ultrasonography was used to detect and facilitate removal of an airgun pellet from the tongue of a 14-year-old boy. Diagnostic ultrasound was crucial in clarifying the positional relation between the foreign body and the instrument used, enabling safe, precise and rapid retrieval during a potentially hazardous surgical operation.


Analysis of the human lumbar cerebrospinal fluid proteome.
Idiopathic low back pain has no known cause, and the molecular basis is unknown. Neuropeptidergic systems have been previously studied, and proteomics methods have been applied in this present study. Proteomics combines high-resolution two-dimensional (2-D) gel electrophoresis, high-sensitivity mass spectrometry, and continuously expanding protein databases. Proteomics offers a comprehensive, bird's-eye view to analyze, at a systems level, all of the proteins in cerebrospinal fluid (CSF) that might contribute to idiopathic low back pain. CSF contains a high salt concentration and low protein concentration. In order to obtain a high-quality 2-D pattern, several sample preparation methods were tested to remove salts - protein precipitation with either acetone or trichloroacetic acid/acetone, or sample treatment with a Bio-Spin column. More spots were visualized on the 2-D gel of human CSF, and a relatively high protein recovery was obtained when a Bio-Spin column was used to process a human CSF sample. Sixty-one protein spots, obtained from 2-D gels with a pH range of either 3-10 or 4-7, were identified by matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS) and MALDI-post-source decay (PSD)-MS. These 61 protein spots represent 22 proteins; six of those proteins were not annotated in any previously published 2-D maps. Those six proteins are PRO2619, pigment epithelium-derived factor, albumin homolog, kallikrein-6 precursor, DJ717I23.1, and AMBP protein precursor. These protein-mapping data will contribute to the database that will be used in the future to compare the proteomes obtained from the CSF of controls and low back pain patients, to characterize differentially expressed proteins, and to elucidate the biological markers for idiopathic low back pain.


[Is endovenous thrombolysis safety and efficacy in ischemic stroke comparable between patients aged over and above 80 years? Experience from an Argentinean cohort].
Enrollment of patients aged above 80 years in trials assessing endovenous thrombolysis (rt-PA) was scarce. The goal of this study is to compare safety and efficacy of endovenous rt-PA between patients aged above 80 and those below 80 years. A cohort of patients who received rt-PA was prospectively followed. Length of hospital stay, bleeding incidence, in-hospital mortality and 90 days' clinical outcome was compared between patients aged above 80 and those below 80 years. Of 1996 patients admitted at our hospital with ischemic stroke between October 2005 and January 2016, 180 received rt-PA (9%). Mean age was 77 ± 10 years, being 55% of the women. Comparing patients aged above 80 with those below 80 years, in the latter the length of hospital stay was longer with a median length of 15 days (IQR: 6-19) vs 7 days (IQR: 4-12; p = 0.001) and 90 days' clinical outcome was worse (modified Rankin scale 0-1 of 24% vs 41%; p = 0.001). Admission ASPECTS score, bleeding incidence and in-hospital mortality showed no significant differences between both groups. Patients aged over 80 arrived to the hospital earlier (97 ± 34 vs 113 ± 45 min; p = 0.01), however door-to-needle time was longer. Endovenous thrombolysis in patients aged above 80 years was safe, although its efficacy in assuring a better clinical outcome was not as pronounced as in patients below 80 years.


Shoulder joint abduction motion test bench: a new shoulder test bench for in vitro experiments with active muscle force simulation.
In our society the average age is increasing, as are the number of proximal humeral head fractures. For fixation of these fractures, an increasing number of implants are available. New fixation devices should be compared biomechanically with established methods in a standardized fashion. The test bench that was designed was intended to simulate abduction motion of the humerus actively induced by muscle forces. We used three pneumatic muscles to apply forces to the tendons of the musculus supraspinatus and the bifid musculus deltoideus. Thus, it was possible to create an active abduction in the scapular plane. Two different fracture models (with and without medial support) were stabilised with an angular stable plate in sawbone models to reproduce a known clinical outcome with the newly designed test setup. The resultant force acting on the proximal humerus reached approximately 47% BW (per cent body weight), which amounted to 329.0 N (SD: 21.76). The supraspinatus reached maximum forces of 254.7 N (SD: 20.1) and the deltoid muscle 258.9 N (SD: 16.5). Fracture gap instrumentation with medial support resulted in a significantly reduced per-cycle fracture gap motion. The performance evaluation showed that the simulator produced predicable, reproducible movements with physiological muscle force magnitudes.


CGS 9343B, a novel, potent, and selective inhibitor of calmodulin activity.
1,3-Dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]- benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-o ne (1:1) maleate was synthesized in six steps from methyl anthranilate and designated CGS 9343B. CGS 9343B inhibited calmodulin-stimulated cAMP phosphodiesterase activity with an IC50 value of 3.3 microM. CGS 9343B was 3.8 times more potent than trifluoperazine (IC50 = 12.7 microM) as an inhibitor of calmodulin activity. CGS 9343B did not inhibit protein kinase C activity at concentrations up to 100 microM, whereas trifluoperazine inhibited protein kinase C activity with an IC50 value of 43.9 microM. CGS 9343B weakly displaced [3H]spiperone from postsynaptic dopamine receptors with an IC50 value of 4.8 microM while the value for trifluoperazine, a potent antipsychotic agent, was 0.018 microM. It is concluded that CGS 9343B is a novel, potent, and selective inhibitor of calmodulin activity. Unlike trifluoperazine, CGS 9343B does not inhibit protein kinase C activity and does not possess potential antidopaminergic activity.