Possible windborne spread of bluetongue to Portugal, June-July 1956.
The possible sources for the epidemic of bluetongue in Portugal at the beginning of July 1956 were examined. Introduction through authorized importation of domestic or wild ruminants was not feasible, since no cattle, sheep or goats were imported and the wild ruminants were confined to Lisbon Zoo, which was too far from the initial outbreaks. Weather maps were examined to see if the wind could have carried infected Culicoides midges from North Africa. On 21 June 1956 infected midges in Morocco could have been taken offshore by southeast winds and then carried by south winds unusual at that time of year to the south coast of Portugal. The 200-300 km sea crossing would have taken some 10 h and been by day when air temperatures near the sea surface were about 18-20 C. Bluetongue had not been reported at that time in Moroccco, and the possibility of the presence of the virus in moroccan animals without clinical signs is discussed.


[Surgical treatment of trigeminal neurinomas].
To investigate the best surgical approach to remove of trigeminal neurinomas (TNs). 75 patients with TNs in Huashan Hospital were reviewed retrospectively. In early group (1978 - 1984) conventional intradural approaches were used, and in late group (1985 - 1995) an epidural approach via the skull-base craniotomy was utilized. Total removal of was achieved in 58% (20/35) in the early group and 80% (32/40) (P < 0.05) in the late group. Temporary or permanent cranial nerves morbidities were 62.7%, 37% in the early group and 28.1%, 10% (P < 0.01) in the late group, respectively. The best surgical approach with microsurgical technique for removal of TNs is epidural approach or epiduro-transduro-transtentorial approach via a skull-base craniotomy except the tumor only confined to the posterior fossa.


Effects of cyclosporin on serum hyaluronan levels in collagen arthritis.
Serum hyaluronan (HA) levels were measured in a rat model of collagen arthritis using a sandwich enzyme-linked immunosorbent assay. Values became elevated as the arthritis developed, correlating with its severity. Daily subcutaneous treatment with cyclosporin at the dose of 25 mg/kg per day for fourteen days completely prevented anti-type II collagen antibody production and the serum HA increase as well as development of collagen arthritis. HA in the blood may thus provide a good quantitative marker for joint disease in rat collagen arthritis with potential as a tool for evaluation of drug efficacy in this experimental model.


Transcultural nursing courses online: implications for culturally competent care.
Cultural diversity must be taken seriously by both faculty and students, and requires action by both parties for successful integration into online learning. Limited diversity in the nursing workforce or student population creates a need for learning cultural competence. Online transcultural nursing courses meet this learning need and provide opportunities for a variety of students and faculty participation from around the world. Successful online learning experiences can contribute to the provision of culturally competent nursing care.


Antioxidant potentials of successive solvent extracts from the unexplored Hedhychium coronarium rhizome.
Hedychium coronarium Koen. is considered as an endemic medicinal plant. In the current research antioxidant potential of six different extracts obtained by the successive solvent extraction method from the unexplored H. coronarium rhizome was evaluated. Various in vitro assays were performed to achieve the aim and variation in scavenging potential of the six extracts, in addition to quantification of phenolic and flavonoid compounds was done by HPLC. Among the six extracts, methanolic extract have showed highest Total phenolic content (TPC), metal chelation activity and free radical scavenging potential against DPPH, ABTS and superoxide anions as compared to other extracts. The highest scavenging potential against nitric oxide and hypochlorus acid was shown by acetone extract. The variation in anti-oxidant activity of the extracts may be due to the phyto-constituents present in different solvents. A significant correlation (r2 = 0.864) was established between antioxidant and TPC of H. coronarium from principle component analysis. Thus the present study provides strong evidence that rhizome extract of H. coronarium is a potential source of bioactive compounds and can be used as a remedy for diseases caused due to oxidative stress. Reported results could be helpful to develop novel drugs for the management of oxidative stress and associated diseases.


An estimate of the auditory-filter bandwidth in the Mongolian gerbil.
Critical ratios (CRs) and the critical band (CB) were determined in six Mongolian gerbils (Meriones unguiculatus) using a GO/NOGO procedure and the method of constant stimuli. The test-tone frequencies were 0.5, 1, 2, 4 and 8 kHz in the CR measurements and 2 kHz in the CB measurement. Critical ratios were independent of the level of the white-noise masker. The lowest CR with a mean of 24.8 dB was found at 1 kHz for maskers with spectrum levels of 20 and 40 dB SPL. The CR increased on average by 2.1 dB per octave between the frequencies 1 and 4 kHz. The CR bandwidth at 2 kHz and at a masker spectrum level of 40 dB SPL was 417 Hz. Using the band-narrowing procedure, we determined a mean CB of 216 Hz at a test-tone frequency of 2 kHz. The results are discussed in comparison to psychophysical data from other rodent species and humans. Finally, the relation of CR and CB bandwidths to the bandwidth of tuning curves of gerbil auditory-nerve fibers and the gerbil's cochlear frequency map are explored.


Relationship between the ocular and systemic disposition of flurbiprofen: the effect of altered protein dynamics at steady state.
The differences in flurbiprofen disposition in the aqueous humor and the plasma were examined after systemic doses. Steady state plasma concentrations of flurbiprofen (20-60 micrograms/mL) were achieved via intravenous infusion to albino rabbits. Flurbiprofen demonstrated linear systemic kinetics throughout the dosing range, with constant body clearance and unbound fraction in plasma. At steady state, aqueous humor drug concentrations depended on the corresponding plasma drug concentration. Two clearance terms--CLS----O, the systemic clearance to ocular tissues, and CLO----S, the ocular clearance to systemic circulation--were used. After systemic doses, the drug concentration in the aqueous humor was related to that in the plasma as well as to the ratio of these two clearances. Flurbiprofen was extensively bound to plasma proteins and showed limited ocular distribution; its CLS----O to CLO----S ratio was very small. Thus, the concentration of flurbiprofen in the aqueous humor after systemic doses was lower than that obtained after ophthalmic doses. A plasmapheresis technique was utilized to lower the plasma protein concentrations to 60% of normal levels. As a consequence, flurbiprofen demonstrated reduced aqueous humor protein concentrations, increased unbound fractions in the plasma and the aqueous humor, elevated aqueous humor drug concentrations, and elevated total body clearance. The unbound body clearance stayed unchanged. Our study indicated that a drug should present a significant CLS----O/CLO----S ratio in order to achieve therapeutic concentrations in the eye via systemic doses. The drug-protein binding kinetics can be different between the plasma and the aqueous humor circulations. Because the ocular compartment is very small compared to the overall systemic distribution of flurbiprofen, it has little effect on the steady state systemic concentrations.


On-chip immunoassay of a cardiac biomarker in serum using a polyester-toner microchip.
An on-chip immunoassay to detect C-reactive protein (CRP) was performed using a polyester-toner (PT) microchip. CRP is a highly conserved plasma protein responding to inflammation and is used for clinical purposes to diagnose an inflammatory state. For rapid analysis and specific interactions in immunoassays, extensive studies using microfluidic chips have been carried out. Recently, a simple technique to fabricate a disposable PT microchip by a direct printing process was developed and several applications were introduced. One major drawback of the PT microchip, however, is the poor separation performance due to the quality of the microfluidic structures. This problem for a PT microchip can be overcome using a cleavable tag immunoassay, which requires minimal separation performance. After analytes are conjugated onto antibodies which are immobilized on the surface of microbeads placed on the PT microchip, a second group of fluorescently tagged antibodies are added and complexed with the analytes. The tag is then cleaved and the solution containing the cleaved tag is analyzed by electrophoresis. The time needed for the complete analysis to be carried out on a PT microchip was less than 35 min. The dynamic range of the CRP in 10-fold diluted serum was 0.3-100 mg/L and the limit of detection was 0.3 mg/L, which demonstrated the possibility of a quantitative analysis of CRP in serum in clinical trials.


15-deoxy Delta12,14-prostaglandin J2 suppresses transcription by promoter 3 of the human thromboxane A2 receptor gene through peroxisome proliferator-activated receptor gamma in human erythroleukemia cells.
In humans, thromboxane (TX) A2 signals through two receptor isoforms, thromboxane receptor (TP)alpha and TPbeta, which are transcriptionally regulated by distinct promoters, Prm1 and Prm3, respectively, within the single TP gene. The aim of the current study was to investigate the ability of the endogenous peroxisome proliferator-activated receptor (PPAR)gamma ligand 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) to regulate expression of the human TP gene and to ascertain its potential effects on the individual TPalpha and TPbeta isoforms. 15d-PGJ2 suppressed Prm3 transcriptional activity and TPbeta mRNA expression in the platelet progenitor megakaryocytic human erythroleukemia (HEL) 92.1.7 cell line but had no effect on Prm1 or Prm2 activity or on TPalpha mRNA expression. 15d-PGJ2 also resulted in reductions in the overall level of TP protein expression and TP-mediated intracellular calcium mobilization in HEL cells. 15d-PGJ2 suppression of Prm3 transcriptional activity and TPbeta mRNA expression was found to occur through a novel mechanism involving direct binding of PPARgamma-retinoic acid X receptor (RXR) heterodimers to a PPARgamma response element (PPRE) composed of two imperfect hexameric direct repeat (DR) sequences centred at -159 and -148, respectively, spaced by five nucleotides (DR5). These data provide direct evidence for the role of PPARgamma in the regulation of human TP gene expression within the vasculature and point to further critical differences in the modes of transcriptional regulation of TPalpha and TPbeta in humans. Moreover, these data highlight a further link between enhanced risk of cardiovascular disease in diabetes mellitus associated with increased synthesis and action of thromboxane A2 (TXA2).


The structure of wakefulness and its relationship to daytime sleep in narcoleptic patients.
Seven patients with narcolepsy-cataplexy were continuously monitored during the day using polygraphy and videotape recording. The patients were free to do whatever they wanted while confined to a sitting-at-a-table situation. Daytime activity was evaluated by distinguishing between two polygraphically defined states, namely active wakefulness and quiet wakefulness. The data from the patients were compared with those from 7 normal subjects who were studied under the same experimental conditions. While all patients had recurrent daytime sleep episodes, none of the controls napped during the recording period. The narcoleptic patients showed an altered structure of wakefulness: they spent more of their time awake in the state of active wakefulness and less in quiet wakefulness than the control subjects. Moreover, the patients remained in the quiet state for shorter periods. Daytime sleep selectively diminished the state of quiet wakefulness, whereas it did not affect the amount of time spent in active wakefulness. In addition, in 3 patients there was a clear-cut alternation of periods of sustained wakefulness and transitional phases with a mixture of sleep and wakefulness which occurred rather regularly, suggesting an ultradian cycle of sleepiness.


PROVE-IT proves that lower is better: a contrary view.
Epidemiological studies have demonstrated that low density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) are both independent risk factors for future cardiovascular events. Statin therapy, initially developed to modify blood lipid concentrations, has also been shown to have potentially important pleiotropic effects, including a reduction in CRP concentrations. Recent clinical trials have demonstrated conflicting results regarding the benefits associated with intensively lowering LDL cholesterol. An analysis of these results suggests that the different effects of specific statins on CRP concentrations may be an important determinant of the observed overall benefit associated with therapy. These studies together prove that while lowering LDL is beneficial, lowering LDL and CRP is better.


5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret.
1. The purpose of the present study was to identify and investigate the role of 5-hydroxytryptamine3 (5-HT3) receptors in the area postrema in the control of cisplatin-induced emesis in the ferret. 2. Homogenate binding and autoradiography experiments using the high affinity 5-HT3 receptor ligand, [3H]-GR65630, identified the presence of a high concentration of 5-HT3 receptors in the area postrema of the ferret. 3. Intraperitoneal injection of the 5-HT3 receptor antagonists, GR38032F, GR65630A and MDL72222, at doses of 1, 0.1 and 1 mg kg-1 respectively, inhibited emesis induced by cisplatin, 9 mg kg-1 i.p. 4. Discrete injection of low doses of the 5-HT3 receptor antagonists directly into the area postrema region also inhibited cisplatin-induced (9 mg kg-1 i.p.) emesis. The dose ranges used were: GR38032F, 0.01-1 microgram; GR65630A, 0.001-0.1 microgram; MDL72222, 0.1-10 micrograms. 5. Cisplatin-induced emesis was not inhibited by discrete injection of ketanserin (30 micrograms) or methiothepin (30 micrograms) into the area postrema. Injection of the 5-HT3 receptor agonist, 2-methyl-5-HT, directly into the area postrema produced an incomplete emetic response. 6. These results confirm a role of 5-HT, and in particular 5-HT3 receptors, in the control of cisplatin-induced emesis, and show that at least one functional site for these receptors in modulating the emetic response is the area postrema, the locus of the chemoreceptor trigger zone.


The biological effects of syngeneic and allogeneic cytokine-expressing prophylactic whole cell vaccines and the influence of irradiation in a murine melanoma model.
Allogeneic whole tumour cell vaccines are inherently practical compared with autologous vaccines. Cell lines are derived from allogeneic tumour, grown in bulk and then administered as a vaccine to the patient, following irradiation, which not only prevents any replication but also enhances antigen presentation. Protection is believed to occur through the presentation of antigens shared between the syngeneic and allogeneic tumours. Although cytokine-transfected tumour whole cell vaccines have been used clinically, little data is available comparing the effects of immunomodulatory cytokine-transfection directly on the same cells when used as both an allogeneic and autologous vaccine. To address this, weakly immunogenic B16-F10 (H-2b) murine melanoma was transfected to secrete either GM-CSF, IL-4 or IL-7. Prophylactic vaccination of both syngeneic C57/BL6 (H-2b) (B6) and allogeneic C3H/Hej (H-2k) (C3H) mice showed the effects of transfected cytokine varied between models. Both GM-CSF and IL-7 significantly (P<0.05) increased the levels of protection within syngeneic B6 mice, but had a diminished effect (P>0.05) within C3H allogeneic mice. Allogeneic B16-F10 cells and syngeneic K1735 cells generated CTL against K1735 suggesting cross-reactive immunity. Using cells labeled with fluorescent dye we demonstrate that irradiated vaccines, of either syngeneic or allogeneic origin, appear to generate potent immune responses and fragments of either vaccine remain at the injection site for up to 9 days. This study shows that protection can be enhanced in vivo by using transfected cytokine, but suggests that irradiated whole cell vaccines, of either tissue-type, are rapidly processed. This leads to the conclusion that the cytokine effects are transient and thus transfection with cytokine may be of limited long-term use in situ.


Cost effectiveness of paliperidone palmitate for the treatment of schizophrenia in Germany.
Treatment with antipsychotic medication is an important element of relapse prevention in the management of schizophrenia, and can reduce inpatient stays. Recently, the long-acting atypical antipsychotic paliperidone long-acting injectable (PLAI), a once-monthly LAI antipsychotic, was approved for treatment of schizophrenia in Germany. To estimate, based on a previously published model, the cost effectiveness of PLAI compared with other common antipsychotic treatment strategies in patients diagnosed with schizophrenia in Germany. A Markov decision analytic model was adapted to the German healthcare system. The model considers the cost effectiveness for PLAI as a maintenance treatment for patients with schizophrenia from the payer perspective. The patients transition between eight health states on a monthly basis over a 5-year time horizon. As therapeutic strategies, PLAI, quetiapine, risperidone long-acting injections (RLAI), oral olanzapine, oral risperidone, zuclopenthixol decanoate, olanzapine long-acting injections (OLAI), oral typical and oral atypical were compared. Probability of relapse, level of adherence, side effects and treatment discontinuation were derived from the Swedish original model. Input factors regarding resource use and costs were estimated and adjusted for the German healthcare system. A probabilistic sensitivity analyses (PSA) using cost-effectiveness scatter plots was performed to visualize the robustness of the results. In base-case scenario, PLAI is superior to RLAI in gained quality-adjusted life-years (QALYs) and avoided relapses. Relative to all other treatment strategies, PLAI is more effective with regard to gained QALYs and avoided relapses but results in higher treatment costs over a 5-year horizon in base-case scenario. The results were tested in PSA. If a cost-effectiveness threshold of <euro>30,000 is assumed, for example, PLAI can be considered to be cost effective compared with RLAI in about 92.5 % of cases regarding gained QALYs, and in 78.6 % of cases regarding avoided relapse. Compared with OLAI, in about 94.4 % of cases regarding gained QALYs and in 99.9 % of cases regarding avoided relapse, cost effectiveness can be considered. Comparing PLAI and zuclopenthixol decanoate, cost effectiveness can be assumed in about 90.4 % of cases regarding gained QALYs, and in all cases regarding avoided relapse. PLAI dominates RLAI and compared with the other treatment strategies PLAI has shown to be more effective but results in higher costs in base-case scenario.


High prevalence of undiagnosed comorbidities among adolescents with obesity.
Metabolic diseases are increasing among adolescents with obesity. Although the reported prevalence of metabolic syndrome is approximately 30% worldwide, its prevalence is largely unknown among New Zealand adolescents. Therefore, we assessed the health of adolescents with obesity (BMI ≥ 30 kg/m2) enrolled in a randomised clinical trial (Gut Bugs Trial), to identify the prevalence of undiagnosed comorbidities. Assessments included anthropometry, 24-h ambulatory blood pressure monitoring, and insulin sensitivity. We report on baseline data (pre-randomisation) on 87 participants (14-18 years; 59% females), with mean BMI 36.9 ± 5.3 kg/m2 (BMI SDS 3.33 ± 0.79). Approximately 40% of participants had undiagnosed metabolic syndrome, which was twice as common among males. Half (53%) had pre-diabetes and 92% a reduction in insulin sensitivity. Moreover, 31% had pre-hypertension/hypertension, 69% dyslipidaemia, and 25% abnormal liver function. Participants with class III obesity had a greater risk of metabolic syndrome than those with classes I/II [relative risk 1.99 (95% CI 1.19, 3.34)]. Risks for pre-hypertension/hypertension and inflammation were also greater among those with class III obesity. We identified a high prevalence of undiagnosed comorbidities among adolescents with obesity in New Zealand. As adolescent obesity tracks into adulthood, early interventions are needed to prevent progression to overt cardiometabolic diseases.


White matter anatomy: what the radiologist needs to know.
Diffusion tensor imaging (DTI) has allowed in vivo demonstration of axonal architecture and connectivity. This technique has set the stage for numerous studies on normal and abnormal connectivity and their role in developmental and acquired disorders. Referencing established white matter anatomy, DTI atlases, and neuroanatomical descriptions, this article summarizes the major white matter anatomy and related structures relevant to the clinical neuroradiologist in daily practice.


Basis for binary comparisons and non-standard probabilities.
To analyse paired comparison outcomes, such as with non-standard probabilities, a basis is created for the space of all binary interactions, whether from probabilities, correlations, etc. In this manner, the source of all transitive and non-transitive behaviours (e.g. path dependencies) can be identified.


5-aminolaevulinic acid-induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer.
To assess the influence of 5-aminolaevulinic acid-induced fluorescence cystoscopy (FC) during transurethral resection (TUR) on the recurrence rate and the length of tumour-free interval in stage Ta/T1 transitional cell carcinoma (TCC) of the urinary bladder. In all, 122 patients with primary or recurrent stage Ta/T1 bladder TCC treated with TUR were enrolled in a prospective randomized study. In group A the TUR was performed with standard white-light endoscopy, and in group B with FC. The patients were followed using standard cystoscopy and urinary cytology. The recurrence-free interval was evaluated in whole groups, for single and multiple, and for primary and recurrent tumours separately. At the time of the first cystoscopy (10-15 weeks after TUR) tumour recurrence was detected in 23 of 62 patients (37%) in group A, but only in five of 60 patients (8%) in group B. The recurrence-free survival rates in group A were 39% and 28% after 12 and 24 months, compared to 66% and 40% respectively in group B (P = 0.008, log-rank test). In separate analyses, the recurrence-free survival rates were significantly higher using FC in multiple (P = 0.001) and in recurrent (P = 0.02) tumours. In solitary and primary tumours the median time to recurrence was also longer in group B, but the difference was not statistically significant. 5-aminolaevulinic acid-induced FC during TUR reduces the recurrence rate in stage Ta/T1 bladder TCC. The most significant benefit is in patients with multiple and recurrent tumours.


A comparative study of the cell cycles of nullipotent and multipotent embryonal carcinoma cell lines during exponential growth.
Three embryonal carcinoma (EC) cell lines F9, PCC4 Azal, and PCC3 N/1 with a common origin from the transplantable ascites teratoma OTT6050 were analyzed with regard to cell cycle characteristics during exponential growth in the undifferentiated state. The three lines, in the sequence mentioned, have been shown to represent successive stages in early normal mouse embryogenesis from morula to blastocyst, as reflected in their cell surface antigens. In the multipotent lines an increased intraclonal variability in intermitotic times was found when analyzing family trees. In the PCC3 N/1 line the distribution was almost bimodal. The increased intermitotic time variability was found to be represented in the G1 period that varied from less than 1 hr up to about 6 hr in the PCC3 N/1 line, with a mean value of 3.4 hr. The G1 period of the F9 line had a range of only 3.5 hr, with a mean value of 1.5 hr. The S-G2 period was found to be very similar in length in all three lines.


Synthesis, pharmacophores, and mechanism study of pyridin-2(1H)-one derivatives as regulators of translation initiation factor 3A.
Twenty-seven 1,5-disubstituted-pyridin-2(1H)-one derivatives were synthesized and evaluated for their anti-cancer and anti-fibrosis activity by A549 and NIH3T3 cell viability assays, respectively. To study the selectivity between the cancer and fibrosis cell lines, pharmacophore models (F1-F4) were built in advance for compounds with pyridin-2(1H)-one scaffold, which revealed the relationship between the occupation of the aromatic sub-site F4 and potent anti-cancer activity. The relationship between structure and anti-cancer activity for all target compounds is also reported herein: 1-Phenyl-5-((m-tolylamino)methyl)pyridine-2(1H)-one (22) displayed both potency and selectivity (IC50=0.13 mM) toward the A549 cell line through the inhibition of translation initiation, especially by eIF3a suppression, and can be treated as a lead for the design of novel eIF3a regulators and anti-lung cancer agents.


Synbiotic (Lactiplantibacillus pentosus GSSK2 and isomalto-oligosaccharides) supplementation modulates pathophysiology and gut dysbiosis in experimental metabolic syndrome.
Metabolic syndrome a lifestyle disease, where diet and gut microbiota play a prodigious role in its initiation and progression. Prophylactic bio-interventions employing probiotics and prebiotics offer an alternate nutritional approach towards attenuating its progression. The present study aimed to evaluate the protective efficacy of a novel synbiotic (Lactiplantibacillus pentosus GSSK2 + isomalto-oligosaccharides) in comparison to orlistat in an experimental model of metabolic syndrome. It was observed that supplementation of synbiotic for 12 weeks to Sprague Dawley rats fed with high fat diet (HFD), ameliorated the morphometric parameters i.e. weight gain, abdominal circumference, Lee's index, BMI and visceral fat deposition along with significantly increased fecal Bacteroidetes to Firmicutes ratio, elevated population of Lactobacillus spp., Akkermansia spp., Faecalibacterium spp., Roseburia spp. and decreased Enterobacteriaceae compared with HFD animals. Additionally, synbiotic administration to HFD animals exhibited improved glucose clearance, lipid biomarkers, alleviated oxidative stress, prevented leaky gut phenotype, reduced serum lipopolysaccharides and modulated the inflammatory, lipid and glucose metabolism genes along with restored histomorphology of adipose tissue, colon and liver compared with HFD animals. Taken together, the study highlights the protective potential of synbiotic in comparison with its individual components in ameliorating HFD-induced metabolic complications.


Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans.
Cilostazol is an antiplatelet agent with vasodilating properties. It has been used to treat patients with peripheral ischemia, such as intermittent claudication. We used a pharmacokinetic-pharmacodynamic model to analyze the relation between the plasma concentration of cilostazol, the inhibitory effect of the drug on platelet aggregation, and the cardiovascular effects of the drug on healthy humans. A single oral dose of 100 mg cilostazol was administered to 20 healthy volunteers. Serial blood sampling and pharmacodynamic measurements were performed up to 48 hours thereafter. The effects of cilostazol on platelet aggregation, blood pressure, and heart rate were measured during the same period. The plasma concentration of cilostazol was measured with a validated HPLC method that entailed ultraviolet detection. The time courses of plasma cilostazol concentration, platelet aggregation, and cardiovascular effects were analyzed by means of pharmacokinetic-pharmacodynamic modeling with the program ADAPT II. The plasma concentration-time course followed a 2-compartment model. Mean peak concentration was 775 ng/ml approximately 3.65 hours after administration of cilostazol. The maximal effect on platelet aggregation was a 31.14% reduction 6.05 hours after administration. No significant difference in systolic blood pressure was found. The maximal increase in heart rate was 13.49%, whereas the maximal decrease in diastolic blood pressure was 29.51%. Both peak effects were detected approximately 6 hours after administration of the drug. Platelet aggregation and cardiovascular effects (change in diastolic blood pressure and heart rate) were analyzed with the effect-link sigmoid maximal effect model. This pharmacokinetic-pharmacodynamic model successfully described the relation between plasma concentration of cilostazol and the antiplatelet and cardiovascular effects of the drug.


The role of factor XIII in surgery for advanced stage of epithelial ovarian cancer.
Hereditary factor (F) XIII-deficiency is a known risk factor for postoperative complications, but data of acquired FXIII-deficiency in malignancies are limited. Therefore, we evaluated the role of acquired FXIII-deficiency in surgery for advanced epithelial ovarian cancer (EOC). We performed a retrospective analysis of patients with known serum FXIII status and treatment between 2011 and 2018 at our center. We defined cohorts according to FXIII with values > 75% as normal (group A), 55-75% as reduced (group B) and < 55% as low (group C). Complications were classified according to the Clavien-Dindo Classification, class III-V complications were defined as severe. 347 patients with EOC were identified. 180 patients (51.2%) were in group A, 82 patients (23.6%) in group B, and 85 patients (24.4%) in group C. Lower levels of FXIII were associated with higher amount of ascites, FIGO IV, high grade serous histology, low albumin, and higher CA-125 levels. Regarding intraoperative variables, low FXIII was associated with longer duration of surgery, higher blood loss, higher surgical complexity score/number of bowel anastomosis and a higher probability for macroscopic residual disease. The risk of severe complications in group A was 12.2%, 24.4% in group B, and 31.8% in group C. In a multivariate model, low FXIII (OR 2.8), > 1 bowel anastomosis (OR 2.7), age-adjusted Charlson comorbidity index ≥ 4 (OR 3.6) and a longer duration of surgery (> 285 min.) were significant predictive factors for severe complications. FXIII is associated with tumor and treatment burden. A low level of FXIII is associated with postoperative complications. The knowledge about the presurgical serum FXIII-level might be helpful to plan the treatment strategy.


Biogenesis of Mesoporous Silica Nanoparticles Enclosed in Extracellular Vesicles by Mouse Renal Adenocarcinoma Cells.
Integrating the versatility of synthetic nanoparticles to natural biomaterials, such as cells or cell membranes, has gained considerable attention as promising alternative cargo delivery platforms in recent years. Extracellular vesicles (EVs), natural nanomaterials composed of a protein-rich lipid bilayer secreted by cells, have also shown advantages and great potential as a nano delivery platform in combination with synthetic particles due to their specific natural properties in overcoming several biology hurdles possessed in the recipient cell. Therefore, the preservation of EV's origin properties is critical for their application as nanocarriers. This chapter will describe the encapsulation procedure of MSN encapsulated in EV membrane derived from mouse renal adenocarcinoma (Renca) cells through biogenesis. The FMSN-enclosed EVs produced through this approach still contain preserved EV's natural membrane properties.


Comparison between linear array real time ultrasonic scanning and conventional compound scanning in the measurement of the fetal biparietal diameter.
Ultrasonic measurements of fetal biparietal diameter (BPD) obtained by the Real Time scanning (Dynamic Section Scan) and conventional compound scanning (Static Section Scan) in twenty patients were compared. A comparison between two operators, one of whom was relatively inexperienced, was also made, both measuring the same BPDs. The mean variance of 20 groups-of-four 'blind' measurements was reduced using dynamic scanning, particularly for the less experienced operator. A significant difference was observed between operators using conventional scanning but not when using dynamic scanning. Both operators were able to obtain results in a shorter time with dynamic scanning, the faster operator averaging less than one minute for each observation. Apparent advantages of dynamic scanning are discussed. The terms 'Dynamic Section Scan' and 'Static Section Scan' are suggested to emphasize the difference between the two imaging systems.


New structural insights provide a different angle on steroid sulfatase action.
A central part of human sulfation pathways is the spatially and temporally controlled desulfation of biologically highly potent steroid hormones. The responsible enzyme - steroid sulfatase (STS) - is highly expressed in placenta and peripheral tissues, such as fat, colon, and the brain. The shape of this enzyme and its mechanism are probably unique in biochemistry. STS was believed to be a transmembrane protein, spanning the Golgi double-membrane by stem region formed by two extended internal alpha-helices. New crystallographic data however challenge this view. STS now is portraited as a trimeric membrane-associated complex. We discuss the impact of these results on STS function and sulfation pathways in general and we hypothesis that this new STS structural understanding suggests product inhibition to be a regulator of STS enzymatic activity.


The H6D genetic variation of GDF15 is associated with genesis, progress and prognosis in colorectal cancer.
Growth differentiation factor 15 (GDF15) plays important roles in the carcinogenesis of many types of tumors. The aim of this study was to investigate whether H6D polymorphism is contributed to the genesis, progress and prognosis of colorectal cancer (CRC) in Chinese population. Pyrosequencing was used to determine the H6D genotypes. The relationship between the genotypes and clinical characteristics was analyzed. The frequency of CG+GG genotype in the GDF15 H6D polymorphism was significantly increased in CRC patients when compared with controls [odds ratio (OR), 1.543; 95% confidence interval (95% CI), 1.138-2.094, P=0.005]. We also found that the patients with CG+GG genotype had an increased risk of death from colon cancer than those carrying homozygote CC [hazard ratio (HR), 2.472; 95% CI, 1.172-5.214; P=0.017] and the patients with CG+GG genotype of colon cancer also have a positive correlation with distant metastasis than those carrying homozygote CC (χ(2)=4.087, P=0.043). For the first time, H6D was also identified as somatic mutation when compared the H6D genotype in tumor tissues and their matched normal tissues, and the mutation rate is 7.2%. The male CRC patients with the H6D mutation were susceptible to distant metastasis (P=0.028, χ(2)=4.820) and had a relatively poor prognosis. Our results suggest that the H6D genetic variant may be considered as a biomarker of tumorgenesis, metastasis and prognosis in colorectal cancer in Chinese population.


Using residual regressions to quantify and map signal leakage in genomic prediction.
Most genomic prediction applications in animal breeding use genotypes with tens of thousands of single nucleotide polymorphisms (SNPs). However, modern sequencing technologies and imputation algorithms can generate ultra-high-density genotypes (including millions of SNPs) at an affordable cost. Empirical studies have not produced clear evidence that using ultra-high-density genotypes can significantly improve prediction accuracy. However, (whole-genome) prediction accuracy is not very informative about the ability of a model to capture the genetic signals from specific genomic regions. To address this problem, we propose a simple methodology that detects chromosome regions for which a specific model (e.g., single-step genomic best linear unbiased prediction (ssGBLUP)) may fail to fully capture the genetic signal present in such segments-a phenomenon that we refer to as signal leakage. We propose to detect regions with evidence of signal leakage by testing the association of residuals from a pedigree or a genomic model with SNP genotypes. We discuss how this approach can be used to map regions with signals that are poorly captured by a model and to identify strategies to fix those problems (e.g., using a different prior or increasing marker density). Finally, we explored the proposed approach to scan for signal leakage of different models (pedigree-based, ssGBLUP, and various Bayesian models) applied to growth-related phenotypes (average daily gain and backfat thickness) in pigs. We report widespread evidence of signal leakage for pedigree-based models. Including a percentage of animals with SNP data in ssGBLUP reduced the extent of signal leakage. However, local peaks of missed signals remained in some regions, even when all animals were genotyped. Using variable selection priors solves leakage points that are caused by excessive shrinkage of marker effects. Nevertheless, these models still miss signals in some regions due to low linkage disequilibrium between the SNPs on the array used and causal variants. Thus, we discuss how such problems could be addressed by adding sequence SNPs from those regions to the prediction model. Residual single-marker regression analysis is a simple approach that can be used to detect regional genomic signals that are poorly captured by a model and to indicate ways to fix such problems.


BbMP-1, a new metalloproteinase isolated from Bothrops brazili snake venom with in vitro antiplasmodial properties.
This study describes the biochemical and functional characterization of a new metalloproteinase named BbMP-1, isolated from Bothrops brazili venom. BbMP-1 was homogeneous on SDS-PAGE, presented molecular mass of 22,933Da and pI 6.4. The primary structure was partially elucidated with high identity with others metalloproteinases from Viperidae venoms. The enzymatic activity on azocasein was evaluated in different experimental conditions (pH, temperature). A significant reduction in enzyme activity after exposure to chelators of divalent cations (EDTA), reducing agents (DTT), pH less than 5.0 or temperatures higher than 45 °C was observed. BbMP-1 showed activity on fibrinogen degrading Aα chain quickly and to a lesser extent the Bβ chain. Also demostrated to be weakly hemorrhagic, presenting however, significant myotoxic and edematogenic activity. The in vitro activity of BbMP-1 against Plasmodium falciparum showed an IC50 of 3.2 ± 2.0 μg/mL. This study may help to understand the pathophysiological effects induced by this group of toxin and their participation in the symptoms observed in cases of snake envenomation. Moreover, this result is representative for this group of proteins and shows the biotechnological potential of BbMP-1 by the demonstration of its antiplasmodial activity.


A major locus controlling malondialdehyde content under water stress is associated with Fusarium crown rot resistance in wheat.
Malondialdehyde (MDA) is a naturally occurring product of lipid peroxidation and the level of MDA in plant is often used as a parameter to evaluate the damage to plants' cells due to stress. Plant with lower amounts of MDA under drought conditions is generally considered as more tolerant to drought. In this study, a population of recombinant inbred lines was used to map the quantitative trait locus (QTLs) that controlled MDA content under well-watered condition (WW) and water deficit (WD) condition. A major QTL, designated as Qheb.mda-3B, was detected on the long arm of chromosome 3B. Based on interval mapping analysis, Qheb.mda-3B explained 31.5 and 39.0 % of the phenotypic variance under WW and WD conditions, respectively. Qheb.mda-3B was located in the same interval as a previously identified QTL (Qcrs.cpi-3B) that controlled resistance to Fusarium crown rot (FCR), a fungal disease caused by Fusarium species. Three pairs of near-isogenic lines (NILs) previously developed for Qcrs.cpi-3B were found to show significant differences in MDA content under WD condition. These results suggested that same set of genes is likely to be involved in drought tolerance and FCR resistance in wheat.


Inhibition of multispecies biofilms by a fluoride-releasing dental prosthesis copolymer.
This study aimed to develop a new mixed-species acidogenic biofilm model and use it to assess the antimicrobial properties of a novel fluoride-releasing copolymer. Stubs composed of a copolymer of methyl methacrylate (MMA) and 2-hydroxyethyl methacrylate (HEMA) with polymethyl methacrylate (PMMA) were produced by chemically-activated free radical polymerization. A fluoride-releasing copolymer was developed by incorporating sodium fluoride in place of a portion of the PMMA. Samples were mounted in polysulfone Modified Robbins Devices (MRDs) and were optimized for single- and mixed-species biofilm formation by Candida albicans, Lactobacillus casei and Streptococcus mutans. Fluoride release was sustained for at least 48h in flowing conditions. Fluoride did not affect the colonization and biofilm growth of any of the microorganisms in monocultures. However, in mixed-species biofilms, cell densities of all three species were reduced approximately ten-fold (p<0.05) on the fluoridated material compared with the non-fluoridated copolymer. These data demonstrate that intermicrobial interactions in mixed-species acidogenic biofilms are sensitive to fluoride, and that the inclusion of fluoride in a denture lining copolymer reduces the formation of polymicrobial biofilms. The growth of acidogenic microorganisms on denture materials is associated with denture stomatitis and dental caries on surrounding teeth. A fluoride-releasing copolymer that inhibits acidogenic mixed-species biofilms, such as the material described in this study, has the potential to control these diseases by limiting biofilm growth.


Indirect intestinal stimulatory effects of heroin: direct action on opiate receptors.
The effects of bolus intra-arterial doses of heroin and other stimulant drugs were studied in vascularly perfused isolated segments of dog small intestine. Heroin caused dose-related increases in intraluminal pressure similar in appearance to those caused by morphine. Perfusion with Krebs bicarbonate solution containing naloxone selectively abolished intestinal responses to heroin. Perfusion with cinanserin, a 5-hydroxytryptamine (5-HT) antagonist, decreased intestinal responses to 5-HT and heroin without affecting responses to dimethylphenylpiperazinium (DMPP) or bethanechol (BeCh). Tetrodotoxin reduced responses to heroin, 5-HT and DMPP but not responses to BeCh. Atropine antagonized contractile responses to all 4 stimulatory agents. These data indicate that heroin interacts with a conventional opiate receptor in the intestine and that the intestinal stimulatory effect of heroin is mediated by the release of endogenous 5-HT which activates intramural cholinergic neurons.


Completion pancreatectomy in the acute management of pancreatic fistula after pancreaticoduodenectomy: a systematic review and qualitative synthesis of the literature.
Pancreatic fistula remains a major complication after pancreaticoduodenectomy (PD). Re-operation is generally considered only after exhaustion of non-surgical options. A variety of pancreas-preserving operations have been proposed, but completion pancreatectomy (CP) stands out in locally complicated cases as a universal approach. This study aims to provide a qualitative synthesis of the peer-reviewed literature regarding emergency CP for post-PD pancreatic fistula. A systematic search of PubMed and EMBASE for all studies reporting clinical outcomes for CP in the acute treatment of pancreatic fistula following PD from January 1975 until May 2016. Eleven patient-series with a total of 5566 PD and 151 (3%) emergency CP were included. Median time from PD to CP ranged from 6 to 17 days (7 studies), and mean operative time and blood loss - reported in only two studies - were 197 min and 2173 mL respectively. Re-laparotomy following CP was required in 35% of patients. Median hospital length-of-stay varied from 21 to 64 days, and postoperative mortality was 42%. Emergency surgery for postoperative pancreatic fistula should only be considered after expert consultation. CP carries a high risk of mortality, and it is most commonly recommended for a selected subgroup of patients with locally complicated fistula.


Proteoforms and Proteoform Families: Past, Present, and Future.
The Human Proteoform Project is an ambitious international effort to accelerate the development of technologies for proteoform analysis and to establish comprehensive atlases of proteoforms for humans and model organisms. Proteoforms are the ultimate molecular effectors of function in biology and are thus central to understanding that function. Proteoform analysis as it is practiced today is almost exclusively accomplished by mass spectrometry (MS) and is rapidly advancing in its capabilities. This volume presents a beautiful snapshot of emerging technologies at the exciting frontier of MS-based proteoform analysis.


Occurrence and mass loadings of n-alkanes in riverine runoff of the Pearl River Delta, South China: global implications for levels and inputs.
Riverine runoff samples were collected monthly from March 2005 to February 2006 from the eight major outlets of the Pearl River Delta (PRD), South China, and analyzed to obtain the concentrations of n-alkanes in both the filtrate and particulate phases. The average concentrations of Sigma(C15-C34) (i.e., sum of C15 to C34 normal alkanes) ranged from 0.06 to 2.97 microg/L (mean, 0.64 microg/L) in filtrate samples and from 1.00 to 98.8 microg/g (average, 19.8 microg/g dry weight) in particulate samples. Compared to results from around the world, the levels of hydrocarbon compounds in the PRD were at the high end of the global range. Evaluation of compositional indices of n-alkanes indicated that petroleum-related sources are the main contributor of n-alkanes found in the PRD, with minor contributions from high plant wax. Regression analyses appeared to suggest that n-alkanes are transported into the aquatic environment of the PRD via various pathways, and the transport mechanisms also are considerably influenced by the complex hydrologic conditions in the PRD. The annual riverine input of Sigma(C15-C34) from the PRD to the coastal ocean was 360 tons/year, or the equivalent of approximately 8,800 tons/year of petroleum hydrocarbons. The emission of Sigma(C15-C34) from all sources in the PRD was estimated at 39,000 tons/year, or 2.4 g/day per capita. Overall, the PRD contributes approximately 0.2% of the annual global input of n-alkanes to the coastal oceans, similar to the contributions of polycyclic aromatic hydrocarbons, further indicating that the PRD has been a significant source of hydrocarbon contamination to the global coastal marine environment.


Adsorption of Bacillus subtilis on single-walled carbon nanotube aggregates, activated carbon and NanoCeram.
Adsorption equilibrium and kinetics of Bacillus subtilis spores on single-walled carbon nanotube aggregates were investigated to explore the possibility of using single-walled carbon nanotubes for concentration, detection and removal of pathogens from contaminated water sources. Batch adsorption experiments were conducted to determine adsorption kinetics and adsorption equilibrium of B. subtilis spores on single-walled carbon nanotube aggregates, activated carbon and NanoCeram. The adsorption kinetics data were analyzed with both the Lagergren pseudo first order and a pseudo second order models. The adsorption equilibrium data on three porous media were quantified by the Henry's law constant. It was observed that both the Lagergren first order rate model and the pseudo second order model correlate the adsorption kinetic data well although the calculated adsorption rate constants vary with adsorbate concentrations. The Henry's law adsorption equilibrium constant of B. subtilis spores on single-walled carbon nanotube aggregates is about 27-37 times higher than those on activated carbon and NanoCeram. The high adsorption affinity of carbon nanotubes towards the B. subtilis spores is due to the mesoporous structure and unique surface properties of carbon nanotubes. These results suggest that single-walled carbon nanotube aggregates are good candidates as biosensors and adsorbent media for concentrating, detecting and removal of pathogens from contaminated water resources.


Effects of a verbal warning and overcorrection on stereotyped and appropriate behaviors.
In Experiment I, the effects of a verbal warning, such as is used in Overcorrection, delivered contingently on the stereotyped mouthing behavior of two autistic/retarded children were examined. A multiple baseline design across subjects was used. The results indicated that the mouthing of one child was reduced to a near-zero level and mouthing of the second child was moderately reduced. Appropriate toy play and inappropriate object manipulation failed to show systematic changes in occurrence when mouthing was decelerated. In Experiment II, the same subjects and experimental design were used to assess the effects of a positive practice Overcorrection procedure delivered contingent on mouthing behavior. Overcorrection reduced the mouthing of both subjects. There were no systematic changes in inappropriate object manipulation but one subject did demonstrate an increased occurrence of appropriate toy play. In addition, this subject often engaged in aggressive/escape behaviors during Overcorrection, suggesting that the procedure was aversive to him.


Amotosalen interactions with platelet and plasma components: absence of neoantigen formation after photochemical treatment.
The INTERCEPT Blood System (Baxter Healthcare Corp., and Cerus Corp.) is a photochemical treatment (PCT) process that uses amotosalen (S-59) and ultraviolet A (UVA) illumination to inactivate a broad spectrum of pathogens. To evaluate the potential of the process to create neoantigens, the amounts of residual amotosalen and photoproducts present in PCT platelets (PLTs) and PCT plasma were quantified. The initial amount of amotosalen was 150 micromol per L. After illumination with 3 J per cm2 UVA and before transfusion, a compound adsorption device was used to substantially reduce the amounts of free amotosalen and unreactive photodegradation products. Patient serum samples from Phase III clinical trials were assayed by enzyme-linked immunosorbent assay (ELISA) for antibodies to potential amotosalen neoantigens. After PCT, 15 percent of the starting amount of amotosalen remains bound to PLTs, and 15 to 22 percent remains bound to plasma components. The majority of bound amotosalen is associated with lipid. Less than 1 percent of PLT-bound amotosalen and approximately 2 percent of plasma-bound amotosalen can be extracted into the water-soluble protein fraction. In seven Phase III clinical trials, 523 patients received more than 8000 units of PCT PLTs or PCT plasma. None of the patients exhibited clinical or laboratory manifestations of neoantigenicity. Furthermore, no other alteration of PLT membrane proteins was identified based on testing for lymphocytotoxic antibodies and PLT-specific alloantibodies. These results indicate that no neoantigens were detected by ELISA after PCT, suggesting that transfusion of PCT PLTs or PCT plasma does not induce adverse immunologic responses.


Hypomyelinated mutant mice. V. Relationship between jp and jpmsd re-examined on identical genetic backgrounds.
jp and jpmsd, two allelic mutations in the mouse that sharply reduce the amount of CNS myelin, produce diseases that can be distinguished morphologically only by their severity. This has raised the question of whether the two mutations are truly distinguishable. Since the two mutations have never been maintained on the same genetic background, correct quantitative and morphological comparison have not been possible. We have prepared a B6C3H stock of jp on the same genetic background as the available stock of jpmsd. In this jp stock, behavioral abnormalities, relative proportion of myelinated axons, and major morphological characteristics of the disease in situ are unchanged from the previous jp stock. The jp disease continues to be more severe than that of jpmsd. However, tissue from the new B6C3H stock myelinates better in organotypic culture than previous jp stocks. The increase in myelination is advantageous, not only for accurate comparison of the two alleles but for all culture studies of jp. Strictly comparable strains or stocks should be utilized in any comparative studies of closely related mutations such as jp and jpmsd.


Crystallization of a chymotrypsin inhibitor from Erythrina caffra seeds.
Crystals of a chymotrypsin inhibitor from Erythrina caffra seeds have been grown out of lithium sulfate, by the hanging drop method of vapor diffusion. The crystals belong to the rhombohedral space group R32, with a = 67.2 A and alpha = 99.4 degrees, and diffract to 3 A resolution.


Molecular weight determination of allergen extracts and isolation of allergenic molecules by high-performance liquid chromatography.
The usefulness of size-exclusion high-performance liquid chromatography (HPLC) for the molecular weight determination of allergen extracts as a method of process control was investigated by measuring seven different batches of timothy pollen extracts. Preparative HPLC was used for the isolation of the major allergen Cat 1, from a crude cat hair and skin scraping (CHSS) extract. The chromatograms of the seven batches of the timothy pollen extracts looked very similar, suggesting the same molecular weight distribution in each extract. The major allergen, Cat 1, could be isolated from the crude CHSS extract by preparative HPLC in acceptable purity, determined by crossed radioimmunoelectrophoresis.


Formation and Luminescent Properties of Al2O3:SiOC Nanocomposites on the Base of Alumina Nanoparticles Modified by Phenyltrimethoxysilane.
Al2O3:SiOC nanocomposites were synthesized by thermal treatment of fumed alumina nanoparticles modified by phenyltrimethoxysilane. The effect of annealing temperature in inert ambient on structure and photoluminescence of modified alumina powder was studied by IR spectroscopy as well as photoluminescence spectroscopy with ultraviolet and X-ray excitation. It is demonstrated that increase of annealing temperature results in formation of silica precipitates on the surface of alumina particles that is accompanied by development and spectral evolution of visible photoluminescence. These observations are discussed in terms of structural transformation of the surface of Al2O3 particles.


"Gut-brain axis": Review of the role of the probiotics in anxiety and depressive disorders.
Depressive disorders are the leading cause of disability worldwide and together with anxiety contribute to a very high burden of disease. Therefore, improving their treatment is a significant medical research target: The role of probiotics is a topic of great interest for the current research in this field. To explore the current literature about the impact of probiotics on anxious and depressive symptoms. Scoping review following the PRISMA guidelines. The selection process yielded 23 studies. Probiotics positively affected depressive symptomatology and anxiety symptoms according to 53.83% and 43.75% of the selected studies, respectively. Among the studies assessing inflammatory biomarkers, 58.31% found they were decreased after administration of probiotics. The results emerging from the existing literature about probiotic supplementation for depression treatment are encouraging, but further research is needed considering the shortage of clinical trials on this topic and the heterogeneity of the samples analyzed.


Spontaneous subdural hematoma in a patient receiving dual antiplatelet therapy following percutaneous coronary intervention: A case report.
and importance: Dual antiplatelet therapy with clopidogrel and aspirin is routinely prescribed after coronary artery stenting, plays a critical role in secondary prevention among patients with acute coronary syndrome and has decreased the rates of re-infarction and stent thrombosis after percutaneous coronary intervention, but they are prone to internal bleeding. Intracranial hemorrhage is the most serious bleeding complication in a patient put on antiplatelet therapy following PCI. Acute spontaneous subdural hematoma (ASSDH) without trauma is a rare event, which needs to be promptly recognized and managed. In this mini-review, we report a case of a 71-year-old man who represented spontaneous acute subdural hematoma receiving dual antiplatelet (aspirin and clopidogrel) following percutaneous coronary intervention for acute coronary syndrome. Rapid discontinuation of all of the antiplatelet drugs and hematoma evacuation were performed with good postoperative evolution. Management of hemorrhagic patients under antithrombotic therapy is very difficult. Resuming the treatment could lead to recurrence bleeding, on the other hand, suspension or stopping of treatment could expand the thrombotic risk. ASSDH after PCI is true diagnostic then therapeutic emergency, especially in patients with rapid neurological degradation. Treatment may be managed by nonoperative conservative approach in selected cases. Spontaneous subdural hematoma is a rare, serious entity, although it can engage the functional and vital prognosis of the patient, hence the interest of diagnosis and prompt treatment to improve the prognosis.


Hemostasis in a giant intraventricular tumor using a saline-cooled radiofrequency bipolar coagulator: technical note.
Meningiomas are relatively rare in children and tend to be intraventricular and cystic, with often malignant behavior. Complete excision is associated with the most favorable outcome; moreover, the size and extent of these lesions often make complete excision in one step impossible because of the risk of intraoperative death from uncontrollable hemorrhage. A 10-year-old girl was admitted for headache in the last 3 months and was found to have a giant left intraventricular lesion with a volume of 166.63 cm3, which caused hydrocephalus and significant mass effect. Very large draining veins were evident within the tumor, draining into the thalamostriates and internal cerebral veins. Cerebral angiography showed multiple feeders originating mainly from branches of the posterior left choroidal artery with distal afferents that could not be embolized. Therefore, a left parietal transcortical approach was chosen. Given the vascularity of the tumor, saline-cooled radiofrequency coagulation (Aquamantys®) was used to reduce blood loss intraoperatively. Gross total resection (GTR) was achieved with an estimated blood loss of 640 mL. Pathology analysis was consistent with WHO grade 1 transitional meningioma. Postoperatively, the patient was neurologically intact, and MRI confirmed complete resection. Aquamantys® is a novel bipolar coagulation device that employs a new bipolar coagulation technique combining radiofrequency energy and saline to achieve hemostatic sealing by denaturing collagen fibers. This offers the possibility of achieving adequate hemostasis even in giant intraventricular tumors in infants to obtain GTR resection with minimal blood loss.


Distribution of monoamine oxidase in hippocampal region of the rat.
The distribution and development of type A and type B monoamine oxidase (MAO) activities in the hippocampal region of the rat was investigated with biochemical microdetermination. Type A MAO is absolutely dominant and unevenly distributed in the hippocampus. The development of type A MAO in the hippocampus seems to be delayed and reachs adult levels by the 30th day after birth.


Orchestrating morphogenesis: building the body plan by cell shape changes and movements.
During embryonic development, a simple ball of cells re-shapes itself into the elaborate body plan of an animal. This requires dramatic cell shape changes and cell movements, powered by the contractile force generated by actin and myosin linked to the plasma membrane at cell-cell and cell-matrix junctions. Here, we review three morphogenetic events common to most animals: apical constriction, convergent extension and collective cell migration. Using the fruit fly Drosophila as an example, we discuss recent work that has revealed exciting new insights into the molecular mechanisms that allow cells to change shape and move without tearing tissues apart. We also point out parallel events at work in other animals, which suggest that the mechanisms underlying these morphogenetic processes are conserved.


Structure and functionality of Rhamnogalacturonan I in the cell wall and in solution: A review.
Rhamnogalacturonan I (RG-I) belongs to the pectin family and is found in many plant cell wall types at different growth stages. It plays a significant role in cell wall and plant biomechanics and shows a gelling ability in solution. However, it has a significantly more complicated structure than smooth homogalacturonan (HG) and its variability due to plant source and physiological state contributes to the fact that RG-I's structure and function is still not so well known. Since functionality is a product of structure, we present a comprehensive review concerning the chemical structure and conformation of RG-I, its functions in plants and properties in solutions.


The association between insecurity and subjective well-being among youth during the COVID-19 outbreak: A moderated mediation model.
Sudden and unpredictable changes caused by the COVID-19 pandemic have profoundly threatened the psychological well-being and increased insecurity among adolescents worldwide. At a critical developmental stage, the well-being of the youth is more vulnerable to adverse environments. This study constructed a moderated mediation model to explore the buffering factors between insecurity and subjective well-being of the youth during the pandemic. During the COVID-19 outbreak in June 2020, data of 5,503 Chinese youth (15-29 years old) were collected via an online questionnaire. Subjective well-being, insecurity, self-control, and hope were measured, and the moderated mediation model was analyzed. Findings from this study showed that with the mediating effect of self-control, insecurity negatively predicted subjective well-being, and hope moderated the association between insecurity and self-control. Specifically, the link between insecurity and self-control was stronger when hope was low but weaker when hope was high. Since this study was mainly conducted in China, and considering the continuous change of the pandemic on a global scale, it is of great significance to conduct cross-cultural and cross-time studies in the future. The results demonstrate that self-control and hope play important roles in buffering the negative effects of insecurity on the subjective well-being of adolescents and young adults. The findings provide implications for reducing the negative impact of insecurity from a positive psychology perspective and for youth mental health interventions during public health crises.


Uncovering variable neoplasms between ATM protein-truncating and common missense variants using 394 694 UK Biobank exomes.
As an essential regulator of DNA damage, ataxia-telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein-truncating variants (PTVs) on neoplasms have not been heavily studied. Whole-exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene-level and variant-level phenome-wide association studies, and conducted a variant-level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene-level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p < 2 × 10-9 ) associated with 31 malignant neoplasm phenotypes. Of 773 distinct protein-coding variants in ATM, three individual missense variants significantly (p < 2 × 10-9 ) associated with nine phenotypes. Remarkably, although the nine phenotypes were tumor-related, none overlapped the established ATM PTV-linked malignancies. A subsequent conditional analysis identified that the missense signals were acting independently of the known clinically relevant ATM PTVs.


Epidemiologic implications of changes in the influenza virus genome.
Among the molecular maneuvers that enable the influenza virus to survive are antigenic variation and functional alterations. Two kinds of minor antigenic variations, producing new strains within type A virus subtypes, have been discovered: antigenic drift, in which the amino acid sequences of the antigens are changed; and antigenic camouflage, in which the antigens are glycosylated. Both kinds of variation are caused by mutations in the viral genome. These mutations produce slightly changed antigens, which many existing antibodies cannot recognize. Major antigenic variations (so-called antigenic shift) are produced by gene reassortment. Two subtypes, coinfecting a host, can reassort their eight ribonucleoprotein gene segments into as many as 256 different combinations. Such recombinations can produce new viruses with the potential for transmission in humans, but whose surface antigens are completely unmatched by antibodies in the population, permitting a pandemic to occur. Functional changes, caused by mutations, alter the interactions between the virus and the host, including virus binding to host receptor sites and fusion of viral and host membranes. All these mechanisms allow the influenza virus to survive in humans, probably perpetually.


Photon channelling in foams.
Experiments by Gittings, Bandyopadhyay and Durian (Europhys. Lett. 65, 414 (2004)) demonstrate that light possesses a higher probability to propagate in the liquid phase of a foam due to total reflection. The authors term this observation photon channelling which we investigate in this article theoretically. We first derive a central relation in the work of Gitting et al. without any free parameters. It links the photon's path-length fraction f in the liquid phase to the liquid fraction epsilon. We then construct two-dimensional Voronoi foams, replace the cell edges by channels to represent the liquid films and simulate photon paths according to the laws of ray optics using transmission and reflection coefficients from Fresnel's formulas. In an exact honeycomb foam, the photons show superdiffusive behavior. It becomes diffusive as soon as disorder is introduced into the foams. The dependence of the diffusion constant on channel width and refractive index is explained by a one-dimensional random-walk model. It contains a photon channelling state that is crucial for the understanding of the numerical results. At the end, we shortly comment on the observation that photon channelling only occurs in a finite range of epsilon.


Ishophloroglucin A-based multifunctional oxidized alginate/gelatin hydrogel for accelerating wound healing.
This study investigated the potential applicability of wound dressing hydrogels for tissue engineering, focusing on their ability to deliver pharmacological agents and absorb exudates. Specifically, we explored the use of polyphenols, as they have shown promise as bioactive and cross-linking agents in hydrogel fabrication. Ishophloroglucin A (IPA), a polyphenol not previously utilized in tissue engineering, was incorporated as both a drug and cross-linking agent within the hydrogel. We integrated the extracted IPA, obtained through the utilization of separation and purification techniques such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR) into oxidized alginate (OA) and gelatin (GEL) hydrogels. Our findings revealed that the mechanical properties, thermal stability, swelling, and degradation of the multifunctional hydrogel can be modulated via intermolecular interactions between the natural polymer and IPA. Moreover, the controlled release of IPA endows the hydrogel with antioxidant and antimicrobial characteristics. Overall, the wound healing efficacy, based on intermolecular interactions and drug potency, has been substantiated through accelerated wound closure and collagen deposition in an ICR mouse full-thickness wound model. These results suggest that incorporating IPA into natural polymers as both a drug and cross-linking agent has significant implications for tissue engineering applications.


[Study of the Wirsung duct by echography (author's transl)].
With the usual echographic technics, the Wirsung duct, when dilated can be only episodically seen: the seesaw motion of the transducer produces some undesirable echoes, which rub out the lumen of the Wirsung duct. In order to obtain steadily pictures of the dilated Wirsung duct, the transducer must be used with a sweep motion in only one direction, while a positive pressure is exerted on the epigastrium. When transversally intersected, the Wirsung duct appears spindle shaped; it can be displayed on a rather good length. When sagittaly intersected, it presents, itself like a curved shaped picture, 4 mm to 2 cm in diameter, empty of echoes, in the center of the pancreatic section. The Wirsung duct, with the former technics, had been displayed 20 times in 140 cases of chronic pancreatitis; whe have found it in 4 cases in our 10 last cases of chronic pancreatitis. These case have been verified by endoscopic Wirsungography.


Immunization of dogs with a Leishmania infantum-derived vaccine.
A partially-purified extract of Leishmania infantum has been administered to healthy dogs. Post-immunization sera were found to neutralize the infectivity of L. infantum and to abate the development of L. major. Muramyl dipeptide and one of its derivates, murabutide, were the best adjuvants.


Math-Map(ic)s.
In this issue of Neuron, Wang et al. and Machold and Fishell present contrasting molecular fate maps of Math1, which redefine the derivatives of the embryonic rhombic lip and offer a conceptual overhaul of cerebellar and precerebellar development. These fate maps identify a common developmental thread linking diverse, functionally associated neurons and reveal an exquisite temporal organization in cell production within a precise spatially defined region of neuroepithelium.


Raman spectroscopy of carbon and solid bitumens in sedimentary and metamorphic rocks.
Different types of carbonaceous matter from rocks display Raman spectral features which knowledge permits to obtain structural information of these materials. Application of Raman microspectroscopy to investigate kerogen, bitumen, fossils, highly carbonified amorphous carbon as well as graphite from different environments is reviewed. Differences in Raman spectra and structural differences between carbonaceous samples differing in their metamorphic history are discussed on the basis of new data.


Water utilization of tropical hardwood hammocks of the Lower Florida Keys.
Predawn water potential of representative plant species, together with stable isotope composition of stem water and potential water sources were investigated in four low-elevation tropical hardwood hammocks in the Lower Florida Keys, during a one year period. Hammock species had the lowest water potentials when soil water content was low and/or soil salinity was high, but differences in groundwater salinity had no effect on the water potential. Comparison of D/H ratio of plant stem water with soil and ground water corroborates the conclusion that they are primarily utilizing soil water and not groundwater. Thus, tropical hardwood hammocks are buffered from saline groundwater, and are able to thrive in areas where groundwater salinity is as high as 25‰. The effect of sea level rise on these forests may depend more on changes in the frequency of tidal inundation of the soil surface than on changes in groundwater salinity.


Intensive treadmill training promotes cognitive recovery after cerebral ischemia-reperfusion in juvenile rats.
Rehabilitation training is routine for children who experience stroke, but its protective mechanism remains unclear. To study the effect of treadmill training intensity on hippocampal synaptic plasticity after cerebral ischemia, a model of middle cerebral artery occlusion (MCAO)/reperfusion was established in young rats to simulate childhood ischemic stroke. The rats were randomly allocated into five groups: sham operation, MCAO, low-intensity exercise and MCAO (5 m/min), medium-intensity exercise and MCAO (10 m/min), and high-intensity exercise and MCAO (15 m/min). Intervention was continued for 14 days, and a series of experimental tests were conducted. After MCAO, the juvenile rats exhibited a series of morphological and functional alterations, including changes in their neurobehavior and cerebral infarct volumes. Compared with control rats, MCAO rats had a longer escape latency and crossed fewer platforms in the water maze test and exhibited decreased hippocampal neuron density and Synapsin I and PSD95 expression. Furthermore, MCAO rats exhibited synapse morphology changes and abnormal serum levels of lactic acid and corticosterone. Treadmill training effectively reduced the neurobehavioral scores and cerebral infarction volumes, with medium-intensity training showing the best effect. Treadmill training shortened the escape latency, increased the number of platform crossings, and improved the spatial cognitive abilities of the rats, with the medium intensity training having the best effect on spatial learning/memory efficiency. Treadmill training increased the neuron density in the hippocampus, with the medium-intensity training resulting in the highest density. Treadmill training had a positive effect on the expression of Synapsin I and PSD95, with the medium-intensity training showing the strongest effect. Treadmill training improved the sub-microstructure synapse morphology, with the medium-intensity training demonstrating the best effect. Treadmill training increased the plasma levels of lactic acid and corticosterone, with the high-intensity training having the most obvious effect. Treadmill training can provide neuroprotection by promoting hippocampal synaptic plasticity, with medium-intensity training showing the most optimal effects.


The stiffness parameter β assessed by an ultrasonic phase-locked echo-tracking system is associated with plaque formation in the common carotid artery.
Assessment of plaque formation in the common carotid artery (CCA) is important for stratification of the risk of subsequent stroke. The stiffness parameter β, which can be assessed using an ultrasonic phase-locked echo-tracking system, was developed to evaluate arterial stiffness. The purpose this study was to examine the relationship of the stiffness parameter β to intima-media thickness (IMT) and plaque formation. The stiffness parameter β and mean IMT were measured using an ultrasonic phase-locked echo-tracking system and an automatic IMT measurement system, respectively, and the presence of plaque was assessed by ultrasonography in 347 subjects who took part in a health check-up program for community-dwelling people in Hokkaido. Values of the stiffness parameter β were significantly higher in subjects with plaque formation than in those without plaque (10.60 ± 0.45 vs. 8.88 ± 0.23, P < 0.005) in whom IMT was not thickened; however, it was not different in subjects with increased IMT (>1.0 mm). The percentage of plaque formation was significantly correlated with the value of the stiffness parameter β. Furthermore, the stiffness parameter β was significantly correlated with plaque formation after adjustment for several clinical variables (odds ratio 1.113-1.178, P < 0.001). The stiffness parameter β is associated with plaque formation in the CCA, especially in subjects with a normal IMT. This could potentially be used as a predictor for plaque formation.


Purification and properies of cAMP dependent and independent histone kinases from human leukocytes.
Histone kinase activity was purified from human polymorphonuclear leukocytes by ammonium sulphate precipitation of a 180 000 x g supernatant, followed by DEAE-cellulose chromatography and gelfiltration. On DEAE-cellulose cAMP dependent kinase activity eluted in two peaks, I and III, at 1.2 mmho and 6.5 mmho, respectively. Catalytic subunit (C) from both peaks had Mr 33 000, 3.0S. Regulatory subunit (R) from peak I and III both had Mr 33 000 upon gelfiltration, but sedimented at 2.8--3.0S and 3.0--3.2S, respectively. R2 and R4 subunits were identified. The R-C dimer from peak I and III sedimented at 4.8S and (4.8)--5.1S, respectively. The holoenzyme from peak I had Mr 165 000, 6.7S, which suggest a R2C2 structure, while that of peak III sedimented at 6.7S, but eluted at Mr 330 000 (2R2C2) by gelfiltration. The Kmapp for peak I and III enzymes were, respectively: histone IIA 0.5 mg/ml (both forms), ATP 18 microM and 23 microM, and cAMP 5 X 10(-8) M and 6.3 x 10(-8) M. Both enzymes had pH optimum 6.7--6.9 and were equally sensitive to Ca2+, temperature and protein kinase inhibitor. The substrate specificity was histone VS greater than histone IIA = histone VIS greater than casein greater than phosvitin. Peak I enzyme, but not peak III enzyme, was dissociated by histone and high ionic strength and reassociation of R and C subunits were facilitated by ATP-Mg. It is concluded that peak I and III enzymes represent type I and II cAMP dependent protein kinases, respectively. Type I comprises 20--30% of cAMP dependent protein kinase activity and is absent from the 180 000 x g supernatant of gently disrupted cells. Purified catalytic subunit had Kmapp (ATP) 20 microM with rabbit muscle glycogen synthease I as substrates. Synthase I from rabbit muscle and human leukocytes were phosphorylated by catalytic subunit to synthase D (ratio of independence less than 0.07). cAMP independent histone kinase activity eluted in one peak (Peak II) at3 mmho. The enzymatic activity sedimented at 3.4S and eluted from gelfiltration with Mr 78 000. Kmapp for ATP was 78 microM and for histone IIA 0.5 mg/ml. The enzyme was sensitive to temperature, but less sensitive than cAMP dependent protein kinase to Ca2+, and insensitive to protein kinase inhibitor. The substrate specificity was histone IIA greater than histone VS = histone VIS, while casein and phosvitin were poor substrates. Glycogen synthase I was not phosphorylated. The cAMP independent histone kinase activity comprised 15% of the total histone kinase activity in a crude homogenate of leukocytes. Its physiological substrate is unknown.


Biogenic rock varnishes of the negev desert (Israel) an ecological study of iron and manganese transformation by cyanobacteria and fungi.
The ecology of the microflora, which produces rock varnishes in the Negev is described. It is shown that biogenic rock varnishes may form within relatively short periods (1967-1981) on places where pre-existing varnishes were eliminated. Rock varnishes are thin coatings, mainly composed of Fe and Mn hydroxides and clay material. Biogenic rock varnishes form at places where "microbial weathering fronts", which destroy the rock substrate, advance extremely slowly or come to stillstand, thus enabling the development of biogenic "protective coatings". Rock varnish is mainly produced by the activity of often lichenised epi- and endolithic cyanobacteria, chemoorganotrophic bacteria, and fungi, which are sometimes associated with the still debatable Metallogenium symbioticum. In cases, where "microbial weathering fronts" reach harder bedrocks during their progress, the then developing rock varnish plays a protective role for the microflora beneath the varnish in formation. This microflora otherwise would be directly exposed to the harsh desert conditions and could not survive. Biogenic rock varnishes are characteristic examples of a microbial ecosystem, which adapted itself to one of the most extreme environments on this planet, i.e. high irradiation, extremely low water activity, no chances of deplacement upwards or downwards and in addition the highest daily changes in temperature and irradiation and humidity one may observe in natural environments. It seems, that the "solution front community" which is trapped on increasingly harder and resistant rocks has evolved the capacity to protect itself from the harsh environmental conditions by the creation of rock varnish as a kind of armour shielding it from the extremes of environmental stress.


Sinonasal inverted papilloma - malignant transformation and non-sinonasal malignancies.
To assess malignant transformation rate, non-sinonasal malignancies, and factors contributing to recurrence in patients treated for sinonasal inverted papilloma (SNIP). Retrospective study. We retrospectively reviewed medical records of all patients treated for SNIP (n = 296) between the years 1984-2014 at Helsinki University Hospital. Data from the Finnish Cancer Registry confirmed the number of those patients with sinonasal and non-sinonasal malignancies. Only 2 of 296 (0.7%) patients primarily diagnosed with benign SNIP developed sinonasal cancer in a mean follow-up of 5.8 years. The most common non-sinonasal cancer sites were similar to those reported for the whole Finnish population. None of the patients presented with an HPV-associated non-sinonasal malignancy. The recurrence rate among patients who underwent attachment-oriented surgery was significantly lower compared to those operated on with other approaches (40.2% vs. 56.6%, p = 0.006). Dysplasia in SNIP was associated with a higher recurrence rate (p < 0.001). Malignant transformation of SNIP was rare. Patients with SNIP were not prone to HPV-associated non-sinonasal malignancies. Endoscopic resection and attachment-oriented surgery have become predominant approaches in the treatment of SNIP; meanwhile, the total number of SNIP recurrences has decreased. 3 Laryngoscope, 133:506-511, 2023.


Sensitivity of mitochondrial peptidyl-prolyl cis-trans isomerase, pyridine nucleotide hydrolysis and Ca2+ release to cyclosporine A and related compounds.
Prooxidants activate a specific Ca2+ release pathway from mitochondria. Here we investigate the inhibitory potency of cyclosporine A and six related compounds with respect to peptidyl-prolyl cis-trans isomerase (PPIase), pyridine nucleotide hydrolysis and Ca2+ release. Whereas the absolute inhibitory potency of the compounds varies by about three orders of magnitude, a given compound is always most effective on PPIase, followed by pyridine nucleotide hydrolysis, and least effective in Ca2+ release inhibition. The data show that pyridine nucleotide hydrolysis is a prerequisite but not a consequence of Ca2+ release. They also strongly suggest that PPIase participates in the Ca2+ release mechanism from intact mitochondria by regulating the intramitochondrial NAD+ glycohydrolase, and thereby ascribe a physiological function to the protein. Furthermore, a complete lack of correlation between the inhibitory potencies described here and the reported immunosuppressive activities of the drugs is evident.


Prenatal aspects in spinal muscular atrophy: From early detection to early presymptomatic intervention.
With the recent advances in spinal muscular atrophy therapies, the complete scenario of standard of care and following up is changing not only in the clinical field with new phenotypes emerging but also with new expectations for patients, caregivers and health providers. The actual evidence indicates that early intervention and treatment is crucial for better response and prognosis. Knowledge of the prenatal and pre-symptomatic postnatal stages of the disease are becoming essential to consider the opportunities of timely diagnosis and to decide the earliest therapeutic intervention.


Bronchogenic sarcomatoid squamous cell carcinoma with osteoclast-like giant cells.
A 60-year-old man developed a widely metastatic spindle cell neoplasm with admixed osteoclast-like giant cells indistinguishable from malignant giant cell tumor of soft parts. Autopsy revealed a bronchogenic sarcomatoid squamous cell carcinoma that was the primary source of the sarcomatoid metastases. The osteoclast-like giant cells in the metastatic lesions were negative for lysozyme on immunoperoxidase staining. This finding suggested that the multinucleated giant cells were not formed as a cellular response to hemorrhage or to cellular debris induced by the tumor. Extraosseous neoplasms with osteoclast-like giant cells are rare neoplasms that may occur in a variety of organs. This case is the second reported case of a primary neoplasm in the lung that contained these osteoclast-like giant cells. These tumors may cause considerable diagnostic confusion.


Chronobiology: Is daylight saving time a deer-saving time?
Earlier human activity relative to sunrise and sunset, the very essence of daylight saving time, is linked with health and safety detriments in humans. A new study predicts that deer, at least, may benefit from earlier human activity through reduced deer-vehicle collisions.


Correction: Relationship between weight and linear dimensions of Bluefin tuna (Thunnus thynnus) following fattening on western Mediterranean farms.
[This corrects the article DOI: 10.1371/journal.pone.0200406.].


Immune checkpoint inhibitors-induced systemic capillary leak syndrome: A report of two cases.
The occurrence of systemic capillary leak syndrome under immune checkpoint inhibitors has seldom been reported in the literature. We report two cases of systemic capillary leak syndrome that occurred with nivolumab (anti-PD-1 antibody) for one, and with an anti-PD-1/CTLA-4 bi-specific antibody for the other. Patients presented with anasarca, hypoalbuminemia, acute kidney injury and, in one case, circulatory collapse. Immune checkpoint inhibitor causality was retained in the lack of evidence for other causes of secondary capillary leak syndrome or for an idiopathic form. The symptoms resolved after a few days of supportive measures (associated with glucocorticoids in one case). A high index of suspicion is required for the diagnosis of immune checkpoint inhibitors-induced systemic capillary leak syndrome because its presentation may differ from that of the idiopathic form. Activated CD8+ T-cells play a prominent role in the occurrence of immune checkpoint inhibitors-induced capillary leakage via their cytolytic action on the vascular endothelium. Treatment relies on supportive measures and discontinuation of the immune checkpoint inhibitor while the place of immunomodulatory drugs remains to be defined.


An overview of current knowledge in biological functions and potential theragnostic applications of exosomes.
Exosomes are cup-shaped structures, made of two lipid layers. Their size is in the range of 30-150 nm. Exosomes are excreted to the extracellular space and function in local and systemic cellular communication. Based on their primary origins, they can contain substantial amounts of RNA, protein, and miRNA; the horizontal transfer of these contents significantly determines the exosome's biological effects. The endosomal origins of exosomes can be deduced based on their surface protein markers. The use of exosomes as a diagnostic biomarker and therapeutic tool, has numerous advantages because they do not pose risks such as aneuploidy and transplant rejection. This - overview highlights the recent findings in exosome development and current knowledge in exosome-based therapies.


Nuclear barrier hypothesis of aging as mechanism for trade-off growth to survival.
When the aging-dependent cellular behaviors toward growth factors and toxic stress have been analyzed, the perinuclear accumulation of the activated signals, either mitogenic or apoptotic, has been observed, suggesting the aging-dependent inefficiency of the nucleocytoplasmic trafficking of the signals. Thereby, it would be natural to assume the operation of the functional nuclear barrier in aging-dependent manner, which would be designated as "Park and Lim's Barrier." And for the ultimate transcriptional factor for these aging-dependent changes of the functional nuclear barrier, Sp1 transcriptional factor has been suggested to be the most probable candidate. This novel mechanism of aging-dependent operation of the functional nuclear barrier is proposed as the ultimate checking mechanism for cellular protection against toxic environment and the general mechanism for the trade-off growth to survival in aging.


T-cell differentiation: MHC class I's sweet tooth lost on maturity.
The addition of sialic acid to O-linked glycans of the T-cell co-receptor CD8 is regulated during thymocyte differentiation. Two recent papers have shown that this glycosylation changes the avidity of the interaction between CD8 and MHC class I proteins, potentially altering signalling thresholds in thymocyte differentiation.


Characteristics of breath sound in infants with risk factors for asthma development.
Breath sound parameters have been suggested as biomarkers of the airway narrowing in children. Using a commercially available breath sound analyzer, the characteristics of the airway condition were investigated in infants with the risk factors for asthma development. A total of 443 infants (mean age, 9.9 months; range, 3-24 months) were included in the present study. The breath sound parameters of the frequency limiting 99% of the power spectrum (F99), the roll-off from 600 to 1200 Hz (Slope) and spectrum curve indices, the total area under the curve of the dBm data (A3/AT) and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF75 and RPF50), were evaluated. Using an ATS-DLD based original Japanese questionnaire, we examined the characteristics of airway condition of infants. Finally, 283 infants in good health were included in the present study. The RPF75, RPF50, Slope and F99 in infants with positive results of allergy and atopic dermatitis were significantly increased more than those in the infants with negative result. Our data highlight the characteristics of breath sounds in infants with risk factors for asthma. The breath sound analysis may be useful for assessing the airways of infants for asthma development.


An older origin for the Acheulean at Melka Kunture (Upper Awash, Ethiopia): techno-economic behaviours at Garba IVD.
In the 1970s and 1980s, the emergence of the Acheulean at Melka Kunture (Upper Awash, Ethiopia) was dated to 1 Ma (million years ago), based on the typo-metrical analysis of the lithic assemblage of Garba XIIJ. Older sites such as Gombore I, Karre I, and Garba IV (1.7-1.5 Ma) were classified as Oldowan/Developed Oldowan. Consequently, the Oldowan and the Acheulean at Melka Kunture were interpreted as two distinct technologies separated by a chronological gap of 0.5 Ma. The archaeostratigraphic unit D of Garba IV, dated to ~1.5 Ma, yielded one of the richest Early Stone Age lithic series in East Africa. In this paper, a review traces methods of technological analysis, based on the concept of chaîne opératoire, to update our knowledge of the techno-economic behaviours at this site. The results show two major elements characteristic of cultural changes in the Melka Kunture sequence: (1) the emergence of a new chaîne opératoire focused on large flake/large cutting tool (LCT) production, and (2) a large variability of small débitage modalities with systematic preparation of the striking platform and the appearance of a certain degree of predetermination. These technological traits are shared by the contemporaneous sites in East Africa and are considered to be typical of the early Acheulean. This suggests an older origin for the Acheulean at Melka Kunture, 0.5 Ma than previously inferred.


Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast.
Despite strong possibility that endothelial cells (ECs) of tumors and normal tissues may differ in various aspects, most previous studies on ECs have used normal cells. Here, we purified ECs from tumorous and normal human breast tissues, and studied the effect of radiation on angiogenesis and relevant molecular mechanisms in these cells. We found that in normal tissue-derived ECs (NECs), 4 Gy irradiation increased tube formation, matrix metalloproteinase 2 (MMP-2) expression and extracellular signal-regulated kinase (ERK) pathway activation. In cancer-derived ECs (CECs), however, 4 Gy irradiation significantly reduced tube formation, increased the production of angiostatin and interleukin-6 (IL-6), and upregulated AKT and c-Jun N-terminal kinase (JNK) pathway activation. Knockdown experiments showed that siMMP-2 efficiently inhibited tube formation by irradiated NECs, whereas siPlasminogen effectively attenuated the radiation-induced suppression of tube formation and the upregulation of angiostatin in CECs. Moreover, siIL-6 clearly inhibited the radiation-induced generation of angiostatin in CECs. Inhibition of ERK with a pharmacological inhibitor or small interfering RNAs (siRNAs) markedly suppressed the radiation-induced tube formation and MMP-2 upregulation in NECs, whereas the inhibition of either AKT or JNK with pharmacological inhibitor or siRNA treatment of CECs markedly attenuated the inhibition of tube formation and the upregulation of angiostatin and IL-6 caused by 4 Gy irradiation. These observations collectively demonstrate that there are distinct differences in the radiation responses of NECs and CECs, and might provide important clues for improving the efficacy of radiation therapy.


Delayed presentation of paracetamol overdose.
Deliberate self-harm, including intentional self-poisoning, remains a major health concern in South Africa. Increasing number of cases place a significant burden on our Emergency Centres (EC's). Paracetamol remains the most frequent drug ingested in intentional self-poisoning. As an antidote, N-acetylcysteine (NAC) is very effective in the management of acute cases of paracetamol overdose. However, it shows less efficacy in cases of delayed presentation, where both liver transplant and mortality rates are significantly higher. We present a case of delayed presentation paracetamol overdose. The patient presented in fulminant hepatic failure with encephalopathy, but made a full recovery after being treated with NAC. This case report highlighted NAC's potential effectiveness in delayed presentations of paracetamol overdose, irrespective of associated fulminant hepatic failure. The effectiveness of NAC in delayed presentations of paracetamol overdose should therefore not be underestimated, and warrants further research.


Molecular Typing and Antimicrobial Susceptibility Profile of Staphylococcus aureus Isolates Recovered from Bovine Mastitis and Nasal Samples.
In the present study, we aimed to determine the antimicrobial resistance and molecular typing of Staphylococcus aureus recovered from transient and persistent intramammary infections and nares/muzzles in dairy cows. We investigated the antimicrobial resistance of 189 S. aureus strains using a broad antimicrobial susceptibility profile. Furthermore, 107 S. aureus isolates were strain-typed using staphylococcal protein-A (spa) typing. A large proportion of strains exhibited multidrug resistance to antimicrobials, including resistance to critically important antimicrobials, although no methicillin-resistant S. aureus strains were found. Our study did not strengthen the idea that extramammary niches (i.e., nares/muzzles) are an important source of S. aureus for bovine mastitis. A discrepancy in the antimicrobial resistance between S. aureus strains isolated from nares/muzzles and milk samples was observed. Furthermore, S. aureus isolates from transient and persistent intramammary infections (IMIs) did not differ by spa typing, suggesting that the persistence of bovine IMIs was determined by cow factors. Thus, the high level of multidrug-resistant S. aureus found in the two herds, considered together with the predominance of a well udder-adapted S. aureus strain, may contribute to our knowledge of the history of the high prevalence of mastitis caused by S. aureus, which is of great concern for animal and public health.


Metabolic syndrome and left ventricular function: is the number of criteria actually important?
Metabolic syndrome (MS) is a clustering of cardiovascular risk factors responsible for the development of target organ damage. The aim of this study was to determine the effect of the increasing number of MS risk factors on left ventricular function assessed by noninvasive methods. The study included 204 subjects with MS and 76 controls with no MS risk factors. MS was defined by the presence of 3 or more of ATP-NCEP III criteria. MS subjects were grouped according to the number of criteria they fulfilled: 3 criteria (n=91), 4 criteria (n=65) and 5 criteria (n=48). All subjects underwent laboratory blood tests, complete 2-dimensional, pulse and tissue Doppler echocardiography. Echocardiography was used to assess systolic (LVEF, sseptal), diastolic function, by pulse-wave Doppler (E/A ratio) and tissue Doppler imaging (E/e'average), and global left ventricular function (Tei index). Appropriate time intervals for the estimation of the Tei index were obtained by tissue Doppler. Transmitral E/A ratio decreased significantly and progressively from the 3 criteria to the 5 criteria group (0.82 ± 0.25 vs. 0.79 ± 0.24 vs. 0.67 ± 0.14, p<0.001). The transmitral E/E'average ratio was significantly and gradually increased from the 3 criteria to the 5 criteria group (7.76 ± 1.81 vs. 9.44 ± 2.35 vs. 10.82 ± 2.56, p<0.001). The left ventricle Tei index progressively increased from the 3 criteria to the 5 criteria group (0.43 ± 0.11 vs. 0.48 ± 0.10 vs. 0.54 ± 0.12, p<0.001). The increasing number of MS criteria is associated with cardiac diastolic dysfunction.