Secochiliolide ester derivatives: Preparation and evaluation of their antitrypanosomal and antimalarial efficacy.
In the present study, a series of new esters of secochiliolide acid (SA), a diterpene isolated from Nardophyllum bryoides, were synthesized in good yield. All compounds were evaluated for their in vitro antiparasitic properties (on Plasmodium falciparum and Trypanosoma brucei brucei) and cytotoxicity (on WI38, normal mammalian cells). They displayed moderate antitrypanosomal activity with IC50 values between 2.55 and 18.14 μm, with selectivity indices >10, and low antiplasmodial effects with IC50 > 29 μm. The only exception was the n-hexyl ester of SA, which showed a strong and selective antiplasmodial activity (IC50 = 1.99 μm and selectivity index = 117.0). The in vivo antimalarial efficacy of this compound was then assessed according to the 4-day suppressive test of Peters in mice. An intraperitoneal treatment at 50 mg kg-1 day-1 induced a slight parasitaemia reduction by 56% which was statistically significant on day 4 post-infection and an increase in the survival time.


The chronological life span of Saccharomyces cerevisiae to study mitochondrial dysfunction and disease.
Saccharomyces cerevisiae has played an important role as a model system to understand the biochemistry and molecular biology of mammalian cells. The genetic tools available and the short life span have also made S. cerevisiae a powerful system to study aging. The yeast chronological life span (CLS) is a measure of the survival of a non-dividing population of cells, and thus can model aging of mammalian non-dividing cells but also of higher eukaryotic organisms. The parallel description of the pro-aging role of homologs of Akt, S6 kinase, adenylate cyclase, and Tor in yeast and in higher eukaryotes, suggests that findings in the S. cerevisiae will be valuable to understand human aging and diseases. Moreover, the similarities between mitochondria and age-dependent mitochondrial damage in yeast and mammalian cells indicate that S. cerevisiae is a valuable model to study mitochondrial dysfunction and diseases that involve this organelle. Here, we describe the use of S. cerevisiae CLS in combination with three methods to quantify age-dependent mitochondrial damage and the accumulation of mitochondrial DNA mutations.


Primary angioplasty reduces the risk of left ventricular free wall rupture compared with thrombolysis in patients with acute myocardial infarction.
This study aimed to evaluate the effect of primary angioplasty (PA) over the risk of free wall rupture (FWR) in reperfused acute myocardial infarction (AMI). It has been suggested that PA reduces the risk of FWR compared with thrombolysis. However, few studies have evaluated this issue, and there are no data demonstrating this hypothesis. A total of 1,375 patients with AMI treated with PA (n = 762, 55.4%) or thrombolysis (n = 613, 44.6%) within 12 h after symptoms onset were included. The diagnosis of FWR was made either in the presence of sudden death due to electromechanical dissociation with large pericardial effusion on an echocardiogram or when demonstrated post mortem or at surgery. A multivariable analysis was performed including type of reperfusion strategy. The overall incidence of FWR was 2.5% (n = 34): 1.8% and 3.3% in patients treated with PA and with thrombolysis, respectively (p = 0.686). The following characteristics were associated with a higher rate of FWR in the univariable analysis: age >70 (5.2% vs. 1.2%, p < 0.001), female gender (5.1% vs. 1.8%, p = 0.006), anterior location (3.3% vs. 1.4%, p = 0.020) and treatment >2 h after symptoms onset (3.6% vs. 1.7%, p = 0.043). In the multivariable analysis, age >70 (odds ratio [OR]: 4.12, 95% confidence interval [CI]: 2.04 to 8.62, p < 0.001) and anterior location (OR: 2.91, 95% CI: 1.36 to 6.63, p = 0.008) were independent risk factors of FWR, whereas treatment with PA was an independent protective factor (OR: 0.46, 95% CI: 0.22 to 0.96, p = 0.0371). In patients with AMI, PA reduces the risk of FWR in comparison with thrombolysis.


MRI findings of renal lymphangiectasia.
We present the case of a 20-year-old male with renal lymphangiectasia who presented with hypertension and hematuria. We discuss the role of magnetic resonance imaging (MRI) with gadolinium-enhanced MR urography in confirming the diagnosis, extensions of this rare benign entity, and associated conditions.


Coupling of C3b to erythrocytes by disulfide bond formation: preparation of EC3b for hemolytic and complement receptor assays.
We describe a new method of preparing C3-coated erythrocytes by coupling C3 to thiol-activated erythrocytes. The procedure involves three steps. Firstly, sheep erythrocytes were treated with N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) to introduce 3-(2-pyridyldithio) propionyl residues into membrane proteins. Secondly, C3 was cleaved with trypsin or CoVF, Bb enzyme to obtain C3b exposing the SH group (C3b-SH). Finally, the C3b-SH was coupled to the thiol-activated erythrocytes (TA-E) through thiol/disulfide exchange to form the TA-EC3b conjugate. E coated with C3d was prepared by treating TA-EC3b with KSCN inactivated serum and plasmin. Studying the rosette formation between TA-EC3b or TA-EC3d and cells expressing C3b (CR1) and C3d (CR2) receptors and the inhibition thereof with anti-CR1 and anti-CR2 antibodies as well as with C3-sheep E membrane protein complexes, we found that TA-EC3b and TA-EC3d bound exclusively to CR1 and CR2, respectively. In addition, TA-EC3b like EAC1423b bound factors B and H as tested by hemolytic and direct binding assays. The advantage of TA-EC3 for complement receptor and hemolytic assays are the simplicity of the preparation method and the general applicability of the TA-EC3.


The Valentines Trial: results of the first one week worldwide multicentre enrolment trial, evaluating the real world usage of the second generation DIOR paclitaxel drug-eluting balloon for in-stent restenosis treatment.
To assess the safety and efficacy of the second generation DIOR paclitaxel drug-eluting balloon (DEB) for in-stent restenosis in a real world setting in a prospective single-arm registry with 8-month clinical outcomes. In this "real world", international prospective registry, patients with in-stent restenosis (bare-metal stent and drug-eluting stent) were enrolled- in a unique study design- with a one week enrolment period, spread over 104 centres worldwide. Patients underwent predilatation with a regular balloon, with subsequent DEB inflation in the target lesion. Additional stenting of the target lesion was left to the operators discretion in case of suboptimal angiographic success (TIMI flow <3 and/or residual stenosis >30%). The primary endpoint was 6-9-month major adverse cardiac events (MACE: all cause death, myocardial infarction, and target vessel revascularisation). A total of 250 evaluable patients were enrolled in a large web-based clinical research form and treated with the second generation DIOR DEB. Of these, 244 had 6-9 month clinical follow-up, with a mean follow-up time of 7.5 months. The cumulative MACE rate at follow-up was 11.1%, with 3 (1.2%) cardiac deaths, 1 (0.4%) non-cardiac death, 5 (2.0%) myocardial infarctions of which 2 (0.8%) periprocedural, 21 (8.6%) target vessel revascularisations, of which 18 (7.4%) target lesion revascularisations. In-stent restenosis treatment with the second generation DIOR DEB is safe and feasible, with high angiographic success and low target lesion revascularisation and overall MACE rates. Moreover this new and unique method of high speed and short duration multicentre study enrolment was very successful.


A new technique for retrograde stone displacement in the tortuous ureter before extracorporeal shock wave lithotripsy.
A tortuous ureter can prevent a ureteral calculus from being manipulated into the kidney before extracorporeal shock wave lithotripsy. We describe a technique using a floppy-tip guide wire and a double channel cystoscope to manipulate a stone from a tortuous ureter into the kidney.


Cyclic voiding cystouretrography without the use of fluoroscopic monitoring.
To determine whether cyclic voiding cystourethrography (VCUG) examinations can be performed without using real-time fluoroscopic monitoring. VCUG examinations were performed in 209 children (133 girls and 76 boys). In each child, it was performed in a cyclic manner (three consecutive cycles) without using fluoroscopic monitoring and one radiograph was taken in each cycle of the examination. All patients were sedated by midazolam prior to examination. The degree of vesicoureteric reflux (VUR) was graded for each of the kidney ureter units (KUU) (total 418 KUU) separately. Statistical analysis included the comparison of the presence and absence of VUR and three ordinal-matched comparisons of each cycle. VCUG was detected in 37.3% of the children (78/209) and 28.7% (120/418) of the KUU. The absence of or same degree of VUR in three consecutive cycles were obtained in 345 KUU and the agreement was calculated as 82.5%. The same degree and presence of reflux were found in 85 and 89 refluxing KUU, the same negative findings (absence of VUR) in 306 and 298 KUU, and discordant findings in 27 and 31 KUU (between the first and second and between first and third cycles), respectively. Therefore, the agreement was 93.5 and 92.5% between the first and second cycles (p=0.70) and between the first and the third cycles (p=0.15), respectively. Both the cyclic nature of this study and the results indicated that VCUG without real-time fluoroscopic monitoring could be used where adequate fluoroscopic examination is not possible for children in whom VUR detection is necessary and impacts treatment. However, the responsibility of pediatric radiologist always must also include the task to provide proper equipment for imaging children with suspected VUR.


Cellular mechanisms of the steroid-induced vascular responses in the rabbit ear artery.
1. In anesthetized rabbits, topical application of dexamethasone to the ear produced an initial vasodilation followed by a vasoconstriction with long delay (120 min). Diphenhydramine inhibited the former, but not the latter. 2. In isolated rabbit ear arteries, dexamethasone reduced the amplitude of contractions of smooth muscles produced by nerve stimulation, noradrenaline and high-K solution, only at high concentrations (> 10(-5) M). 3. The initial vasodilation induced by topical application of dexamethasone may be related to endogenous histamine, while the delayed constriction response may not be direct actions of steroid to smooth muscles.


Mechanisms of TGFβ3 Action as a Therapeutic Agent for Promoting the Synthesis of Extracellular Matrix Proteins in Hyaline Cartilage.
Hyaline cartilage is a nonvascular connective tissue covering the joint surface. It consists mostly of the extracellular matrix proteins and a small number of highly differentiated chondrocytes. At present, various techniques for repairing joint surfaces damage, for example, the use of modified cell cultures and biodegradable scaffolds, are under investigation. Molecular mechanisms of cartilage tissue proliferation have been also actively studied in recent years. TGFβ3, which plays a critical role in the proliferation of normal cartilage tissue, is one of the most important protein among cytokines and growth factors affecting chondrogenesis. By interacting directly with receptors on the cell membrane surface, TGFβ3 triggers a cascade of molecular interactions involving transcription factor Sox9. In this review, we describe the effects of TGFβ3 on the receptor complex activation and subsequent intracellular trafficking of Smad proteins and analyze the relation between these processes and upregulation of expression of major extracellular matrix genes, such as col2a1 and acan.


Liver X Receptors differentially modulate central myelin gene mRNA levels in a region-, age- and isoform-specific manner.
Liver X Receptors (LXRs) α and β are nuclear receptors able to bind oxidative forms of cholesterol. They play important roles in the central nervous system (CNS), through their implication in a large variety of physiological and pathological processes among which modulation of cholesterol homeostasis and inflammation. Besides, we recently revealed their crucial role in myelination and remyelination in the cerebellum. Given the pleiotropic effects of such receptors on CNS functioning, we studied here the influence of LXRs on myelin gene mRNA accumulation in the major myelinated regions of the CNS in vivo. We show that both LXR isoforms differentially affect mRNA amount of myelin genes (PLP and MBP) in highly myelinated structures such as spinal cord, corpus callosum, optic nerve and cerebellum. In the adult, LXR activation by the synthetic agonist TO901317 significantly increases myelin gene mRNA amount in the cerebellum but not in the other regions studied. Invalidation of the sole LXRβ isoform leads to decreased PLP and MBP mRNA levels in all the structures except the spinal cord, while the knock out of both isoforms (LXR dKO) decreases myelin gene mRNA amounts in all the regions tested except the corpus callosum. Interestingly, during myelination process (post-natal day 21), both cerebellum and optic nerve display a decrease in myelin gene mRNA levels in LXR dKO mice. Concomitantly, PLP and MBP mRNA accumulation in the spinal cord is increased. Relative expression level of LXR isoforms could account for the differential modulation of myelin gene expression in the CNS. Altogether our results suggest that, within the CNS, each LXR isoform differentially influences myelin gene mRNA levels in a region- and age-dependant manner, participating in the fine regulation of myelin gene expression.


Experiencing Health Advocacy During Cervical Cancer Awareness Week: A National Initiative for Obstetrics and Gynaecology Residents.
The Royal College of Physicians and Surgeons of Canada requires that residents demonstrate competence in health advocacy (HA). We sought to develop and implement a national educational module for obstetrics and gynaecology residents to address the role of HA. This pilot program was centred on cervical cancer prevention, which lends itself to applying the principles of advocacy. An educational module was developed and disseminated to all obstetrics and gynaecology residency programs in Canada. The module describes options for HA involving cervical dysplasia screening, such as an outreach clinic or a forum for public/student education, which were to be implemented during Cervical Cancer Awareness Week. The measures of success were the number of programs implementing the curriculum, number of residents who participated, diversity of projects implemented, individuals (patients or learners) reached by the program, and the overall experience of the trainees. Three programs implemented the curriculum in 2011, one in 2012, and seven in 2013. After three years, the module has involved seven of 16 medical schools, over 100 residents, and thousands of women either directly or indirectly. Additionally, attributes of HA experienced by the residents were identified: teamwork, leadership, increased systems knowledge, increased social capital within the community, creativity, innovation, and adaptability. We have demonstrated that an educational module can be implemented nationally, helping our residents fulfill their HA requirements. Other specialties could use this module in building HA into their own programs.


Infertile Men Have Higher Prostate-specific Antigen Values than Fertile Individuals of Comparable Age.
Infertile men are at greater risk for oncological and nononcological chronic disease than fertile individuals. To investigate prostate-specific antigen (PSA) values in men presenting for primary couple's infertility compared with a cohort of fertile individuals, according to the recommendation of the European Association of Urology guidelines that a first PSA assessment should be done at 40-45 yr of age. This is a cross-sectional study. Data from 956 (90%) infertile men and 102 (9.6%) fertile participants were analysed. Circulating hormones, total PSA, and semen parameters were investigated in every man. Descriptive statistics, local polynomial smoothing, and linear regression models were used to test potential associations with PSA levels. Overall, PSA >1 ng/ml was found in 318 (30%) men. Serum PSA was higher (p = 0.02), while serum testosterone (p < 0.01) was lower in infertile than in fertile men. In participants younger than 40 yr, 176 (27%) men had PSA >1 ng/ml; of them, a greater proportion were infertile (28% infertile vs 17% fertile, p = 0.03). At multivariable linear regression analysis, infertile status (coefficient 0.21; 95% confidence interval 0.02-0.39) was associated with higher PSA values, after adjusting for age and serum testosterone level. This was a single-centre study, raising the possibility of selection biases. Infertile men have higher PSA values than fertile individuals. Of all, almost one out of three primary infertile men younger than 40 yr has a first total PSA value of >1 ng/ml. In this study, we observed that (1) infertile men have higher prostate-specific antigen (PSA) values than fertile individuals and (2) a greater proportion of infertile men younger than 40 yr had total PSA >1 ng/ml at the first assessment. These data might be relevant to study the potential clinical impact of more rigorous screening in primary infertile men.


Extreme temperatures and thermal tolerances for seedlings of desert succulents.
Extreme temperatures near the soil surface, which can reach 70°C at the main study site in the northwestern Sonoran Desert, markedly affect seedling survival. Computer simulations indicated that for the rather spherical barrel cactus Ferocactus acanthodes (Lem.) Britt. & Rose the maximum surface temperature decreased 8°C and the minimum temperature increased 3°C as the seedling height was increased from 1 mm up to 50 mm. Simulated changes in shortwave and longwave irradiation alone showed that shading could decrease the maximum temperature by about 5°C for the common desert agave, Agave deserti Engelm., and raise the minimum 1°C. Actual field measurements on seedlings of both species, where shading would affect local air temperatures and wind speeds in addition to irradiation, indicated that shading decreased the average maximum surface temperature by 11°C in the summer and raised the minimum temperature by 3°C in winter.Seedlings grown at day/iight air temperatures of 30°C/20°C tolerated low temperatures of about -7°C and high temperatures of about 56°C, as measured by the temperature where stain uptake by chlorenchyma cells was reduced 50%. Seedling tolerance to high temperatures increased slightly with age, and F. acanthodes was more tolerant than A. deserti. Even taking the acclimation of high temperature tolerance into account (2.7°C increase per 10°C increase in temperature), seedlings of A. deserti would not be expected to withstand the high temperatures at exposed sites, consistent with previous observations that these seedlings occur only in protected microhabitats. Based primarily on greater high temperature acclimation (4.3°C per 10°C), seedlings of F. acanthodes have a greater high temperature tolerance and can just barely survive in exposed sites. Wide ranges in photoperiod had little effect on the thermal sensitivities of either species. When drought increased the chlorenchyma osmotic pressure from about 0.5 MPa to 1.3 MPa, seedlings of both species became about 2°C less tolerant of high temperatures, which would be nonadaptive in a desert environment, and 2°C more tolerant of low temperatures, which also occurs for other species.In conclusion, seedlings of A. deserti and F. acanthodes could tolerate tissue temperatures over 60°C when acclimated to high temperatures and below -8°C when acclimated to low temperatures. However, the extreme environment adjacent to desert soil requires sheltered microhabitats to protect the plants from high temperature damage and also to protect them from low temperature damage at their upper elevational limits.


Influence of proximal femur fractures in the autonomy and mortality of elderly patients submitted to osteosynthesis with cephalomedullary nail.
To determine the autonomy and mortality of elderly patients submitted to proximal femoral osteosynthesis with cephalomedullary nail after hip fracture. Retrospective study with 61 patients with proximal femoral fractures submitted to cephalomedullary nail osteosynthesis. The authors analyzed the medical records and collected information from the preoperative period. Patients were questioned regarding pain, postoperative autonomy, and degree of satisfaction. The total number of deaths was verified. The results were then correlated. The mean age was 84 years, predominantly female (82%). In the postoperative evaluation, 45% of the patients presented worsened levels of autonomy. The majority of patients presented mild pain (61%) on the VAS scale. The mortality rate was 24.6%, and the mean time of preoperative hospitalization was three days. The factors that presented statistical significance regarding postoperative autonomy were the time elapsed from the trauma until the moment of surgery, ASA score, fracture stability, and previous functional status of the patients. The mortality rate was associated with three main factors: advanced age, ASA score, and preoperative hospitalization time. The patient's previous autonomy positively influenced the functional outcome and postoperative recovery. Unstable fractures presented worse results for pain and ambulation in a follow-up of 27 months. Hip fracture is a risk factor associated with mortality and decreased independence in patients over 65 years of age.


Change and stability in cellular organisms.
The living cell is characterized by both its potential for change and its tendency towards a stable state. The interaction between the DNA information system and the metabolic steady state is described. A model based on this interaction leads to the conclusions that change can only be initiated from the environment but that the direction of any change is determined by the cell.


Impact of distance from surgery department on the outcome of patients followed for non-small-cell lung cancer in the respiratory department of nonacademic hospitals: Results of the KBP-2010-study.
Increased postoperative mortality in low volume centers has contributed to merge and space thoracic surgical centers. Some studies have showed that the likelihood of receiving surgery was lower in lung cancer patients living far from a thoracic surgery center. Our objective was thus to determine whether surgery and survival rates in patients with non-small-cell lung cancer (NSCLC) were influenced by the distance between the respiratory and thoracic surgery departments. KBP-2010-CPHG is a prospective multicenter epidemiological study including 6083 patients followed in 104 nonacademic hospitals for primary NSCLC diagnosed in 2010. Distance between respiratory and thoracic surgery departments were obtained retrospectively. Predictive factors for surgery and mortality were identified by logistic regression and Cox hazard model. Twenty-three percent of hospitals had a thoracic surgery department; otherwise, mean distance between the hospital and the surgery center was 65km. Nineteen percent of patients underwent surgery. Distance was neither an independent factor for surgery (odds-ratios [95% CI]: 0.971 [0.74-1.274], 0.883 [0.662-1.178], and 1.015 [0.783-1.317] for 1-34, 35-79, and ≥80km vs. 0km) nor for mortality (hazard-ratios [95% CI]: 1.020 [0.935-1.111], 1.003 [0.915-1.099], and 1.006 [0.927-1.091]) (P>0.05). This result supports the French national strategy which merges surgery departments and should reassure patients (and physicians) who could be afraid to be lately addressed to surgery or loose chance when being followed far from the thoracic surgical center.


Reduced frontal-subcortical white matter connectivity in association with suicidal ideation in major depressive disorder.
Major depressive disorder (MDD) and suicidal behavior have been associated with structural and functional changes in the brain. However, little is known regarding alterations of brain networks in MDD patients with suicidal ideation. We investigated whether or not MDD patients with suicidal ideation have different topological organizations of white matter networks compared with MDD patients without suicidal ideation. Participants consisted of 24 patients with MDD and suicidal ideation, 25 age- and gender-matched MDD patients without suicidal ideation and 31 healthy subjects. A network-based statistics (NBS) and a graph theoretical analysis were performed to assess differences in the inter-regional connectivity. Diffusion tensor imaging (DTI) was performed to assess topological changes according to suicidal ideation in MDD patients. The Scale for Suicide Ideation (SSI) and the Korean version of the Barrett Impulsiveness Scale (BIS) were used to assess the severity of suicidal ideation and impulsivity, respectively. Reduced structural connectivity in a characterized subnetwork was found in patients with MDD and suicidal ideation by utilizing NBS analysis. The subnetwork included the regions of the frontosubcortical circuits and the regions involved in executive function in the left hemisphere (rostral middle frontal, pallidum, superior parietal, frontal pole, caudate, putamen and thalamus). The graph theoretical analysis demonstrated that network measures of the left rostral middle frontal had a significant positive correlation with severity of SSI (r=0.59, P=0.02) and BIS (r=0.59, P=0.01). The total edge strength that was significantly associated with suicidal ideation did not differ between MDD patients without suicidal ideation and healthy subjects. Our findings suggest that the reduced frontosubcortical circuit of structural connectivity, which includes regions associated with executive function and impulsivity, appears to have a role in the emergence of suicidal ideation in MDD patients.


Hypoxia-driven proliferation of embryonic neural stem/progenitor cells--role of hypoxia-inducible transcription factor-1alpha.
We recently reported that intermittent hypoxia facilitated the proliferation of neural stem/progenitor cells (NPCs) in the subventricule zone and hippocampus in vivo. Here, we demonstrate that hypoxia promoted the proliferation of NPCs in vitro and that hypoxia-inducible factor (HIF)-1alpha, which is one of the key molecules in the response to hypoxia, was critical in this process. NPCs were isolated from the rat embryonic mesencephalon (E13.5), and exposed to different oxygen concentrations (20% O(2), 10% O(2), and 3% O(2)) for 3 days. The results showed that hypoxia, especially 10% O(2), promoted the proliferation of NPCs as assayed by bromodeoxyuridine incorporation, neurosphere formation, and proliferation index. The level of HIF-1alpha mRNA and protein expression detected by RT-PCR and western blot significantly increased in NPCs subjected to 10% O(2). To further elucidate the potential role of HIF-1alpha in the proliferation of NPCs induced by hypoxia, an adenovirus construct was used to overexpress HIF-1alpha, and the pSilencer 1.0-U6 plasmid as RNA interference vector targeting HIF-1alpha mRNA was used to knock down HIF-1alpha. We found that overexpression of HIF-1alpha caused the same proliferative effect on NPCs under 20% O(2) as under 10% O(2). In contrast, knockdown of HIF-1alpha inhibited NPC proliferation induced by 10% O(2). These results demonstrated that moderate hypoxia was more beneficial to NPC proliferation and that HIF-1alpha was critical in this process.


Pembrolizumab in combination with tocilizumab in high-risk hospitalized patients with COVID-19 (COPERNICO): A randomized proof-of-concept phase II study.
Severe COVID-19 is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated interleukin 6. Pembrolizumab (P; immune-activating anti-programmed cell death-1 antibody) plus tocilizumab (TCZ; anti- interleukin 6 receptor antibody) might interrupt the hyperinflammation and restore cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care (SOC) in high-risk, hospitalized patients with COVID-19 pneumonia without mechanical ventilation. Randomized, controlled, open-label, phase II trial in patients with severe SARS-CoV-2 infection to assess the hospitalization period to discharge. A total of 12 patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41-79) years. The median time to discharge for P + TCZ + SOC and SOC was 10 and 47.5 days (P = 0.03), with zero (n = 1 patient had P-related grade 5 myositis) and two COVID-19-related deaths, respectively. The addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone.


High-level production of Aspergillus niger prolyl endopeptidase from agricultural residue and its application in beer brewing.
Prolyl endopeptidase from Aspergillus niger (AN-PEP) is a prominent serine proteinase with various potential applications in the food and pharmaceutical industries. However, the availability of efficient and low-cost AN-PEP remains a challenge owing to its low yield and high fermentation cost. Here, AN-PEP was recombinantly expressed in Trichoderma reesei (rAN-PEP) under the control of the cbh1 promoter and its secretion signal. After 4 days of shaking flask cultivation with the model cellulose Avicel PH101 as the sole carbon source, the extracellular prolyl endopeptidase activity reached up to 16.148 U/mL, which is the highest titer reported to date and the secretion of the enzyme is faster in T. reesei than in other eukaryotic expression systems including A. niger and Komagataella phaffii. Most importantly, when cultivated on the low-cost agricultural residue corn cob, the recombinant strain was found to secret a remarkable amount of rAN-PEP (37.125 U/mL) that is twice the activity under the pure cellulose condition. Furthermore, treatment with rAN-PEP during beer brewing lowered the content of gluten below the ELISA kit detection limit (< 10 mg/kg) and thereby, reduced turbidity, which would be beneficial for improving the non-biological stability of beer. Our research provides a promising approach for industrial production of AN-PEP and other enzymes (proteins) from renewable lignocellulosic biomass, which provides a new idea with relevant researchers for the utilization of agricultural residues.


Synthesis and Characterization of Reduced Graphene Oxide-Supported Nanoscale Zero-Valent Iron (nZVI/rGO) Composites Used for Pb(II) Removal.
Reduced graphene oxide-supported nanoscale zero-valent iron (nZVI/rGO) composites were prepared by chemical deposition method and were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Raman spectroscopy, N₂-sorption and X-ray photoelectron spectroscopy (XPS). Operating parameters for the removal process of Pb(II) ions, such as temperature (20-40 °C), pH (3-5), initial concentration (400-600 mg/L) and contact time (20-60 min), were optimized using a quadratic model. The coefficient of determination (R² > 0.99) obtained for the mathematical model indicates a high correlation between the experimental and predicted values. The optimal temperature, pH, initial concentration and contact time for Pb(II) ions removal in the present experiment were 21.30 °C, 5.00, 400.00 mg/L and 60.00 min, respectively. In addition, the Pb(II) removal by nZVI/rGO composites was quantitatively evaluated by using adsorption isotherms, such as Langmuir and Freundlich isotherm models, of which Langmuir isotherm gave a better correlation, and the calculated maximum adsorption capacity was 910 mg/g. The removal process of Pb(II) ions could be completed within 50 min, which was well described by the pseudo-second order kinetic model. Therefore, the nZVI/rGO composites are suitable as efficient materials for the advanced treatment of Pb(II)-containing wastewater.


Ground level ozone concentrations at a rural location in northern Spain.
A systematic analysis of surface ozone observations at a rural area of the upper Spanish plateau is presented. A near four-year study of ozone concentrations was carried out between February 2000 and October 2003. Diurnal and monthly variations of ozone are studied. The peak concentration levels are obtained between 13:00 and 15:00 GMT and the lowest levels at 4:00 and 5:00 GMT. The highest values together with a slight increase in data variability are found from April to August, when spring and summer maxima are appreciated. The relationship between synoptic-scale atmospheric transport patterns and the maximum ozone concentrations was also examined. Analysis of the 500-hPa synoptic weather patterns revealed that the highest values occur during continental and Atlantic ridges in summer and, to a lesser extent, during troughs in the east-northeast of the Iberian Peninsula in spring. Our approach entailed calculating 3-day isobaric backward air mass trajectories at the observational site sorted on the following main origins: European continent, African continent, Atlantic Ocean and local. The assessment of the results showed the influence of local conditions on the daily maximum ozone concentrations. Moreover, continental air masses provide certain evidence of long-range transport added to the local or regional contribution of the main cities affecting the sampling site. Conversely, Atlantic trajectories show the least contribution to ozone levels.


Activation mapping of reentry around an anatomical barrier in the canine atrium: observations during the action of the class III agent, d-sotalol.
In the chronically instrumented animal and the isolated blood perfused heart, atrial reentry via a fixed path around an anatomical obstacle has been described and is terminated by the Class III antiarrhythmic agent, d-sotalol. The precise mechanism by which d-sotalol terminates this arrhythmia is not known. In the present study, right atrial (RA) activation sequences in the isolated, coronary artery perfused canine heart during episodes of sustained flutter (n = 7) and drug administration were determined. A fixed array of bipolar electrodes was used to record endocardial electrograms from 96 sites on the RA simultaneously. Maps of all control flutters showed that the rhythm was due to persistent circus movement of the impulse around the tricuspid valve ring. D-sotalol was effective in terminating atrial reentry in this model. In all episodes, block of the excitatory impulse in a specific region of the reentrant circuit accompanied these terminations. However, the events preceding the occurrence of block of the impulse were not similar. Two different modes of termination are described. The Class III antiarrhythmic agent d-sotalol can terminate atrial reentry in several ways. In one mode, complete conduction block of the reentering impulse within the fixed path occurs to terminate the rhythm. In the other mode, interruption of the original reentrant circuit occurs when there is failure of a lateral boundary. Often in this latter case, interruption of the original circuit is by an extra impulse that is secondary to a change in the path of the impulse. In both modes cycle length oscillations are observed.


Intra-arterial thrombolysis of a distal internal carotid artery occlusion in an adolescent.
This article describes the first reported case of an adolescent being treated with intra-arterial urokinase for a distal internal carotid artery occlusion. A 15-year-old male presenting with an acute ischemic stroke caused by a distal internal carotid artery occlusion was treated with intra-arterial urokinase at 5 hours and 45 minutes after symptom onset. The artery completely recanalized, and the patient improved significantly from an admission National Institutes of Health Stroke Scale (NIHSS) score of 28 to a NIHSS score of 8 at a 2.5-month follow-up, despite an asymptomatic intraparenchymal hemorrhage. This article reviews the only two reported cases of intravenous thrombolysis and three cases of intra-arterial thrombolysis in children with ischemic stroke and suggests that thrombolytic therapy should be considered a treatment option in selected pediatric patients with stroke, especially in adolescents who are generally treated as young adults.


Thiamethoxam adsorption by ZnCl2 modified cow manure biochar: Mechanism and quantitative prediction.
The overuse of thiamethoxam (THM) has threatened the survival of living organisms and it is necessary to find an environmentally friendly material to remove THM frequently detected in water. Biochar prepared from cow manure modified with ZnCl2 (Zn-CBC) was used to remove THM. Compared to the unmodified cow manure biochar (CBC), the removal ratio of THM by Zn-CBC was enhanced 35 times. In the mechanistic analysis, SEM and BET showed that Zn-CBC had a good pore structure and its specific surface area (166.502 m2 g-1) increased to 17 times that of CBC, indicating that Zn-CBC had good pore adsorption properties. The adsorption kinetic and isotherm implied that the main mechanism was chemisorption including π-π interaction and H-bonding. Furthermore, the stable graphitized structure of Zn-CBC allowed for efficient adsorption and reusability. In addition, this study constructed an intelligent prediction model using batch experiment data, and the high R2 (0.978) and low RMSE (0.057) implied that the model could accurately and quantitatively predict the adsorption efficiency. This paper provides a novel perspective to simultaneously remove the neonicotinoid insecticides and realize the resource utilization of cow manure.


Roles of miRNA-24 in regulating endothelial nitric oxide synthase expression and vascular endothelial cell proliferation.
This study is to investigate the effect of miRNA-24 on endothelial nitric oxide synthase (eNOS) expression and vascular endothelial cell proliferation. Constructed high expression miRNA-24 plasmids were introduced into human umbilical vein endothelial cells (HUVECs) by liposome. Cell numbers were counted by a Hemocytometer, and cell proliferation was detected by MTT assay. The expression levels of eNOS and specificity protein 1 (Sp1) at mRNA and protein levels were, respectively, examined by real-time PCR, immunohistochemistry, and Western blotting. Compared with the control group, endothelial cell proliferation in miRNA-24 group significantly decreased by 64.24 % (6.53 ± 0.11 vs 18.26 ± 0.45, P < 0.01). The expression of eNOS at mRNA and protein levels in miRNA-24 group decreased by 64.21 % (0.34 ± 0.01 vs 0.95 ± 0.02, P < 0.05) and 82.86 % (0.072 ± 0.06 vs 0.42 ± 0.06, P < 0.05), respectively. Meanwhile, the expression of Sp1 at mRNA and protein levels in miRNA-24 group decreased by 64.64 % (0.35 ± 0.01 vs 0.99 ± 0.03, P < 0.05) and 60.34 % (0.23 ± 0.05 vs 0.58 ± 0.07, P < 0.05), respectively. In anti-miRNA-24 group, endothelial cell proliferation decreased by 33.46 % compared with the control group (12.15 ± 0.21 vs 18.26 ± 0.45, P < 0.01), while it increased by 46.25 % compared with the miRNA-24 group (12.15 ± 0.21 vs 6.53 ± 0.11, P < 0.01). The expression of eNOS at mRNA and protein levels in anti-miRNA-24 group decreased by 44.21 % (0.53 ± 0.04 vs 0.95 ± 0.02, P < 0.05) and by 30.95 %(0.29 ± 0.05 vs 0.42 ± 0.06, P < 0.05) compared with the control group, while it increased by 35.84 % (0.53 ± 0.04 vs 0.34 ± 0.01, P < 0.05) and by 75.17 % (0.29 ± 0.05 vs 0.072 ± 0.06, P < 0.05) compared with miRNA-24 group. The expression of Sp1 at mRNA and protein levels in ant-miRNA-24 group decreased by 36.36 % (0.63 ± 0.04 vs 0.99 ± 0.03, P < 0.05) and by 22.41 % (0.45 ± 0.06 vs 0.58 ± 0.07, P < 0.05) compared with the control group, while it increased by 44.44 % (0.63 ± 0.04 vs 0.35 ± 0.01, P < 0.05) and by 48.88 % (0.45 ± 0.06 vs 0.23 ± 0.05, P < 0.05) compared with miRNA-24 group. HUVECs proliferation and eNOS expression are significantly inhibited by miRNA-24. Sp1, which is regulated by miRNA-24, might act as one of the important factors involved in eNOS gene expression.


National Electrical Manufacturers Association NU-4 performance evaluation of the PET component of the NanoPET/CT preclinical PET/CT scanner.
The NanoPET/CT represents the latest generation of commercial preclinical PET/CT systems. This article presents a performance evaluation of the PET component of the system according to the National Electrical Manufacturers Association (NEMA) NU-4 2008 standard. The NanoPET/CT consists of 12 lutetium yttrium orthosilicate:cerium modular detectors forming 1 ring, with 9.5-cm axial coverage and a 16-cm animal port. Each detector crystal is 1.12 × 1.12 × 13 mm, and 1 module contains 81 × 39 of these crystals. An optical light guide transmits the scintillation light to the flat-panel multianode position-sensitive photomultiplier tubes. Analog-to-digital converter cards and a field-programmable gate array-based data-collecting card provide the readout. Spatial resolution, sensitivity, counting rate capabilities, and image quality were evaluated in accordance with the NEMA NU-4 standard. Energy and temporal resolution measurements and a mouse imaging study were performed in addition to the standard. Energy resolution was 19% at 511 keV. The spatial resolution, measured as full width at half maximum on single-slice rebinning/filtered backprojection-reconstructed images, approached 1 mm on the axis and remained below 2.5 mm in the central 5-cm transaxial region both in the axial center and at one-quarter field of view. The maximum absolute sensitivity for a point source at the center of the field of view was 7.7%. The maximum noise equivalent counting rates were 430 kcps at 36 MBq and 130 kcps at 27 MBq for the mouse- and rat-sized phantoms, respectively. The uniformity and recovery coefficients were measured with the image-quality phantom, giving good-quality images. In a mouse study with an (18)F-labeled thyroid-specific tracer, the 2 lobes of the thyroid were clearly distinguishable, despite the small size of this organ. The flexible readout system allowed experiments to be performed in an efficient manner, and the system remained stable throughout. The large number of detector crystals, arranged with a fine pitch, results in excellent spatial resolution, which is the best reported for currently available commercial systems. The absolute sensitivity is high over the field of view. Combined with the excellent image quality, these features make the NanoPET/CT a powerful tool for preclinical research.


Welan gum promoted the growth of rice seedlings by enhancing carbon and nitrogen assimilation.
Based on the characteristics of natural polysaccharides in film-forming, chelating, and environmental friendly, a natural polysaccharide fertilizer agent was selected to increase the utilization of nitrogen fertilizer and increase plant growth. Five polysaccharides: xanthan gum, guar gum, fenugreek gum, welan gum and chitosan were screened for plant growth promoting effect. The results showed that welan gum had the most significant effect on promoting the growth of rice seedlings, and the concentrations of 0.1 mg mL-1 and 0.15 mg mL-1 showed the best growth effects. The effects of welan gum on nitrogen utilization in rice seedlings were investigated. Results showed welan gum increased the contents of ammonium, nitrate, free amino acids, and proteins in rice seedlings. There were four key enzymes of nitrogen metabolism which are nitrate reductase, glutamine synthetase, glutamate synthase, and glutamate dehydrogenase significantly enhanced by welan gum though up-regulating the transcriptional levels of these enzymes. Therefore, nitrogen uptake and nitrogen metabolism in rice seedlings were promoted to increase the biomass of rice seedlings. Based on the research, results showed that welan gum could constitute a promising fertilizer in the future.


The burden of HIV-associated neurocognitive disorder (HAND) in the Asia-Pacific region and recommendations for screening.
HIV-associated neurocognitive disorder incurs a significant burden on HIV patients in Asia-Pacific countries; however, the incidence is difficult to estimate due to a lack of local epidemiological data. The impact of neurocognitive impairment in HIV patients is often underestimated due to a lack of education and awareness, and there are consequently gaps in the provision of screening and diagnosis to enable earlier intervention to limit neurocognitive impairment. This review seeks to redress the imbalance by promoting awareness and education among physicians concerning the neurovirulence of HIV and thereby increase screening efforts to improve diagnosis rates and clinical outcomes for underserved patients in this region. The Asia, Australia, and Middle East (AAME) HAND Advisory Board convened expert regional representatives to review current practice and recommend appropriate measures related to the implementation of standardised screening programmes and treatment recommendations to curb the developing HAND epidemic in the region. In particular, we recommend basic neuropsychological testing protocols that could be efficiently introduced into clinical practice for routine screening. We also propose simple guidelines for the management of HAND. We believe that HAND is a significant and under-reported diagnosis in HIV patients that warrants both greater recognition and further clinical investigation of the underlying pathophysiology and the impact of HIV disease progression, with HAND being associated with worse medication adherence and therefore possibly increased risk of ARV treatment failure. Widespread screening will lead to greater recognition of HAND and earlier intervention, which may lead to improved management strategies in the future.


Meningoencephalitic African trypanosomiasis: Brain IL-10 and IL-6 are associated with protection from neuro-inflammatory pathology.
The relationship of neuropathology to CNS inflammatory and counter-inflammatory cytokine production in African trypanosome-infected mice was studied using an infection model with a defined disease progression. The initial phase of CNS infection by trypanosomes, where only mild neuropathology is evident, was characterised by high levels of IL-10 and IL-6. In the later phase of CNS infection and in a post-drug treatment model, moderate to severe neuropathology was associated with high levels of IFN-gamma and TNF-alpha. The relationship of these cytokines to neuropathological grade suggests that IL-10 and IL-6 protect the CNS from inflammatory pathology when parasites first enter the brain and the data reconcile previously contradictory clinical measurements of CSF cytokines in meningoencephalitic patients with post-mortem histopathology observations.


Beyond income: material hardship and the health and healthcare of premature children.
To estimate national prevalence of household hardships (food insufficiency, financial hardship, and difficulty paying medical bills) among children born term and preterm; and examine associations of household hardships with preterm children's outcomes (health status, emergency room visits, and unmet healthcare needs). We studied 24,026 children aged 0-3 years born term, preterm with moderately low birth weight (1501-2499 grams) and preterm with very low birth weight (VLBW; ≤1500 grams). Using propensity score matching to control for correlates of poverty, we examined associations of hardships and child outcomes. Compared with term, households with preterm VLBW children had >2-fold higher odds of financial hardship (aOR:2.63; 95% CI: 1.26-5.46) and >5-fold higher odds of difficulty paying bills (aOR:5.60; 95% CI: 2.35-10.35). Matching for sociodemographics, special healthcare needs, income and receipt of public benefits, hardships were independently associated with adverse preterm children's outcomes. Addressing household hardships is needed to optimize preterm child outcomes.


[Measure of lead exposure in a group of young girls].
In January--February 1976 blood analyses were performed for two groups (rural and urban) of young girls aged 11--16 years. The following parameters were measured: PbB, ALAD, FEP, haemoglobin and hematocrit. Results indicate only low blood lead levels (PbB less than or equal to 20 microgram/100 ml: ALAD by European method greater than or equal to 33 U/1. A small but statistically significant difference was observed in case of rural/urban ALAD values.


The reproductive autoimmune failure syndrome.
The association between reproductive failure and abnormal autoimmune function has been recognized for decades in association with such established autoimmune diseases as systemic lupus erythematosus. Recent investigations have expanded this association to women who demonstrate similar humoral abnormalities as patients with defined autoimmune diseases but do not express any of the clinical symptoms required for the diagnosis of an autoimmune disease. The observation that abnormal autoimmune function in clinically asymptomatic patients can lead to reproductive failure has led us to define the reproductive autoimmune failure syndrome as a diagnostic entity. The present article summarizes evidence suggesting that the occurrence of reproductive autoimmune failure syndrome may be teleologically related to the woman's need for increased self-tolerance in face of antigenic exposure to the maternal haplotype of the fetus during normal pregnancy. This need for increased self-tolerance is documented by higher normal autoantibody levels in women than in men and may also be responsible for the highly increased incidence of autoimmune diseases in women in comparison with men. Under this concept, abnormal autoimmune function may lead to reproductive failure at different stages of the reproductive process, depending on the quality and possibly quantity of the abnormal autoimmune response.


Effect of abstinence from alcohol on survival of patients with alcoholic cirrhosis: A systematic review and meta-analysis.
To address the questions of whether abstinence improves survival of patients with alcoholic cirrhosis (AC) and how long it takes for the effect to be significant. A systematic review and a meta-analysis are performed to assess the effect of abstinence on the survival of patients with AC. Seven cohort studies involving 1235 patients with AC were included. No differences were found in 0.5-year survival (hazard ratio [HR] = 0.48, 95% confidence interval [CI] = 0.23-1.03, P = 0.06) and 1-year survival (HR = 0.58, 95% CI = 0.32-1.03, P = 0.06) between the abstinent and continue drinking groups. However, differences were found in 1.5-year survival (HR = 0.51, 95% CI = 0.33-0.81, P = 0.004), 2-year survival (HR = 0.55, 95% CI = 0.38-0.78, P = 0.0008), 2.5-year survival (HR = 0.54, 95% CI = 0.38-0.77, P = 0.0005), 3-year survival (HR = 0.54, 95% CI = 0.40-0.74, P = 0.0001), 3.5-year survival (HR = 0.56, 95% CI = 0.44-0.73, P < 0.00001), 4-year survival (HR = 0.60, 95% CI = 0.48-0.73, P < 0.00001), 4.5-year survival (HR = 0.61, 95% CI = 0.49-0.76, P < 0.0001) and 5-year survival (HR = 0.63, 95% CI = 0.52-0.76, P < 0.00001) between the two groups. Alcohol abstinence does improve the survival of patients with AC, and it takes at least 1.5 years of alcohol abstinence before a statistically significant difference in survival can be observed between the abstinent and the continue drinking groups.


The Gap in Knowledge about Tapering Targeted Therapy being used as Monotherapy in Rheumatoid Arthritis: A Systematic Review.
Up to 30% of patients with RA are being treated with biologic (b)-disease modifying anti-rheumatic drugs (DMARDs) as monotherapy. Monotherapy with Interleukin (IL)-6 inhibitors(i) and Janus-kinase (JAK)-i has been shown to be effective. Whether patients can taper targeted therapy (bDMARDs and JAK-i) used as monotherapy (targeted monotherapy) is unknown. To determine the feasibility of tapering of targeted monotherapy in patients with controlled RA. We conducted a literature search in Medline, Embase and Cochrane Library for prospective studies reporting remission outcomes after tapering targeted monotherapy in RA patients, from 1/2014 - 8 /2021. 5 randomized studies which met our inclusion criteria, evaluating tapering of monotherapy with tumor necrosis factor-inhibitors, tocilizumab, abatacept and baricitinib in RA. Studies were heterogeneous. Three trials studied early RA. Three studies gradually tapered therapy, including 1 dose reduction study. Three studies tapered both biological and conventional-synthetic (cs)-DMARDs. No study compared stopping targeted monotherapy to continuing it. Remission rates were low 14-28% across all studies that stopped targeted monotherapy. The highest remission rate of 72% was reported by the dose reduction study. Trials that studied early RA reported remission rates after tapering ranging 27-72%. Trials tapering therapy in established RA reported rates of remission from 14-20%. There is a crucial gap in published literature to inform on tapering targeted monotherapy in patients with RA. Stopping targeted monotherapy is unlikely to maintain disease control in RA. Dose reduction strategies and early treatment of disease may be associated with more successful tapering, and warrant future study.


Acute phase reactants, challenge in the near future of animal production and veterinary medicine.
The future of acute phase proteins (APPs) in science is discussed in this paper. Many functions and associated pathological processes of APPs are unknown. Extrahepatic formation in local tissues needs attention. Local serum amyloid A (SAA) formation may be involved in deposition of AA-amyloid induced by conformational change of SAA resulting in amyloid formation, having tremendous food safety implications. Amyloidogenesis is enhanced in mouse fed beta pleated sheet-rich proteins. The local amyloid in joints of chicken and mammary corpora amylacea is discussed. Differences in glycosylation of glycoproteins among the APPs, as has been shown for alpha1-acid glycoprotein, have to be considered. More knowledge on the reactivity patterns may lead to implication of APPs in the diagnostics and staging of a disease. Calculation of an index from values of several acute phase variables increases the power of APPs in monitoring unhealthy individuals in animal populations. Vaccinations, just as infections in eliciting acute phase response seem to limit the profitability of vaccines because acute phase reactions are contra-productive in view of muscle anabolism. Interest is focused on amino acid patterns and vitamins in view of dietary nutrition effect on sick and convalescing animals. When inexpensive methodology such as liquid phase methods (nephelometry, turbidimetry) or protein array technology for rapid APP measurement is available, APPs have a future in routine diagnostics. Specific groups of patients may be screened or populations monitored by using APP.


[The professional and private situation of male and female physicians entering postgraduate medical education in Germany].
This study investigated the professional and the private situation of medical interns at the onset of their postgraduate training in Germany. We analysed the contractual situation and the working hours in the hospital, the professional situation of the partner and the number of hours invested in private life with special reference to gender and children. A standardised postal survey was conducted among all last year medical students in the medical faculties of Erlangen, Giessen, Hamburg, Heidelberg, Cologne, Leipzig and Magdeburg after entering postgraduate training. 1 009 were contacted for a first follow-up one year later and 87% responded. Descriptive statistics and regression analysis were performed. The analysis shows that female physicians are disadvantaged compared to males with regard to various professional and private conditions relevant for career development, especially when children are present. We found a large number of hints pointing towards a persistence of traditional role patterns within the couple relationship. These conditions differed substantially between the regions of former German Federal and former German Democratic Republic. A growing number of children in the study population in the course of the longitudinal analysis will show if these gender-related differences persist in the course of the training period and which influences on career development can be observed.


A soil productivity system reveals most Brazilian agricultural lands are below their maximum potential.
Food production is extremely dependent on the soil. Brazil plays an important role in the global food production chain. Although only 30% of the total Brazilian agricultural areas are used for crop and livestock, the full soil production potential needs to be evaluated due to the environmental and legal impossibility to expand agriculture to new areas. A novel approach to assess the productive potential of soils, called "SoilPP" and based on soil analysis (0-100 cm) - which express its pedological information - and machine learning is presented. Historical yields of sugarcane and soybeans were analyzed, allowing to identify where it is still possible to improve crop yields. The soybean yields were below the estimated SoilPP in 46% of Brazilian counties and could be improved by proper management practices. For sugarcane, 38% of areas can be improved. This technique allowed us to understand and map the food yield situation over large areas, which can support farmers, consultants, industries, policymakers, and world food security planning.


Diplostomum (Austrodiplostomum) compactum (Lutz, 1928) (Platyhelminthes, Digenea) metacercariae in fish from the floodplain of the Upper Paraná River, Brazil.
Diplostomum (Austrodiplostomum) compactum (Lutz, 1928) metacercariae (Platyhelminthes, Digenea) were found in six fish species, belonging to two orders (Characiformes and Perciformes) and three families (Erythrinidae, Sciaenidae and Cichlidae). A total of 477 individuals were collected, from August 1999 to May 2001, in the upper Paraná River floodplain, Brazil. The metacercariae were infecting the eyes of six host species and the brain of five of them. Plagioscion squamosissimus, Satanoperca pappaterra and Cichla monoculus presented the highest values of prevalence, mean intensity and mean abundance. Diplostomum (A.) compactum was over-dispersed in the population of Hoplias aff. malabaricus, S. pappaterra, P. squamosissimus, Crenicichla britskii and C. monoculus. No significant difference was observed in the metacercariae distribution in the right and left eyes. The abundance of D. (A.) compactum metacercariae was positively correlated with the host's relative condition factor in H. aff. malabaricus and S. pappaterra. No significant difference of the abundance of parasitism between the sex of the hosts was evidenced. In relation to the prevalence, significant difference was observed only in C. britskii. Positive correlations were verified between the prevalence of infection and the standard length of the specimens in C. britskii and the intensity of infection and the standard length of the hosts in P. squamosissimus and C. monoculus. In relation to parasite abundance and the standard length class of the host, significant differences were observed in P. squamosissimus, C. britskii and C. monoculus.


Target-site resistance to bensulfuron-methyl in Sagittaria trifolia L. populations.
Sagittaria trifolia L. is one of the most serious weeds in paddy fields in northeast of China and cannot be controlled effectively by bensulfuron-methyl in recent years. In this study, two suspected resistant S. trifolia populations (R1 and R2) were collected in Liaoning province of China. Whole-plant dose-response studies showed that R1 and R2 were highly resistant to bensulfuron-methyl, with the GR50 R/S ratios of 76.99 and 49.94 respectively. In vitro acetolactate synthase (ALS) assays revealed that resistance was due to reduced sensitivity of the ALS to bensulfuron-methyl inhibition, with I50 R/S ratios of 81.86 and 67.48 for R1 and R2, respectively. Total ALS activity was similar for the S and R2 populations, whereas the R1 population displayed significantly higher ALS activity than did the S population. The mutations Pro-197-Leu and Pro-197-Ser were identified in the ALS gene of the R1 and R2 populations, respectively. This is the first report examining bensulfuron-resistant S. trifolia in Liaoning province, China. The Pro197 mutation is likely responsible for resistance to bensulfuron-methyl in S. trifolia populations.


Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial.
Despite biochemically responding to injectable somatostatin receptor ligands (iSRLs), many patients with acromegaly experience treatment burdens. We aimed to assess maintenance of biochemical response and symptomatic control with oral octreotide capsules versus iSRLs in patients with acromegaly who previously tolerated and responded to both. This global, open-label, randomised controlled phase 3 trial was done in 29 clinical sites in Austria, France, Germany, Hungary, Italy, Lithuania, Russia, Serbia, Spain, and the USA. Eligible patients were adults aged 18-75 years with acromegaly who were receiving iSRLs (long-acting octreotide or lanreotide autogel) for at least 6 months before baseline with a stable dose for at least 4 months, and were deemed to be biochemically responding (insulin-like growth factor I [IGF-I] <1·3 × upper limit of normal [ULN] and mean integrated growth hormone <2·5 ng/mL). In the 26-week run-in phase, all patients received oral octreotide (40 mg a day, optional titration to 60 or 80 mg a day). Eligibility for the randomised treatment phase was completion of the run-in phase as a biochemical responder (IGF-I <1·3 × ULN and mean integrated growth hormone <2·5 ng/mL at week 24) and investigator assessment of acromegaly being adequately controlled. Patients were randomly assigned (3:2) to oral octreotide capsules or iSRL at the same dose and interval as before enrolment. Randomisation and drug dispensing were conducted through a qualified randomisation service provider (eg, interactive web or voice response system). The primary endpoint was a non-inferiority assessment (margin -20 percentage points) of proportion of participants maintaining biochemical response throughout the randomised treatment phase (IGF-I <1·3 × ULN using time-weighted average; assessed by comparing the lower bound of the 2-sided 95% CI for the difference in biochemical response between groups). IGF-I was assessed once a month during the run-in and randomised treatment phases (single sample). Efficacy and safety assessments were performed on the randomised population. This trial is registered with ClinicalTrials.gov, NCT02685709. Between Feb 11, 2016, and Aug 20, 2020, 218 patients were assessed for eligibility. 72 patients were excluded, and 146 participants were enrolled into the run-in phase. 116 patients completed the run-in phase and 30 participants discontinued treatment. 92 participants were randomly assigned to oral octreotide (n=55) or iSRL (n=37). 50 (91%) of 55 participants who received oral octreotide (95% CI 44-53) and 37 (100%) of 37 participants who received iSRLs (34-37) maintained biochemical response. The lower bound of the 2-sided 95% CI for the adjusted difference in proportions between the two treatment groups achieved the prespecified non-inferiority criterion of -20% (95% CI -19·9 to 0·5). 19 (35%) of 55 participants in the oral octreotide group and 15 (41%) of 37 participants in the iSRL group had treatment-related adverse events; the most common of which in both groups were gastrointestinal. Oral octreotide was non-inferior to iSRL treatment, and might be a favourable alternative to iSRLs for many patients with acromegaly. Chiasma. For the Russian translation of the abstract see Supplementary Materials section.


The occurrence of lower-than-expected bulk NCCN values over the marginal seas of China - Implications for competitive activation of marine aerosols.
In this study, we combined the measured bulk particle number concentration (NCN), particle number size distribution (PNSD) and bulk cloud condensation nuclei concentration (NCCN) at various supersaturation (SS) levels to investigate competitive activation of aerosols in the marine atmospheres over the marginal seas of China during two winter campaigns Campaign A (December 9-19, 2019) and Campaign B (December 28, 2019-January 16, 2020). During the two campaigns, we observed various categories of aerosols, i.e., long-range transport continental aerosols, clean marine aerosols, grown new particles ranging from nucleation mode to larger sizes, and grown pre-existing particles ranging from Aitken mode to accumulation mode size, etc. We found that the measured NCCN increased by only approximately 30 % with increases in SS levels from 0.2 % to 1.0 %, e.g., (1.8 ± 1.4) × 103 cm-3 at SS = 0.2 % and (2.4 ± 1.4) × 103 cm-3 at SS = 1.0 % during Campaign A. We further calculated the hygroscopicity parameter kappa (κ) by combining simultaneously measured PNSD and bulk NCCN to explore the causes. The calculated κ values were below 0.1 at SS = 0.4 % during the 72 % (or 88 %) period of Campaign A (or Campaign B). When κ values below 0.1 (or 0.2) were excluded, the remaining κ values were apparently reasonable, with an average of 0.22 (or 0.36) and a standard deviation of 0.10 (or 0.21) at SS = 0.4 % during Campaign A (or Campaign B). The unexpectedly lower κ values were discussed in terms of competitive activation of aerosols in marine atmospheres together with its net contribution to lowering the measured bulk NCCN below the expected value.


Increased action of pulsatile compared to non-pulsatile insulin delivery during a meal-like glucose exposure simulated by computerized infusion in healthy humans.
It has previously been demonstrated that pulsatile insulin has a greater hypoglycemic effect than non-pulsatile insulin during euglycemic conditions. The aim of the present study was to examine the effect of pulsatile versus non-pulsatile insulin delivery during a meal-like iv-glucose challenge. Ten healthy young subjects were examined on two occasions. A pancreatic-pituitary clamp was maintained with somatostatin infusion and replacement of glucagon and growth hormone at baseline levels. During the first three hours on both study days, insulin was infused in a pulsatile manner. Hereafter glucose and insulin were infused by computer-controlled pumps for four hours in a pattern mimicking the postprandial glucose and insulin profiles. At one study day, insulin infusion was done in a continuous manner, while at the other study day this profile was done in a pulsatile pattern. The hypoglycemic effect of insulin was measured as the integrated area under the curve of glucose during the four-hour infusion period. The mean insulin concentration measured as the integrated area under the curve was identical (P > .9). The hypoglycemic effect of insulin was significantly augmented by 13% during pulsatile delivery as compared to continuous delivery (P = .015). Likewise was the maximal glucose concentration significantly lower at the day of the pulsatile profile (9.9 ± 1.0 vs. 11.4 ± 2.3 mmol/l, P = .036). Pulsatile insulin release plays an important role in the postprandial glucose homeostasis. The disturbed insulin pulsatility in type 2 diabetes mellitus may contribute to the postprandial hyperglycemia.


Multiple Promoter Targeting Sequences exist in Abdominal-B to regulate long-range gene activation.
In complex genomes, insulators set up chromatin domain boundaries and protect promoters from inappropriate activation by enhancers from neighboring genes. The Drosophila Abdominal-B locus uses insulator elements to organize its large regulatory region into several body segment-specific chromatin domains. This organization leads to a problem in enhancer-promoter communication, that is, how do distal enhancers activate the Abd-B promoter when there are several insulators in between? This issue is partially resolved by the Promoter Targeting Sequence, which can overcome the enhancer blocking effect of an insulator. In this study, we describe a new Promoter Targeting Sequence, PTS-6, from the Abd-B 3' regulatory region. PTS-6, comprised of approximately 200 bp, was found to bypass both homologous Abdominal-B insulators, such as Fab-7 and Fab-8, and a heterologous insulator, suHw. Most importantly, it also overcomes a combination of two insulators such as Fab-7/Fab-8. Thus, PTS-6 could, in principle, target remote enhancers that are separated from the Abd-B promoter by multiple insulators. In addition, PTS-6 selectively targets the distal enhancer to only one transgenic promoter, and it strongly facilitates Abd-B enhancers. These results suggest that promoter targeting is necessary for long-range enhancer-promoter communication in Abd-B, and PTS elements could be a common occurrence in large, complex genetic loci.


Biosignatures as revealed by spectropolarimetry of Earthshine.
Low-resolution intensity spectra of Earth's atmosphere obtained from space reveal strong signatures of life ('biosignatures'), such as molecular oxygen and methane with abundances far from chemical equilibrium, as well as the presence of a 'red edge' (a sharp increase of albedo for wavelengths longer than 700 nm) caused by surface vegetation. Light passing through the atmosphere is strongly linearly polarized by scattering (from air molecules, aerosols and cloud particles) and by reflection (from oceans and land). Spectropolarimetric observations of local patches of Earth's sky light from the ground contain signatures of oxygen, ozone and water, and are used to characterize the properties of clouds and aerosols. When applied to exoplanets, ground-based spectropolarimetry can better constrain properties of atmospheres and surfaces than can standard intensity spectroscopy. Here we report disk-integrated linear polarization spectra of Earthshine, which is sunlight that has been first reflected by Earth and then reflected back to Earth by the Moon. The observations allow us to determine the fractional contribution of clouds and ocean surface, and are sensitive to visible areas of vegetation as small as 10 per cent. They represent a benchmark for the diagnostics of the atmospheric composition, mean cloud height and surfaces of exoplanets.


C-type natriuretic peptide inhibits upregulation of alpha1-adrenoceptor and inositol 1,4,5-trisphosphate receptor in rat vascular smooth muscle after vascular endothelial injury.
In a model of balloon injury of rat aortic endothelium, the effects of C-type natriuretic peptide (CNP) on alpha1-adrenoreceptor and inositol 1,4,5-triphosphate (IP3) receptor were studied. Aortic injuries were produced by vascular endothelium-denudation. Alpha1-adrenoreceptor in smooth muscle sarcolemma and IP3 receptor in smooth muscle sarcoplasmic reticulum in the rat aorta were assayed by radioactive analysis method. It was found that neointima was formed and the contents of DNA, collagen and elastin of each intima-media were sigificantly increased in 7 days and 21 days after balloon injury of rat aorta. Alpha1-adrenoreceptor in smooth muscle sarcolemma and IF3 receptor in sarcoplasmic reticulum were also upregulated. Results also showed that the administration of CNP i.p. significantly decreased the contents of DNA, collagen and elastin of each intima-media, and inhibited the up-regulation of alpha1-adrenoreceptor and IP3 receptor. The inhibition of the up-regulation of alpha1-adrenoreceptor and IP3 receptor by CNP might be one of the mechanisms of its suppressive action on intimal proliferation.


Immunohistochemical and ultrastructural demonstration of keratin in epi-myoepithelial islands of autoimmune sialadenitis in man.
Immunohistochemistry of salivary gland suggested that keratin is a specific marker of duct-epithelial cells and myosin for myoepithelial cells. Epi-myoepithelial islands found in some autoimmune sialadenitis, such as Sjögren's syndrome, were mainly composed of keratin-positive cells. Keratin filaments, with bundles and desmosome-attachments were invariably found in epithelial cells with electron microscopy. The islands contained no cells with myoepithelial characteristics. The findings show that there is no obvious participation of myoepithelial cells in the growth of the epi-myoepithelial islands.


Craniocerebral Gunshot Injuries in Chad: A Study of 44 Cases.
Firearm head injuries cause great public health concern because of their severity. They are life-threatening due to intracranial lesions and sepsis risks. This prospective study evaluates the management of craniocerebral wounds in Chad. This is an observational study conducted over a period of 65 months with 44 patients with a ballistic craniocerebral wound (BCW), of which only 7.18% were assessed by neurosurgeons with gunshot wound. The mean age was 30.57 ± 13 years (range:2-60 years). The 21-30 age group was the most affected (31.8%). The sex ratio was 21. A total of 63.6% of cases involved military personnel. The average admission time was 24.95 ± 12 hours (range: 1-72 hours). Explosive device attacks represented 29.5% of cases, of which 53.3% occurred in civilian practice. Point-blank shooting was reported in 70.5% of cases. The entry hole of the projectile was frontal in 40.9%. Intracranial sequestration of the projectile was found in 56.8%. Association of upper limb trauma was found in 9.1% of cases. Brain scans were performed in 95.5% of cases. Surgical treatment was undertaken in 68.18% of cases. The recovery process was marked by brain abscess in 6.8% of cases. Seven deaths were recorded. This study shows that BCW is frequent and mainly affects young male individuals in Chad. Many of the cases were related to improvised explosive device attacks, especially in civilian practice (70.5%). The delay in diagnostic and therapeutic management favors the high rate of sequelae.


Suturing large therapeutic corneal grafts based on donor size: A simplified technique for the novice corneal surgeon.
We describe a simple technique for achieving radial and equally spaced sutures by novice corneal surgeon in cases of large penetrating keratoplasties. A simple mathematical equation was derived for precise calculation of spacing between interrupted sutures in large grafts (n = 50). The ubiquitous and easily available Castroviejo calipers were used to mark the donor cornea according to the derived formula. Interrupted sutures were passed over the pre-marked points and tied. Radiality was assessed in the post-operative period. A total of 50 eyes undergoing therapeutic keratoplasty with graft size between 9 and 12 mm were enrolled. Equally spaced and radially aligned sutures were achieved in all cases postoperatively with watertight apposition of the graft host junction using our simple technique. The Castroviejo caliper can be effectively used for equidistant spacing of interrupted sutures in large therapeutic grafts by a novice surgeon thereby simplifying the procedure and reducing the surgical time.


Keeping the customers stratified: moving toward genetics-based treatment options in childhood NS.
In this issue, Bierzynska et al. report the results of analyzing a cohort of children with steroid-resistant nephrotic syndrome (SRNS) of childhood, correlating genetic studies with clinical outcomes. This approach has the potential to advance both our research into the causes and treatments of childhood SRNS and our ability to stratify patients into groups that are likely to be responsive to specific treatments. Here, we discuss some of the strengths and limitations of this report.


HLA-DR antigens on lymphoid cells differ from those on myeloid cells.
The human HLA-D region-related loci encode antigens which are structurally homologous and functionally analogous to the murine Ia molecules in mice. In addition to a role in immune regulation, it has been shown that the human D region-associated molecules are expressed on immature haematopoietic precursors and may also be involved in the regulation of haematopoiesis. Here we present evidence that distinct 'Ia-like' antigens are found on different haematopoietic cells. Approximately half of the Ia-like molecules expressed by B cells and activated T cells have an 'epitope' which is unique to lymphocytes and is not detectable on the Ia-like molecules of haematopoietic precursors or monocytes. This kind of lineage-restricted variation in Ia expression is a potential basis for selective compartmentalization and regulation of DR-associated function.


Pharmacological studies on zymosan inflammation in rats and mice. 2: Zymosan-induced pleurisy in rats.
Injection of zymosan in rat pleural cavity provokes an exudate which is already detectable at 15 min and which is maximum at 24 h. The leucocyte count (mostly neutrophils) increases at 2-4 h and is maximum at 48 h. In this paper the reaction has been studied up to 6 h. Evidence of histamine release, of mast cell degranulation and of reduction of the exudate by anti-H1 compounds, as well as by sodium cromoglycate, proves the active role played by histamine in the early stage of pleurisy. Serotonin (whose role was studied exclusively using antagonists) seems to have only a minor part in the early phase of the reaction. Some metabolites of arachidonic acid were determined in the pleural exudate at 1 h and 6 h. The concentration of leukotriene B4 was high at 1 h and decreased at 6 h. The thromboxane B2 level was already high at 1 h and was neatly augmented at 6 h while the amount of prostaglandin F1 alpha was high at both times. The non-steroidal anti-inflammatory substances studied all reduced the pleural exudate at 1 h but their activity then varied from each other at 6 h. Cyclooxygenase and lipoxygenase inhibitors (phenidone, BW755C) induced a reduction of the exudate at both times. Zymosan-induced pleurisy seemed thus to be an excellent model for the investigation of antiallergic and anti-inflammatory compounds active on histamine and cyclooxygenase and lipoxygenase pathways.


Editorial Commentary: Gait Symmetry After Anterior Cruciate Ligament Reconstruction Is Improved Using Functional Rehabilitation Braces That Resist Knee Motion.
The effort of the rehabilitation journey to solve the several known functional and clinical problems after anterior cruciate ligament reconstruction should be directed toward implementing effective recovery strategies starting the day after surgery. Resistance training is a reliable approach to restore general knee function, but in the early postoperative stages, it may be difficult to apply proper loading strategies to obtain tangible improvements owing to surgery-related impairments. Accordingly, applying continuous light resistance during functional tasks such as gait may help to address this issue. As such, bracing models that provide resistance to knee motion have recently been developed and have been shown to help in restoring a proper walking pattern in terms of moment and range-of-motion symmetry. Therefore, the adoption of such bracing models may be regarded as a suitable option to consider to boost the achievement of rehabilitative milestones, therefore generally improving rehabilitation quality.


Natural killer cell-dendritic cell crosstalk in the initiation of immune responses.
Dendritic cells (DCs) and natural killer (NK) cells play a critical role in early defences against cancer and infections. They specialise in complementary functions, including IL-12 or IFN-alpha/beta secretion and antigen presentation for the former, and IFN-gamma secretion and killing of infected or tumour cells for the latter. Both DCs and NK cells are also sensors of the immune system that have developed different, but partially overlapping, systems to identify pathology associated danger signals. Evidence of NK-DC interaction has accumulated recently. This interaction may lead to NK cell activation, DC activation, or apoptosis depending on the activation status of both cell types. Thus, the outcome of NK-DC crosstalk is likely to influence both innate and adaptive immune responses. This review addresses the molecular mechanisms under-lying the different NK-DC interactions, and their in vivo significance in anti-tumour or antimicrobial immunity. Finally, we discuss the potential clinical implications of this new field.


A connectionist model for convex-hull of a planar set.
A neural network model is proposed for computation of the convex-hull of a finite planar set. The model is self-organizing in that it adapts itself to the hull-vertices of the convex-hull in an orderly fashion without any supervision. The proposed network consists of three layers of processors. The bottom layer computes the activation functions, the outputs of which are passed onto the middle layer. The middle layer is used for winner selection. These information are passed onto the topmost layer as well as fed back to the bottom layer. The network in the topmost layer self-organizes by labeling the hull-processors in an orderly fashion so that the final convex-hull is obtained from the topmost layer. Time complexities of the proposed model are analyzed and are compared with existing models of similar nature.


Colonic tuberculosis presenting with massive rectal bleeding.
Colonic tuberculosis manifests in many diverse ways, of which massive rectal bleeding is a rare feature requiring surgical treatment by resection. We report such a case and review the literature of the last 15 years.


Anterior segment complications and neovascular glaucoma following implantation of a posterior chamber intraocular lens.
Lens implantation is now a highly successful operation. Although follow-up over 5 to 10 years with posterior chamber lenses is incomplete, the complication rate appears to be as low or lower than other lens styles. We present an exception: a clinicopathologic analysis of a globe, enucleated 4 years postoperatively, which in spite of uneventful implantation of a posterior chamber lens, developed neovascular glaucoma. Microscopic studies suggest several mechanisms for this rare complication including deep erosion of a prolene loop into the ciliary body, anterior segment ischemia, and breakdown of the blood-aqueous barrier. Scanning microscopy showed cracking of this deeply embedded loop, a finding we interpret as possible stress cracking and/or oxidation. The more flexible loops now used in modern lenses may decrease the chance of deep erosion. Implantation of a loop in the capsular bag may minimize the danger of both erosion and loop degradation. Patients should be followed long-term in order to recognize and treat these rare, but potentially disastrous complications.


Reversed-phase liquid chromatographic determination of phytometallophores from Strategy II Fe-uptake species by 9-fluorenylmethyl chloroformate fluorescence.
An HPLC method to quantitate phytometallophores (phytosiderophores) exuded from roots of barley (Hordeum vulgare L.) growing in nutrient solution culture was developed. 9-Fluorenylmethyl chloroformate (FMOC) derivatives of phytometallophores were separated on a C18 reverse-phase column using a sodium acetate (pH 7.2) and acetonitrile-methanol gradient over 20 min followed by fluorescence detection. Detection limits ranged from 15 to 370 pmol depending on the particular phytometallophore. The effectiveness of this method was demonstrated using the response of barley seedlings to Fe-sufficient and Fe-deficient nutrient solution conditions. Phytometallophores collected in root washings of Fe-deficient barley seedlings increased with plant age while phytometallophore release from Fe-adequate roots was negligible.


Risk Factors for Postoperative Cerebrospinal Fluid Leakage After Intradural Spine Surgery.
Well-defined risk factors for cerebrospinal fluid leakage (CSFL) after intradural spine surgery are scarce in the literature. The aim of the present study was to identify patient- and surgery-related risk factors and the incidence of CSFL. For the present retrospective cohort study, we identified consecutive patients who had undergone intradural spine surgery between 2009 and 2021 at our department. The primary endpoint was the incidence of clinically or radiologically proven CSFL. The effects of the clinical and surgical factors on the occurrence of CSFL were analyzed. A total of 375 patients (60.3% women; mean age, 54 ± 16.5 years) were included. Of the 375 patients, 30 (8%) had experienced postoperative CSFL and, thus, a significantly greater risk of wound healing disorders (odds ratio [OR], 24.9; 95% confidence interval [CI], 9.3-66.7) and surgical site infections (OR, 8.4; 95% CI, 2.6-27.7; P < 0.01 for each). No patient-related factors were associated with the development of CSFL. Previous surgery at the index level correlated significantly with the occurrence of postoperative CSFL (OR, 2.76; 95% CI, 1.1-6.8; P = 0.03) on multivariate analysis. Furthermore, patients with intradural tumors tended to have a greater risk of CSFL (OR, 2.3; 95% CI, 0.9-5.8; P = 0.07). Surgery-related factors did not influence the occurrence of CSFL. Surgery on the thoracic spine had resulted in a significantly lower postoperative CSFL rate compared with surgery on the cervical or lumbar spine (OR, -2.5; 95% CI, 1.3-4.9; P = 0.02). Our study found no modifiable risk factors for preventing CSFL after intradural spine surgery. Patients with previous surgery at the index level had a greater risk of CSFL. The occurrence of CSFL resulted in significantly more wound healing disorders and surgical site infections, necessitating further therapy.


Penetration of ofloxacin in human aqueous and vitreous humors following oral and topical administration.
To determine aqueous and vitreous humor ofloxacin levels following oral and topical application of ofloxacin in patients with noninflamed cornea and intact crystalline lens, and to compare the drug levels provided by each route. Twenty-six patients undergoing pars plana vitrectomy for various ocular pathologies were divided into two groups. Fourteen patients received two drops of 0.3% ophthalmic solution of ofloxacin every 30 minutes for 3 hours and every 60 minutes for the next 3 hours, and 12 patients received a single oral dose of 400 mg ofloxacin 8 hours before surgery. The aqueous and vitreous humor samples were simultaneously collected after oral or topical administration during pars plana vitrectomy to assess penetration of the drug. Samples were assayed for ofloxacin concentrations by a previously described method using high-performance liquid chromatography. The aqueous and vitreous humor levels of ofloxacin were 1.54 +/- 0.27 microg/mL (mean +/- standard error) and 1.77 +/- 0.24 microg/mL after oral and 1.44 +/- 0.24 microg/mL and 0.37 +/- 0.05 microg/mL after topical ofloxacin administration, respectively. Aqueous humor levels were not statistically different following oral or topical administration (P > 0.8). However, vitreous level of the drug after oral administration was significantly higher than that after topical administration (P < 0.001). Ocular bioavailability of ofloxacin in aqueous humor after oral and topical administration is similar when the drug is applied as described. Penetration of ofloxacin into vitreous humor is less than that into aqueous humor following topical application. The aqueous humor levels of ofloxacin via both routes and the vitreous level of the drug after oral route exceed the minimum inhibitory concentrations for certain bacterial species that frequently cause intraocular infection.


Cigarette smoking and risk of stroke in the chinese adult population.
We studied the relationship between cigarette smoking and stroke incidence and mortality in the Chinese adult population. We conducted a prospective cohort study in a nationally representative sample of 169 871 Chinese men and women aged 40 years and older. Data on cigarette smoking and other covariables were collected at a baseline examination in 1991 using a standard protocol. Follow-up evaluation was conducted in 1999 to 2000, with a response rate of 93.4%. During an average of 8.3 years follow-up, a total of 6780 stroke events (3979 fatal strokes) were observed. The multivariate-adjusted relative risks (95% confidence interval) of stroke incidence and mortality associated with present cigarette smoking were 1.28 (1.19 to 1.37) and 1.13 (1.03 to 1.25) in men and 1.25 (1.13 to 1.37) and 1.19 (1.04 to 1.36) in women, respectively. The corresponding population attributable risks were 14.2% and 7.1% in men and 3.1% and 2.4% in women. Compared to never-smokers, the multivariate-adjusted relative risks of stroke incidence (95% confidence interval) were 1.21 (1.12 to 1.31), 1.21 (1.11 to 1.32), and 1.36 (1.25 to 1.47) for those who smoked 1 to 9, 10 to 19, and >/=20 cigarettes per day; and 1.18 (1.09 to 1.28), 1.25 (1.15 to 1.35), and 1.34 (1.24 to 1.44) for those who smoked 1 to 11, 12 to 26, and >26 pack-years, respectively (both P<0.0001 for linear trends). Our study identified a positive and dose-response relationship between cigarette smoking and risk of stroke. Smoking prevention and cessation programs should be an important strategy for reducing the burden of stroke in Chinese adults.


Biotinidase deficiency--a treatable entity.
Biotinidase deficiency is a well recognised treatable cause of a wide spectrum of progressive neurological symptoms. Recent reports have stressed the need to screen children with early onset of seizures, encephalopathy, neurodevelopmental delay, skin rash and alopecia. Enzyme estimation remains the conclusive test. We present a patient with biotinidase deficiency suspected on the above clinical grounds and diagnosed on the basis of metabolic acidosis, raised blood lactate, ketonuria and positive dinitrophenylhydrazine (DNPH) test and confirmed on urinary organic acid profile. Supplementation with biotin resulted in marked clinical improvement and normalisation of metabolic parameters. Thus the clinician should be alert to simple clinical pointers which aid in early diagnosis of these disorders.


Repeat autoclaving does not remove protein deposits from the classic laryngeal mask airway.
We tested the hypothesis that repeated autoclaving removes protein deposits from the classic laryngeal mask airway (LMA). Twenty previously used LMAs were hand washed, machine washed, dried, autoclaved and randomly allocated into four equal-sized groups for repeat autoclaving on 0 (control), 1, 2 and 3 occasions. After the final autoclave cycle, the LMAs were immersed in a protein-staining solution, rinsed, dried and a high-resolution digital image taken of the dorsal and ventral surfaces. The severity of staining was scored by two blinded observers. All LMAs were stained. There was no reduction in staining with repeat autoclaving. Repeat autoclaving does not remove protein deposits from the LMA.


Assessing global developmental delay across instruments in minimally verbal preschool autistic children: The importance of a multi-method and multi-informant approach.
Intellectual assessment in preschool autistic children bears many challenges, particularly for those who have lower language and/or cognitive abilities. These challenges often result in underestimation of their potential or exclusion from research studies. Understanding how different instruments and definitions used to identify autistic preschool children with global developmental delay (GDD) affect sample composition is critical to advance research on this understudied clinical population. This study set out to examine the extent to which using different instruments to define GDD affects sample composition and whether different definitions affect resultant cognitive and adaptive profiles. Data from the Mullen Scales of Early Learning and the Vineland Adaptive Behavior Scales-Second Edition, a parent-report tool, were analyzed in a sample of 64 autistic and 73 neurotypical children (28-69 months). Our results highlight that cognitive assessment alone should not be used in clinical or research practices to infer a comorbid diagnosis of GDD, as it might lead to underestimating autistic children's potential. Instead, using both adaptive and cognitive levels as a stratification method to create subgroups of children with and without GDD might be a promising approach to adequately differentiate them, with less risk of underestimating them.


The neglected perioperative population of undiagnosed diabetics - a retrospective cohort study.
Diabetes is known to increase morbidity and 30-day mortality in adults undergoing non-cardiac surgery, but longer term outcomes are less studied. This study was done to explore how undiagnosed and known diabetes affect 30-day and one-year morbidity and mortality outcomes. The secondary aim was to study the prevalence of undiagnosed diabetics in our perioperative Asian surgical population. A retrospective cohort study of 2106 patients aged > 45 years undergoing non-cardiac surgery in a single tertiary hospital was performed. Undiagnosed diabetics were identified (HbA1c ≥6.5% or fasting blood glucose ≥126 mg/dL) and relevant demographic, clinical and surgical data were analyzed to elicit the relationship to adverse outcomes. Univariate analysis was first performed to identify significant variables with p-values ≤0.1, which were then analyzed using multiple logistic regression to calculate the adjusted odds ratio. The prevalence of undiagnosed diabetes was 7.4%. The mean and median HbA1c of known diabetics were 7.9 and 7.5%, while the mean and median HbA1c for undiagnosed diabetics were 7.2 and 6.8% respectively. 36.4% of known diabetics and 20.5% of undiagnosed diabetics respectively had a random blood glucose > 200 mg/dL. Undiagnosed diabetics had a three-fold increase in 1-year mortality compared to non-diabetics (adjusted OR 3.46(1.80-6.49) p < 0.001) but this relationship was not significant between known and non-diabetics. Compared to non-diabetics, known diabetics were at increased risks of new-onset atrial fibrillation (aOR 2.48(1.01-6.25) p = 0.047), infection (aOR 1.49(1.07-2.07) p = 0.017), 30-day readmission (aOR 1.62(1.17-2.25) p = 0.004) and 30-day mortality (aOR 3.11(1.16-8.56) p = 0.025). Although undiagnosed diabetics have biochemically less severe disease compared to known diabetics at the point of testing, they are at a one-year mortality disadvantage which is not seen among known diabetics. This worrying trend highlights the importance of identifying and treating diabetes. Congruent to previous studies, known diabetics have higher morbidity and 30-day mortality compared to non-diabetics.


A simple method for immunocytochemical staining with multiple rabbit polyclonal antibodies.
We report a single step, simple, repeatable, rapid and reliable technique for simultaneous immunocytochemical staining with two or more rabbit polyclonal antibodies. This technique, which we have dubbed the "Pretty Poly" method, is based on conjugating the antibodies with commercially available, fluorophore-tagged Staphylococcal protein-A (SP-A). Staining is illustrated at the calyx type presynaptic nerve terminal of the chick ciliary ganglion with antibodies directed against three nerve terminal proteins: neurofilaments of the axonal cytoskeleton, and two secretory vesicle proteins, SV2 and cysteine string protein (CSP). Images were deblurred with an iterative deconvolution protocol. Staining with a single polyclonal antibody was bright and had a resolution approaching light microscope limit. Treatment with two different polyclonal antibodies conjugated with contrasting dye-tagged protein-A resulted in double staining without significant crossover that was fully equivalent to the standard primary/secondary technique. The same single step protocol was used to stain with all three rabbit polyclonal antibodies or to combine the technique with a standard monoclonal primary/secondary antibody stain. Thus, the Pretty Poly protocol is a highly flexible, simple and yet effective staining technique that essentially solves the problem of co-staining with multiple polyclonal rabbit antibodies.


Ethylene Vinyl Alcohol Nanocomposite Films: Comparison of Their Properties at Various Equibiaxial Stretching Ratios.
Ethylene vinyl alcohol (EVOH) hybrid films containing 3 wt% Cloisite 10A were stretched equibiaxially at various stretching ratios in the range 100-200% to investigate the thermo-optical properties and oxygen permeabilities of the films in detail. The effects that variations in the equibiaxial stretching ratio had on clay dispersion and morphology were also determined. The optical transparency and oxygen barrier property were almost constant irrespective of the increase in the stretching ratio from 125 to 200%.


Work engagement, emotional disorders and conflict management styles in paediatric nurse: A mediating effect model.
The mediating role of emotional disorders between conflict management styles and work engagement was explored based on constructing structural equation models in paediatric nurses. A cross-sectional study. According to a cross-sectional survey, 300 paediatric nurses were selected from three tertiary hospitals (Chang sha, China), the data were collected using demographic questionnaires, the Rahim Organizational Conflict Inventory-II, Depression, Anxiety and Stress Scales and the Utrecht Work Engagement Scale. The Structural Equation Model was employed to investigate the mediating role of emotional disorders between conflict management styles and work engagement. Among conflict management styles, emotional disorders and work engagement, the associations were all significant (p < .05). In the mediation models, emotional disorders partially mediate the relationships between conflict management styles and work engagement (indirect effect 0.095, p < .01; direct effect -0.330, p < .01; total effect -0.330, p < .01) and between conflict management styles and work engagement (indirect effect 0.095, p < .01; direct effect 0.329, p < .01; total effect 0.424, p < .01).