OxyR2 Functions as a Three-state Redox Switch to Tightly Regulate Production of Prx2, a Peroxiredoxin of Vibrio vulnificus.
The bacterial transcriptional regulator OxyR is known to function as a two-state redox switch. OxyR senses cellular levels of H2O2 via a "sensing cysteine" that switches from the reduced to a disulfide state upon H2O2 exposure, inducing the expression of antioxidant genes. The reduced and disulfide states of OxyR, respectively, bind to extended and compact regions of DNA, where the reduced state blocks and the oxidized state allows transcription and further induces target gene expression by interacting with RNA polymerase. Vibrio vulnificus OxyR2 senses H2O2 with high sensitivity and induces the gene encoding the antioxidant Prx2. In this study, we used mass spectrometry to identify a third redox state of OxyR2, in which the sensing cysteine was overoxidized to S-sulfonated cysteine (Cys-SO3H) by high H2O2 in vitro and in vivo, where the modification deterred the transcription of prx2 The DNA binding preferences of OxyR25CA-C206D, which mimics overoxidized OxyR2, suggested that overoxidized OxyR2 binds to the extended DNA site, masking the -35 region of the prx2 promoter. These combined results demonstrate that OxyR2 functions as a three-state redox switch to tightly regulate the expression of prx2, preventing futile production of Prx2 in cells exposed to high levels of H2O2 sufficient to inactivate Prx2. We further provide evidence that another OxyR homolog, OxyR1, displays similar three-state behavior, inviting further exploration of this phenomenon as a potentially general regulatory mechanism.


IFNG/IFNG-AS1 expression level balance: implications for autism spectrum disorder.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different epidemiological, genetic, epigenetic, and environmental factors. Although its etiology is not fully understood, immune dysfunction is implicated in this disease. Recently, a large number of genes encoding long noncoding RNAs (lncRNAs) were discovered which act as positive or negative regulators of neighboring target genes. The lncRNA, Interferon gamma-antisense RNA (IFNG-AS1), regulates expression levels of the Interferon gamma (IFNG) gene. In the present study, we investigated expression of IFNG and IFNG-AS1 in 50 children with ASD (15 females and 35 males, mean age: 6 ± 1.4 years) and 50 healthy controls (14 females and 36 males, mean age: 6 ± 1.74 years) by real time PCR technique. The results showed significant up-regulation of IFNG and down-regulation of IFNG-AS1 expression in children with ASD compared to controls (Fold change = 1.5, P < 0.0001; Fold change = -0.143, P = 0.013, respectively). The IFNG expression level increase was more pronounced in male ASD children (Fold change = 1.621; p < 0.0001). Our data reveal a functional disruption in the interactive network of IFNG/IFNG-AS1 regulation, which could be a contributing factor in the chronic inflammatory aspect of ASD. Our findings can help understanding the underlying contributors to ASD pathogenesis and find novel treatment options for children with ASD.


Impact of botulinum toxin-A on corneal curvature assessed with Scheimpflug and Placido systems.
To evaluate the effect of eyelid spasm treatment with botulinum toxin-A (BTX-A) on corneal curvature assessed with Scheimpflug (Pentacam) and Placido (Atlas) systems. Federal University of São Paulo, São Paulo, Brazil. Prospective interventional case series. Patients with hemifacial spasm were evaluated. Steep keratometry (K) and corneal astigmatism (magnitudes and treatment-induced astigmatism) obtained with the Placido and Scheimpflug systems were evaluated before BTX-A application and after 15 days and 2, 3, and 4 months. The study evaluated 48 eyes (24 affected and 24 normal contralateral eyes) of 24 patients. The mean steep K and astigmatism values obtained with the Placido system on the affected side before treatment were 46.91 diopters (D) ± 3.57 (SD) and 2.63 ± 2.46 D, respectively. A significant decrease in steep K (45.14 ± 1.20 D) and astigmatism (1.01 ± 0.58 D) was observed 2 months (P = .003 and P = .0004, respectively) and 3 months (45.64 ± 1.77 D and 1.36 ± 1.31 D, respectively) (P = .03 and P = .01, respectively) after treatment. The Scheimpflug system did not show significant changes in steep K measurements during the 4-month period. The mean astigmatism in the affected eye before treatment was 1.27 ± 0.88 D. A significant reduction was observed at 15 days (1.16 ± 1.16 D) and at 4 months (0.91 ± 0.59 D) (P = .02 and P = .03, respectively). The Placido system was more sensitive in detecting a temporary reduction in corneal curvature after eyelid-spasm treatment. None of the authors has a financial or proprietary interest in any material or method mentioned.


Trends in utilization rates of the various imaging modalities in emergency departments: nationwide Medicare data from 2000 to 2008.
To study utilization trends in the various imaging modalities in emergency departments (EDs) over a recent multiyear period. The nationwide Medicare Part B databases for 2000 to 2008 were queried. Medicare's location codes were used to identify imaging examinations done on ED patients. All diagnostic imaging Current Procedural Terminology(®) codes were grouped by modality. For each code, the database provides procedure volume; utilization rates per 1,000 beneficiaries were then calculated. Medicare's physician specialty codes were used to determine provider specialty. Utilization trends were studied between 2000 and 2008. The overall utilization rate per 1,000 beneficiaries for all imaging in EDs increased from 281.0 in 2000 to 450.4 in 2008 (+60%). The radiography utilization rate rose from 227.3 in 2000 to 294.3 in 2008 (+29%, 67 accrued new studies per 1,000). The CT rate rose from 40.0 in 2000 to 130.7 in 2008 (+227%, 90.7 accrued new studies per 1,000). The ultrasound rate rose from 9.6 in 2000 to 18.7 in 2008 (+95%, 9.1 accrued new studies per 1,000). Other modalities had much lower utilization. In 2000, CT constituted 14% of all ED imaging, but by 2008, it constituted 29%. In 2008, radiologists performed 96% of all ED imaging examinations. The rate of utilization of imaging is increasing in EDs. Growth is by far the most pronounced in CT, in terms of both the growth rate itself and the actual number of accrued new studies per 1,000 beneficiaries. Radiologists strongly predominate as the physicians of record for all ED imaging.


Prevalence and Predictors of Sleep-Disordered Breathing in Men Participating in the Multicenter AIDS Cohort Study.
Data on the prevalence of sleep-disordered breathing (SDB) in people with HIV are limited. Moreover, whether the associations between SDB and age or BMI differ by HIV status is unknown. Is SDB more prevalent in men with HIV than those without HIV, and do the predictors of SDB differ between the two groups? Home polysomnography was used in the Multicenter AIDS Cohort Study to assess SDB prevalence in men with (n = 466; 92% virologically suppressed) and without (n = 370) HIV. SDB was defined using the oxygen desaturation index (ODI) and the apnea-hypopnea index (AHI), using four definitions: ≥ 5 events/h based on an ODI with a 3% (ODI3) or 4% (ODI4) oxygen desaturation, or an AHI with a 3% oxygen desaturation or EEG arousal (AHI3a) or with a 4% oxygen desaturation (AHI4). SDB prevalence was similar in men with and without HIV using the ODI3 and AHI3a definitions. However, SDB prevalence was higher in men with than without HIV using the ODI4 (55.9% vs 47.8%; P = .04) and the AHI4 definitions (57.9% vs 50.4%; P = .06). Mild and moderate SDB were more common in men with than without HIV. Associations between SDB prevalence and age, race, and BMI were similar in men with and without HIV. Among men with HIV, viral load, CD4 cell count, and use of antiretroviral medications were not associated with SDB prevalence. SDB prevalence was high overall but greater in men with than without HIV using the ODI4 threshold definition. Efforts to diagnose SDB are warranted in people with HIV, given that SDB is associated with daytime sleepiness and impaired quality of life.


Effect of natural fermentation on carbohydrates, riboflavin and trypsin inhibitor activity of lentils.
Lentils were subjected to natural fermentation for 4 days at 30 degrees C. The pH value fell to 3.8 during the process. alpha-Galactosides and sucrose were not detected in fermented lentils but a significant increase in the fructose content was observed. In fermented lentils the neutral detergent fibre, cellulose and hemicellulose contents decreased and the lignin content increased. After fermentation the riboflavin content was higher and the trypsin inhibitor activity decreased.


Survival Outcome and Prognostic Factors of Corneal Transplantation: A 15-Year Retrospective Cohort Study at King Chulalongkorn Memorial Hospital.
To evaluate long-term survival outcomes and determine the prognostic factors of corneal transplantation performed at a tertiary referral hospital in Thailand. A 15-year retrospective cohort study. One corneal graft per patient was selected; graft failure was defined as graft opacity due to recurrent disease or endothelial cell dysfunction. Kaplan-Meier survival analysis was performed. Median time to failure was compared using the Log rank test. Prognostic factors were identified using the Cox proportional hazards model. We enrolled 704 transplanted grafts. Surgical indications were optical (88.5%), therapeutic (10.2%), and tectonic (1.3%). The most common diagnoses were corneal opacity (25.3%), bullous keratopathy (15.8%), and regraft (14.8%). The overall survival rates at 1, 3, 5, and 10 years were 87.5%, 72.0%, 59.2%, and 41.7%, respectively. Univariate analysis identified age, primary diagnosis, graft size, pre-existing glaucoma, prior lens status, prior intraocular surgery, indication for surgery, donor endothelial cell density, and previous graft rejection as prognostic factors for graft failure. Multivariate analysis revealed three prognostic factors: primary diagnosis of perforation/peripheral ulceration/Mooren's ulcer (hazard ratio [HR]=28.57; 95% confidence interval [CI], 6.32-129.16; P<0.001), active keratitis (HR=24.30; 95% CI, 5.88-100.43; P<0.001), regraft (HR=9.37; 95% CI, 2.27-38.66; P=0.002), and pseudophakic/aphakic bullous keratopathy (HR=7.97; 95% CI, 1.93-32.87; P=0.004); pre-existing glaucoma (HR=1.52; 95% CI, 1.13-2.04; P=0.006); and previous graft rejection (HR=1.95; 95% CI, 1.54-2.48; P<0.001). Overall corneal graft survival rate was high in the first postoperative year and decreased after that. Primary diagnosis, pre-existing glaucoma, and previous graft rejection negatively influenced graft survival.


Crystallization of an NADP+-dependent malic enzyme from rat liver.
Crystals of a tetrameric NADP+-dependent malic enzyme from rat liver have been grown in the presence of NADP+ using the hanging-drop method of vapour diffusion with ammonium sulphate as the precipitant. Measurement of the crystal density and calculation of the values of Vm for different numbers of polypeptide chains in the unit cell indicate that the asymmetric unit of the crystal contains a complete tetramer, allowing the application of non-crystallographic symmetry to the determination of the molecular structure of this enzyme. This structure would provide only the second example for an enzyme involved in oxidative decarboxylation, the other being 6-phosphogluconate dehydrogenase. In addition, then, to providing an insight into the structure-function relationship in malic enzyme, the successful structure determination would permit valuable comparisons to be made between these two and other enzymes with this catalytic activity.


Prehypertension is real and can be associated with target organ damage.
Prehypertension (systolic blood pressure 120-139 or diastolic blood pressure 80-89 mm Hg) confers a risk of progression to hypertension, impairment of cognitive function, increased left ventricular mass, risk of end-stage renal disease, and an association with arteriosclerosis. Recent studies provide data that could support the rationale for treating prehypertensives subjects with antihypertensive medications in addition to lifestyle modification, especially if they have concomitant cardiovascular risk factors.


Tetrahydro-4-quinolinamines identified as novel P2Y(1) receptor antagonists.
High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.


Effects of urban sprawl on agricultural land: a case study of Kahramanmaraş, Turkey.
The main objective of this study is to quantify areal loss of olive groves due to urban sprawl of the city of Kahramanmaraş, Turkey. Spatial changes were analysed by interpreting the digitized data derived from a black-white monoscopic aerial photograph taken in 1985, panchromatic IKONOS image of 2000 and two pan-sharpened Quickbird images of 2004 and 2006. Data obtained revealed that the area of olive groves decreased by 25% from 460.55 ha in 1985 to 344.46 in 2006, while the number of parcels increased from 170 to 445. Of the total areal loss, 60% was due to building constructions, with the rest being due to clear-cut for new residential gardens composed of exotic plants, new buildings, or new roads. Rapid population growth, increased land prices due to urban expansion, and abandonment of agricultural practices to construction of multi-storey buildings were the main causes of the process that transformed the olive groves into urbanized areas. Results pointed to an urgent need to (1) revise the national and municipal land management practices, (2) balance the gap between the short- and long-term economic benefits that urban and community development plans ignore, and (3) monitor land-use changes periodically by using high resolution satellite images.


[Analysis of 54 mental disability reappraisal cases due to brain damage].
To investigate the different kinds of controversial cases of mental disability after brain damage, to analysis the problems in the first appraisal, and to explore solutions of the problems. The reappraisals of mental disorders after traumatic brain damage were collected from 2007-2011 in Shanghai forensic center, and the first appraisal and reappraisal cases were analyzed and compared. The changes of conclusion in reappraisal cases showed the following major reasons: inappropriate appraisal time, not comprehensive and object investigation of mental state of patients in first appraisal, misunderstanding the standards, etc. The quality improvement of appraisal should adopt the following measures: regulating the practice, improvement of the professional skills of experts, choosing appropriate appraisal time, improvement of appraisal standards, etc.


Ambient fine particles modify heart rate variability in young healthy adults.
Particulate air pollution has been related with cardiopulmonary morbidity and mortality. Recent studies have shown that an increase in particulate matter (PM)(2.5) ambient concentrations was associated with a decrease in heart rate variability (HRV) in the elderly with cardiovascular conditions, which could increase the risk of death. In order to assess if this association could also be observed in young adults, we studied 40 young healthy residents of the Mexico City Metropolitan Area (MCMA) who underwent 13 h Holter electrocardiographic and PM(2.5) personal monitoring. HRV was evaluated in time domain: the standard deviation of normal RR intervals (SDNN) and the percentage of differences between adjacent normal RR intervals larger than 50 ms (pNN50). In multivariate analysis with mixed effects models, a significant negative association of pNN50 with PM(2.5) accumulative exposure was found. An increase in 30 microg/m(3) of the average PM(2.5) personal exposure in the previous 2 h decreased the pNN50 in 0.08% (P=0.01). This observation revealed an acute effect related to environmental exposure to PM(2.5) with regard to HRV in normal youngsters. The long-term health consequences of this association in young healthy adults remain to be clarified.


Complete genomic sequence of Pepper vein banding virus (PVBV): a distinct member of the genus Potyvirus.
The complete genomic sequence of Pepper vein banding virus (PVBV), a potyvirus infecting chilli and other solanaceous plants in south India, was determined and compared with those of other potyviruses. The viral genome contained 9711 nucleotides, excluding the poly-A tail. The length of the 5'- and 3'-untranslated regions (UTR) were 163 and 281 nucleotides respectively. As for other potyviruses, the PVBV genome has a single open reading frame (ORF) starting at nucleotide 164 and ending at nt 9430, which encodes a polyprotein of 3088 amino acid residues. There are nine putative conserved cleavage sites within the polyprotein, which can result in ten functionally distinct protein products. Phylogenetic analysis of the potyviral polyprotein sequences showed that PVBV is a distinct species of this genus.


Investigation of the interaction between cholinergic and nitrergic neurotransmission in the pig gastric fundus.
1. The interaction between the cholinergic and nitrergic innervation was investigated in circular muscle strips of the pig gastric fundus. 2. In physiological salt solution containing 4 x 10(-6) M guanethidine, electrical field stimulation (EFS; 40 V, 0.5 ms, 0.5-32 Hz, 10 s at 4 min intervals) induced small transient relaxations at 0.5-4 Hz, and large frequency-dependent contractions, sometimes followed by off-relaxations, at 8-32 Hz. 3. In the presence of L-NG-nitroarginine methyl ester (L-NAME; 3 x 10(-4) M) or physostigmine (10(-6) M), relaxations were reversed into contractions and contractions were enhanced. Physostigmine added to L-NAME further enhanced contractions, while addition of L-NAME to physostigmine had no additional effect. Off-relaxations were enhanced in the presence of L-NAME and physostigmine. L-NAME and physostigmine consistently increased basal tone. 4. Tissues contracted by 5-hydroxytryptamine or by acetylcholine responded to EFS in a similar way as in basal conditions and L-NAME reversed the relaxations at the lower stimulation frequencies into contractions and enhanced the contractions at the higher stimulation frequencies. 5. Off-relaxations in the presence of L-NAME were partially reduced by alpha-chymotrypsin (10 U ml(-1)). 6. In the absence of physostigmine, the concentration-response curve to exogenous acetylcholine was not influenced by L-NAME. 7. Contractions of the same amplitude induced by EFS at 4 Hz and by exogenous acetylcholine were either decreased or enhanced to the same extent by sodium nitroprusside (SNP; 10(-5) M), depending upon the degree of relaxation by SNP. 8. These experiments suggest that endogenous nitric oxide interferes with cholinergic neurotransmission in the pig gastric fundus by functional antagonism at the postjunctional level. The interaction is independent of the degree of contraction.


Effects of bis(2-ethylhexyl) phthalate (DEHP) on secondary sex ratio of mice in a cross-mating study.
Bis(2-ethylhexyl) phthalate (DEHP) was given in the diet to provide levels of 0 (C) or 0.03% (T) from 5 weeks of age of the F(0) generation to birth of the F(1) generation in mice. At 9 weeks of age, each female was paired with one male from the same or another treatment groups (cross-mating: C/C, T/C, C/T, T/T), for a period of 5 days. The males were removed from females after 5 days, and the females were allowed to carry their litters to term and deliver. There were no adverse effects of DEHP on either litter size, litter weight and sex ratio at birth. The average body weight of male offspring was significantly increased in all treatment groups at birth. There were no adverse effects of DEHP on female offspring weight at birth. The dose level of DEHP in the present study produced no adverse effects on secondary sex ratio, which meant sex ratio at birth, in mice.


[Artificial ossification of muscular flap after plastic surgery of the bone cavity under the effect of electric current].
Experiments in rabbits revealed that transplantation of a muscular flap on the central feeding pedicle in the tibis medullary canal and its electro-stimulation with direct microelectric current of 18-20 muA with the alternating polarity speeded up the process of reorganization of the muscular flap in the depth of which new osseous tissue was forming. Electrostimulation of osteogenesis in case of the muscular plastic transplantation promotes restoration of the anatomic integrity of the bone.


Synergistic effect of lipoprotein (a) and C-reactive protein on prognosis of familial hypercholesterolemia.
The synergistic effect of lipoprotein (a) [Lp(a)] and C-reactive protein (CRP) on major adverse cardiovascular events (MACE) among patients with familial hypercholesterolemia (FH) is unknown. This study aimed to investigate the relations between Lp(a) and CRP levels and MACE in patients with FH whose Lp(a) levels are elevated. We retrospectively investigated associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of MACE among patients with FH (N = 786, male/female: 374/412). A Cox proportional hazard model was used to identify factors associated with MACE, adjusting for traditional risk factors. Patients with FH were divided into four groups, based on their Lp(a) and CRP levels, and assessed using Kaplan-Meier curves. The median follow-up was 12.6 years (interquartile range [IQR], 9.5-17.9 years). During follow-up, 129 MACE were observed. Median Lp(a) and CRP levels were 21.4 (10.9-38.3) mg/dL and 0.20 (0.11-0.29) mg/dL, respectively. Under these conditions, natural log-transformed Lp(a) and CRP were not associated with MACE (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.91-1.25; P = 0.220; and HR, 1.12; CI, 0.96-1.28; P = 0.190, respectively). However, in Group 4, Lp(a) and CRP were significantly associated with MACE (HR, 2.44; CI, 1.42-3.46; P = 1.8 × 10-7). In patients with FH, Lp(a) was significantly associated with MACE only when the CRP level was elevated. Patients with FH whose Lp(a) and CRP levels are elevated should be treated aggressively.


Analysis of exosomal competing endogenous RNA network response to paclitaxel treatment reveals key genes in advanced gastric cancer.
Exosome is an important component of the tumor immune microenvironment and plays critical role in cancer pathogenesis. The exosome transcriptome of gastric cancer (GC) response to paclitaxel chemotherapy has not been investigated in the past. ceRNA microarrays were performed in exosomes from six advanced GC patients before and after paclitaxel treatment. Bioinformatics tools were used to identify differential expressing genes and construct competing endogenous RNA (ceRNA) networks. The importance of hub genes in the ceRNA network was confirmed by survival analysis and functional analysis. A total of 213 differential mRNAs, 370 lncRNAs, and 376 circRNAs were identified, and hub genes in ceRNA networks were screened. The differential genes were associated with GO terms SNAP complex, gap junction, protein transporter activity, cytokine receptor, and KEGG pathways synaptic vesicle cycle, propanoate metabolism, Epstein-Barr virus infection, heparin, and steroid biosynthesis, and beta-alanine metabolism. ULK2, CYP2R1, BTLA, and miR-105-5p are prognostic genes for overall survival. Paclitaxel may target ULK2 which is involved in mitosis and cell cycle. miR-105-5p may target ULK2 3'UTR. The work for the first time identified exosomal RNA biomarkers and constructed a ceRNA network in GC response to paclitaxel, revealed novel molecular mechanisms of GC, and provided new candidates for GC diagnosis and treatment.


Associations of long-term mortality with serum uric acid at admission in acute decompensated heart failure with different phenotypes.
It remains unclear whether the long-term prognostic value of serum uric acid (SUA) at admission differs in acute decompensated heart failure (HF) patients across the spectrum of left ventricular ejection fraction (EF). In 2375 patients (38.9% women; mean age, 68.8 years), we assessed the risk of long-term (>1 year) all-cause mortality associated with per 1-SD increase in SUA at admission, using multivariable Cox regression in HF with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) EF. During a median follow-up of 4.1 years, the long-term mortality rate was 39.9%. In all patients, the multivariable-adjusted hazard ratio (HR) expressing the risk of long-term mortality associated with SUA was 1.18 (95% CI, 1.11-1.26; P < 0.001). Compared with the low tertile of the SUA distribution, the sex- and age-adjusted cumulative incidence of long-term mortality was higher in the top tertile. In patients with HFpEF and HFrEF, SUA predicted the risk of long-term mortality with HRs amounting to 1.12 (95% CI, 1.02-1.21; P = 0.012) and 1.28 (95% CI, 1.12-1.47; P < 0.001), respectively. However, there were no associations between the risk of mortality and SUA in HFmrEF. Furthermore, age, sex, NYHA class, and the prevalence of coronary heart disease interacted significantly with SUA for predicting long-term mortality. Higher levels of SUA at admission were associated with higher risk of long-term mortality in patients with different HF subtypes. The risk conferred by SUA was age and sex dependent. Our observations highlight that measuring SUA at admission may help to improve risk stratification.


The status of neck node metastases in breast cancer--loco-regional or distant?
Metastases to cervical lymph nodes do not exclusively derive from malignancies of the head and neck area. In the literature the region where distant metastases of breast carcinomas to the neck occur is exclusively named "supraclavicular". The system established by head and neck surgeons regarding neck node topography allows interdisciplinary management of patients with cervical lymph node metastases from breast cancer. Twelve patients suffering from breast cancer who presented with cervical masses have been examined. Most lymph node metastases were found in the posterior triangle of the neck and at the caudo-jugular level, but some metastases were even found in the upper jugular levels. The results presented show that neck node metastases of breast cancer are located superiorly to the supraclavicular region in more than 50% of the cases. According to the AJCC Staging System for Breast Cancer metastases located in the supraclavicular fossa are assessed as loco-regional metastases (N3c). Lymph node metastases situated above the supraclavicular region are not mentioned, but should be considered as distant metastases. This important question remains unanswered and deserves clarification in the current classification of the AJCC Staging System for Breast Cancer.


Injectable antibacterial cellulose nanofiber/chitosan aerogel with rapid shape recovery for noncompressible hemorrhage.
Here an injectable antibacterial aerogel was fabricated with oxidized cellulose nanofiber and chitosan for rapid hemostasis of noncompressible hemorrhage application. Especially, cellulose nanofiber was modified with carboxyl groups by pre-oxidizing in 2,2,6,6-tetramethylpiperidine-1-oxyl combined with high pressure homogenization. Whereafter, the realized carboxyl group of cellulose nanofiber was reacted with the amidogen of chitosan to yield a strong composite aerogel with a nanofiber/nanosheet interlaced structure, which increased the compressive mechanical strength up to 75.4 kPa. In addition, the nanocellulose/chitosan composite aerogel exhibits high water absorption capacity, rapid shape recovery and good antibacterial ability (via Escherichia coli and Staphylococcus aureus). Once absorbing water, the nanocellulose5/chitosan5 compressed aerogel could rapidly recover its shape within 30 s. The in vitro coagulation ability measurement showed that the composite aerogel has a good adhesion and aggregation effect to red blood cells and platelets. Hemolysis and cytotoxicity analysis results indicated a good biocompatibility for the composite aerogel.


Implications of atrial volumes in surgical corrected Tetralogy of Fallot on clinical adverse events.
While left atrial (LA) size has been shown as a strong predictor of cardiovascular diseases in various studies, the role of right atrial (RA) enlargement, especially in the growing population of patients with congenital heart diseases (CHD) is largely unknown. We sought to evaluate (1) RA and LA volumes in patients with repaired Tetralogy of Fallot (TOF) and assess correlations to (2) functional parameters and (3) clinical adverse events. 169 patients with repaired TOF were enrolled following a targeted protocol for Cardiovascular magnetic resonance imaging (CMR), Cardiopulmonary exercise tests (CPET), Echocardiography and Measurement of NT-proBNP. Clinical history was assessed at enrollment and during a median Follow-up of 23 months (IQR 9-40). The primary clinical endpoint was a composite of all cause mortality, aborted sudden cardiac death and sustained VT. Prespecified secondary surrogate endpoint included worsening heart failure (NYHA III-IV), non-sustained VT and sustained supraventricular tachycardia. RA Systolic indexed volume (RASVi) correlated with LA Systolic indexed volume (LASVi) (r = 0.59, p < 0.001) and both correlated with the patient age (r = 0.52, p < 0.001; r = 0.59, p < 0.001 respectively). Patients in the upper tertil of RASVi (>58 ml/m2) had higher NT-proBNP levels, longer QRS duration, larger ventricle diameters, higher RV mass and lower peak oxygen uptake. RASVi was associated with the primary composite adverse event at univariate Cox-regression analysis (HR: 1.044, CI: 1.008-1.08, p = 0.01). Bayesian Multivariate model averaging revealed RASVi as predictor of secondary surrogate adverse outcome (HR: 1.06, CI: 1.053-1.068, Pb = 0,889). Among patients with repaired TOF, RA dilatation is an independent predictor for adverse clinical events. As such, routine assessment of RA volumes could be useful to further improve decision-making and management of these patients in the future.


Healthcare resource utilization at different stages of amyotrophic lateral sclerosis: Results from a real-world survey.
People with amyotrophic lateral sclerosis (pALS) require complex, multi-disciplinary care, resulting in extensive healthcare resource utilization (HCRU). To investigate the relationship between HCRU and ALS progression, the study objectives were (i) to characterize HCRU in pALS and (ii) to establish whether this varied according to disease stage, as defined using three different methodologies: neurologist-defined early/mid/late stage, the King's clinical staging system for ALS, and the Milan Torino Staging system for ALS (MiToS). Real-world data were drawn from the Adelphi ALS Disease-Specific Programme™, a point-in-time survey of neurologists in France, Germany, Italy, Spain, the UK, and the USA conducted July 2020-March 2021. The analysis included survey responses from 142 physicians with respect to 880 pALS. With advancing ALS stage, significant differences were observed in the number of healthcare professional consultations and X-rays per person (both p < 0.05 for all staging systems), and the proportion of pALS with emergency room admissions, intensive care unit admissions, and assisted ventilation (all p < 0.05 for all staging systems). Across stages, >55% of pALS received care from a general neurologist and a general/primary care practitioner. With increasing stage, there was a significant difference in the proportion receiving care from a physical therapist, pulmonologist/respiratory care practitioner, respiratory therapist, speech/language therapist, and palliative care team, and in the proportion receiving care only from professional caregivers (all p < 0.05 for all staging systems). This study confirmed the substantial HCRU required to support pALS through all stages of ALS and highlighted an increasing need for healthcare resources as the disease progresses.


Respiratory infections caused by Branhamella catarrhalis. Selected epidemiologic features.
This work reviewed existing literature pertaining to the epidemiologic aspects of respiratory tract infections caused by Branhamella catarrhalis, examined certain epidemiologic features of B. catarrhalis infections occurring at this facility, and identified relevant areas in need of further study. Literature dealing with the epidemiology of B. catarrhalis infections was reviewed. Records in this Veterans Administration hospital microbiology laboratory were reviewed and all B. catarrhalis isolates and pure cultures of Hemophilus influenzae and Streptococcus pneumoniae were noted for the January 1986 to June 1989 study period. B. catarrhalis is now recognized as a disease-causing pathogen that is particularly noted for its association with acute otitis media in children and lower respiratory tract infections in adults with underlying cardiopulmonary disease. It was recovered from 2.7 percent of all respiratory specimens submitted over a 42-month period at this Veterans hospital. When compared with H. influenzae and S. pneumoniae, B. catarrhalis was found to be the second most commonly isolated respiratory pathogen. It was frequently found in pure culture (53 percent) or in combination with H. influenzae, gram-negative bacilli, or S. pneumoniae. The seasonal recovery of B. catarrhalis was apparent for the November to May period compared with the June to October period (p less than 0.001). B. catarrhalis has emerged as a major respiratory pathogen in pediatric and adult patient populations. There is a distinct seasonal pattern associated with its recovery and reasons for this are unclear. Prevalence studies aimed at identifying colonization rates among "low" and "high" risk groups are needed. The availability of restriction endonuclease analysis as a typing system for B. catarrhalis should favorably impact upon future epidemiologic studies. Many B. catarrhalis isolates produce beta-lactamase, and therapeutic options must reflect this.


Traditional and evidence-based acupuncture: history, mechanisms, and present status.
In 1983, the Southern Medical Journal advised its readers that a scientific basis might underlie the popular practice of ancient Chinese acupuncture. Recent studies have proven this to be correct, and a 1997 National Institutes of Health consensus panel recommended acupuncture as a useful clinical procedure. Pertinent articles in the literature were reviewed, including our own research. Significantly, we had access to recent important studies from China. Most of the 10,000 acupuncturists in the country today practice metaphysically explained "meridian theory" acupuncture using needles to supposedly remove blockages of a hypothesized substance "Qi." Scientific research has shown that healing is not by manipulating Qi but rather by neuroelectric stimulation for the gene expression of neuropeptides. Needles are not necessary. Evidence-based neuroelectric acupuncture requires no metaphysical rituals. It is a simple, useful clinical tool for pain modulation and other conditions and can be easily taught to physicians.


Automated localization of nerve damage: hypothesis, technique and performance appraisal.
Needle-EMG is a common procedure performed and relied on by neurologists, physiatrists and neurosurgeons to localize focal nerve damage. However, despite its popularity, there is no standardization of this diagnostic process rendering it error prone. An automated diagnostic program may help the electromyographer by providing an objective second opinion and a statistical measure of its strength. Such a program is presented and evaluated in this manuscript. The electromyographer samples a set of muscles and grades each muscle for neuropathic changes. The Program accepts the electromyographer's graded muscle set. The Program then compares it to muscle-sets derived from all possible combinations of nerve damage and finds that combination that results in the best match. The latter is the anatomical diagnosis. Eighty-five cases from the literature, each with an impartial expert diagnosis, were analyzed using this Program. The Program precisely matched the expert electromyographers' diagnoses in 79% of the cases, partially matched in 15%, and did not match in 6% of the cases. In the latter, not necessarily the Program was in error. The Program proved to be a reliable diagnostic tool that may help electromyographers by offering a second opinion. It may also assist in teaching of residents and fellows.


Beta Trace Protein does not outperform Creatinine and Cystatin C in estimating Glomerular Filtration Rate in Older Adults.
Despite intense research the optimal endogenous biomarker for glomerular filtration rate (GFR) estimation has not been identified yet. We analyzed if ß-trace protein (BTP) improved GFR estimation in elderly. 566 participants aged 70+ from the population-based Berlin Initiative Study were included in a cross-sectional validation study. BTP, standardized creatinine and cystatin C were measured in participants with iohexol clearance measurement as gold standard method for measured GFR (mGFR). In a double logarithmic linear model prediction of mGFR by BTP was assessed. Analyses with BTP only and combined with creatinine and cystatin C were performed. Additionally, performance of GFR estimating equations was compared to mGFR. We found that the combination of all three biomarkers showed the best prediction of mGFR (r2 = 0.83), whereat the combination of creatinine and cystatin C provided only minimally diverging results (r2 = 0.82). Single usage of BTP showed worst prediction (r2 = 0.67) within models with only one biomarker. Subgroup analyses (arterial hypertension, diabetes, body mass index ≤23 and >30) demonstrated a slight additional benefit of including BTP into the prediction model for diabetic, hypertensive and lean patients. Among BTP-containing GFR equations the Inker BTP-based equation showed superior performance. Especially the use of cystatin C renders the addition of BTP unnecessary.


Organization of postural equilibrium in several planes in ballet dancers.
This study analyzed the balance strategies of ballet dancers during postural equilibrium in three single leg balance conditions with and without vision and regard to age. Dancers participating formed two groups of 20 dancers each, one aged between 8 and 16 years (young group) and the other aged between 17 and 30 years (adult group). Ground reaction forces (GRFs) (mediolateral (ML), anteroposterior (AP) components, vertical (V)) were recorded. Results analysis enabled us to extract some spatiotemporal data for each component of the GRF (number of GRF oscillations, variability and impulses). Young dancers are characterized, compared to adult dancers, by an instability combined with an increase of oscillations number and a decrease variability mainly visible on the ML component. In the two groups, the absence of vision implies an increase of AP, ML and V impulsions and GRF variability. Balance with the gesturing limb to the rear increases the age and vision effect compared to balances with the limb forward or to the side. Young dancers are less efficient at controlling their balance than adult dancers. This observation may be related to the number of hours practicing dance, which differs between groups. The dancers have a visual dependence to control the postural balance.


Overlap of latent pathogens in the Botryosphaeriaceae on a native and agricultural host.
Some species of the Botryosphaeriaceae are capable of infecting a broad range of host plants. We studied the species diversity of Botryosphaeriaceae associated with marula (Sclerocarya birrea subsp. caffra, Anacardiaceae) trees in South Africa over two seasons, as well as species common to both S. birrea and adjacent mango (Mangifera indica, Anacardiaceae) trees in a subset of sites. Gene flow amongst populations of Botryosphaeriaceae shared on these tree species was tested using microsatellite markers. Twelve species were identified from S. birrea and eleven species were found on M. indica trees. From isolations done in 2006, the dominant species on S. birrea was Neofusicoccum vitifusiforme, while N. parvum was the dominant species isolated from M. indica. Neofusicoccum parvum was dominant in isolations from both hosts in 2012. Isolates of Botryosphaeria fabicerciana, Lasiodiplodia mahajangana, L. pseudotheobromae, L. theobromae, N. mediterraneum, and N. umdonicola were also collected from both hosts. Population genetic analyses on isolates of N. parvum suggested that three populations were present, each comprising isolates from both hosts. There was significant gene flow between N. parvum populations on these hosts. This ability to infect multiple hosts and to migrate amongst them facilitates the establishment and spread of species and genotypes of the Botryosphaeriaceae, such as N. parvum, in new areas.


The presence of spontaneous portosystemic shunts increases the risk of complications after transjugular intrahepatic portosystemic shunt (TIPS) placement.
The goal of this study was to identify clinical and imaging variables that are associated with an unfavorable outcome during the 30 days following transjugular intrahepatic portosystemic shunt (TIPS) placement. Fifty-four consecutive patients with liver cirrhosis (Child-Pugh 6-13, Model for End-stage Liver Disease 7-26) underwent TIPS placement for refractory ascites (n=25), recurrent or uncontrolled variceal bleeding (n=23) or both (n=6). Clinical, biological and imaging variables including type of stent (covered n=40; bare-stent n=14), presence of spontaneous portosystemic shunt (n=31), and variations in portosystemic pressure gradient were recorded. Early severe complication was defined as the occurrence of overt hepatic encephalopathy or death within the 30days following TIPS placement. Sixteen patients (30%) presented with early severe complication after TIPS placement. Child-Pugh score was independently associated with complication (HR=1.52, P<0.001). Among the imaging variables, opacification of spontaneous portosystemic shunt during TIPS placement but before its creation was associated with an increased risk of early complication (P=0.04). The other imaging variables were not associated with occurrence of complication. Identification of spontaneous portosystemic shunt during TIPS placement reflects the presence of varices and is associated with an increased risk of early severe complication.


Effects on capacitance by overexpression of membrane proteins.
Functional Channelrhodopsin-2 (ChR2) overexpression of about 10(4)channels/mum(2) in the plasma membrane of HEK293 cells was studied by patch-clamp and freeze-fracture electron microscopy. Simultaneous electrorotation measurements revealed that ChR2 expression was accompanied by a marked increase of the area-specific membrane capacitance (C(m)). The C(m) increase apparently resulted partly from an enlargement of the size and/or number of microvilli. This is suggested by a relatively large C(m) of 1.15+/-0.08 microF/cm(2) in ChR2-expressing cells measured under isotonic conditions. This value was much higher than that of the control HEK293 cells (0.79+/-0.02 microF/cm(2)). However, even after complete loss of microvilli under strong hypoosmolar conditions (100 mOsm), the ChR2-expressing cells still exhibited a significantly larger C(m) (0.85+/-0.07 microF/cm(2)) as compared to non-expressing control cells (0.70+/-0.03 microF/cm(2)). Therefore, a second mechanism of capacitance increase may involve changes in the membrane permittivity and/or thickness due to the embedded ChR2 proteins.


[Influence of occupational environment on coronary heart disease incidence in automobile transport drivers].
The authors revealed quite high incidence of coronary heart disease and its risk factors among automobile transport drivers due to occupational peculiarities, deterioration in operative response system in patients with coronary heart disease and arterial hypertension. The suggestion is to review official medical indications for driving license.


Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial.
The concentration of osteopontin (SPP1) in plasma is associated with tumour hypoxia. The DAHANCA 5 trial found that the hypoxia radiosensitiser nimorazole significantly improved the outcome of radiotherapy for patients with head and neck cancer compared with placebo. However, whether all patients benefit from such modification of hypoxia is unclear. We aimed to assess whether the concentration of plasma osteopontin could predict response to the hypoxia radiosensitiser. Plasma concentrations of osteopontin were measured by use of ELISA from stored samples of 320 patients randomised in the DAHANCA 5 trial. Samples were grouped into tertiles according to high (167-1382 microg/L), intermediate (69-166 microg/L), or low (0-68 microg/L) concentrations of plasma osteopontin, and analysed for locoregional tumour control and disease-specific survival at 5 years. Overall, locoregional tumour failure and disease-specific mortality were more frequent in patients assigned placebo than in those assigned nimorazole (relative risk [RR] 0.51 [95% CI 0.32-0.79] and 0.54 [0.35-0.85], respectively). Locoregional tumour failure was more frequent in patients with high concentrations of osteopontin assigned placebo than in those with high concentrations assigned nimorazole (0.19 [0.08-0.44]), as was disease-specific mortality (0.25 [0.11-0.59]). However, neither locoregional tumour failure nor disease-specific mortality differed between groups for patients with low concentrations of plasma osteopontin (0.79 [0.26-1.70]) and (0.69 [0.31-1.51]) or for those with intermediate concentrations (0.90 [0.41-1.98] and 0.89 [0.41-1.96], respectively). High plasma concentrations of osteopontin are associated with a poor outlook after radiotherapy for patients with head and neck cancer, but can be improved by use of nimorazole. High concentrations of osteopontin can predict clinically relevant hypoxia, and might identify patients who will benefit from modification of hypoxia during radiotherapy.


Enkephalin and other peptides reduce passiveness.
Enkephalin and other brain peptides previously have been shown to be active in the dopa potentiation test which may be considered an animal model of mental depression. A recently described model of passive immobility during swimming, also sensitive to tricyclic antidepressants, was therefore used to study a large number of naturally occurring peptides and some of their analogues. It was found that several enkephalins with no opiate activity after peripheral injection reduced the immobility and thus increased the activity of swimming rats. alpha-MSH, but not its 4--10 core or a 4--9 analogue, also caused significantly more swimming than did the diluent control. As we have previously found in several animal and clinical studies, a smaller dose of MIF-I was more effective than larger doses. The results confirm our concept of the CNS actions of brain peptides and support the suggestion that some of them, like the enkephalins, might be useful after peripheral administration in mental depression or other CNS disorders.


Interrupter resistance short-term repeatability and bronchodilator response in preschool children.
Interrupter resistance (Rint) technique can be easily and successfully performed in preschool children. The establishment of Rint short-term repeatability is essential to interpret any Rint change after a pharmacological intervention. In preschool children with asthma or chronic cough: (1) to assess two indices of short-term repeatability: (a) intra-measurement and (b) within-occasion between-test repeatability; (2) to study the relationship between short-term repeatability and bronchodilator response (BDR). Rint intra-measurement repeatability assessed by the coefficient of variation was similar at baseline and after bronchodilator in asthmatics and in coughers (median 10% and 12%, respectively). There was no significant difference between asthmatics and coughers for both coefficient of repeatability (CR) (0.25 kPa L(-1)s and 32% of predicted vs 0.16 kPa L(-1) s and 21% of predicted, respectively) and BDR (median -14.7% vs -21.1% of predicted, respectively). However, in 20% of the study children, baseline variability of Rint modified the significance of the BDR. In the present study, Rint short-term repeatability was similar to that of previous studies. Similar Rint repeatability in coughers and in asthmatic children favored the use of asthmatic CR for both populations, and a -35% cut-off as a positive BDR. In 20% of study children, baseline Rint variability could influence the significance of the BDR. In order to improve assessment of BDR using Rint, further studies are needed (1) to compare the variability of Rint to other resistance measurement techniques and (2) to define the best method for Rint calculation and for expression of BDR.


Response of aged neurons to super-hypotonic environment.
Cultured sensory neurons from aged mice (24 months old) lost capability of cell volume auto-regulatory mechanism after the rapid treatment with a hypotonic solution of 1/4 the normal osmolarity or lower. However, they could survive and extend neurites in super-hypotonic media such as 1/4 osmolar and even 1/8 osmolar culture media when the osmolarity was reduced gradually to such a low level.


A Cyclophilin OsCYP20-2 Interacts with OsSYF2 to Regulate Grain Length by Pre-mRNA Splicing.
Grain size is one of the key agronomic traits that impact grain yield. Several regulatory pathways had been reported to participate in grain size determination via cell expansion or proliferation in rice. However, little is known about cyclophilin and spliceosome participation in grain shape regulation. Here, we identified OsCYP20-2, a cyclophilin that influences spliceosome assembly to determine grain length. oscyp20-2 t1, a knock out mutant of OsCYP20-2 caused by T-DNA insertion, produced shorter grains with deficient cell elongation. Through yeast two-hybrid screening and pull-down assays, OsSYF2, a pre-mRNA splicing factor, was identified as an interacting protein of OsCYP20-2. The phenotypes of transgenic lines indicated that OsSYF2 positively regulates grain length via its influence on cell expansion. Transcriptomic analysis showed that OsSYF2 controls the expression and pre-mRNA alternative splicing of genes involved in sugar metabolism. In addition, these two genes have similar effects on panicle architecture. Taken together, OsSYF2, an interacting protein of OsCYP20-2, controls grain length and panicle architecture by regulating the alternative splicing of pre-mRNA involved in cell elongation and sugar metabolism.


Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury.
Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.


An algorithm for calculating exam quality as a basis for performance-based allocation of funds at medical schools.
The amendment of the Medical Licensing Act (ÄAppO) in Germany in 2002 led to the introduction of graded assessments in the clinical part of medical studies. This, in turn, lent new weight to the importance of written tests, even though the minimum requirements for exam quality are sometimes difficult to reach. Introducing exam quality as a criterion for the award of performance-based allocation of funds is expected to steer the attention of faculty members towards more quality and perpetuate higher standards. However, at present there is a lack of suitable algorithms for calculating exam quality. In the spring of 2014, the students' dean commissioned the "core group" for curricular improvement at the University Medical Center in Rostock to revise the criteria for the allocation of performance-based funds for teaching. In a first approach, we developed an algorithm that was based on the results of the most common type of exam in medical education, multiple choice tests. It included item difficulty and discrimination, reliability as well as the distribution of grades achieved. This algorithm quantitatively describes exam quality of multiple choice exams. However, it can also be applied to exams involving short assay questions and the OSCE. It thus allows for the quantitation of exam quality in the various subjects and - in analogy to impact factors and third party grants - a ranking among faculty. Our algorithm can be applied to all test formats in which item difficulty, the discriminatory power of the individual items, reliability of the exam and the distribution of grades are measured. Even though the content validity of an exam is not considered here, we believe that our algorithm is suitable as a general basis for performance-based allocation of funds.


Antibody to the inositol trisphosphate receptor blocks thimerosal-enhanced Ca(2+)-induced Ca2+ release and Ca2+ oscillations in hamster eggs.
The sulfhydryl reagent thimerosal enhanced the sensitivity of hamster eggs to injected inositol 1,4,5-trisphosphate (InsP3) or Ca2+ to generate regenerative Ca2+ release from intracellular pools. A monoclonal antibody (mAb) to the InsP3 receptor blocked both the InsP3-induced Ca2+ release (IICR) and Ca(2+)-induced Ca2+ release (CICR). The mAb also blocked Ca2+ oscillations induced by thimerosal. The results indicate that thimerosal enhances IICR sensitized by cytosolic Ca2+, but not CICR from InsP3-insensitive pools, and causes repetitive Ca2+ releases from InsP3-sensitive pools.


A single screen-printed electrode in tandem with chemometric tools for the forensic differentiation of Brazilian beers.
In the present study a single screen-printed carbon electrode (SPCE) and chemometric techniques were utilized for forensic differentiation of Brazilian American lager beers. To differentiate Brazilian beers at the manufacturer and brand level, the classification techniques: soft independent modeling of class analogy (SIMCA), partial least squares regression discriminant analysis (PLS-DA), and support vector machines discriminant analysis (SVM-DA) were tested. PLS-DA model presented an inconclusive assignment ratio of 20%. On the other hand, SIMCA models had a 0 inconclusive rate but an sensitivity close to 85%. While the non-linear technique (SVM-DA) showed an accuracy of 98%, with 95% sensitivity and 98% specificity. The SPCE-SVM-DA technique was then used to distinguish at brand level two highly frauded beers. The SPCE coupled with SVM-DA performed with an accuracy of 97% for the classification of both brands. Therefore, the proposed electrochemicalsensor configuration has been deemed an appropriate tool for discrimination of American lager beers according to their producer and brands.


Diagnostic Yield, Outcomes, and Resource Utilization With Different Ambulatory Electrocardiographic Monitoring Strategies.
Accurate diagnosis of arrhythmias is improved with longer monitoring duration but can risk delayed diagnosis. We compared diagnostic yield, outcomes, and resource utilization by arrhythmia monitoring strategy in 330 matched adults (mean age 64 years, 40% women, and 30% non-White) without previously documented atrial fibrillation or atrial flutter (AF/AFL) who received ambulatory electrocardiographic monitoring by 14-day Zio XT (patch-based continuous monitor), 24-hour Holter, or 30-day event monitor (external loop recorder) between October 2011 and May 2014. Patients were matched by age, gender, site, likelihood of receiving Zio XT patch, and indication for monitoring, and subsequently followed for monitoring results, management changes, clinical outcomes, and resource utilization. AF/AFL ≥30 seconds was noted in 6% receiving Zio XT versus 0% by Holter (p = 0.04) and 3% by event monitor (p = 0.07). Nonsustained ventricular tachycardia was noted in 24% for Zio XT patch versus 8% (p <0.001) for Holter and 4% (p <0.001) for event monitor. No significant differences between monitoring strategies in outcomes or resource utilization were observed. Prolonged monitoring with 14-day Zio XT patch or 30-day event monitor was superior to 24-hour Holter in detecting new AF/AFL but not different from each other. Documented nonsustained ventricular tachycardia was more frequent with Zio XT than 24-hour Holter and 30-day event monitor without apparent increased risk of adverse outcomes or excess utilization. In conclusion, additional efforts are needed to further personalize electrocardiographic monitoring strategies that optimize clinical management and outcomes.


Platelet pro-aggregatory effects of CD40L monoclonal antibody.
An unexpected high incidence of thromboembolic complications has been described in patients with systemic autoimmune diseases treated with CD40L immunotherapy. Since activated platelets express CD40L, we aimed to investigate the effects of CD40L mAb in platelet aggregation induced by physiological stimuli. Optical aggregometry was performed on platelet-rich plasma and washed platelets obtained from systemic venous blood (0.38% citrate) of anesthetized pigs. CD40L mAb clone 5c8, used in clinical trials for autoimmune diseases, was used. In platelet-rich plasma, CD40L mAb neither induced platelet aggregation per se, nor significantly affected maximal aggregation or slope of ADP-induced aggregation curves. However, it dose-dependently inhibited spontaneous deaggregation observed in ADP-stimulated samples. This effect was not observed with an irrelevant isotype-matched immunoglobulin. The stabilizing effect on platelet aggregates was neither glycoprotein IIb/IIIa-mediated nor Ca2+-dependent but was abolished by acetylsalicylic acid pretreatment. F(ab')2 fragments did not stabilize ADP-induced platelet aggregates but inhibited the stabilizing effect of CD40L mAb. Similar results were obtained with washed platelets, although higher amplification of ADP-induced aggregation was observed. In conclusion, CD40L expression produced by physiological or pathophysiological platelet activation can sustain a pro-aggregatory effect of CD40L mAb by a mechanism involving mAb Fc domain. These results could help to explain the mechanism of CD40L mAb-induced thromboembolic complications.


Adsorptive removal of benzene and toluene from aqueous solutions by oxygen-functionalized multi-walled carbon nanotubes derived from rice husk waste: A comparative study.
One of the current directions for sustainable development is to use waste resources to create materials that reduce environmental pollution. In this study, multi-walled carbon nanotubes (MWCNT) and their oxygen-functionalized forms (HNO3/H2SO4-oxidized MWCNT, NaOCl-oxidized MWCNT, and H2O2-oxidized MWCNT) were first synthesized from activated carbon (AC) derived from rice husk waste. A comprehensive comparison of the morphological and structural properties of these materials was conducted using FT-IR, BET, XRD, SEM, TEM, TGA, Raman spectroscopy, and surface charge analysis. The morphology study suggests that the synthesized MWCNTs have an average outer and inner diameter of about 40 and 20 nm, respectively. Additionally, the NaOCl-oxidized MWCNT possesses the largest interspaces between nanotubes, while the HNO3/H2SO4-oxidized CNT has the most oxygen-functional groups, including -COOH, (Ar)-OH, and C-OH. The adsorption capacities of these materials were also compared for the removal of benzene and toluene. Experimental results have shown that while porosity is the primary factor governing the benzene and toluene adsorption onto AC, functionalization degree and surface chemical characteristics are the determining factors in the adsorption capacity of the as-prepared MWCNTs. The adsorption capacity of these aromatic compounds in an aqueous solution increases in the following order: AC < MWCNT < HNO3/H2SO4-oxidized MWCNT < H2O2-oxidized MWCNT < NaOCl-oxidized MWCNT, and in all cases, toluene is more readily adsorbed than benzene under similar adsorption conditions. Wherein the uptake of both pollutants by the prepared adsorbents in this study is best described by the Langmuir isotherm and obeys the pseudo-second-order kinetic model. The adsorption mechanism was discussed in a detailed manner.


Interactions of heme with hepatic microsomal mono-oxygenase. Effect on benzpyrene hydroxylation.
The addition of heme (1-10 muM) to liver microsomes from phenobarbital (PB)-treated and 3-methylcholanthrene (MC)-treated male rats increased the rate of benzpyrene (BP) hydroxylation by about 20-40%. On the other hand, protoporphyrin IX caused only inhibition of BP hydroxylation. There was no increase of enzymatic activity by heme when solubilized preparations of liver microsomes were used. This suggested the possibility that an apo-cytochrome P-450 was present in intact microsomes. Higher concentrations of heme inhibited BP hydroxylation by either intact or solubilized microsomes. The inhibition by heme with solubilized microsomal preparations was noncompetitive, "mixed-type". However, with intact microsomes, the lack of linearity, precluded the determination of the type of inhibition. To examine possible effects of heme on the binding of BP to microsomal cytochrome P-450, the spectrum elicited by the addition of BP to microsomes was obtained in the presence or absence of added heme. The addition of heme to liver microsomes produced a marked increase in the trough (419-420 nm) of the difference spectrum formed by the subsequent addition of BP. These findings would suggest that heme increased the binding of BP to microsomes. However, the possibility that BP merely displaces the bound heme of the microsomes to yield, as expected, a trough at 413-416 nm (the addition of heme to microsomes yields a peak of 413-416 nm, unpublished) cannot be ruled out. Nevertheless, independent of our understanding of the mechanism involved in the spectral interactions between heme and BP with liver microsomes it is clear that an effect at their binding site(s) must have been elicited by the presence of both compounds.


Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation.
Bcl-2 protects cells from apoptosis and provides a survival advantage to cells over-expressing this oncogene. In addition, over expression of Bcl-2 renders cell resistant to radiation therapy. Recently, dichloroacetate (DCA) was proven to potentiate the apoptotic machinery by interacting with Bcl-2. In this study, we investigated whether treating human prostate cancer cells with DCA could modulate Bcl-2 expression and if the modulation in Bcl-2 expression could render the Bcl-2 over expressing cells more susceptible to cytotoxicity effects of radiation. PC-3-Bcl-2 and PC-3-Neo human prostate cancer cells treated with DCA in addition to irradiation were analyzed in vitro for changes in proliferation, clonogenic survival, apoptosis, cell cycle phase distribution, mitochondrial membrane potential, and expression of Bcl-2, Bcl-xL, Bax, or Bak proteins. DCA alone produced significant cytotoxic effects and was associated with G1 cell cycle arrest. Furthermore, DCA was associated with an increased rate of apoptosis. The combination of DCA with irradiation sensitized both cell lines to radiation's killing effects. Treatment of PC-3-Bcl-2 or PC-3-Neo with DCA and irradiation resulted in marked changes in various members of the Bcl-2 family. In addition, DCA therapy resulted in a significant change in mitochondria membrane potential, thus supporting the notion that DCAs effect is on the mitochondria. This is the first study to demonstrate DCA can effectively sensitize wild-type and over expressing Bcl-2 human prostate cancer cells to radiation by modulating the expression of key members of the Bcl-2 family. Together, these findings warrant further evaluation of the combination of DCA and irradiation.


An in vitro embryotoxicity assay based on the disturbance of the differentiation of murine embryonic stem cells into endothelial cells. I: Establishment of the differentiation protocol.
The aim of the present study was to establish an experimental protocol to differentiate murine embryonic stem (ES) cells into endothelial cells in vitro. The spinner flask technique as well as the hanging drop method were used to generate so-called embryoid bodies (EBs). In order to find out the optimal differentiation environment, EBs were cultured under various experimental conditions for up to 14 days. The influence of basic fibroblast growth factor (bFGF) alone, vascular endothelial growth factor (VEGF) alone, bFGF and VEGF together and a cocktail consisting of bFGF, VEGF, interleukin-6 (IL-6) and erythropoietin (Epo) on the induction of differentiation of ES cells into endothelial cells was studied. Different concentrations of growth factors and times of treatment were applied. Endothelial cells were characterized by analyzing the expression of platelet-endothelial cell adhesion molecule (PECAM-1), the endothelial-specific vascular endothelial cadherin (VE-Cadherin), the angiopoietin receptor Tie-2, VEGF receptors 1 and 2 (Flt-1 and Flk-1, respectively) and the soluble form of Flt-1 (sFlt) at the mRNA level. PECAM-1 and VE-Cadherin were also studied at the protein level. The data clearly showed that EBs generated by the hanging drop method, followed by their transfer into suspension culture on day 3 of differentiation and their subsequent plating on day 5 is the best of the studied methods to differentiate ES cells into endothelial cells. Addition of VEGF alone or a cocktail consisting of VEGF, bFGF, IL-6 and Epo resulted in the strongest gene expression levels of the above mentioned endothelial cell markers in the differentiated ES cells.


A phase II study of m-AMSA in patients with primary liver cancer.
Thirty-five evaluable patients with histologically confirmed primary liver cancer (PLC) were treated with m-AMSA. All patients had measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 1, 2, or 3. m-AMSA 120 mg/M2 IV was given every 21 days. Hemopoietic suppression was the major side-effect. In 26 of 35 patients (25 with leukopenia and five with thrombocytopenia), this toxic effect was documented. There was only one patient who had a partial remission (PR) of 51 weeks' duration, but a no change (NC) status was maintained in 28 patients for at least 6 weeks. The median survival time of all patients on this study was 13 weeks, which compares favorably with most previous studies.


A cross-sectional assessment of stroke rehabilitation in Nebraska hospitals.
To assess the structure and process of stroke rehabilitation in Nebraska hospitals. Cross-sectional mail survey using the Dillman tailored-design method of administration. Hospitals in Nebraska. Approximately 77% of the 84 Nebraska hospitals that provide stroke rehabilitation are critical access hospitals (CAHs) that are limited to 25 beds. Our study sample of hospitals (N=53) included the 19 hospitals licensed for 47 to 689 beds (non-CAHs) and a stratified random sample of 34 of the 65 CAHs. Not applicable. Self-reported stroke rehabilitation team structure and processes, purposes of and barriers to the use of evidence-based standardized assessments, specific assessments used, and access to specialized stroke rehabilitation services and community resources. Thirty-six (68%) of the 53 hospitals responded to the survey. Approximately 61% of the hospitals used an organized team to provide stroke rehabilitation; 8% of the hospitals-all non-CAHs-had a team dedicated to stroke rehabilitation. After adjusting for hospital size, having an organized team was significantly associated with the use of standardized assessments to improve communication, measure progress and outcomes, evaluate effectiveness of practice, and compare patient outcomes across conditions. Access to specialized stroke rehabilitation professionals and services was significantly greater in non-CAHs. Hospital size and the presence of a team are determinants of the structure and process of stroke rehabilitation in Nebraska hospitals. Further research is needed to determine (1) whether team structure is a determinant of stroke rehabilitation outcomes across the continuum of care settings, (2) the needs of rural stroke survivors, and (3) whether technology can facilitate the use of stroke rehabilitation standardized assessments by rural health care professionals.


Systemic Treatments in Pregnancy-Associated Breast Cancer.
Available data on systemic treatments in pregnancy-associated breast cancer (PABC) is reviewed in this section. These treatments include chemotherapy, endocrine therapy (ET), small molecule inhibitors, monoclonal antibodies against human epidermal growth factor receptor 2 (EGFR-2) also known as HER2; and human epidermal growth factor receptor 3 (EGFR-3), also known as HER3.In local disease, systemic treatment can be delivered as neoadjuvant (before surgery) or adjuvant (after surgery) treatment. In metastatic disease, systemic therapy is the main modality of treatment.Approach to PABC is based on available data in the general population, limited only by safety issues for use of medications during gestation and lactation. Therefore, treatments are similar to non-PABC patients while trying to minimize the risk to the fetus. Available data on different chemotherapies, anti-HER2 monoclonal antibodies, ET and small molecule inhibitors are discussed in detail.


The optimal dosage of ketanserin for patients with severe hypertension in pregnancy.
To establish the optimal dosage of ketanserin in the treatment of severe hypertension in pregnancy. A double blind prospective randomised controlled trail, comparing 10 mg ketanserin given as intravenous boluses either every 10 or 20 min, until the therapeutic goal of 90 mmHg (diastolic blood pressure) was reached, to a maximum of eight boluses. Main outcome measures were treatment failures and caesarean sections for fetal distress. There was no difference in reaching the therapeutic goal between patients receiving 10 mg ketanserin either every 10 or 20 min. Ketanserin appears to be an attractive medicine in the treatment of severe hypertension in pregnancy, but the optimal dosage could not be established.


Tolcapone-related liver dysfunction: implications for use in Parkinson's disease therapy.
Levodopa is the cornerstone of idiopathic Parkinson's disease (PD) treatment. However, after long-term use of levodopa, a significant percentage of patients experience motor fluctuations, which worsen their quality of life. Catechol-O-methyltransferase (COMT) inhibitors reduce levodopa metabolism and enhance the respective plasma levels, resulting in improvements in symptoms and overall quality of life. Tolcapone was the first drug of this class to be marketed, but was withdrawn in the European Union due to its implication in the deaths of three PD patients due to hepatic failure. Three deaths from fulminant hepatic failure in 40000 patient-years is a number that is 10-100 times higher than the expected incidence in the general population and, according to the manufacturer's own information, the number is probably underestimated due to under-reporting of cases. In the US, tolcapone was not withdrawn, but restrictive liver enzyme monitoring measures were issued by authorities, which severely limited its use. No further deaths from hepatic failure were reported since these measures were implemented. The mechanisms by which tolcapone may induce liver toxicity are still under debate. It was thought that mitochondrial uncoupling of oxidative phosphorylation by tolcapone, and consequent impairment of energy production by hepatocytes, could be responsible for the observed effects. Some experts consider that the restrictive guidelines issued in the US regarding tolcapone use may be loosened with no consequential reductions in safety. It was suggested that ongoing clinical information about safety should be considered and periodical revisions of the restrictions made accordingly. The identification of the molecular and biochemical basis of tolcapone hepatotoxicity, when completed, should also provide important indications for the clinical use of this drug. In conclusion, appropriate monitoring of liver function can ensure adequate safety in PD patients receiving tolcapone, who can therefore benefit from the symptomatic improvements obtained with this drug.


Prior testosterone replacement therapy may impact spermatogenic response to combined gonadotropin therapy in severe congenital hypogonadotropic hypogonadism.
To study the effect of prior testosterone replacement therapy (TRT) on the spermatogenic response to combined gonadotropin therapy (CGT) in severe and partial phenotype congenital hypogonadotropic hypogonadism (CHH) patients. Retrospective cohort study. Tertiary care center. Patients of CHH without (n = 17) and with prior TRT (n = 18) were subdivided into severe and partial groups, based on mean testicular volume ≤ 3 cc and > 3 cc respectively. Participants were treated with hMG at a dose of 75-150 U 3/week and gradually escalating doses of hCG until maximum dose (2000 U 3/week or 5000 U 2/week) or serum total testosterone of ≥ 3.5 ng/ml was reached. Final mean TV, trough serum testosterone (T), sperm concentration RESULTS: Thirty-five patients (20 severe, baseline mean TV of 3.6 ± 2.7 ml) were started on CGT at 24.8 ± 6.1 years. The median duration of prior TRT was 38 (IQR 10-63.75) months in the exposed group. After 33 ± 12 months, final mean TV was 8.9 ± 5.5 ml, 86% achieved serum testosterone > 3.5 ng/ml and 70% achieved spermatogenesis [median 5 (0-12.6) million/ml]. Patients without prior TRT had significantly higher peak sperm count than those with prior- TRT (median 9 vs 0.05 million/ml, p = 0.004). This effect of prior TRT was more pronounced in severe phenotype patients (median 7 vs 0 million/ml, p = 0.01). Prior-TRT may interfere with spermatogenic response to CGT in CHH patients, especially in those with a severe phenotype.


External validation of Solomon-Greenwell nomogram for female bladder outlet obstruction.
There is no unified diagnostic standard for female bladder outlet obstruction (BOO) to date. The Solomon-Greenwell (S-G) nomogram was developed to indicate the probability of female BOO by performing a pressure-flow study, and the equation of the BOO Index in females (BOOIf) is PdetQmax - 2.2 × Qmax. We aimed to validate the diagnostic value of the S-G nomogram in female BOO. We retrospectively reviewed a videourodynamic study (VUDS) cohort in our institution. Between 2015 and 2020, 192 female patients underwent VUDS for lower urinary tract dysfunction (LUTD). We excluded patients with neurogenic LUTD (n = 30) and patients with no detrusor contraction and/or no void during VUDS (n = 51). The diagnosis of female BOO was based on the Nitti criteria (radiological evidence of urethral narrowing in the presence of a sustained detrusor pressure). BOOIf was calculated for each enrolled patient. The cutoff values of BOOIf were set at <0, >5, and >18 as the original S-G nomogram proposed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each threshold to diagnose female BOO were calculated. Out of the 111 enrolled patients, 43 (38.7%) were diagnosed as having female BOO by VUDS. The most common etiology of female BOO was dysfunctional voiding (19/43, 44.2%), followed by primary bladder neck obstruction (PBNO, 15/43, 34.9%). When the cutoff value was <0 (low probability of obstruction), the sensitivity, specificity, PPV, and NPV were 90%, 91%, 92%, and 87%, respectively; when >5 (likely obstructed), the values were 79%, 96%, 92%, and 88%, respectively; and when >18 (obstruction almost certain), the values were 47%, 100%, 100%, and 75%, respectively. Fourteen of 15 PBNO patients would be classified as non-BOO if the cutoff value was >18. Six PBNO patients would not be diagnosed as female BOO if the threshold was >5. A BOOIf <0 showed good diagnostic value for excluding female BOO. A BOOIf >18 had perfect specificity and PPV for diagnosing female BOO. However, the sensitivity of the S-G nomogram for detecting female BOO was unsatisfactory, especially for patients with PBNO. VUDS remains the examination of choice for patients with suspected female BOO.


Portal Vein Thrombosis Secondary to COVID-19: A Rare Complication.
The novel coronavirus disease 2019 (COVID-19) pandemic has created a lasting impact in the world. It presents with various clinical manifestations, ranging from an asymptomatic state to respiratory system abnormalities, multi-organ involvement, thrombosis, and death. This case describes a 46-year-old female presenting with intractable abdominal pain leading to portal vein thrombosis (PVT), a diagnosis attributed to an unresolved COVID-19 infection.


The quality of children's home environment and attachment security in Indonesia.
The authors examined the relation of the Home Observation for Measurement of the Environment (HOME) Inventory (B. M. Caldwell & R. H. Bradley, 1984) for 0- to 6-year-old Sundanese Indonesian children with the quality of the mother-child attachment relationship (n=44) and attachment-related behaviors during play interactions (n=37) and with characteristics of the Indonesian caregiving context (N=77). Results showed that infants and toddlers with secure attachment relationships lived in higher quality home environments than did children with insecure attachment relationships. In particular, children with insecure-resistant attachment relationships lived in more unsafe and less organized homes with less play material available. For preschoolers, a lower quality home environment predicted more negativity and noncompliance toward their mothers in a play setting outside the home. With regard to the caregiving context, the socioeconomic status of the family was strongly related to the quality of preschoolers' home environment. Scores on the HOME Inventory for Infants/Toddlers and the HOME Inventory for Early Childhood were related to other culture-specific contextual characteristics for 0- to 6-year old Indonesian children as well. As a whole, the HOME was a good indicator of the general quality of the Sundanese Indonesian home environment.


Tactical medical skill requirements for law enforcement officers: a 10-year analysis of line-of-duty deaths.
In the absence of other data, military Tactical Combat Casualty Care (TCCC) precepts are increasingly being adapted to law enforcement needs. The purpose of this study is to better describe the nature of potentially preventable law enforcement Line-of-Duty Deaths (LODDs) occurring as a result of felonious assaults. A retrospective analysis was performed of open source data available through the US Federal Bureau of Investigation Uniform Crime Reporting (UCR) Law Enforcement Officers Killed and Assaulted (LEOKA) program for the years 1998-2007 inclusive. After applying exclusion criteria, 341 victim officers were included in the study. The most common cause of death was head trauma (n=198), followed by chest trauma (n=90). There were 123 victim officers that suffered potentially preventable deaths; the majority of these injuries involved the chest. Over the 10-year study period, only two officers (0.6%) died from isolated extremity hemorrhage. The current emphasis of TCCC on control of exsanguinating extremity hemorrhage may not meet the needs of law enforcement personnel in an environment with expedited access to well-developed trauma systems. Further study is needed to better examine the causes of preventable deaths in law enforcement officers, as well as the most appropriate law enforcement tactical medical skill set and treatment priorities.


How Important Is Reprocessing in Personalized Multicomponent Therapy? Analyzing Longitudinal Data of Inpatients With Severe PTSD.
Treatment guidelines for complex presentations of posttraumatic stress disorder (PTSD) are often cautious about the reprocessing of traumatic memories and recommend multicomponent treatments that are widely used in clinical practice. Yet, the role of reprocessing in these multicomponent treatments remains unknown. Using naturalistic data of 97 patients treated for PTSD, we used a linear mixed model to investigate the role of reprocessing for the outcome at discharge and at 6-month follow-up. Treatment effects were significant and large ( g = 0.91-1.05). The final model showed good fit and explained 51% of the variance. There was a significant main effect of time ( B = -8.1 [-11.5; -4.8], p < 0.001), as well as a reprocessing by time interaction ( B = -17.2 [-30.5; -3.8], p = 0.012), indicating better outcomes with higher levels of reprocessing. Hence, maximizing the amount of reprocessing used in multicomponent treatments for PTSD may significantly enhance outcomes.


Freshwater-related species richness in Natura 2000 sites strongly depends on the surrounding land use besides local habitat conditions.
The Birds and Habitats Directive are the cornerstones of Europe's nature conservation policy and the resulting Natura 2000 (N2k) sites form the largest coordinated network of protected areas in the world. Despite the ambitious targets of these directives and decades of efforts, biodiversity, especially of freshwater-related species, continues to decline in Europe. While multiple stressors at larger spatial scales are known to limit the effect of river restoration projects, the importance of surrounding land use outside the N2k sites for freshwater-related species richness inside N2k sites has rarely been studied. Conditional inference forests were used to assess the importance of land use in the surrounding and upstream of the German N2k sites compared to local habitat conditions inside. Freshwater-related species richness depended on land use in the surrounding besides local habitat conditions. Results indicated that this was especially true for birds in small N2k sites embedded in a wet, diverse, and patchy landscape and for non-birds due to the provision of additional habitats outside the N2k sites. Given that most N2k sites in Europe are rather small, the surrounding habitat conditions and land use potentially influences and affects freshwater-related species in many N2k sites across Europe. The additional conservation and restoration areas to be designated under the EU Biodiversity Strategy and upcoming EU restoration law should either be large enough or surrounded by extensive land use to optimize their effect on freshwater-related species.


The morphological changes of the pancreas in hypovolemic shock and the effect of pretreatment with steroids.
Previous reports from this laboratory have described the effect of hypovolemic shock of varying duration on the exocrine function of the pancreas, and the ability of steroids to reverse the inhibition of secretion observed. This report is a study of pancreatic morphology in prolonged hypovolemia, as well as the effect of steroid pretreatment on the pathology observed. Twelve mongrel dogs were divided into two groups, one with and one without steroid pretreatment. The animals were bled until at least 30-35% of their blood had been withdrawn, or until mean blood pressure (BP) dropped to around 60 mmHg. When BP dropped to 80-90% mmHg, six animals received intravenous (i.v.) prednisolone in 50 cc of 0.9% NaCl, at the rate of 10 cc/min, for a dosage of 30 mg/kg. Of the twelve dogs, six were exposed to 120 min of hypovolemia, and six to 180 min. At the end of the observed hypovolemic period, the blood withdrawn was quickly retransfused. After an hour of recovery, the animals were killed and their pancreases removed. The pancreases were weighed, fixed and examined by light microscopy. Three pancreases were obtained as control from animals not subjected to shock or steroids. The steroid-treated animals displayed an insignificant (5%) increase in pancreatic weight following prolonged hypovolemia. Untreated canine pancreases, on the other hand, showed a significant weight gain (37%, P less than 0.001) after 3 h of hypovolemia. Microscopically, the untreated group revealed marked interstitial edema, hemorrhage and inflammation, as well as focal acinar cell necrosis and fat necrosis, while in the steroid group only very mild edema and inflammatory changes were seen. This study indicates a beneficial effect of steroids on the morphological changes seen in shock-induced pancreatitis in canines and a possible use in the therapy of acute pancreatitis in man.


Diurnal type and hemispheric asymmetry.
Monk and Leng (1986) postulated that Morning-types (M-types) rely more than Evening-types (E-types) on subvocalization strategies, indirectly suggesting a difference in their habitual mode of hemispheric engagement. To evaluate this hypothesis, 48 right-handed women, 24 M-types and 24 age-matched E-types, performed verbal and spatial hemifield tachistoscopic tasks and recorded oral temperature at four separate times of day. Oral temperature curves were larger in amplitude and phase delayed for E-types. Reaction time curves were slower for E-types, without M-E phase differences. Error rate curves showed significant time-of-day effects at left-visual-field verbal tasks for M-types and at right-visual-field spatial tasks for E-types, indicating a selective trend in relying on left hemispheric mode for M-types and on right hemispheric mode for E-types. Implications for circadian oscillatory control are discussed.


Seronegative spondarthritides.
We have attempted to review the epidemiology of a group of diseases collectively termed the seronegative spondarthritides. In discussing environmental influences on these diseases we have reviewed shared aetiological hypotheses and how these have been, and may be, manipulated to influence disease development. The socioeconomic impact of disease has been discussed, together with some of the strategies we might adopt to prevent further disability and handicap. Recent developments, particularly in the laboratory, promise imminent advances in the aetiopathogenesis of this group of chronic inflammatory disorders.


Cereal grains and coronary heart disease.
Cereal grains and their products provide around 30% of total energy intake in British adults, (much more than any of the other major food groups). Coronary heart disease (CHD) is the largest single cause of death in Britain and many other Western countries. This review examines the question whether there is a relation between cereal consumption and CHD. Several of the nutrients in cereals have known potential for reducing risk factors for CHD: the linoleic acid, fibre, vitamin E, selenium and folate. Cereals also contain phytoestrogens of the lignan family and several phenolic acids with antioxidant properties. Processing generally reduces the content of these nutrients and bioprotective substances. Although cereals at the farm gate are very low in salt, processed cereal foods, eg bread and some breakfast cereals, are high-salt foods and thus could contribute to raising blood pressure. Human experiments have clearly shown that oat fibre tends to lower plasma total and LDL cholesterol but wheat fibre does not. Rice bran and barley may also lower cholesterol but most people do not eat enough barley to have an effect. Cereal foods with low glycaemic index such as pasta and oats are beneficial for people with diabetes and might lower plasma lipids. Between 1996 and 2001 an accumulation of five very large cohort studies in the USA, Finland and Norway have all reported that subjects consuming relatively large amounts of whole grain cereals have significantly lower rates of CHD. This confirms an earlier report from a small British cohort. The protective effect does not seem to be due to cholesterol-lowering. While cohort studies have shown this consistent protective effect of whole grain cereals, there has been (only one) randomised controlled secondary prevention trial of advice to eat more cereal fibre. In this there was no reduction of the rate of reinfarction. The trial had some weaknesses, eg there were eight different diets, compliance was not checked objectively, and duration was for only 2 y. It appears valid to make health claims (as now permitted by the US FDA) that whole grain cereal foods and oat meal or bran may reduce the risk of CHD.


Demonstration of oestrogen receptor in symptomatic breast carcinoma, using fine needle aspiration cytology.
Oestrogen receptor immunocytochemical assay (ER-ICA) was used to determine oestrogen receptor (ER) content of cells in fine needle aspirate (FNA) specimens from 88 breast carcinomas. In 49 of these the radioligand binding assay for oestradiol was available for comparison. The predictive value of ER-ICA staining for a positive radioligand binding assay (greater than 10 fmol/mg protein) was 95%. Although the predictive value of negative staining was only 66%, 34 out of 37 ER-ICA negative tumours had radioligand binding assays below 60 fmol/mg protein. ER-ICA staining showed a strong positive correlation with age of the patient, positivity being rare before the menopause. There was a weak inverse correlation with tumour grade but none with tumour size or lymph node status. The assessment of ER by immunocytochemistry using FNA cytology is a rapid technique, which may easily be repeated and provides a pre-operative assessment of ER status. It allows confirmation that tumour cells are present in the sample and an assessment of tumour heterogeneity.


A tw0-component ribonucleotidyl transferase from E. coli.
Some properties of an enzyme designated as a two component ribonucleotidyl transferase from E. coli are presented. The enzyme in the presence of magnesium ions catalyzes the synthesis of polyribonucleotide chains using all four nucleoside triphosphates as substrates. The enzyme consists of two components; component A in the presence of Mg2+ catalyzes the synthesis of homo- and heteropolymers using ATP, CTP and UTP but not GTP as substrates. Component B itself does not catalyze any synthesis at all, but its addition to component A affects this component in two ways: quantitatively- the activity of component A considerably increases, and qualitatively- both components together are capable of catalyzing the synthesis of polyribonucleotides consisting of all four ribonucleotides.


Structure of the replication fork in ultraviolet light-irradiated human cells.
The DNA extracted from xeroderma pigmentosum human fibroblasts previously irradiated with 12.5 J/m2 of UV light and pulse-labeled for 45 min with radioactive and (or) heavy precursors, was used to determine the structural characteristics of the replication fork. Density equilibrium centrifugation experiments showed that a fork moved 6 micrometer in 45 min and bypassed 3 pyrimidine dimers in both strands. The same length was covered in 15-20 min in control cells. The delay in irradiated cells was apparently due to pyrimidine dimers acting as temporary blocks to the fork movement. Evidence for this interpretation comes from kinetics of incorporation of [3H]thymidine into DNA, which show that the time necessary to attain a new stable level of DNA synthesis in irradiated cells is equivalent to that required for the replication fork to cover the interdimer distance in one strand. On the other hand, the action of S1 nuclease on DNA synthesized soon after irradiation gives rise to a bimodal distribution in neutral sucrose gradients, one peak corresponding to 43 X 10(6) daltons and the other to 3 X 10(6) daltons. These two DNA species are generated by the attack of the S1 nuclease on single-stranded regions associated with the replication fork. A possible explanation for these results is given by a model according to which there is a delayed bypass of the dimer in the leading strand and the appearance of gaps opposite pyrimidine dimers in the lagging strand, as a direct consequence of the discontinuous mode of DNA replication. In terms of the model, the DNA of 43 X 10(6) daltons corresponds to the leading strand, linked to the unreplicated branch of the forks, whereas the piece of 3 X 10(6) daltons is the intergap DNA coming from the lagging strand. Pulse and chase experiments reveal that the low molecular weight DNA grows in a pattern that suggests that more than one gap may be formed per replication fork.


Effect of benztropine on the diurnal prolactin responses to haloperidol.
Prolactin (PRL) responses to haloperidol were investigated at 0900 and 1800 h in six young healthy men under basal conditions and after benztropine mesylate administration. Haloperidol administration induced significantly higher PRL release during the evening compared to the morning. The anticholinergic drug, benztropine, potentiated the PRL responses to haloperidol both in the morning and in the evening. The possible mechanisms of these findings are discussed.


Correspondence between neuroevolution and gradient descent.
We show analytically that training a neural network by conditioned stochastic mutation or neuroevolution of its weights is equivalent, in the limit of small mutations, to gradient descent on the loss function in the presence of Gaussian white noise. Averaged over independent realizations of the learning process, neuroevolution is equivalent to gradient descent on the loss function. We use numerical simulation to show that this correspondence can be observed for finite mutations, for shallow and deep neural networks. Our results provide a connection between two families of neural-network training methods that are usually considered to be fundamentally different.


Response to insulin glargine 100 U/mL treatment in newly-defined subgroups of type 2 diabetes: Post hoc pooled analysis of insulin-naïve participants from nine randomised clinical trials.
To assess insulin glargine 100 U/mL (IGlar-100) treatment outcomes according to newly-defined subgroups of type 2 diabetes mellitus (T2DM). Insulin-naïve T2DM participants (n = 2684) from nine randomised clinical trials initiating IGlar-100 were pooled and assigned to subgroups "Mild Age-Related Diabetes (MARD)", "Mild Obesity Diabetes (MOD)", "Severe Insulin Resistant Diabetes (SIRD)", and "Severe Insulin Deficient Diabetes (SIDD)", according to age at onset of diabetes, baseline HbA1c, BMI, and fasting C-peptide using sex-specific nearest centroid approach. HbA1c, FPG, hypoglycemia, insulin dose, and body weight were analysed at baseline and 24 weeks. Subgroup distribution was MARD 15.3 % (n = 411), MOD 39.8 % (n = 1067), SIRD 10.5 % (n = 283), SIDD 34.4 % (n = 923). From baseline HbA1c 8.0-9.6% adjusted least square mean reductions after 24 weeks were similar between subgroups (1.4-1.5 %). SIDD was less likely to achieve HbA1c < 7.0 % (OR: 0.40 [0.29, 0.55]) than MARD. While the final IGlar-100 dose (0.36 U/kg) in MARD was lower than in other subgroups (0.46-0.50 U/kg), it had the highest hypoglycemia risk. SIRD had lowest hypoglycemia risk and SIDD exhibited greatest body weight gain. IGlar-100 lowered hyperglycemia similarly in all T2DM subgroups, but level of glycemic control, insulin dose, and hypoglycemia risk differed between subgroups.


Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.
A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC₅₀ values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC₅₀ values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC₅₀ values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC₅₀ values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC₅₀ values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC₅₀ determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided.