Metachromatic activity of heparin and heparin fragments.
Heparin of an average molecular weight of 13,000 was fractionated on the basis of size into five fractions of different weight-average molecular weight ranging from 8500 to 20,000. The heparin was also degraded using microbial heparinase resulting in products ranging from a disaccharide of molecular weight 500 to an oligosaccharide of molecular weight 3100. These products were also size fractionated. The individual heparin fractions and products were tested for metachromatic activity with Azure A. The metachromatic activity of the heparin fractions was independent of molecular weight, while the metachromatic activity of the products was dependent on molecular weight. Metachromatic activity was found in a fragment as small as a tetrasaccharide. Anticoagulant activity was found in fragments of tetrasaccharide or larger by a Factor Xa clotting assay and in fragments of hexasaccharide or larger by a Factor Xa amidolytic chromogenic assay.


Insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme and myocardial infarction.
Male (n = 185) and female (n = 49) survivors of myocardial infarction (MI) below 56 and 61 years of age, respectively, were compared to 366 controls with respect to distribution of genotypes in an insertion/deletion (ID) polymorphism at the angiotensin I-converting enzyme (ACE) locus. The frequency of the DD genotype (homozygosity for the deletion allele) was significantly lower among male patients than controls (22.7% versus 34.9%, p = 0.011). In a "low-risk" group, defined as having less than the sex-specific, age-adjusted median values of body mass index (BMI) and apolipoprotein B (apoB), respectively, and absence of treatment with lipid-lowering drugs, the prevalence of the DD genotype was not statistically different between male patients and controls. In a male "high-risk" group (those individuals who had not been defined as "low-risk" subjects), the prevalence of the DD genotype was 20.9% in patients and 38.3% in controls (p = 0.002). In women, no significant differences in genotype frequencies between patients and controls were found in the whole sample or in any subgroup. These results appear to be at variance with data reported recently by Cambien et al. (1992). The difference may be due to chance, undetected selection biases, different gene-environment interactions between Norway and France or Ireland, or to preferential loss of DD individuals in our male "high-risk" group.


Influence of supramammary lymph node extract on in vitro cell proliferation.
Experiments were conducted to evaluate whether or not bovine supramammary lymph node extract (LNE) could support cell proliferation when it was substituted for bovine growth serum (BGS) in cell culture media. Two different preparations of LNE were tested. The first yielded protein concentration of 3 mg/mL and the second contained 27 mg/mL protein. Three cell lines (MDA-MB-435, MAC-T and 1C6) were used in serum starvation assays to evaluate LNE. Cell proliferation assays were used to determine growth stimulation in the presence of LNE, and short-term or rapid adaptation cultures were evaluated for LNE effects on cell survival. Heat-inactivated preparation 1 supported cell proliferation as well as or better (12-39%) than BGS following 2 days of serum starvation in culture. The second lymph node preparation provided a stimulatory effect (263-702% greater than BGS across all cell lines) following serum starvation at 2.7 and 5.4 mg/mL protein supplementation. A gradual adaptation process with lymph node supplementation into media maintained cell population growth on a short-term basis. However, once cells were trypsinized or scraped and re-seeded into 2.7 mg/mL LNE protein containing media, cells were unable to re-adhere, leaving them detached, and eventually appearing to be dead. Substitution of BGS with LNE protein dramatically stimulated cells to proliferate, but did not allow for rapid cell population growth adaptation in vitro.


Designing Orthodontic Craniofacial Templates for 8-14 year-old Iranian Girls Based on Cephalometric Norms.
Cephalometry and its related analyses have an important role in the evaluation of orthodontic patients. Access to an analysis that gives maximum information in the least possible time is an effective way to indicate craniofacial disharmony; therefore, craniofacial templates are very useful tools. The purpose of the present study was to provide orthodontic craniofacial templates for 8-14-year-old Iranian girls. One thousand two-hundred and nine girls (age range, 8-14 years) were examined. Eighty of these cases were finally chosen for the study and their lateral cephalograms were traced. Both Basion-Nasion (Ba-N) and Sella-Nasion (S-N) lines were selected for superimposition in this study. Based on these two mentioned lines, a template for each age was designed. Simple linear regression and multivariant regression analysis were used to evaluate the angles and to landmark the vectors, respectively. Findings show that most points change significantly at different ages in the S-N method. In the Ba-N method, all points except for S and Ba have significant changes at different ages. Templates that resulted from both methods were the same and alteration in the reference line and points does not change the total form of the average tracings of each age.


Association of Nutrients with Biomarkers of Alzheimer's Disease.
Prospective cohort studies, cross-sectional surveys, autopsy studies and intervention clinical trials that investigated the association between nutrients and Alzheimer's disease (AD) have been reviewed. To estimate the relationship between specific nutrient intake and the risk of AD, Cochrane Library, PubMed, EMBASE, and the Fisher Center for Alzheimer's Research Foundation were searched for this purpose. Most published observational studies found an inverse relationship between vitamins, n-3 fatty acids and AD. The majority of intervention studies support the beneficial effect of combined vitamins and n-3 fatty acids providing them in the early stages of the disease. Only vitamin E and Zn supplementation failed to show any significant difference on the study population. On the other hand, high dietary intake of saturated fat and brain metal accumulation were positively associated with the incidence of AD.


Spatial aspects of pain modulation are not disrupted in adolescents with migraine.
To compare spatial pain modulation capabilities between adolescents with and without migraine. Conditioned pain modulation (CPM) responses at the leg are similar in adolescents with versus without migraine. However, the anatomical region of testing may affect spatial pain modulation capabilities as differences in nociceptive processing between patients with migraine and healthy controls are found in local areas that are near the site of clinical pain but not in nonlocal areas. This study aimed to examine spatial pain modulation capabilities tested by the CPM paradigm using test stimulus applied to a local body area. Nineteen adolescents with migraine (age 14.9 ± 2.3, mean ± SD; 16 female) and 20 healthy adolescents (age 13.8 ± 2.5, mean ± SD; 16 female) completed this case-control study at Cincinnati Children's Hospital Medical Center. Pressure pain thresholds (PPT) were assessed at the trapezius before and during immersion of the foot in a cold water bath (8°C). In the migraine group (146.0 ± 79.1, mean ± SD), compared to healthy controls (248.0 ± 145.5, mean ± SD), significantly lower PPT (kilopascal) values were found (estimate = 124.28, 95% CI: 58.98, 189.59, p < 0.001; effect size: d = 1.40). No differences between the groups were found for pain intensity and unpleasantness ratings of cold-water immersion nor the CPM response. This study found altered ascending nociceptive processing of mechanical stimuli at the neck in adolescents with migraine. However, endogenous pain modulatory mechanisms were functional and not altered. In light of other studies, impairments in inhibitory control may not be involved in migraine pathophysiology in pediatric patients regardless of stimulus location.


BDNF serum levels in schizophrenic patients during treatment augmentation with sarcosine (results of the PULSAR study).
Finding a relationship between schizophrenia symptoms severity and initial level of BDNF and its changes during augmentation of antipsychotic treatment with sarcosine. 57 individuals with schizophrenia with predominantly negative symptoms completed a 6-month RCT prospective study. The patients received 2g of sarcosine (n=27) or placebo (n=30) daily. At the beginning, after 6 weeks and 6 months BDNF levels were measured. Severity of symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS). BDNF serum levels were stable after 6 weeks and 6 months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group comparing to placebo, however there was no correlations between serum BDNF concentrations and PANSS scores in all assessments. Initial serum BDNF concentrations cannot be used as a predictor of the improvement resulting from adding sarcosine. Our results indicate that either BDNF is not involved in the NMDA-dependent mechanism of sarcosine action or global changes in BDNF concentrations induced by amino-acid cannot be detected in blood assessments.


Bexarotene Attenuates Focal Cerebral Ischemia-Reperfusion Injury via the Suppression of JNK/Caspase-3 Signaling Pathway.
Apolipoprotein E (APOE) is implicated not only in chronic degenerative neurological diseases, such as Alzheimer's disease, but also in acute brain disorders, including traumatic brain injury. Bexarotene, a selective agonist of the retinoid X receptor, has been reported to enhance markedly the expression of APOE. Previous studies have indicated that bexarotene exerts neuroprotective effects in animal models of ischemic stroke by modulating the peripheral immune response and autophagy. However, the role of this drug in neuronal apoptosis and the potential mechanisms involved have yet to be elucidated. The present study employed transient middle cerebral artery occlusion (t-MCAO) as a model of acute cerebral ischemia/reperfusion injury. The experiments were performed in wild-type C57BL/6 mice and APOE gene knockout (APOE-KO) mice. After t-MCAO, mice received intraperitoneal injection of bexarotene (5 mg/kg) or an equal volume of the vehicle. The outcome measurements included neurological deficits, learning ability, spatial memory, infarct volume, histopathology, magnitude of apoptosis, and the level of expression of proteins of the JNK/caspase-3 signaling pathway. The obtained results demonstrated that bexarotene administration significantly improved neurological function, learning ability, and spatial memory in C57BL/6 mice, but not in APOE-KO mice. Infarct volume, tissue damage, neuronal apoptosis rate, and the expression of proteins involved in the JNK/caspase-3 signaling pathway were markedly increased after t-MCAO in both C57BL/6 and APOE-KO mice. Importantly, bexarotene treatment significantly ameliorated all these changes in C57BL/6, but not in APOE-KO mice. In conclusion, bexarotene markedly alleviates the neurological deficits, improves the histological outcome, and inhibits cell apoptosis in mice after t-MCAO. This effect is mediated, at least in part, by up-regulation of APOE. Thus, bexarotene may be a candidate drug for the treatment of cerebral ischemia patients.


Sphenoid Sinus and Related Neurovascular Structures-Anatomical Relations and Variations on Radiology-A Retrospective Study.
The aim of this study was to evaluate sphenoid sinus pneumatisation and its anatomical relation with adjacent neurovascular structures in Indian population. We performed a retrospective cross-sectional study, in which the pattern of sphenoid sinus pneumatization was studied on high-resolution computed tomography scans (n = 400), and association of the optic nerve, vidian canal and foramen rotundum along with related morphometric measurements were studied. Out of 400 CT scans, 60.5% were males. Majority had sellar type of pneumatization (89.5%) and single intersinus septum (68%). The most common configuration of relation of optic nerve canal was DeLano type 2 (34.75%). Vidian canal (VC) and Foramen rotundum (FR) were found dehiscent in 40.5% and 6.38% respectively. Average distance of FR from midline on right and left side was 16.3 ± 2.19 mm and 16.7 ± 2.23 mm respectively. Average distance of VC from midline on right and left side was 12.4 ± 5.84 mm and 12.4 ± 4.18 mm respectively. Average right FR to VC distance was 4.17 ± 2.16 mm and left FR to VC was 4.44 ± 2.20 mm. Anatomical variations of the sphenoid sinus are well known. In the present study, we have tried to highlight the importance of knowledge of various anatomical variations in relations to sphenoid sinus as they are critical in planning of surgery. Pre-operative radiological study and correlation is inevitable to assess type and extent of sinus pneumatisation, bony dehiscence and septal terminations to avoid injury to vital structures.


Dpb2 integrates the leading-strand DNA polymerase into the eukaryotic replisome.
The eukaryotic replisome is a critical determinant of genome integrity with a complex structure that remains poorly characterized. A central unresolved issue is how the Cdc45-MCM-GINS helicase is linked to DNA polymerase epsilon, which synthesizes the leading strand at replication forks and is an important focus of regulation. Here, we use budding yeast to show that a conserved amino-terminal domain of the Dpb2 subunit of Pol ε (Dpb2NT) interacts with the Psf1 component of GINS, via the unique "B domain" of the latter that is dispensable for assembly of the GINS complex but is essential for replication initiation. We show that Dpb2NT is required during initiation for assembly of the Cdc45-MCM-GINS helicase. Moreover, overexpressed Dpb2NT is sufficient to support assembly of the Cdc45-MCM-GINS helicase during initiation, upon depletion of endogenous Dpb2. This produces a replisome that lacks DNA polymerase epsilon, and although cells are viable, they grow extremely poorly. Finally, we use a novel in vitro assay to show that Dpb2NT is essential for Pol ε to interact with the replisome after initiation. These findings indicate that the association of Dpb2 with the B domain of Psf1 plays two critical roles during chromosome replication in budding yeast. First, it is required for initiation, because it facilitates the incorporation of GINS into the Cdc45-MCM-GINS helicase at nascent forks. Second, it plays an equally important role after initiation, because it links the leading strand DNA polymerase to the Cdc45-MCM-GINS helicase within the replisome.


Alveolar soft part sarcoma of the head and neck. A disease of children and young adults.
Alveolar soft part sarcoma (ASPS) is a rare malignancy of uncertain histologic origin that predominantly afflicts female children and young adults. Forty-three cases occurring in the head and neck have been identified, to which we add a case. The most frequent sites of occurrence in the head and neck are orbit and tongue. Treatment is universally surgical, with limited roles for adjuvant radiotherapy and chemotherapy. Representative populations of patients with orbital, non-orbital and extremity ASPS are compared statistically. Improved disease-free intervals in orbital ASPS vs non-orbital ASPS and head and neck ASPS vs extremity ASPS are documented. Debate exists regarding the histologic origin of ASPS. The additional case presented does not corroborate recent immunohistochemical studies suggesting myogenic origin. Nevertheless, the clinical pattern of disease offers additional support to the myogenic hypothesis of histologic origin.


Synthesis of water-soluble, ring-substituted squaraine dyes and their evaluation as fluorescent probes and labels.
A series of ring-substituted squaraines absorbing and emitting in the red and NIR spectral region was synthesized and their spectral and photophysical properties (quantum yields, fluorescence lifetimes) and photostabilities were measured and compared to Cy5, a commonly used fluorescent label. The absorption maxima in aqueous media were found to be between 628 and 667 nm and the emission maxima are between 642 and 685 nm. Squaraine dyes exhibit high extinction coefficients (163,000-265,000 M(-1) cm(-1)) and lower quantum yields (2-7%) in aqueous buffer but high quantum yields (up to 45%) and long fluorescence lifetimes (up to 3.3 ns) in presence of BSA. Dicyanomethylene- and thio-substituted squaraines exhibit an additional absorption around 400 nm with extinction coefficients between 21,500 and 44,500 M(-1) cm(-1). These dyes are excitable not only with red but also with blue diode lasers or light emitting diodes. Due to the favourable spectral and photophysical properties these dyes can be used as fluorescent probes and labels for intensity- and fluorescence lifetime-based biomedical applications.


Hypercalciuria related to cadmium exposure.
A work force has been investigated for possible cadmium intoxication. One group who are coppersmiths have an 18.5 per cent prevalence of upper urinary tract stone disease associated with a statistically highly significant hypercalciuria and reduced serum inorganic phosphate. Proof of exposure to cadmium has been confirmed in all workers. The trace element cadmium should be kept in mind when investigating stone formers who exhibit an unexplained hypercalciuria.


Effectiveness of antipsychotic drugs in schizophrenia: a 10-year retrospective study in a Korean tertiary hospital.
Extensive research has been carried out on the comparative effectiveness of antipsychotic medications. Most studies, however, have been performed in Western countries. The purpose of this study was to compare the effectiveness, indicated by time to any-cause discontinuation, of antipsychotic drugs in a large number of patients with schizophrenia in South Korea. We identified 1458 patients with schizophrenia or schizophreniform disorder who were treated with antipsychotic medications using a clinical data warehouse at the Seoul National University Hospital between March 2005 and February 2014. Kaplan-Meier survival analyses were used to estimate the time to discontinuation of antipsychotic drugs. We compared the survival curves of different antipsychotics using log-rank tests. Overall, the median time to discontinuation for any cause was 133 days (95% CI, 126-147). The longest time to discontinuation was observed for clozapine, followed by aripiprazole, paliperidone, olanzapine, amisulpride, risperidone, quetiapine, ziprasidone, and haloperidol. Specifically, clozapine was significantly different from all other antipsychotic drugs (all p < 0.001). Aripiprazole also had a significantly longer time to discontinuation than amisulpride (p = 0.001), risperidone (p < 0.001), quetiapine (p < 0.001), ziprasidone (p < 0.001), and haloperidol (p < 0.001). In Asian patients with schizophrenia, clozapine was the most effective antipsychotic in terms of time to discontinuation, followed by aripiprazole. This study extends the findings of previous effectiveness studies from Western populations and suggests the need to develop guidelines for the pharmacotherapy of schizophrenia tailored to Asian individuals.


The Short-Term Remission of Diabetic Nephropathy After Roux-en-Y Gastric Bypass in Chinese Patients of T2DM with Obesity.
The study aimed to examine the effect of gastric bypass on diabetic nephropathy (DN) in Chinese patients. A retrospective study of 101 samples with DN stages I to IV underwent Roux-en-Y gastric bypass. Anthropometric and biochemical parameters were assessed during a 1-year follow-up. Binary logistic regression analysis was used for predictors and ROC for cutoff points. There was significant reduction of medication for diabetes and hypertension. Overall remission of T2DM was 80.2 %. Preoperative albumin/creatinine ratio (ACR) and serum creatinine (SCr) levels could be predictors for DN remission, and the cutoff points were 126 mg/g cr and 57 μmol/L, respectively. Gastric bypass showed improvement of T2DM and DN. Gastric bypass may be more beneficial for those with lower preoperative ACR and SCr.


Generation and regulation of microtubule network asymmetry to drive cell polarity.
Microtubules control cell architecture by serving as a scaffold for intracellular transport, signaling, and organelle positioning. Microtubules are intrinsically polarized, and their orientation, density, and post-translational modifications both respond and contribute to cell polarity. Animal cells that can rapidly reorient their polarity axis, such as fibroblasts, immune cells, and cancer cells, contain radially organized microtubule arrays anchored at the centrosome and the Golgi apparatus, whereas stably polarized cells often acquire non-centrosomal microtubule networks attached to the cell cortex, nucleus, or other structures. Microtubule density, longevity, and post-translational modifications strongly depend on the dynamics of their plus ends. Factors controlling microtubule plus-end dynamics are often part of cortical assemblies that integrate cytoskeletal organization, cell adhesion, and secretion and are subject to microtubule-dependent feedback regulation. Finally, microtubules can mechanically contribute to cell asymmetry by promoting cell elongation, a property that might be important for cells with dense microtubule arrays growing in soft environments.


Different Doses of Intravenous Tranexamic Acid in Revision Total Knee Arthroplasty: A Retrospective Study.
This article assessed the efficacy and safety of different doses of intravenous tranexamic acid (TXA) in revision total knee arthroplasty (TKA). We retrospectively identified 122 patients in our institution who underwent revision TKA with a history of perioperative intravenous TXA utilization. According to the sum of intravenous TXA documented, all patients were divided into three groups: 1 g intravenous TXA, 2 g intravenous TXA, and equal or greater than 3 g intravenous TXA. The primary outcomes included total blood loss (TBL), hidden blood loss (HBL), transfusion rate, and the incidence of symptomatic venous thromboembolism among the three groups. A correlation analysis was conducted to analyze the correlation between the dose of TXA and the blood loss. In total, there was no significance difference in TBL and revised HBL (rHBL) between the first two groups (1 g/dL for intravenous TXA, 2 g/dL for intravenous TXA; p = 0.486; p = 0.525). Equal or greater than 3 g intravenous TXA (≥3 g/dL for intravenous TXA) reached a significant reduction in TBL, rHBL, and length of stay compared with the first two groups (p = 0.01; p = 0.01; p = 0.01). The rate of transfusion between the three groups did not differ significantly (p = 0.21). Due to the limitations in sample size, only one symptomatic venous thromboembolism was reported in the 1 g intravenous TXA group. Applying the dose of intravenous TXA equal or greater than 3 g in revision TKA might further reduce the blood loss and shorten the length of stay.


Deoxycytidine kinase is downregulated under hypoxic conditions and confers resistance against cytarabine in acute myeloid leukaemia.
Leukaemia initiating cells reside within specialised niches in the bone marrow where they undergo complex interactions with different stromal cell types. The bone marrow niche is characterised by a low oxygen content resulting in high expression of hypoxia-inducible factor 1 α in leukaemic cells conferring a negative prognosis to patients with acute myeloid leukaemia (AML). In the current study, we investigated the impact of hypoxic vs. normoxic conditions on the sensitivity of AML cell lines and primary AML blasts to cytarabine. AML cells cultured under 6% oxygen were significantly more resistant against cytarabine compared to cells cultured under normoxic conditions in proliferation and colony-formation assays. Interestingly upon cultivation under hypoxia, the expression of the cytarabine-activating enzyme deoxycytidine kinase was downregulated in all analysed AML cell lines and primary AML samples representing a possible mechanism for resistance to chemotherapy. Furthermore, the downregulation of deoxycytidine kinase could be associated with hypoxia-inducible factor 1 α as treatment with its inhibitor BAY87-2243 hampered the downregulation of deoxycytidine kinase expression under hypoxic conditions. In conclusion, our data reveal that hypoxia-induced downregulation of deoxycytidine kinase represents one stroma-cell-independent mechanism of drug resistance to cytarabine in acute myeloid leukaemia.


The repeating sequence of the capsular polysaccharide of Staphylococcus aureus M.
The anomeric configuration of the sugar residues of the capsular polysaccharide antigen of Staphylococcus aureus M were established by 13C-n.m.r. spectroscopy, and the linkage positions by g.l.c.-m.s. after methylation, indicating a leads to 4)-O-(2-acetamido-2-deoxy-alpha-D-galactopyranosyluronic acid)-(1 leads to 4)-O-(2-acetamido-2-deoxy-alpha-D-galactopyranosyluronic acid)-(1 leads to 3)-O-(2-acetamido-2-deoxy-alpha-D-fucopyranosyl)-(1 leads to repeating unit. A taurine residue is linked by an amide bond, on the average, to every fourth 2-acetamido-2-deoxy-D-galactopyranosyluronic acid residue.


[Structural characteristics of plasma lipoproteins studied with spin-labelled fatty acids].
As shown by means of electrone paramagnetic resonance of spin probes, a magnitude of ordering of lipoprotein molecular arrangement both internal and external parts of molecule was decreased in a following sequence: high density lipoproteins greater than low density greater than very low density lipoproteins. Permeability towards a reducing agent - ascorbic acid - was altered similarly in the lipoprotein surface monolayer.


Evaluation of domain prediction in CASP6.
We present an analysis of the domain boundary prediction, a new category, in the sixth community-wide experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP6). There were 1011 predictions submitted for 63 targets. Each prediction was compared to the set of domains defined manually by visual inspection of the experimental structure. The comparison was scored using a new domain prediction scoring scheme. As the definition of a domain is subjective, many targets were assigned alternate definitions. For such targets, each prediction was compared with all different definitions and the best score was chosen. The predictors found it difficult to accurately predict domain boundaries when the target protein contained many domains or domains made of multiple sequence segments. The CBRC-DR (P0536) and Sternberg (P0237) groups were the most successful among human experts, while Baker-Rossettadom (P0353) and Baker-Robetta-Ginzu (P0421) did well among servers.


Associations between problematic internet use, life satisfaction, and deliberate self-harm among Chinese adolescents: A multi-centered longitudinal study.
Problematic Internet use (PIU), which is associated with deliberate self-harm (DSH), has become a common problem among adolescents. Life satisfaction (LS) may be able to mitigate the negative influences of PIU and DSH. But the longitudinal associations among them are yet to be well-researched. A longitudinal study with three-wave data collection involving 6092 adolescents was carried out in China. PIU, LS, and DSH were assessed using the Young Internet Addiction Test, the Satisfaction with Life Scale, and the Deliberate Self-Harm Inventory Nine-Item Version, respectively. A cross-lagged model was used to analyze the longitudinal interactions between them. Generalized Estimating Equations were adopted to identify their influential factors. The prevalence of single DSH behaviors from wave 1 to wave 3 was 5.04%, 5.00%, and 4.67%, and the repeated DHS from wave 1 to wave 3 was 2.9%, 3.2%, and 3.4%, respectively. Bidirectional longitudinal predictive associations were revealed between PIU and LS (p<0.001), and LS and DSH (p<0.001). DSH could longitudinally predict PIU (p<0.001). Gender and age were associated with PIU, LS, and DSH (p<0.001), and PIU was influenced by ethnicity (p<0.001). PIU and LS, LS and DSH were associated bidirectionally. Adolescents with more severe DSH behaviors were inclined to become addicted to the Internet, and adolescents with a history of DSH had a higher risk of recurring DSH. Parents, schools, and administrators need to improve the LS of adolescents, with a particular focus on older, female adolescents.


MiRNAs as biomarkers of phenotype in neutral lipid storage disease with myopathy.
Neutral lipid storage disease with myopathy (NLSDM) is a rare lipid metabolism disorder. In this study, we evaluated some circulating miRNAs levels in serum samples and the MRI of three affected siblings. Three members of one NLSDM family were identified: two brothers and one sister. Muscles of lower and right upper extremities were studied by MRI. Expression profile of miRNAs, obtained from serum samples, was detected using qRT-PCR. Two brothers presented with progressive skeletal myopathy, while the sister had severe hepatosteatosis and diabetes. NLSDM patients showed a significant increase of muscle-specific miRNAs expression compared with healthy subjects. We found a correlation between hepatic damage and elevation of miRNAs expression profile of liver origin. The dysregulation of miRNAs might represent an indicator of skeletal and hepatic damage and it might be useful to monitor the progression of NLSDM.


Ligand-accelerated vanadium-catalysed epoxidation in water.
Vanadium-catalysed epoxidation of allylic alcohols, a classical example of ligand-decelerated catalysis, in water it turns into a ligand-accelerated process.


Quantification of patch test reactions by transcutaneous PO2 measurement.
The usefulness of transcutaneous oxygen tension (tc-PO2) measurement for quantification of positive patch test reactions was studied. A significant correlation was found between the visual grading and the quantitative tc-PO2 values. Tc-PO2 discriminated between visual grade 0 to 1+, 1+ to 2+, and 2+ to 3+ reactions. The results obtained by this method were compared with those obtained by other quantitative methods. Tc-PO2 measurement can be regarded as complementary to the laser Doppler technique, since it lacks the sensitivity of the laser Doppler technique in the range in negative to 1+ patch reactions, but it does discriminate between 2+ and stronger reactions.


Italian drug information centres: benchmark report.
Pharmacist-operated Drug Information Centres (DICs) in Italy were surveyed to gather current information concerning the status, availability and scope of their services. 40 DICs were identified and a questionnaire was mailed to them. Topics covered in the questionnaire included staffing, resources, activities and services. The results were compared with previous survey results to identify trends. Information from 36 DICs was analysed (response rate = 90%). Almost all regions of the country are represented. Pharmacists, part-time or full-time, are the most frequent employees working in the DICs. 91% of DICs participate in the P/T committee, 74% takes part in the technical scientific committee for clinical experimentation and/or to the Medical Ethics committee and 60% participate in the hospital infection committee. 90% of DICs produce newsletters and/or bulletins and are involved in research projects. Regarding the question-answer service, requests are mainly concerned with clinical comparative efficacy, therapeutic use, adverse effects. The most frequent users are physicians (67%) followed by pharmacists (16%) while other professionals use DICs to lesser extent. The most frequently used information sources, include "Goodman and Gilman's the pharmacological basis of therapeutics", Martindale: the Extra Pharmacopeia and Physician's Desk Reference; journals such as the Medical Letter, Adverse Drug Reactions Bulletin and Drug and Therapeutic Bulletin, Micromedex, Medline and IOWA databases. Data collected through the questionnaire and details about organisation and activity of Italian DICs are available in "Eupharma", the web-site of the Italian Society of Hospital Pharmacy (SIFO) at the URL http://www.sifo.it. The results parallel the European and American trends. In future communication and collaboration at European level could help to identify best practice models that would result in the standardisation of the activities and in the harmonisation of programs in common areas of interest.


Leaf longevity in evergreen shrubs: variation within and among European species.
Leaf longevities were determined for 16 species of evergreen shurbs (Ericaceae and Empetraceae) at different habitats at three latitudes (c. 47°, 55-58° and 68°N) in central and north Europe to determine whether any general trends exist in variation in leaf longevity within and among species. Among these species and sites, mean leaf longevity varied between 1.4 and 3.8 seasons, which is similar to the values reported for other evergreen shrubs, but shorter than for many evergreen conifers. Consistent differences in leaf longevity were found when comparing latitudes (ignoring altitude and habitat type): longevities were longer at 68°N than at the two lower latitudes. No consistent trends were found among species within altitudes.


Cost Effectiveness of Sacral Neuromodulation and OnabotulinumtoxinA in Managing Refractory Idiopathic Overactive Bladder.
Little information from clinical and modelled studies are available on cost effectiveness of OnabotulinumtoxinA and SNM for the treatment of idiopathic overactive bladder. We aimed to summarize the evidence in this regard from different healthcare systems. Seven studies from 5 countries were reviewed. Some modelled studies with a 10-year time frame showed that sacral neuromodulation became dominant long-term; others suggested OnabotulinumtoxinA was more cost effective at <5 years. There was considerable heterogeneity in the base case/sensitivity analysis and statistical modelling among the studies. Clinical studies with longer term follow-up will help determine cost effectiveness more accurately.


Keratoconus and the Impact of Treatment on Patients' Quality of Life: A Qualitative Study.
Keratoconus has a significant impact on patients' quality of life (QoL), from diagnosis to the advanced stages of the disease. The aim of this research was to identify domains of QoL affected by this disease and its treatment. Phone interviews were conducted using a semi-structured interview guide, with patients with keratoconus stratified according to their current treatment. A board of keratoconus experts helped identify the guide's main themes. Thirty-five patients (rigid contact lenses, n = 9; cross-linking, n = 9; corneal ring implants, n = 8; and corneal transplantation, n = 9) were interviewed by qualitative researchers. Phone interviews revealed several QoL domains affected by the disease and its treatments: "psychological", "social life", "professional life", "financial costs" and "student life". All domains were impacted, independently of the treatment history. Few differences were found between treatment regimens and keratoconus stages. Qualitative analysis enabled the development of a conceptual framework based on Wilson and Cleary's model for patient outcomes common to all patients. This conceptual model describes the relationship between patients' characteristics, their symptoms, their environment, their functional visual impairment and the impact on their QoL. These qualitative findings supported the generation of a questionnaire to evaluate the impact of keratoconus and its treatment on patients' QoL. Cognitive debriefings confirmed its content validity. The questionnaire is applicable for all stages of keratoconus and treatments and may help tracking change over time in regular clinical settings. Psychometric validation is yet to be performed before its use in research and clinical practices.


DMEK after penetrating keratoplasty: cohort with DMEK grafts and descemetorhexis larger than full-thickness graft.
The study aims to evaluate visual outcome, central corneal thickness, and rebubbling rate in a cohort with oversized DMEK grafts after failed penetrating keratoplasty (PK). The unique feature of the study is a descemetorhexis diameter larger than the full-thickness graft, i.e., peripheral to the PK interface. A monocentric, retrospective evaluation of all patients with endothelial graft failure after PK treated with an oversized DMEK graft and descemetorhexis outside of the PK interface (i.e., in host tissue) between January 2015 and July 2019 at the Department of Ophthalmology at the University of Düsseldorf (Germany) was performed. Eleven eyes of 10 patients were identified. Mean age was 69 years. On average (arithmetic mean ± standard deviation), 1.7 ± 1.0 previous PKs have been performed per eye in this cohort. The mean time between last PK and DMEK was 10.1 ± 7.3 years (range 2 to 23 years). In all cases, the graft diameter exceeded the diameter of the previous PK and descemetorhexis was performed in host tissue, that is, peripheral to the graft-host interface. Rebubbling was performed in 18.2% of the patients (n = 2 eyes) because of central graft detachment. Mean central corneal thickness showed a statistically significant improvement at 5.3 ± 3.5 months after surgery from 688.23 ± 151.01 to 527.75 ± 88 µm (p = 0.002). Visual acuity increased significantly by 5 lines from 1.24 ± 0.5 logMAR (range from 0.5 to 2) to 0.73 ± 0.76 logMAR (range from 0.1 to 2) within 3 months (p = 0.006). Excluding patients without visual potential and transplant failure, visual acuity improved significantly by 8 lines (p < 0.001), and stayed stable until the last follow-up at 15.1 ± 11.4 months (range 6 to 39 months, p < 0.001, n = 8) after surgery. DMEK can be successfully used to treat endothelial cell failure after PK, and can provide good postoperative results with regards to visual acuity. This study shows that stripping of Descemet's membrane (DM) peripheral to the PK interface is surgically feasible. Overlapping, larger DMEK grafts with more endothelial cells can be used without increasing rebubbling rates and may potentially improve long-term graft survival.


Increased expression of the N-myc gene during normal and neoplastic rat liver growth.
The activation of N-myc and c-myc genes has been implicated in the genesis of a variety of cancers. In order to determine whether this activation is related to the process of cell growth, we examined N-myc and c-myc expression in rat hepatocytes when growth was stimulated by partial hepatectomy and in rat liver during neoplastic growth induced by diethylnitrosamine. The levels of N-myc and c-myc mRNAs, which are very low in hepatocytes from normal rats, were increased at least 20-fold within 3 h after partial hepatectomy and decreased rapidly by 6 h. A second transient peak of c-myc and N-myc mRNAs occurred around 9 and 48 h, respectively. N-myc and c-myc expressions were also induced in carcinoma nodules by diethylnitrosamine. A high level of N-myc transcript was observed in hepatocytes as early as 1 month after the carcinogen administration, whereas c-myc transcript was detected at a high level only several months later in carcinoma nodules. Our results suggest that the transient expression of N-myc and c-myc oncogenes during the prereplicative stage of liver regeneration may be associated with the entry of hepatocytes into the cell cycle, and that N-myc expression is not limited to tumors of neural characteristics as has been previously shown but is also observed in cancer from epithelial origin.


RNA N6-methyladenosine reader IGF2BP3 interacts with MYCN and facilitates neuroblastoma cell proliferation.
Neuroblastoma (NB) is a kind of typical life-threatening extracranial tumor in children. N6-methyladenosine (m6A) modification is closely related to multiple cancer pathological processes. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is a top-ranked prognostic risk gene in NB; however, its function is uncertain. The expression of m6A-associated enzymes in patients with NB was analyzed using the Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. The IGF2BP3 level in NB cell lines and primary samples was tested using quantitative real-time polymerase chain reaction (qRT-PCR), western blot method, and immunohistochemical analysis. The IGF2BP3 function in cell proliferation was clarified based on many functional in vitro and in vivo experiments. The interaction between IGF2BP3 and N-myc was researched via RNA immunoprecipitation (RIP), m6A RNA immunoprecipitation (MeRIP), and chromatin immunoprecipitation (ChIP) assays. The 16 m6A-regulated enzymes in NB were researched, and the result indicated that IGF2BP3 overexpression was related to cancer progression, COG risk, and survival based on the GEO and TARGET databases. Besides, the IGF2BP3 and MYCN levels were positively correlated. IGF2BP3 expression levels increased in MYCN-amplified NB clinical samples and cells. Knockdown of IGF2BP3 inhibited N-myc expression and NB cell proliferation in vitro and in vivo. IGF2BP3 regulates MYCN RNA stability by modifying m6A. In addition, we demonstrated that N-myc is a transcription factor that directly promotes IGF2BP3 expression in NB cells. IGF2BP3 regulates the proliferation of NB cells via m6A modification of MYCN. N-myc also acts as a transcription factor that regulates IGF2BP3 expression. A positive feedback loop between IGF2BP3 and N-myc facilitates NB cell proliferation.


Motile cilia genetics and cell biology: big results from little mice.
Our understanding of motile cilia and their role in disease has increased tremendously over the last two decades, with critical information and insight coming from the analysis of mouse models. Motile cilia form on specific epithelial cell types and typically beat in a coordinated, whip-like manner to facilitate the flow and clearance of fluids along the cell surface. Defects in formation and function of motile cilia result in primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder with a well-characterized phenotype but no effective treatment. A number of model systems, ranging from unicellular eukaryotes to mammals, have provided information about the genetics, biochemistry, and structure of motile cilia. However, with remarkable resources available for genetic manipulation and developmental, pathological, and physiological analysis of phenotype, the mouse has risen to the forefront of understanding mammalian motile cilia and modeling PCD. This is evidenced by a large number of relevant mouse lines and an extensive body of genetic and phenotypic data. More recently, application of innovative cell biological techniques to these models has enabled substantial advancement in elucidating the molecular and cellular mechanisms underlying the biogenesis and function of mammalian motile cilia. In this article, we will review genetic and cell biological studies of motile cilia in mouse models and their contributions to our understanding of motile cilia and PCD pathogenesis.


The effect of osteopathic manual therapy with breathing retraining on cardiac autonomic measures and breathing symptoms scores: A randomised wait-list controlled trial.
Breathing retraining and manual therapy (MT), delivered independently or together, influence autonomic activity, and improve symptoms in patients with chronic conditions. This study evaluated the effects of breathing retraining and osteopathic MT on cardiac autonomic measures and breathing symptoms during spontaneous breathing in healthy active adults. Participants (n = 18) received breathing retraining and four, weekly manual therapy sessions, randomised to start immediately, or after 6-week delay. Heart-rate (HR) variability was assessed as a 7-day average of waking 6-min electrocardiograms, using time (logarithm of root-mean-square of successive differences; LnRMSSD) and frequency domain (logarithm of high-frequency; LnHF) measures. Recordings were taken before, one week following intervention or delay, and then following the later intervention for those with delayed starts. Changes were compared between those who received and had yet to receive the intervention, and before and after treatment for the whole cohort. Following the intervention, HR-variability measures increased 4% overall (Effect Sizes: 1.0-1.1) for the whole cohort. Between-group analyses showed that the immediate-start group increased more than the delayed start group: LnRMSSD 0.27 (0.02-0.52; 95%CI) ln.ms, and LnHF 0.41 (-0.01-0.84) ln.ms2 for immediate start; compared with LnRMSSD -0.09 (-0.29-0.11) ln.ms, and LnHF -0.19 (-0.59-0.22) ln.ms2 (P = 0.02-0.03 for interaction) for delayed start. Resting HR decreased following intervention in the whole cohort (Effect Size -0.8; P = 0.02). A 6-week osteopathic treatment consisting of breathing retraining and MT is beneficial in raising HR-variability compared to no treatment, and may induce favourable (parasympathetic over sympathetic) autonomic modulation. ACTRN12614001119684.


S100A6 promotes proliferation of intrahepatic cholangiocarcinoma cells via the activation of the p38/MAPK pathway.
We explored the expression of S100A6 and its role in intrahepatic cholangiocarcinoma (ICC). The expression of S100A6 in ICC samples was detected by immunohistochemistry. In vitro experiments, we silenced and overexpressed S100A6 to investigate its role in cell functions. The expression of S100A6 was markedly increased in ICC tissues and cell lines. S100A6 overexpression was an independent risk factor for patients' survival. Silencing S100A6 resulted in a suppression of proliferation and p38/MAPK activity, while overexpressing S100A6 caused a promotion of proliferation and p38/MAPK. S100A6 participated in the proliferation of ICC cells and correlated with a more aggressive behavior of ICC. Conclusion: S100A6 may serve as a novel prognostic marker and a potential therapeutic target for ICC patients.


Visual field findings after a ruptured intracranial aneurysm.
Visual field defects (VFDs) negatively affect activities of daily living and rehabilitation following aneurysmal subarachnoid haemorrhage (aSAH). The aim here was to assess VFDs in patients with aSAH and their associations with age, gender, aSAH severity, and clinical outcome. Patients admitted to Helsinki University Central Hospital and treated during 2011 were participants in this prospective study. Findings obtained with the Octopus 900 perimeter (Haag-Streit Inc, Koenic, Switzerland), the Goldmann perimeter (Haag-Streit Inc, Bern, Switzerland), or the confrontation visual field test on admission and 3 days, 14 days, 2 to 4 months, and 6 months postoperatively were assigned to 16 classes. Associations between post-chiasmal VFDs and relevant clinical, radiological, and demographic data were analysed with uni- and multivariate logistic regression. Of 105 survivors at 6 months, 20 (19 %) had VFDs occurring for aneurysm- or operation-related reasons; homonymous hemianopias or quadrantanopias were the most common finding, occurring in 16 patients (15 %). Posterior ischaemic optic neuropathy presented in two patients (2 %). Ten survivors (10 %) no longer fulfilled visual field requirements for driving licences. Significant associations emerged between VFDs at 6 months and the Hunt and Hess (H&H), World Federation of Neurosurgical Societies (WFNS), and Fisher grades on admission, presence of intracerebral haemorrhage (ICH), hydrocephalus, or postoperative infarction, and higher modified Rankin Scale scores at 6 months. Multivariate logistic regression showed the H&H grade and presence of ICH to independently predict VFDs. Assessing VFDs is advisable, especially among patients with poor-grade aSAH (H&H grade IV or V) and ICH.


An R-shiny application to calculate optimal designs for single substance and interaction trials in dose response experiments.
Optimal experimental design theory proposes choosing specific settings in experimental trials in order to maximize the precision of the resulting parameter estimates. In dose response experiments, this corresponds to choosing the optimal dose levels for every available observation, and can be applied both to singular dose-response relationships and to interaction experiments where two substances are given simultaneously at several different mixture ratios ("ray designs"). While the theory of experimental design for this situation is well developed, the mathematical complexity prevents widespread use in practical applications. A simple to use application making the theory accessible to practitioners is thus very desirable. Results from established optimal experimental design theory are applied to dose response applications, focusing on log-logistic and Weibull class dose response functions. Suitable optimal design algorithms to solve these problems are implemented into an R-shiny based online application. The application provides an interface to easily calculate D-optimal designs not only for singular dose experiments, but also for interaction trials with several combination rays of substances. Furthermore, the app also allows evaluating the efficiency of existing candidate designs, and finally allows construction of designs which perform robustly under different assumptions in regard to the true parameters.


Prevalence of malocclusion and its relationship with caries among school children aged 11 - 15 years in southern India.
To assess the prevalence of malocclusion and its relationship with dental caries among school children in southern India. This cross-sectional study included 1,800 students aged 11 - 15 years whose Dental Aesthetic Index (DAI) and dentition status were recorded and analyzed. The chi-square test, ANOVA, and Spearman's correlation tests were carried out. The mean DAI score ± the standard deviation was 18.61 ± 6.1. Approximately 85% of the students (83.0% males, 86.8% females) had DAI scores of < 26 and were classified as not requiring orthodontic treatment. One tenth of the sample had mean DAI scores between 26 - 30 (indicating definite malocclusion and elective treatment), while about 3% had mean scores between 31 - 35 (indicating severe malocclusion and treatment desirability). Only 29 children (1.6%; 16 boys, 13 girls) had a DAI score of > 35, which suggested very severe or handicapping malocclusion requiring mandatory treatment. The mean decayed, missing, filled teeth (DMFT) was 2.28 ± 1.47. A DMFT of > 0 was observed in 91.8% of the study subjects. Children with a DAI score of > 35 were found to have significantly (p < 0.001) higher caries experience as compared to other children. Moreover, the DAI scores showed a significant correlation with the mean DMFT scores (r = 0.368, p < 0.05). A positive correlation was found between the severity of malocclusion and dental caries.


Poor bone health in underprivileged Indian girls: an effect of low bone mass accrual during puberty.
A socio-economic gradient exists for most reasons of morbidity and mortality including delayed puberty in lower (LSES) as compared to higher (HSES) socio-economic stratum and puberty is an important factor affecting bone status in children and adolescents. Thus, a cross-sectional study was conducted on 195 age-matched pairs of girls (8-17years) from LSES and HSES in Pune City, India to assess the hypothesis that socio-economic factors working through late puberty would have a negative association with bone status of adolescents. Height, weight and Tanner stage were assessed. Total body bone mineral content (TBBMC), total body bone area (TBBA), total body bone mineral density (TBBMD), lean body mass (LBM) and total body fat mass (TBFM) were measured using GE Lunar DPX Pro Pencil Beam DXA (Wisconsin, USA) scanner. Mean TBBMC (1172±434g), TBBA (1351±356cm(2)), TBBMD (0.846±0.104g/cm(2)), LBM (21,622±5306g) and TBFM (7746±5194g) in LSES girls were significantly lower than that of HSES girls [TBBMC (1483±525g), TBBA (1533±380cm(2)), TBBMD (0.942±0.119g/cm(2)), LBM (24,308±5829g) and TBFM (12,196±7404g)] (p<0.01). There was a significant effect of age and puberty on all bone parameters. The differences in TBBMC, TBBA, LBM and TBFM between the 2 socio-economic strata at Tanner stage I were not significant (p>0.1) whereas there were significant differences in these parameters from Tanner stages II to V (p<0.05). The percentage difference between LSES and HSES girls in TBBMC, TBBA, TBBMD, LBM and TBFM was 3.4%, 0%, 3.7%, 0.2% and 17.3% respectively at Tanner stage I which increased to 19.1%, 9.7%, 10.4%, 8.8% and 31.2% respectively at Tanner stage V. In conclusion, our results suggest that pubertal years may provide a window of opportunity to promote bone health in adolescent girls from the lower socio-economic stratum.


Cerebrocystatin suppresses degradation of myelin basic protein by purified brain cysteine proteinase.
Procedures are described for extraction or release, assay and purification of cerebrocystatin an inhibitor of brain cathepsin B or of papain. Neurosecretory regions of rat brain contained significantly higher amounts of cerebrocystatin compared to cortex, cerebellum, mid- and lower brain regions, and spinal cord. Inhibitor was purified to apparent homogeneity by alkaline treatment of rat brain cytosol, followed by gel-filtration and affinity chromatography on Reacti-gel coupled to alkylated papain. Purified cerebrocystatin was a single polypeptide of Mr 12,500 as shown by gel-electrophoresis on urea-SDS slab gels. Cerebrocystatin inhibited the hydrolysis of BANA by papain (Ki, 1 nM) or by purified rat brain cathepsin B (Ki, 10 nM) and suppressed the hydrolysis of myelin basic protein (MBP) by cathepsin B (I50, 0.8 microM) and prevented its cleavage to form polypeptides of Mr 15,000-17,000.


Enzyme and organic solvents: horse liver alcohol dehydrogenase in non-ionic microemulsion: stability and activity.
In a microemulsion made with Triton X-100, the stability of the enzymatic activity was higher than in ionic microemulsions. The stability increased with water content. The kinetic constants (Michaelis constant of NAD+ and maximum velocity) were close to those found in the previously studied microemulsions. The Michaelis constant of NAD+ expressed with respect to the buffer volume was higher than in water. The pH dependence of the kinetic constants in this microemulsion was determined. The activity determined by NAD+ reduction decreased with water content, whereas the redox activity determined via butanol oxidation coupled to retinal reduction was only slightly reduced.


The transition temperature (42 °C) from mesophilic to thermophilic micro-organisms enhances biomethane potential of corn stover.
Mesophilic and thermophilic digestion has long been considered as preferred temperature ranges for anaerobic digestion. However, in this study, the effects of temperatures (37, 42, 47, and 55 °C) on the biomethane potential of corn stover were conducted with batch experiments, and the highest biomethane potential was at 42 °C. It was inferred that the change of feed materials, e.g., pretreatment caused by acidification (pH 6.0) during the lag time (4 days), was the main driver for higher biomethane potential. The natural pretreatment stimulated by a slight digestive temperature increase to 42 °C can enhance the biomethane potential of corn stover without adding extra acid. Meanwhile, metabolic pathways of methanogens changed from acetoclastic to mixotrophic and hydrogenotrophic methanogenesis. Based on these results, the transition temperature (42 °C) from mesophilic to thermophilic micro-organisms could be a promising option for corn stover anaerobic digestion.


Quantitative fetal fibronectin and cervical length to predict preterm birth in asymptomatic women with previous cervical surgery.
Quantitative fetal fibronectin testing has demonstrated accuracy for prediction of spontaneous preterm birth in asymptomatic women with a history of preterm birth. Predictive accuracy in women with previous cervical surgery (a potentially different risk mechanism) is not known. We sought to compare the predictive accuracy of cervicovaginal fluid quantitative fetal fibronectin and cervical length testing in asymptomatic women with previous cervical surgery to that in women with 1 previous preterm birth. We conducted a prospective blinded secondary analysis of a larger observational study of cervicovaginal fluid quantitative fetal fibronectin concentration in asymptomatic women measured with a Hologic 10Q system (Hologic, Marlborough, MA). Prediction of spontaneous preterm birth (<30, <34, and <37 weeks) with cervicovaginal fluid quantitative fetal fibronectin concentration in primiparous women who had undergone at least 1 invasive cervical procedure (n = 473) was compared with prediction in women who had previous spontaneous preterm birth, preterm prelabor rupture of membranes, or late miscarriage (n = 821). Relationship with cervical length was explored. The rate of spontaneous preterm birth <34 weeks in the cervical surgery group was 3% compared with 9% in previous spontaneous preterm birth group. Receiver operating characteristic curves comparing quantitative fetal fibronectin for prediction at all 3 gestational end points were comparable between the cervical surgery and previous spontaneous preterm birth groups (34 weeks: area under the curve, 0.78 [95% confidence interval 0.64-0.93] vs 0.71 [95% confidence interval 0.64-0.78]; P = .39). Prediction of spontaneous preterm birth using cervical length compared with quantitative fetal fibronectin for prediction of preterm birth <34 weeks of gestation offered similar prediction (area under the curve, 0.88 [95% confidence interval 0.79-0.96] vs 0.77 [95% confidence interval 0.62-0.92], P = .12 in the cervical surgery group; and 0.77 [95% confidence interval 0.70-0.84] vs 0.74 [95% confidence interval 0.67-0.81], P = .32 in the previous spontaneous preterm birth group). Prediction of spontaneous preterm birth using cervicovaginal fluid quantitative fetal fibronectin in asymptomatic women with cervical surgery is valid, and has comparative accuracy to that in women with a history of spontaneous preterm birth.


Differentiation of subtypes B and E of human immunodeficiency virus type 1 by polymerase chain reaction using novel env gene primers.
Novel sets of env gene PCR primers for distinguishing human immunodeficiency virus type 1 (HIV-1) subtypes B and E were designed. These primers anneal to different regions of the env gene and amplify DNA fragments of distinct sizes in a subtype-specific manner. Blood samples from 11 HIV-1 carriers in Thailand and 46 carriers in Japan were examined by PCR. The new env primers detected HIV-1 proviral DNA in 100% (11/11) and 88% (37/42) of the subtype B and E infection cases, respectively. The env primers also detected proviral DNA in saliva and breast milk samples in seven of 11 cases and two of three cases, respectively. The PCR subtyping results matched completely with those obtained by nucleotide sequencing of the env V3 region. The results suggest that the PCR using the env primers designed in this study may be an accurate and cost-effective method for differentiating subtypes B and E of HIV-1 in a large number of clinical samples. However, subtype E specific primer cross-react with subtype A, C, G, the new primer in this study is useful for regions in South East Asia where subtype E is predominant.


Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.
Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the β-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment.


Pentoxifylline as an adjunctive in treatment of negative symptoms in chronic schizophrenia: A double-blind, randomized, placebo-controlled trial.
The aim of this study was to explore the effectiveness and safety of pentoxifylline as an adjuvant to risperidone in mitigating the negative symptoms in patients with chronic schizophrenia. In this randomized, placebo-controlled study, eighty outpatients with chronic schizophrenia were given risperidone for 8 weeks along with either pentoxifylline or a placebo. The positive and negative syndrome scale (PANSS) was used to assess patients at the start of the trial, as well as at 2, 4, 6, and 8 weeks. Pre- and posttreatment serum levels of cAMP, TNF-α-, and IL-6 were measured. The pentoxifylline group revealed a significant effect for time-treatment interaction on PANSS-negative subscale scores (p < 0.001), PANSS general psychopathology subscale scores (p < 0.001), and PANSS total scores (p < 0.001), but not on PANSS-positive subscale scores (p = 0.169). Additionally, when compared to the placebo group, the pentoxifylline group demonstrated a statistically significant increase in cAMP serum level and a statistically significant decrease in TNF-α and IL-6 serum levels. Pentoxifylline adjunctive therapy with risperidone for 8 weeks was found to be promising in mitigating the negative symptoms in patients with chronic schizophrenia. NCT04094207.


HLA phenotype A2;B12 in vitamin B12 neuromyelopathy.
Severe neurological complications (either peripheral neuropathy, subacute combined degeneration of the cord or cerebral changes) are a characteristic feature in some patients with marked vitamin B12 deficiency. Although Addisonian pernicious anaemia (PA) is the major cause of this neurological syndrome, the disorder has been described in association with other conditions in which there is a profound depletion of vitamin B12 stores. Sixteen patients with vitamin B12 neuromyelopathy, associated with PA, have been HLA-typed for 27 alleles of the A and B loci and compared with 53 cases of PA without neurological damage and 60 controls of the same ethnic group. There is a significantly increased frequency of the HLA phenotype. A12;B12 (44% instead of 4% in PA patients without neurological damage) in the disease group studied (P less than 0.0005). The signficance of these findings in relation to the pathogenesis of vitamin B12 neuromyelopathy is discussed.


Association between serum malondialdehyde levels and depression during early methamphetamine withdrawal.
Some evidence suggested that malondialdehyde (MDA) as a marker of oxidative stress played an important part in modulating the activities of depression. Methamphetamine (METH) dependence often lead to depression that may associate with MDA. In this study, our purpose was to explore the association between serum MDA levels and depression during METH withdrawal. 179 METH-dependent patients were recruited in this study and 144 (80.4%) finished the assessment. We measured serum MDA at 532 nm spectrophotometrically at admission. The short form of the Beck Depression Inventory (BDI-13) was used to evaluate depression symptoms. Patients were identified to have depression symptoms with the BDI score ≥ 8. As a result, 89 (61.8%) of the remaining 144 METH-dependent patients were identified to have depression symptoms. Patients with depression symptoms showed significantly higher serum MDA levels than non-depression patients (3.42 ± 1.60 nmol/ml vs. 2.43 ± 1.25 nmol/ml; p < 0.001). After controlling for potential confounding variables in our logistic model, serum MDA levels were independently associated with the development of depression during early METH withdrawal (OR =1.952, 95% CI, 1.414-2.694, p < 0.001). Furthermore, our study found a positive association between Beck Depression Inventor (BDI) score in early METH abstinence and serum MDA levels (r =0.185; p = 0.026). Our results indicated that higher serum MDA levels were related to higher risk of depression symptoms during early METH withdrawal.


Lack of serum cholesterol-lowering effect of skimmed milk and butter milk under controlled conditions.
The effects of skimmed milk and butter milk on the plasma concentration of cholesterol, triglyceride and high density lipoprotein cholesterol were studied in voluntary male prisoners under carefully controlled conditions. No significant differences were observed in the serum lipid or lipoprotein levels between the groups ingesting the control diet and the diets containing 2.71 of skimmed milk or 2.01 of butter milk per day for 3 weeks.


Altered netrin-1 receptor expression in dopamine terminal regions following neonatal ventral hippocampal lesions in the rat.
Neonatal ventral hippocampal (nVH) lesions in rats, which model certain features of schizophrenia, alter dopamine (DA)-mediated behaviors in adulthood. The precise mechanisms underlying these effects remain elusive; however, neuronal reorganization within the medial prefrontal cortex (mPFC) has been suggested. Netrins are developmental cues that organize brain wiring, including the mesocorticolimbic DA circuitry. We showed recently that the netrin-1 receptors DCC and UNC5H are highly expressed by DA neurons and that variation in DCC levels during development lead to profound changes in mesocorticolimbic DA function and behavior in adulthood. We hypothesized that changes in netrin-1 receptor function could be one of the mechanisms producing enduring changes in DA function in nVH-lesioned animals. To begin to explore this idea, we examined the effects of nVH lesions on DCC and UNC5H expression in brain regions receiving robust DA innervation; the mPFC, striatum, and nucleus accumbens (NAcc) at three developmental time points; 3 days after lesion, before puberty and during early adulthood. Expression was also examined in the cerebellar simple lobule; a brain region deprived of DA innervation. Neonatal VH lesions produced dynamic changes in DCC expression in the mPFC and NAcc. The direction and magnitude of these changes depended on the developmental age and brain region examined and were specific to regions receiving DA innervation. Although further studies are required to understand the functional significance of these changes, these results raise the interesting possibility that nVH lesions, and perinatal insults in general, may exert their neuronal reorganizational effects by modulating netrin-1 function.


Effect of glyprolines on norepinephrine tone of isolated rat aortic rings.
Glyprolines, short proline-containing peptides (Pro-Gly-Pro, Pro-Gly, and Gly-Pro) in concentrations of 10(-8)-10(-4) M decreased norepinephrine tone of the isolated rat aortic rings. The vasodilatory effect of Pro-Gly-Pro and Pro-Gly was associated with NO release from endotheliocytes, while Gly-Pro directly affected vascular smooth muscle cells.


Synthesis and biodistribution of no-carrier-added [1-11C]putrescine.
No-carrier-added [1-11C]putrescine was synthesized in 20% radiochemical yield in a synthesis time of 50 min by the Michael addition of potassium [11C]cyanide to acrylonitrile followed by reduction of the [11C]dinitrile with borane-methyl sulfide complex. Biodistribution in mice at 5, 30, and 60 min showed low uptake in normal brain tissue.


Experimental drusen formation induced by intravitreal aminoglycoside injection.
A single intravitreal injection of aminoglycoside antibiotics in the rabbit induces changes in the retinal pigment epithelial layer that consist of disseminated yellow-white dots that are apparent six to ten months after injection. With fluorescein angiography, these dots have the characteristics of window defects or drusen. Histologic examination disclosed subepithelial amorphous material that stained positively with both periodic acid-Schiff and oil red O. Ultrastructural examination disclosed lipidic inclusions in the retinal pigment epithelial cells, basally directed cellular evagination, and basal accumulation of granular material, findings consistent with the reported morphologic features of hard drusen. These findings suggest that aminoglycoside-induced lesions may represent a model for retinal pigment epithelial degeneration and drusen formation.


Dynamic changes in T-cell subsets and C-reactive protein after radiation therapy in lung cancer patients and correlation with symptomatic radiation pneumonitis treated with steroid therapy.
To investigate relationships among serum T-cell subsets, CRP, levels and radiation pneumonitis (RP) in lung cancer patients receiving radiotherapy. A case-control study with frequency matching was carried out. The case group comprised 36 lung cancer patients who had developed grade ≥2 RP after thoracic radiotherapy. The control group was 36 patients with lung cancer without RP. Patients in the case group received steroid therapy for 1 month after diagnosis of RP and were followed up for 3 months. T-cell subsets, CRP, and pulmonary function were detected at three time points (onset of RP and 1 and 3 months after diagnosis). Data for the control group were collected 3 months after radiotherapy. Treatment effectiveness was evaluated at 1 and 3 months after diagnosis of RP. Of the 36 patients in the case group, three with grade5 RP died from respiratory failure. The other 33 cases had all improved with steroid therapy at 3 months after RP diagnosis. In these 33, CD3+T-cell quantity, CD4+T-cell quantity, and of CD4+:CD8+ ratio in T-cell subsets decreased significantly and CRP increased (P<0.05) at the onset of RP compared with the control group. After steroid therapy, CD4+T-cell quantity increased significantly compared to before treatment. The same change was seen in CD4+:CD8+ ratio, whereas CRP levels decreased obviously, with treatment effectiveness improved. In addition, with the damage level of RP increased, CD4+ T -cell quantity decreased obviously and CRP levels increased accordingly at the onset of RP (P<0.05). T-cell subsets and CRP may become effective immunological biomarkers for predicting damage from RP and evaluating treatment effectivesness of steroid therapy.


Herbicide glufosinate inhibits yeast growth and extends longevity during wine fermentation.
Glufosinate ammonium (GA) is a widely used herbicide that inhibits glutamine synthetase. This inhibition leads to internal amino acid starvation which, in turn, causes the activation of different nutrient sensing pathways. GA also inhibits the enzyme of the yeast Saccharomyces cerevisiae in such a way that, although it is not used as a fungicide, it may alter yeast performance in industrial processes like winemaking. We describe herein how GA indeed inhibits the yeast growth of a wine strain during the fermentation of grape juice. In turn, GA extends longevity in a variety of growth media. The biochemical analysis indicates that GA partially inhibits the nutrient sensing TORC1 pathway, which may explain these phenotypes. The GCN2 kinase mutant is hypersensitive to GA. Hence the control of translation and amino acid biosynthesis is required to also deal with the damaging effects of this pesticide. A global metabolomics analysis under winemaking conditions indicated that an increase in amino acid and in polyamines occurred. In conclusion, GA affects many different biochemical processes during winemaking, which provides us with some insights into both the effect of this herbicide on yeast physiology and into the relevance of the metabolic step for connecting nitrogen and carbon metabolism.


Indomethacin as a means of preventing cystoid macular edema following intracapsular cataract extraction.
It has been theorized that prostaglandins E1 and E2 may be responsible for the vascular leakage leading to cystoid macular edema following cataract extraction. Indomethacin is a known inhibitor of prostaglandin synthesis. A prospective, double-blind study to evaluate the effect of oral indomethacin on four and eight week cases of postoperative CME following intracapsular cataract extraction as determined by fluorescein angiography was carried out on 42 patients. Twenty patients received 25 mg of indomethacin three times a day for three days preoperatively and three weeks postoperatively. Twenty-two patients received a placebo on an identical schedule. Four (20%) patients in the indomethacin group and five (22.7%) patients in the placebo group had positive angiograms for CME. No contributory factor resulting in CME was found.


Evaluation of quantity and staining pattern of human papillomavirus (HPV)-infected epithelial cells in thin-layer cervical specimens using optimized HPV-CARD assay.
Testing for human papillomavirus (HPV) is used in the triage of women with a cervical cytology of atypical squamous cells of undetermined significance (ASCUS). A fluorescent in situ hybridization assay was developed for the detection of HPV using the catalyzed receptor deposition technique (HPV-CARD). In this study, the utility of this assay was tested for the detection of HPV in liquid-based cervical cytology specimens. A total of 195 liquid-based cytology specimens were analyzed using the HPV-CARD assay. The results from the assay were compared with HPV polymerase chain reaction (PCR) and typing results. The number of HPV-infected cells and the staining pattern was correlated with the cytology classification. A 91% concordance between HPV-CARD and PCR was observed for the detection of high-risk HPV viruses. A 78% concordance was observed for specimens that were negative for HPV. In ASCUS, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) categories, the average number of HPV-positive cells per slide was 19 cells, 127 cells, and 450 cells, respectively. The number of cells with a punctate staining, suggestive of HPV integration, was 21% in ASCUS, 34% in LSIL, and 46% in HSIL specimens. The results of the current study indicate positive correlations between the severity of the disease and the increased overall quantity of HPV-positive epithelial cells in cervical cytology specimens and accumulation of cells with punctate staining suggestive of integrated HPV. In summary, the developed HPV-CARD assay was found to provide novel information regarding the proportion and staining pattern of HPV-infected epithelial cells in different cytologic categories of cervical specimens.


EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma.
We conducted this research to explore the role of latent membrane protein 1 (LMP1) encoded by the Epstein-Barr virus (EBV) in modulating the DNA damage response (DDR) and its regulatory mechanisms in radioresistance. Our results revealed that LMP1 repressed the repair of DNA double strand breaks (DSBs) by inhibiting DNA-dependent protein kinase (DNA-PK) phosphorylation and activity. Moreover, LMP1 reduced the phosphorylation of AMP-activated protein kinase (AMPK) and changed its subcellular location after irradiation, which appeared to occur through a disruption of the physical interaction between AMPK and DNA-PK. The decrease in AMPK activity was associated with LMP1-mediated glycolysis and resistance to apoptosis induced by irradiation. The reactivation of AMPK significantly promoted radiosensitivity both in vivo and in vitro. The AMPKα (Thr172) reduction was associated with a poorer clinical outcome of radiation therapy in NPC patients. Our data revealed a new mechanism of LMP1-mediated radioresistance and provided a mechanistic rationale in support of the use of AMPK activators for facilitating NPC radiotherapy.


Evaluation of partial genotyping with HPV16/18 for triage of HPV positive, cytology negative women in the COMPACT study.
While cytology-based screening programs have significantly reduced mortality and morbidity from cervical cancer, the global consensus is that primary human papillomavirus (HPV) testing increases detection of high-grade cervical intraepithelial neoplasia (CIN) and invasive cancer. However, the optimal triage strategy for HPV+ women to avoid over-referral to colposcopy may be setting specific. We compared absolute and relative risk (RR) of >CIN2/3 within 12 months of a negative cytologic result in women HPV16/18+ compared to those with a 12-other high-risk HPV (hrHPV) genotype to identify women at greatest risk of high-grade disease and permit less aggressive management of women with other hrHPV infections. Participants were 14,160 women aged 25-69 years with negative cytology participating in the COMparison of HPV genotyping And Cytology Triage (COMPACT) study. Women who were HPV16/18+ were referred to colposcopy. Those with a 12-other hrHPV type underwent repeat cytology after 6 months and those with >abnormal squamous cells of undetermined significance went to colposcopy. Absolute risk of >CIN2 in HPV16/18+ women was 19.5% (95% CI=12.4%-29.4%). In women 25-29 years and HPV16+ it was 40.0% (95% CI=11.8%-76.9%). Absolute risk of >CIN3 in women HPV16/18+ was 11.0% (95% CI=5.9%-19.6%). For women 30-39 years and HPV16+ it was 23.1% (95% CI=5.0%-53.8%). Overall risk of >CIN2, >CIN3 in women with a 12-other hrHPV HPV type was 5.6% (95% CI=3.1%-10.0%) and 3.4% (95% CI=1.6%-7.2%) respectively. RR of >CIN2, >CIN3 in HPV16/18+ vs. 12-other hrHPV was 3.5 (95% CI=1.7-7.3) and 3.3 (95% CI=1.2-8.8), respectively. Primary HPV screening with HPV16/18 partial genotyping is a promising strategy to identify women at current/future risk of >CIN2 in Japan without over-referral to colposcopy. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000013203.


How does the COVID-19-related restriction affect the spatiotemporal variability of ambient air quality in a tropical city?
The ambient air, a significant hazard to human health in most Indian cities, including Rourkela, is something we are strangely neglecting in the age of industrialization and urbanization. High levels of particulate matter released from various anthropogenic sources over the past decade have had a significant negative impact on the city. The COVID-19 lockdown situation brings understanding and realization towards the improvement of air quality and its subsequent effects. The present study investigates the impact of the COVID-19-related lockdown on the spatiotemporal variation of the ambient air quality in Rourkela City with a tropical climatic setup. The concentration and distribution of various pollutants are well explained by the wind rose and Pearson correlation. There is considerable spatiotemporal variation in the city's ambient air quality, as determined by a two-way ANOVA test comparing sampling sites and months. During the COVID-19 lockdown phases, the air quality of Rourkela witnessed an improvement in annual AQI ranging from 12.64 to 26.85% across the city. However, the air quality in the city deteriorated by 13.76-65.79% after the revocation of COVID-19 restrictions. The paired sample T-test justified that the air quality of Rourkela was significantly healthier in 2020 compared to both 2019 and 2021. Spatial interpolation reveals that the ambient air quality of Rourkela ranged from satisfactory to moderate categories throughout the entire study period. 31.93% area of the city has experienced an improvement in AQI from the Moderate to the satisfying category from 2019 to 2020, whereas about 68.78% area of the city has witnessed a decline in AQI from satisfactory to moderate category from 2020 to 2021.


Genetic transformation of fruit trees: current status and remaining challenges.
Genetic transformation has emerged as a powerful tool for genetic improvement of fruit trees hindered by their reproductive biology and their high levels of heterozygosity. For years, genetic engineering of fruit trees has focussed principally on enhancing disease resistance (against viruses, fungi, and bacteria), although there are few examples of field cultivation and commercial application of these transgenic plants. In addition, over the years much work has been performed to enhance abiotic stress tolerance, to induce modifications of plant growth and habit, to produce marker-free transgenic plants and to improve fruit quality by modification of genes that are crucially important in the production of specific plant components. Recently, with the release of several genome sequences, studies of functional genomics are becoming increasingly important: by modification (overexpression or silencing) of genes involved in the production of specific plant components is possible to uncover regulatory mechanisms associated with the biosynthesis and catabolism of metabolites in plants. This review focuses on the main advances, in recent years, in genetic transformation of the most important species of fruit trees, devoting particular attention to functional genomics approaches and possible future challenges of genetic engineering for these species in the post-genomic era.


[Frequency of cervical epithelial lesions reported in the Regional Laboratory of Exfoliative Cytology in Jalisco].
The Official Mexican Norm for the prevention, treatment and control of Cervical Cancer (CC) indicates that the Papanicolau (Pap) is the procedure for the detection of this neoplasia; therefore, it is of interest to know the prevalence of suspected cases by this technique in Mexican population. In this study, we show the diagnosed cases in the State of Jalisco, México. A retrospective study was made to the samples that arrived for their analysis to the Laboratorio Regional de Citología Exfoliativa (LARCE), of the Instituto Mexicano del Seguro Social (IMSS) in Guadalajara, Jalisco. We considered all cases from January 2010 to December 2012. We analyzed 188 095 cases, from which 5.3 % had a diagnosis of low dysplasia, 0.18 % of moderated dysplasia and 0.05 % of high dysplasia. Microinvasive and invasive cancer showed a low frequency (0.03 %). The frequency of abnormal findings identified by vaginal cervical cytology is relatively low. The number of inadequate and limited samples for cytological assessment is high; there is a high proportion of women attending for the first time in life to cytology evaluation in older age groups.


Reinnervation aspects of laryngeal transplantation.
Although restoration of laryngeal function after laryngeal transplantation depends on appropriate reinnervation, non-selective reinnervation procedures result in synkinesis and poor function restoration. This study was performed to test the feasibility of selective reinnervation procedures to restore laryngeal function. Three surgical reinnervation procedures were studied each in a group of ten cats: in group 1 a non-selective procedure in which the recurrent laryngeal nerve (RLN) was cut and reanastomosed; in group 2 selective abductor reinnervation was performed with the phrenic nerve; in group 3 selective abductor reinnervation with the phrenic nerve (PN) was combined with selective adductor reinnervation with the ansa cervicalis. Ten weeks after surgical reinnervation abductor and reflex adductor functions were evaluated with videolaryngoscopy and electromyography. Findings demonstrated that non-selective reinnervation not only gave poor abduction during inspiration but even resulted in paradoxical movement during reflex adduction. Selective abductor reinnervation resulted in good abductor function. Selective adductor reinnervation with the ansa cervicalis brought about muscle tonus in the animals studied but no restoration of reflex adduction. Enhanced activity during respiratory distress gave only slight compromise to the abductor function. In all, selective laryngeal reinnervation with the PN and ansa cervicalis produced good restoration of respiratory laryngeal function. However, deglutition following laryngeal motor and sensory reinnervation with protection of the respiratory tract is probably not sufficient, as in the present group of animals no reflex glottic closure was achieved. More research is required.


Effects of endorphin blocking on conditioned SCR in humans.
In order to test the hypothesis that low levels of endogenous opioids (endorphins) predispose to strong conditioning effects, female Ss (N = 36) were assigned to a placebo group, a low-dose naltrexone group, or a high-dose naltrexone group and then underwent a classical conditioning procedure. This procedure consisted of an acquisition phase in which all Ss received 5 pairings of a CS+ (neutral picture) and a UCS (100 dB white noise). The CS- (neutral picture) was never followed by a UCS. During extinction, Ss received 4 unreinforced presentations of CS+ and CS-. Throughout the experiment, skin conductance responses (SCRs) to the CSs and UCSs were recorded. Acquisition was successful in that CS+ slides elicited stronger SCRs than CS- slides. However, during acquisition, there was no interaction between drug and differential response (CS+ vs CS-). During extinction, there was no overall remaining effect of conditioning. Again, no evidence was found to suggest that (remaining) effects of conditioning were stronger in the naltrexone treated Ss than in the placebo Ss. If anything, the opposite seemed to be true with especially high-dose naltrexone Ss showing relatively weak conditioning effects.


High-resolution color video cytophotometry.
Comparison was made between cytophotometric measurements obtained using two data acquisition systems, one a microphotometer and the other a rapid video camera system, to ascertain whether the degradation of data with the faster video acquisition system still results in recorded images of sufficient quality to permit computer discrimination between cells of very similar appearance. Normal-appearing intermediate cells from cases with normal cytology and those from patients with dysplasia or malignant disease, as well as the subvisual markers within these cells that have rendered them capable of cytophotometric discrimination, were used for the study. Comparison of the data recorded by the two systems indicates that the diagnostic information is preserved in the change-over to a full-field, video-rate scanning system, with differences in the data caused primarily by differences in the spectral response of the two systems. This was reflected in the substantial differences observed in the color-related features and the lesser differences seen in the textural features, while the morphometric features (outline and shape) were virtually unaffected. The differences were primarily expressed on a cell-to-cell basis; in sets of about 300 cells, which would be used in patient-to-patient comparisons, the feature values showed remarkable consistency between the two systems.


Management of optic neuritis and impact of clinical trials: an international survey.
1) To evaluate the management of acute isolated optic neuritis (ON) by ophthalmologists and neurologists; 2) to evaluate the impact of clinical trials; 3) to compare these practices among 7 countries. A survey on diagnosis and treatment of acute isolated ON was sent to 5,443 neurologists and 6,099 ophthalmologists in the southeast-USA, Canada, Australia/New Zealand, Denmark, France, and Thailand. USA data were compared to those of other countries. We collected 3,142 surveys (1,449 neurologists/1,693 ophthalmologists) (29.8% response rate). In all countries, ON patients more frequently presented to ophthalmologists, and were subsequently referred to neurologists or subspecialists. Evaluation and management of ON varied among countries, mostly because of variations in healthcare systems, imaging access, and local guidelines. A brain MRI was obtained for 70-80% of ON patients; lumbar punctures were obtained mostly in Europe and Thailand. Although most patients received acute treatment with intravenous steroids, between 14% and 65% of neurologists and ophthalmologists still recommended oral prednisone (1 mg/kg/day) for the treatment of acute isolated ON. In all countries, steroids were often prescribed to improve visual outcome or to decrease the long-term risk of multiple sclerosis. Although recent clinical trials have changed the management of acute ON around the world, many neurologists and ophthalmologists do not evaluate and treat acute ON patients according to the best evidence from clinical research. This confirms that evaluation of the impact of major clinical trials ("translational T2 clinical research") is essential when assessing the effects of interventions designed to improve quality of care.


General orientation transform for the estimation of fiber orientations in white matter tissues.
The orientation distribution function (ODF), which is obtained from the radial integral of the probability density function weighted by rn$$ {r}^n $$ ( r$$ r $$ is the radial length), has been used to estimate fiber orientations of white matter tissues. Currently, there is no general expression of the ODF that is suitable for any n value in the HARDI methods. A novel methodology is proposed to calculate the ODF for any n>-1$$ n>-1 $$ through the Taylor series expansion and a generalized expression for -1<n<4$$ -1<n<4 $$ is provided. Then a series of single-shell HARDI methods, termed the general orientation transform (GOT), is developed based on the obtained expression. By combining complementary GOTs, a composite estimator is obtained and further optimized via constrained optimization to take full advantage of individual merits. The final optimized HARDI method is termed the combined GOT with constrained optimization (coGOT). The proposed method is compared with other commonly used HARDI methods on the simulated data, the physical phantom data, the ISMRM 2015 Tractography challenge data, and in vivo HCP datasets. coGOT can resolve crossing fibers with higher resolution, performs better robustness, generates fewer spurious lobes in glyphs, and thus provides distinct improvement in the tractography. The evaluations show coGOT's superior capability in reconstructing the fiber orientations from dMRI signals. Generalization of the ODF allows us to obtain a wide range of HARDI estimators to select suitable candidates for composite formulation. The optimized estimator coGOT has great potential for studying neural architecture and serving as fiber tracking tools.


Microdrop screening: a rapid method to optimize solvent conditions for NMR spectroscopy of proteins.
Determining appropriate solvent conditions is a crucial first step for carrying out NMR spectroscopy of proteins, but rapid and efficient methods for doing so are currently lacking. Microdrop screening examines a large number of different solvent conditions using very small amounts of protein and minimal labor. Starting from one initial buffer condition, small aliquots of protein solution are combined with an array of solutions in which concentration, pH, buffer type, and added stabilizers are systematically varied. The protein concentration of each microliter-sized test drop ('microdrop') is gradually changed using vapor diffusion, and the solubility of the protein is determined by visual examination. A variety of analytical techniques may be applied to the contents of the microdrops to monitor enzymatic activity, aggregation, ligand binding, and protein folding.


Social signalling as a framework for second-person neuroscience.
Despite the recent increase in second-person neuroscience research, it is still hard to understand which neurocognitive mechanisms underlie real-time social behaviours. Here, we propose that social signalling can help us understand social interactions both at the single- and two-brain level in terms of social signal exchanges between senders and receivers. First, we show how subtle manipulations of being watched provide an important tool to dissect meaningful social signals. We then focus on how social signalling can help us build testable hypotheses for second-person neuroscience with the example of imitation and gaze behaviour. Finally, we suggest that linking neural activity to specific social signals will be key to fully understand the neurocognitive systems engaged during face-to-face interactions.


Stereolithography: A new method for processing dental ceramics by additive computer-aided manufacturing.
The aim of this study was to compare the physical and mechanical properties of stereolithography (SLA)- manufactured alumina ceramics of different composition to those of subtractive- manufactured ceramics and to produce suitable dental crown frameworks. The physical and mechanical properties of a control and six experimental SLA ceramics prepared from slurries with small (S) and large (L) particles (0.46±0.03 and 1.56±0.04μm, respectively) and three dry matter contents (70%, 75%, 80%) were evaluated by dynamic rheometry, hydrostatic weighing, three3-point flexural strength measurements, and Weibull analyses, and by the micrometrics measurement of shrinkage ratio before and after the heat treatments. S75 was the only small particle slurry with a significantly higher viscosity than L70. The viscosity of the S80 slurry made it impossible to take rheological measurements. The viscosities of the S75 and S80 slurries caused deformations in the printed layers during SLA manufacturing and were excluded from further consideration. SLA samples with low dry matter content had significantly lower and densityflexural strengths. Only SLA samples with a large particle size and high dry matter content (L75 and L80) were similar in density and flexural strength to the subtractive- manufactured samples. The 95% confidence intervals of the Weibull modulus of the L80 ceramic were higher (no overlap fraction) than those of the L75 ceramic and were similar to the control (overlap fraction). The Weibull characteristics of L80 ceramic were higher than those of L75 ceramic and the control. SLA can be used to process suitable crown frameworks but shows results in anisotropic shrinkage. The hH High particle size and dry matter content of the L80 slurry allowed made it possible to produce a reliable ceramic by SLA manufacturing with an anisotropic shrinkage, and a density, and flexural strength similar to those of a subtractive-manufactured ceramic. SLA allowed made it possible to build up a dense 3D alumina crown framework with controlled shape. Further studies on the marginal adaptation and shrinkage model of alumina crown frameworks will be required to optimize the process.


Enhanced photovoltaic performance and long-term stability of quasi-solid-state dye-sensitized solar cells via molecular engineering.
Organic dyes with long alkyl chains have been synthesized and demonstrated to be highly efficient sensitizers for liquid and quasi-solid-state solar cells, giving power conversion efficiencies of 8.31-8.39% and 7.03-7.31% under AM 1.5 G irradiation, respectively.


Trajectories of depressive symptoms among community-dwelling Korean older adults: findings from the Korean longitudinal study of aging (2006-2016).
Depression among older adults is an important public health concern associated with increased risk of suicide and decreased physical, cognitive, and social functioning. This study identified trajectories of depressive symptoms and investigated predictive variables of group-based trajectory modeling among Korean community-dwelling older adults. Participants comprised 2016 community-dwelling Korean adults over 65 years. Data from the years 2006-2016 of the Korean Longitudinal Study of Aging, a nationally representative panel survey that has been conducted every two years since 2006, were used. We employed a group-based trajectory modeling analysis to identify depressive symptom trajectories. Multinomial logistic regression analysis was conducted to identify predictors of each class of depressive symptoms. Five depressive symptom trajectory groups were identified: Group 1, "None" (28.9%); Group 2, "Slowly worsening" (24.3%); Group 3, "Rapidly worsening" (17.5%); Group 4 "Improving" (12.4%); and Group 5, "Persistently severe" (16.9%). Older adults followed five distinct depressive symptom trajectories over 10 years. Mini-Mental State Examination scores, number of chronic diseases, educational level, and social activity were predictors associated with increasing depressive symptoms. This study showed that many older adults living in the community have depressive symptoms. To prevent and treat depression and aid successful mental health aging among older adults, the development of interventions should be tailored to target specific needs for each symptom trajectory. It is necessary to develop community-based interventions and strategies to identify and prevent depressive symptom trajectories among older adults.