Illuminating the druggable genome through patent bioactivity data.
The patent literature is a potentially valuable source of bioactivity data. In this article we describe a process to prioritise 3.7 million life science relevant patents obtained from the SureChEMBL database (https://www.surechembl.org/), according to how likely they were to contain bioactivity data for potent small molecules on less-studied targets, based on the classification developed by the Illuminating the Druggable Genome (IDG) project. The overall goal was to select a smaller number of patents that could be manually curated and incorporated into the ChEMBL database. Using relatively simple annotation and filtering pipelines, we have been able to identify a substantial number of patents containing quantitative bioactivity data for understudied targets that had not previously been reported in the peer-reviewed medicinal chemistry literature. We quantify the added value of such methods in terms of the numbers of targets that are so identified, and provide some specific illustrative examples. Our work underlines the potential value in searching the patent corpus in addition to the more traditional peer-reviewed literature. The small molecules found in these patents, together with their measured activity against the targets, are now accessible via the ChEMBL database.


The allure of equality: uniformity in probabilistic and statistical judgment.
Uniformity, that is, equiprobability of all available options is central as a theoretical presupposition and as a computational tool in probability theory. It is justified only when applied to an appropriate sample space. In five studies, we posed diversified problems that called for unequal probabilities or weights to be assigned to the given units. The predominant response was choice of equal probabilities and weights. Many participants failed the task of partitioning the possibilities into elements that justify uniformity. The uniformity fallacy proved compelling and robust across varied content areas, tasks, and cases in which the correct weights should either have been directly or inversely proportional to their respective values. Debiasing measures included presenting individualized and visual data and asking for extreme comparisons. The preference of uniformity obtains across several contexts. It seems to serve as an anchor also in mathematical and social judgments. People's pervasive partiality for uniformity is explained as a quest for fairness and symmetry, and possibly in terms of expediency.


Assessment of food safety knowledge, attitudes and practices of fish farmers and restaurants food handlers in Bangladesh.
The study was conducted to assess the present status of knowledge, attitudes and practices (KAP) concerning the food safety and hygiene issues among fish farmers and food handlers in Noakhali, Bangladesh. Data were collected from 100 respondents (50 fish farmers and 50 food handlers) through face to face interviews. All the respondents agreed that training on hygiene practices was necessary and they were interested to attend training in their spare time. Food handlers (88%) agreed that raw foods must be kept separate from prepared foods and 68% of them believed that improper preservation of foods is harmful to health. About 52% of farmers used a face mask when spreading insecticides, fertilizers, and chemicals. Food handlers were wearing protective clothing (32%) and masks (12%) when touching and distributing unwrapped foods, however no handlers used a cap. A significant strong correlation coefficient (rs) was found between knowledge with attitudes, knowledge with practices and attitudes with practices of 0.73-0.99 among the three domains for fish farmers and food handlers. The correlation among the three levels was satisfactory, however, some food safety concepts and practices regarding hygiene were still insufficient. Therefore, an effective and appropriate training program on food safety and hygiene should be launched in a holistic approach for all fish farmers and food handlers to increase awareness and ensure safe food for consumers with a view to reducing the possibility of disease outbreak.


HSV targeting of the host phosphatase PP1α is required for disseminated disease in the neonate and contributes to pathogenesis in the brain.
Newborns are significantly more susceptible to severe disease after infection with herpes simplex virus (HSV) compared with adults, with differences in the host response implicated as a major factor. To understand host response differences between these age groups, we investigated the shutoff of protein synthesis by the host and the retargeting of host phosphatase PP1α by the HSV-1 protein γ34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1α binding resulted in complete absence of disease. PP1α-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1α-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1α-binding mutant virus, suggesting an IFN-independent role for eIF2α kinases during infection. When we investigated the contribution of PP1α targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1α increased survival time in both newborn and adult mice. Unlike disseminated disease, type I IFN signaling in the brain was required to attenuate disease following PP1α-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2α dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal age-dependent differences in γ34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for γ34.5 in neonatal infections in contrast to other studies indicating that the autophagy-inhibiting function of γ34.5 is dispensable for pathogenesis in the newborn brain.


Predictors of adverse pregnancy outcomes among Kenyan women with HIV on antiretroviral treatment in pregnancy.
The aim of this study was to understand predictors of adverse pregnancy outcomes (APOs) among women on antiretroviral treatment (ART). A longitudinal cohort. Participants from the Mobile WAChX trial were evaluated for APOs, including stillbirth (fetal death at ≥20 weeks' gestation), preterm birth (PTB, livebirth at <37 weeks' gestation,) and neonatal death (NND, ≤28 days after live birth). Predictors were determined by univariable and multivariable Cox proportional hazards and log-binomial models. Among 774 women included, median age was 27 years and 29.0% had unsuppressed HIV viral load (>1000 copies/ml) at enrollment. Half (55.1%) started ART prepregnancy, 89.1% on tenofovir-based regimens. Women with depression had a higher risk of stillbirth (adjusted hazard ratio [aHR] 2.93, 95% confidence interval (95% CI) 1.04-8.23), and women with lower social support score had higher risk of late stillbirth (aHR 11.74, 2.47-55.86). Among 740 livebirths, 201 (27.2%) were preterm and 22 (3.0%) experienced NND. PTB was associated with unsuppressed maternal viral load (adjusted prevalence ratio [aPR] 1.28, 95% CI 1.02-1.61), intimate partner violence (IPV) in pregnancy (aPR 1.94, 95% CI 1.28-2.94), and history of any sexually transmitted infection (STI) (aPR 1.63, 95% CI 1.06-2.51). NND was associated with PTB (aPR 2.53, 95% CI 1.10-5.78) and STI history (aPR 4.25, 95% CI 1.39-13.06). Most associations retained significance in the subgroup of women with viral suppression. Maternal viremia during pregnancy predicted PTB as did IPV, lower education, and STI history, while psychosocial stressors predicted stillbirth. Implementing mental health services, ART adherence, partner support, and routine STI screening and treatment could reduce APOs among women with HIV in sub-Saharan Africa settings.


Cervical sagittal balance after consecutive three-level hybrid surgery versus anterior cervical discectomy and fusion: radiological results from a single-center experience.
According to the different numbers and relative locations of cervical disc replacement (CDR) and anterior cervical discectomy and fusion (ACDF), three-level hybrid surgery (HS) has many constructs. The purpose of this retrospective study was to compare the sagittal alignment parameters of HS and ACDF for cervical degenerative disc disease (CDDD) and the association of the respective parameters. This study involved patients with three-level CDDD who underwent ACDF or HS at our institution between June 2012 and August 2021. This follow-up included one-level CDR and two-level ACDF (type I group), two-level CDR and one-level ACDF (type II group) and three-level ACDF. Cervical sagittal alignment parameters included cervical lordosis (CL), segment alignment (SA), T1 slope (T1S), C2-C7 sagittal vertical axis (SVA), T1S-CL, C2 slope (C2S), occipital to C2 angle (O-C2A) and segment range of motion (ROM). Postoperative complications included adjacent segment degeneration, imbalance, prosthetic subsidence and heterotopic ossification. The three groups with a total of 106 patients were better matched in terms of demographics. Patients who underwent HS had significantly higher CL than those who underwent ACDF at 1 week, 6 months, 12 months and the final follow-up after surgery, as well as significantly better SA at 12 months and the final follow-up. There was no significant difference in T1S, SVA, T1S-CL, C2S, O-C2A or segment ROM among the three groups after surgery. The T1S-CL was significantly associated with C2S in the type I and type II groups at the preoperative and final follow-up. There was no significant difference in postoperative complications among the three groups. Most improvements in cervical sagittal alignment (CL, SA, T1S, SVA, T1S-CL, C2S, O-C2A, and segmental ROM) were observed in all three groups postoperatively. HS was more advantageous than ACDF in the maintenance of postoperative CL and SA. Thus, three-level HS may be better for maintaining cervical curvature. The number of replacement segments differed in those who underwent HS but did not affect the correlation between T1S-CL and C2S, both of which are well balanced.


Spontaneous intracranial hypotension: the syndrome and its complications.
Spontaneous intracranial hypotension (SIH) is a syndrome that was largely unknown until the advent of MRI. The incidence of SIH is estimated at 5 per 100,000, which is half the incidence of subarachnoid hemorrhage. The major feature is a postural headache of acute or subacute onset. This headache is absent or minimal when the patient is lying down and rapidly worsens to great intensity when the patient sits or stands. Other features may include nausea, vomiting, vertigo, tinnitus, and marked exacerbation by Valsalva maneuver. SIH is due to a leak of cerebrospinal fluid from a tear in the dural membrane, which occurs most often at the exit zones where the cervical spinal roots leave the subarachnoid space. Other leak sites may be the vestibular system, the cribriform plate, or the pituitary fossa. If the leak continues, the brain loses buoyancy within the cranial space and sags toward the foramen magnum. This, in turn, may produce subdural hygroma or hematoma, brainstem compression, focal cranial nerve palsies, or cerebellar tonsillar herniation. The initial therapy is generally strict bed rest. If this fails, an epidural blood patch is usually successful in sealing the leak and restoring brain buoyancy. A significant minority of patients require a repeat epidural blood patch. If the blood patch fails, a surgical approach may be needed. Repair of the leak and restoration of brain buoyancy will stop the postural headache and, in most cases, will reverse the complications.


Associative interference between cues and between outcomes presented together and presented apart: an integration.
In recent years, 'stimulus competition' in the study of acquired behavior has referred exclusively to (a) associative competition between cues trained in compound (e.g. overshadowing and blocking). Rarely cited are older experiments cast in the verbal learning tradition, now complemented with data from humans and rats in Pavlovian preparations, that demonstrate (b) competition between cues separately trained with a common outcome (i.e. proactive and retroactive interference). Similarly neglected are numerous examples of (c) competition between outcomes separately trained with a common cue within the verbal learning literature (also proactive and retroactive interference) as well as within the Pavlovian literature (i.e. counterconditioning). Recent data demonstrate (d) competition between outcomes trained in compound, thereby completing the four cells of a 2x2 matrix (competing stimuli trained together vs. trained apart and the competing stimuli being cues or outcomes) which highlights the ubiquitous nature of associative stimulus interference/competition. Most contemporary theories of acquired behavior can account for the phenomena in one or at most two cells of this matrix. Whether a common mechanism underlies the phenomena in all four cells of the matrix is currently unclear, but until such time as data preclude a common mechanism, parsimony encourages efforts to develop a model that encompasses all four cells. Here we offer a tentative model that addresses all four cells, albeit with two processes.


Association between intake of dairy products and short-term memory with and without adjustment for genetic and family environmental factors: A twin study.
Previous studies have indicated associations between intake of dairy products and better cognitive function and reduced risk of dementia. However, these studies did not adjust for genetic and family environmental factors that may influence food intake, cognitive function, and metabolism of dairy product nutrients. In the present study, we investigated the association between intake of dairy products and short-term memory with and without adjustment for almost all genetic and family environmental factors using a genetically informative sample of twin pairs. A cross-sectional study was conducted among twin pairs aged between 20 and 74. Short-term memory was assessed as primary outcome variable, intake of dairy products was analyzed as the predictive variable, and sex, age, education level, marital status, current smoking status, body mass index, dietary alcohol intake, and medical history of hypertension or diabetes were included as possible covariates. Generalized estimating equations (GEE) were performed by treating twins as individuals and regression analyses were used to identify within-pair differences of a twin pair to adjust for genetic and family environmental factors. Data are reported as standardized coefficients and 95% confidence intervals (CI). Analyses were performed on data from 78 men and 278 women. Among men, high intake of dairy products was significantly associated with better short-term memory after adjustment for the possible covariates (standardized coefficients = 0.22; 95% CI, 0.06-0.38) and almost all genetic and family environmental factors (standardized coefficients = 0.38; 95% CI, 0.07-0.69). Among women, no significant associations were found between intake of dairy products and short-term memory. Subsequent sensitivity analyses were adjusted for small samples and showed similar results. Intake of dairy product may prevent cognitive declines regardless of genetic and family environmental factors in men.


Successful management of a retained host Descemet's membrane after penetrating keratoplasty (PKP) - A case report.
To report the 21st case showing the rare occurrence of retained Descemet's membrane (DM) following penetrating keratoplasty (PKP). We intend to investigate possible etiologies, expected sequelae, and outcome of neodymium-dpoed yttrium alumnium garnet (Nd: YAG) laser membranectomy. Our case is a 74-year-old male who underwent PKP surgery in the right eye secondary to corneal decompensation following cataract surgery in addition to corneal thinning secondary to superficial keratectomy related to the pre-existing climatic droplet keratopathy (CDK). Postoperative assessment revealed a retro-corneal membrane within the anterior chamber, which was affecting his vision. Based on the post-operative course and the decreased vision as an indication for intervention, it was decided to excise the retained DM. Membranectomy with Nd: YAG laser was performed, and the patient's visual acuity measurement improved from 20/400 to 20/25. However, the endothelial cell count decreased from 1479 to 520 cells/mm2 (35 % loss) at 15 months post YAG membranectomy with clear graft. Histopathological examination confirmed the clinical suspicion of a retained DM, since it was absent in the submitted host corneal tissue in addition to the pre-existing CDK. Retention of DM following PKP is a rare but possible complication and high index of suspicion is required for proper diagnosis and management to obtain better visual outcome. Nd: YAG laser membranectomy was effective in excising the retained DM and improving vision. Endothelial cell loss following Nd: YAG laser membranectomy as a complication was observed and should be addressed during the treatment plan.


Immunogenicity of recombinant DNA human insulin.
We postulated that human insulin of recombinant DNA origin would be a poor immunogen and might prove to be less immunogenic than purified pork insulin. Results are reported for 100 diabetic subjects not previously treated with insulin. Individuals completed the first 12 months of a clinical trial of human insulin of recombinant DNA origin. These patients are contrasted with 121 similar individuals who are taking part in a trial of purified pork insulin. Prior to therapy, species-specific binding of 125I human insulin and pork insulins and insulin bound to antibody were undetectable in all individuals. In patients treated with human insulin of recombinant DNA origin, binding of 125I human insulin increased to 10 +/- 1.2% at 12 months versus increases in binding of 125I pork insulin in pork insulin-treated patients to 12.6 +/- 1.4% (NS). Mean percentages of species-specific binding tended to reach a plateau in the human insulin-treated group but continued to increase in the pork insulin group (p less than 0.001). Median bound values were nil throughout in patients treated with human insulin, but increased to 52 mU/l in the pork insulin group with significantly less bound insulin seen in the former group at all visits (p less than 0.001). The percentage of individuals who remained antibody free at 12 months, as indicated by bound insulin, was 56% in the human insulin-treated patients and 40% in the patients treated with pork insulin (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Systematic source estimation of spikes by a combination of independent component analysis and RAP-MUSIC. II: Preliminary clinical application.
We tried to estimate epileptic sources by a combination of independent component analysis (ICA) and recursively applied and projected multiple signal classification (RAP-MUSIC) in real epileptiform EEG discharges. EEG data including an array of spikes from 3 patients were decomposed by ICA, and source estimation was performed by applying RAP-MUSIC to the spatial information defined by the set of ICA components that showed epileptiform activity in their waveform. Sources were also estimated from the same data using RAP-MUSIC based on eigen-decomposition of the covariance matrix of averaged spikes, and common spatial pattern decomposition for comparison. RAP-MUSIC based on ICA could estimate generally correct epileptic sources in the 3 patients, and its results were better than those of the other methods, when compared to intracerebral data. The present analysis proceeded without introduction of subjective decision after data selection. The separation of epileptiform discharges from the background is essential for this analysis, and was successfully performed in the real EEG data. RAP-MUSIC based on ICA appears promising for estimation of epileptic sources with minimal dependence on subjective decisions in the process of analysis. In particular, it was not necessary to select the number of sources.


Health plan notification and feedback to providers is associated with increased filling of preventer medications for children with asthma enrolled in Medicaid.
To test the hypothesis that children enrolled in Medicaid managed care health plans that provide asthma-specific communication to providers would be more likely to have adequate asthma medication filling. We conducted a historical cohort study of 4498 children (2-17 years old) with moderate-severe asthma in Washington State and Tennessee Medicaid managed care programs from 2000 to 2002. Interviews with health plans were conducted to identify communication strategies health plans used to improve asthma care by providers in the plan. The main outcome measure was guideline-recommended filling of asthma preventer medications. Children in plans that provided specific feedback to providers about asthma quality and notified providers when children had an asthma-related event had the highest mean days plus or minus SE of filling in the 365-day follow-up period (164.6 +/- 13 days) compared with children in plans with neither (135.3 +/- 10.8 days; P < .05). In children with the greatest asthma severity, enrollment in a plan with both features was associated with 27.1 additional days of filling (95% CI, 0.7-53.4 days) during the follow-up period. Health plan communication to providers was associated with increased preventer filling in children with moderate-severe asthma in 2 state Medicaid programs.


An RNA Interference/Adeno-Associated Virus Vector-Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus.
Hepatitis E virus (HEV) is a major public health problem with limited therapeutic options. Here, we engineered adeno-associated viral vectors of serotype 6 (AAV6) to express short hairpin RNAs (shRNAs) against HEV transcripts with the prospect of down-regulating HEV replication in vivo. We designed 20 different shRNAs, targeting the genome of the HEV genotype 3 (GT3) Kernow-C1 p6 strain, for delivery upon AAV6 transduction. Using an original selectable HEV GT3 reporter replicon, we identified three shRNAs that efficiently down-regulated HEV replication. We further confirmed their inhibitory potency with full-length HEV infection. Seventy-two hours following transduction, HEV replication in both systems decreased by up to 95%. The three most potent inhibitory shRNAs identified were directed against the methyltransferase domain, the junction region between the open reading frames (ORFs), and the 3´ end of ORF2. Targeting all three regions by multiplexing the shRNAs further enhanced their inhibitory potency over a prolonged period of up to 21 days following transduction. Conclusion: Combining RNA interference and AAV vector-based gene therapy has great potential for suppressing HEV replication. Our strategy to target the viral RNA with multiplexed shRNAs should help to counteract viral escape through mutations. Considering the widely documented safety of AAV vector-based gene therapies, our approach is, in principle, amenable to clinical translation.


Machine Learning Techniques for Prediction of Early Childhood Obesity.
This paper aims to predict childhood obesity after age two, using only data collected prior to the second birthday by a clinical decision support system called CHICA. Analyses of six different machine learning methods: RandomTree, RandomForest, J48, ID3, Naïve Bayes, and Bayes trained on CHICA data show that an accurate, sensitive model can be created. Of the methods analyzed, the ID3 model trained on the CHICA dataset proved the best overall performance with accuracy of 85% and sensitivity of 89%. Additionally, the ID3 model had a positive predictive value of 84% and a negative predictive value of 88%. The structure of the tree also gives insight into the strongest predictors of future obesity in children. Many of the strongest predictors seen in the ID3 modeling of the CHICA dataset have been independently validated in the literature as correlated with obesity, thereby supporting the validity of the model. This study demonstrated that data from a production clinical decision support system can be used to build an accurate machine learning model to predict obesity in children after age two.


Flexible scaffolding made of rigid BARs.
Crescent-shaped BAR domains are generic actors in the creation of membrane curvature. In this issue, Frost et al. (2008) reveal how collective twisting of rigid F-BAR domains on a soft membrane surface may lead to different membrane curvatures.


The selective binding of HMG1 to the cruciform DNA structure and the subsequent resumption of transcription.
The binding of DNA binding protein HMG1 to palindromic sequences that can form the cruciform structure in supercoiled DNA and the subsequent effects on the transcription of the sequence were examined. The results show that the cruciform structure formed under negative supercoiling is a block to transcription and that HMG1, which bound selectively to single-stranded region within the cruciform, can remove the block by altering DNA conformation to allow the stalled RNA polymerase at the block to resume transcription.


Thermo- and salt-tolerant chitosan cross-linked γ-glutamyl transpeptidase from Bacillus licheniformis ER15.
Gamma-glutamyl transpeptidase enzyme, from Bacillus licheniformis ER15 (BLGGT), was produced extracellularly using a complex medium with high enzyme titers. Enzyme was concentrated and purified using ultra-filtration and ion exchange chromatography, respectively, with a purification fold of 4.6 and 50.11% yield. Enzyme was covalently immobilized onto chitosan microspheres (CMS). Immobilization was standardized with respect to pH, enzyme load and time. Immobilization efficiency of 11.9U/mg dry weight of microsphere was obtained in Tris-HCl buffer (pH 9.0) at 18°C in 4h. Immobilized enzyme (CMS-GGT) exhibited improved thermal stability (t1/2 of 70.7min at 60°C), activity in a broader pH range and improved salt stability in 18% (3M) sodium chloride solution as compared to free enzyme. Both free and immobilized enzymes specifically converted glutamine to glutamic acid in a mixture of amino acids. CMS-GGT had a better shelf life and high recyclability retaining 90% catalytic efficiency upto 10 reaction cycles. For long-term storage, CMS-GGT can be disinfected using either sodium azide or sodium hypochlorite solution without affecting enzyme activity. Thus, the present study provides an easy and efficient method for GGT enzyme immobilization that results in an improved and robust enzyme preparation.


An in vitro validation of a commercially available metabolic cart using pediatric ventilator volumes.
Our objective was to determine the validity of the SensorMedics 2900 Metabolic Measurement Cart (SensorMedics Corp., Yorba Linda, CA) for use at pediatric ventilator volumes by designing an in vitro validation study. The study was performed using a previously described nitrogen dilution, carbon dioxide infusion technique in which known amounts of nitrogen (N2) and carbon dioxide (CO2) are infused while a test lung is ventilated. Metabolic measurements were made at tidal volumes (Vt) varying from 50-500 mL at a peak end-expiratory pressure (PEEP) of 0 and 12 cm H2O and at inspiratory oxygen fractions (Fi,O2s) ranging from 0.21-0.60. Each study was repeated six times to assess reproducibility of measurements. At a PEEP of 0 cm H2O, the measurement of oxygen consumption (V'O2), carbon dioxide production (V'CO2), and minute ventilation (V'E) were all within +/-10% of predicted values at all Fi,O2S except when Vt(t) was 50 mL. When PEEP was increased to 12 cm H2O, error in measurement of V'O2 increased and became unacceptably large as Fi,O2 was increased. Each study consisted of six trials, and results showed acceptable reproducibility as demonstrated by narrow 95% confidence intervals. For V(t)s of 100-500 mL, the metabolic monitor provided accurate and reproducible results under in vitro testing conditions when PEEP was low. Accurate results could not be obtained with a Vt of 50 mL or at elevated PEEP.


Resistance and Security Index of Networks: Structural Information Perspective of Network Security.
Recently, Li and Pan defined the metric of the K-dimensional structure entropy of a structured noisy dataset G to be the information that controls the formation of the K-dimensional structure of G that is evolved by the rules, order and laws of G, excluding the random variations that occur in G. Here, we propose the notion of resistance of networks based on the one- and two-dimensional structural information of graphs. Given a graph G, we define the resistance of G, written , as the greatest overall number of bits required to determine the code of the module that is accessible via random walks with stationary distribution in G, from which the random walks cannot escape. We show that the resistance of networks follows the resistance law of networks, that is, for a network G, the resistance of G is , where and are the one- and two-dimensional structure entropies of G, respectively. Based on the resistance law, we define the security index of a network G to be the normalised resistance of G, that is, . We show that the resistance and security index are both well-defined measures for the security of the networks.


Follicular non-Hodgkin's lymphoma.
FL is usually widely disseminated at presentation and responds to radiotherapy, single agent chemotherapy and combination therapy. The disease pursues a remitting and relapsing course with continuing sensitivity to brief periods of treatment until a terminal phase of drug resistance, transformation, or bone marrow failure is reached. Newly recognized prognostic factors indicative of tumour bulk include hepatosplenomegaly, B symptoms, anaemia and abnormal liver function. Using these factors it is possible to identify those patients at first diagnosis for whom conservative management is appropriate and those with a much less favourable prognosis for whom experimental treatments are being investigated.


Platelet count in normal, small, and anemic fetuses.
A reference range for fetal platelet count with gestation was established from the study of samples obtained by cordocentesis from 229 pregnancies that had prenatal diagnosis. The mean platelet count increased from 187 +/- 47 x 10(9)/L at 15 weeks to 274 +/- 47 x 10(9)/L at 40 weeks' gestation. In 113 red cell-isoimmunized pregnancies, the moderately anemic fetuses were significantly thrombocythenic, whereas the severely anemic fetuses were thrombocytopenic. In 136 small-for-gestational-age fetuses the platelet count was reduced and there were significant correlations between the magnitude of the thrombocytopenia and the degree of fetal smallness, hypoxemia, and acidemia.


Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.
The dopamine system is unique among the brain's modulatory systems in that it has discrete projections to specific brain regions involved in motor behaviour, cognition and emotion. Dopamine neurons exhibit several activity patterns - including tonic and phasic firing - that are determined by a combination of endogenous pacemaker conductances and regulation by multiple afferent systems. Emerging evidence suggests that disruptions in these regulatory systems may underlie the pathophysiology of several psychiatric disorders, including schizophrenia and depression.


Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease.
Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study.


Antistreptococcal treatment of guttate psoriasis: a controlled study.
The role of streptococcal infection in the initiation of guttate psoriasis is well-recognized. But the treatment results with oral erythromycin and phenoxymethylpenicillin are conflicting. Our purpose was to evaluate the effectiveness of these antibiotics in the treatment of streptococcus associated guttate psoriasis comparing with a control group. A total of 43 male patients with serologic evidence of a recent streptococcal infection were studied. Their mean age was 21 years (ranged between 19 and 23 years). These 43 patients were randomly allocated into three groups (no treatment group n = 15, erythromycin group n = 14, phenoxymethylpenicillin group n = 14). Both the treatment groups were treated for 14 d. All the groups were followed up for additional 4 weeks. There were no statistically significant improvement in any group and among the groups. There was no statistically significant improvement in streptococcus associated guttate psoriasis with or without a course of oral penicillin or erythromycin.


Selective inhibition of low affinity IgE receptor (CD23) processing.
A series of hydroxamic acids related to the non-selective matrix metalloproteinase inhibitor Batimastat has been prepared, some members of which are potent inhibitors of the processing of the low affinity IgE receptor (CD 23). Increased activity is obtained by appropriate substitution at the alpha-position, whilst selectivity is gained by use of a P1' benzyl group in conjunction with a C-terminal primary amide.


Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure.
Recent clinical observations reported the occurrence of amino acid substitutions at position 181 of the HBV polymerase, associated with a viral breakthrough under lamivudine or adefovir therapy. In this study, we characterized the main variants harboring the rtA181T/V mutation isolated from 10 consecutive patients who developed lamivudine and/or adefovir resistance. We performed a clonal analysis of the HBV polymerase gene amplified by PCR from serum samples during viral breakthrough. The main mutants were then tested after transfection of Huh7 cells for their resistance profile to nucleoside analogs. Clonal analysis revealed the co-localization on the same HBV genome of rtA181T/V with rtN236T, but not with rtM204V/I mutations following lamivudine, adefovir or lamivudine+adefovir breakthrough. In cell culture, the rtA181T/V mutation induced a decreased susceptibility to lamivudine (<10-fold), adefovir (2- to 8-fold) and tenofovir (2- to 3-fold). Interestingly, the association of rtA181T with rtN236T on one clinical isolate genome increased the resistance to these three drugs. All the tested mutants remained sensitive to entecavir. Our observations suggest that a single amino acid change at position rt181 may induce cross-resistance to lamivudine and adefovir. These data emphasize the clinical relevance of genotypic and phenotypic analysis in the management of antiviral drug resistance.


Accuracy and Practical Considerations for Doubly Labeled Water Analysis in Nutrition Studies Using a Laser-Based Isotope Instrument (Off-Axis Integrated Cavity Output Spectroscopy).
Given the utility of the doubly labeled water (DLW) method for determination of energy expenditure, additional techniques for isotope analysis of the samples are welcome. Laser-based instruments are one such new analytical tool, but their accuracy and feasibility for DLW studies are grossly understudied. We assessed the accuracy of laser-based isotope ratio measurements as part of the DLW method for estimation of carbon dioxide production rate (rCO2) and total energy expenditure (TEE), in between-group comparison study designs. Urine samples from a previous study were analyzed with a laser-based instrument [off-axis integrated cavity output spectroscopy (OA-ICOS)]. In that study, participants consumed a high-, moderate-, or low-carbohydrate diet for 20 wk; urine samples were obtained in weeks 18-20 before and after a 2H- and 18O-enriched water dose. Isotope ratios (δ2H and δ18O), rCO2, and TEE calculated by standard methods were compared to results previously obtained with the standard technique of isotope ratio mass spectrometry (IRMS). Bias, SD, and bias ± 1.96SD bands between IRMS and OA-ICOS were computed. The between OA-ICOS and IRMS rCO2 and TEE trends were equivalent (within 1.2% and 4.1%, respectively), in spite of the differences in measured δ18O values at high enrichment levels. The OA-ICOS δ18O values displayed an increasing offset from the IRMS results as the 18O enrichment increased (mean ± SD 4.6-5.7‰ ± 2‰ offset at the time point with highest 18O enrichment, ∼135‰), whereas the hydrogen isotope ratio (δ2H) differed only slightly between the methods (mean offset -4.9‰ for all time points). The between-diet differences in TEE from the previous study were recapitulated with a smaller subset of participants and time points. OA-ICOS analysis is an accurate and feasible technique for the DLW method. Given the δ18O offset observed at high enrichment, validation of each OA-ICOS instrumental setup against established methods (e.g., IRMS) is recommended.


Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis.
In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors. The dataset was split into learning and validation cohorts (ratio 1:2). The individual modelled KELIM values were estimated, standardised by the median value, then scored as unfavourable (<1.0) or favourable (≥1.0). Overall survival (OS) and progression-free survival (PFS) analyses were performed with a two-step meta-analytic approach and surrogacy through a two-level meta-analytic model. KELIM was assessed in 5884 patients from eight first-line trials (learning, 1962; validation, 3922). A favourable KELIM score was significantly associated with longer OS (validation set, median, 78.8 versus 28.4 months, hazard-ratios [HR] 0.46, 95% confidence interval [CI], 0.41-0.50, C-index 0.68), and longer PFS (validation set, median 30.5 versus 9.8 months, HR 0.49, 95% CI, 0.45-0.54, C-index 0.68), as were International Federation of Gynaecology and Obstetrics (FIGO) stage and debulking surgery outcome. Three prognostic groups were identified based on the surgery outcome and KELIM score, with large differences in OS (105.1, ∼45.0, and 22.1 months) and PFS (58.1, ∼15.0, and 8.0 months). Surrogacy for OS and for PFS was not established. KELIM is an independent prognostic biomarker for survival, complementary to surgery outcome, representing a new determinant of first-line treatment success.


Psychometric Properties of Generic Preference-Weighted Measures for Children and Adolescents: A Systematic Review.
Preference-weighted measures (PWMs)-also referred to as preference-based measures in the literature-of health status/health-related quality of life plays an essential role in estimating quality-adjusted life-years (QALY) for use in economic evaluations of healthcare products and interventions. However, as PWMs are first and foremost intended to accurately reflect respondent health status, they should ideally demonstrate good psychometric properties for the population in question. This study aimed to systematically review published evidence on the measurement properties of commonly used PWMs for children and adolescents. Three electronic databases (PubMed, Medline, and PsycINFO) were searched for articles assessing the psychometric properties (content validity, construct validity-including convergent validity and known-group validity, test-retest reliability, and responsiveness) of the PWMs of interest (AQoL-6D, CHU9D, HUI2, HUI3, and EQ-5D-Y). The COsensus-based Standards for the selection of health Measurement INstruments methodology (COSMIN) guidelines were used to assess (a) the methodological quality of the studies included and (b) the psychometric performance of the instruments covered. Data were analysed overall as well as by population (country and disease group) and perspective (self-report or proxy-report). The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021277296). In total, 53 articles were included in this systematic review. Health Utilities Index (HUI) was tested only in patient populations, CHU9D was most frequently tested in general population samples, while EQ-5D-Y was tested in both populations. Overall, there was high-quality evidence supporting sufficient construct validity for all instruments except AQoL-6D. Evidence supporting test-retest and responsiveness was scarce. There was high-quality evidence supporting sufficient responsiveness of HUI2 and HUI3, and inconsistent test-retest reliability of CHU9D and EQ-5D-Y. Evidence for content validity was minimal and therefore not extracted and synthesized for any PWMs. This review provides updated evidence on the measurement properties of existing generic PWMs for children and adolescents. High-quality evidence for all relevant psychometric properties and across a range of populations was not available for any of the instruments included, indicating that further work is needed in this direction. This study has identified some of the most noticeable evidence gaps for each of the individual measures. Users can use this information to guide their decision on the choice of PWM to administer.


VITAMIN 'K' DEFICIENCY HAEMORRHAGIC DISEASE OF NEW-BORN AND PRESENT CONTROVERSIES.
Vitamin K deficiency haemorrhagic disease of newborn (HDN) is a well known entity and presents in 3 different clinical forms - early, classical and late. The coagulopathy is due to deficiency of vitamin K dependent procoagulant factors II, VII, IX, X. In the event of vitamin K deficiency Protein Induced in Vitamin K Absence (PIVKA) arc in excess and its estimation is very helpful in diagnosis even after starting the treatment. The bleeding defects are usually corrected within few hours after administration of vitamin K. All newborn babies require vitamin K prophylaxis. Oral route is effective like parenteral route but require higher and more doses. Intra muscular route is safe and does not increase the risk of childhood cancer. All breast fed babies with diarrhoea, malabsorption require another dose of vitamin K in postneonatal period to prevent late vitamin K deficiency bleeding.


Nuclear ingression of cytoplasmic bodies accompanies a boost in autophagy.
Membrane contact sites are functional nodes at which organelles reorganize metabolic pathways and adapt to changing cues. In Saccharomyces cerevisiae, the nuclear envelope subdomain surrounding the nucleolus, very plastic and prone to expansion, can establish contacts with the vacuole and be remodeled in response to various metabolic stresses. While using genotoxins with unrelated purposes, we serendipitously discovered a fully new remodeling event at this nuclear subdomain: the nuclear envelope partitions into its regular contact with the vacuole and a dramatic internalization within the nucleus. This leads to the nuclear engulfment of a globular, cytoplasmic portion. In spite of how we discovered it, the phenomenon is likely DNA damage-independent. We define lipids supporting negative curvature, such as phosphatidic acid and sterols, as bona fide drivers of this event. Mechanistically, we suggest that the engulfment of the cytoplasm triggers a suction phenomenon that enhances the docking of proton pump-containing vesicles with the vacuolar membrane, which we show matches a boost in autophagy. Thus, our findings unveil an unprecedented remodeling of the nucleolus-surrounding membranes with impact on metabolic adaptation.


Alveolar ridge augmentation with collagen tubes containing bone and hydroxylapatite.
The use of collagen tube containers with implants of an autogenous bone and particulate hydroxylapatite composite is reported. The tubes were used to shape the mixture and to facilitate its implantation in cases of severe mandibular resorption. Following a minimum of 60 months after implant placement and a minimum of 48 months of denture wear, the implant and overall prosthodontic success were rated favorably by the patient and the prostodontist. Individual implants were evaluated with polarized and fluorescent light microscopy and with microradiography. While the clinical results were good, the microscopic evaluation showed the amount of bone present within the implant to be variable.


(-)-Epigallocatechin-3-gallate induced apoptosis by dissociation of c-FLIP/Ku70 complex in gastric cancer cells.
Anti-cancer properties of (-)-epigallocatechin-3-gallate (EGCG) are mediated via apoptosis induction, as well as inhibition of cell proliferation and histone deacetylase. Accumulation of stabilized cellular FLICE-inhibitory protein (c-FLIP)/Ku70 complex in the cytoplasm inhibits apoptosis through interruption of extrinsic apoptosis pathway. In this study, we evaluated the anti-cancer role of EGCG in gastric cancer (GC) cells through dissociation of c-FLIP/Ku70 complex. MKN-45 cells were treated with EGCG or its antagonist MG149 for 24 h. Apoptosis was evaluated by flow cytometry and quantitative RT-PCR. Protein expression of c-FLIP and Ku70 was analysed using western blot and immunofluorescence. Dissociation of c-FLIP/Ku70 complex as well as Ku70 translocation were studied by sub-cellular fractionation and co-immunoprecipitation. EGCG induced apoptosis in MKN-45 cells with substantial up-regulation of P53 and P21, down-regulation of c-Myc and Cyclin D1 as well as cell cycle arrest in S and G2/M check points. Moreover, EGCG treatment suppressed the expression of c-FLIP and Ku70, decreased their interaction while increasing the Ku70 nuclear content. By dissociating the c-FLIP/Ku70 complex, EGCG could be an alternative component to the conventional HDAC inhibitors in order to induce apoptosis in GC cells. Thus, its combination with other cancer therapy protocols could result in a better therapeutic outcome.


Evaluation of the effects of acoustic stimulation and feeding mother stimulation on non-reactive non-stress test: a randomized clinical trial.
Non-stress test (NST) is known as one of the most common assessments for evaluation of fetus well being. Since the prevalence of its false positive results is high and majority of fetuses with non-reactive results are not at risk, it is important to find out effective approaches to identify such results to avoid unnecessary interventions. So this survey was conducted with the aim of comparing the effects of acoustic stimulation with feeding mothers stimulation on non-reactive NST results. This study preformed on 104 healthy pregnant women with non-reactive NST results and gestational ages between 32 and 42 weeks in Tabriz Alzahra hospital. Subjects were divided into two groups for acoustic stimulation and feeding mother stimulation. Half an hour later NST repeated for participants of each group in the same environmental condition and again the results evaluated. According to our findings, 75 % of subjects with non-reactive NST results changed to reactive after acoustic stimulation group. However, 80 % of participants with non-reactive NST results changed into reactive after feeding stimulation. No significant differences found while comparing test results. Both stimulating approaches were effective in the identification of false positive NSTs and might be useful in preventing the unnecessary interventions.


Using standardized patient outcome to measure the effect of teaching asthma-related patient education and information-giving skills to medical students.
Patient education and giving information is a core skill that improves patient adherence and medical outcomes. To evaluate the impact of a teaching intervention on 3rd-year students' competency in patient education and information giving about asthma medication delivery. Students (n=81) completed a 1-hr teaching intervention of didactics followed by role playing of asthma patient education scenarios. Using a standardized patient post intervention, patient education and information-giving skills about spacer/metered dose inhalers were scored overall and on a 12-item checklist and compared to a control group (n=70). Students' knowledge was evaluated using a short answer test. The performance of intervention students on overall patient education, 10 of the 12 checklist items, and the test was significantly higher than controls but did not approach competency. The 1-hr intervention improved clinical performance and knowledge, but students did not become competent. Future studies should investigate how competence in this and other core patient education skills can be successfully achieved.


Mechanism of Phospholipid Hydrolysis for Oyster Crassostrea plicatula Phospholipids During Storage Using Shotgun Lipidomics.
A fast and efficient shotgun lipidomics strategy was applied to analyze phospholipids (PL) in the oyster Crassostrea plicatula, including 29 species of phosphatidylcholine (PtdCho), 23 species of phosphatidylethanolamine (PtdEtn), 11 species of phosphatidylserine (PtdSer), 6 species of phosphatidylinositol (PtdIns), and 17 species of lysophospholipids (Lyso-PL). During storage at 4 °C for 7 days, the PL content decreased by 68.08%, but a significant increase in the FFA content was observed (from 63.11 to 318.72 μg/g). PtdCho and PtdIns decreased relatively by 64.97 and 67.49%, and PtdSer decreased most markedly by 74.15%. However, the PtdEtn content increased slightly during the early stages of storage but subsequently began to decrease. Moreover, PL with eicosapentaenoic acid (EPA-PL) and docosahexaenoic acid (DHA-PL) decreased by 51.77 and 50.61%, whereas plasmalogens were relatively stable showing only a 25.46% decrease. In particular, through enzyme activity analysis of lipase, phospholipase A1 (PLA1), phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD), it was observed that the activities of all these enzymes increased at the early stage at 4 °C, but their activities were at lower levels when the oysters were stored at -20 °C. During the storage period at 4 °C, correlation analysis suggests that the degradation of PtdCho was mostly correlated to PLA2 (p < 0.05), whereas PtdEtn and PtdSer were more markedly correlated to lipase and PLD, respectively. The above result indicates that the hydrolysis mechanism of PL during seafood storage was correlated to the lipid hydrolytic enzyme activities under different storage temperatures.


Percutaneous transluminal angioplasty and enclosed thrombolysis versus percutaneous transluminal angioplasty in the treatment of femoropopliteal occlusions: results of a prospective randomized trial.
To determine whether percutaneous transluminal angioplasty (PTA) and enclosed thrombolysis (ET) is superior to PTA alone in the treatment of femoropopliteal occlusions. Twenty-five patients with 5-15-cm-long occlusions in the femoropopliteal segments, with otherwise normal run-in arteries and at least one normal tibioperoneal artery to the foot, were randomized to ET/PTA or PTA alone. Ankle brachial systolic index (ABI) was measured before the procedure and at 24 hr and 12 months after the procedure, when a duplex scan was also carried out. End points in the study were patency at, or repeat intervention before, 12 months. Procedures were successful in 23 of 25 patients. There was one immediate occlusion of tibioperoneal arteries, and one early reocclusion of a reopened segment in the ET/PTA group. There was one early reocclusion in the PTA group. At 12 months patency was 70% and 69.2% in the ET/PTA and PTA groups respectively. Covariant analysis showed no significant difference in ABI between the two groups at any of the three measurement times. This trial demonstrated no difference between ET/PTA and PTA alone in femoropopliteal occlusions associated with normal proximal arteries and at least one normal tibioperoneal artery.


Intraocular lens calculations in patients with corneal scarring and irregular astigmatism.
To compare various methods of estimating corneal power for intraocular lens (IOL) calculation in patients with irregular corneal astigmatism. Pepose Vision Institute, St. Louis, Missouri, USA. Case reports and review of the medical literature. Two patients with irregular corneal astigmatism had an IOL exchange after a "surprise" post-cataract-surgery refraction. In the first case, the patient had a post-cataract-surgery refraction of +5.50 -0.75 x 69 and in the second case, a refraction of -7.00 -1.00 x 180. The central corneal power before IOL exchange was assessed using manual keratometry, various computerized videokeratography curvature and power maps, and contact lens overrefraction. The total axial power map (Orbscan(R), Bausch & Lomb), total optical power map (Orbscan), and contact lens overrefraction method provided the most accurate estimates of central corneal power in these 2 patients. Computerized scanning-slit videokeratography, which analyzes the anterior and posterior surfaces of the cornea, and the contact lens overrefraction method gave good estimations of corneal power in patients with irregular corneal astigmatism. This type of analysis may improve the accuracy of IOL calculation in patients with corneal pathology and irregular astigmatism.


Primary clear cell carcinoma of the ovary. An analysis of 15 cases with review of the literature.
The clinical and pathological findings in 15 primary "pure" clear cell carcinoma of the ovary included in the Magee-Womens Hospital Tumor Registry from 1947 through 1974 are discussed. The ages of the patients ranged from 35 to 75 years (mean 53). The most common clinical finding was an abdominal mass in 14 cases. At surgery, five patients had extraovarian spread, one accompanied by ascitis. The tumors varied in diameter from 4 cm to 17 cm (mean 10.5 cm); grossly, about one-third were cystic, one-third solid and one-third had combined cystic and solid areas. Microscopically, four basic patterns were seen: papillary, tubular, solid, and cystic, and in several an admixture of the above. Clear cells predominated in 48% of the cases and 23% displayed hobnail cells. Most patients were treated by TAH & BSO or variants thereof, some followed by radiation or chemotherapy. Four patients died with cancer within 35 months after diagnosis; two others died of unrelated causes three and 12 years later. The actuarial survival was computed as 55% at five years. Five patients were stages as IIb (FIGO classification); four died with tumor and the remaining patient is alive with recurrent tumor in the pelvis 18 months after the original diagnosis. Three patients with tumors displaying the cystic pattern are still alive; two with a predominantly papillary pattern and vascular permeation are dead. It is suggested that survival rates in these 15 cases may be related more to the extent of the lesion at the initial presentation than to the gross or microscopic pattern.


Older age and multi-joint external fixator are two risk factors of complications in ulnar lengthening in children with hereditary multiple exostosis.
Hereditary multiple exostosis (HME) often involves forearm deformities. The aim of this study was to present the clinical results of 37 children who underwent ulnar lengthening with two different types of unilateral external fixators and to investigate the risk factors of complications. We evaluated 37 children with forearm deformities caused by HME treated in our hospital from January 2008 to July 2019. The surgical procedures included resection of exostosis, osteotomy of the ulna, and gradual lengthening of the ulna with a unilateral external fixator. According to the type of fixator they received, the children were divided into two groups: group A received monorail fixators and group B received multi-joint fixators. Radiographic and functional parameters were assessed. Complications were recorded. All patients were followed-up for an average of 4.6 years (3.0 to 6.5). In both group A and group B, the ulna shortening (US), radial articular angle (RAA), carpal slip (CS), elbow flexion, forearm pronation, supination, and Mayo Elbow Performance Score (MEPS) values improved significantly from preoperatively to postoperatively (p < 0.05). However, the ulnar deviation was observed in 4 cases in group B and no cases in group A. According to logistic regression, the difference was only related to age (p < 0.05) and the type of external fixator (p < 0.05). Ulnar lengthening with unilateral external fixation is a safe and effective procedure for the treatment of HME. Regarding complications, deviation of the ulna axis was more likely to occur in older children with multi-joint external fixators.


Autologous chondrocyte implantation in the knee is effective in skeletally immature patients: a systematic review.
This systematic review evaluated the efficacy and safety of autologous chondrocyte implantation (ACI) for chondral defects of the knee in skeletally immature patients. Current available data from patients reported outcome measures (PROMs) and complications were collected, analyzed, and discussed. This systematic review was conducted according to the PRISMA guidelines. The following databases were accessed in May 2022: PubMed, Google scholar, Embase, and Scopus. All the clinical studies investigating the efficacy of ACI to manage chondral defects of the knee in skeletally immature patients were accessed. Articles treating patients with surgical procedures other than ACI were not eligible, nor were studies with a follow-up shorter than 12 months. Data from 9 studies (251 procedures) were collected. 32% (80 of 251) of patients were females. The mean length of follow-up was 44.2 ± 29.4 (range, 12-115) months. The mean age of the patients was 16.4 ± 0.7 (range, 15-17) years. The Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Document Committee (IKDC) increased of + 41.9/100 (P = 0.003) and + 33.2/100 (P = < 0.0001) points, respectively. The Lysholm Knee Score improved of + 20.6/100 (P = 0.02) points. The Visual Analogue Scale (VAS) for pain reduced of - 3.6/10 (P = 0.004) points. The Tegner scale did not show any statistically significant improvement from baseline to follow-up (P = n.s.). The rate of graft hypertrophy was 12.5% (5 of 40 patients), and the rate of failure 5.6% (8 of 142 patients). ACI for chondral defects of the knee is effective to improve PROMs in skeletally immature patients. The safety profile of ACI still remains controversial. III.


Three-dimensional characterization of epiretinal membrane using spectral domain optical coherence tomography.
To describe epiretinal membrane (ERM) features using spectral domain optical coherence tomography "SD OCT" and to delineate the three-dimensional (3D) relationship in eyes with epiretinal membrane. Fifty-two eyes of 44 patients with ERM were classified into two groups: idiopathic ERM and secondary ERM. Posterior vitreous face was evaluated. Pattern of ERM attachment was divided into: focal and global. A 3D SD OCT system (5 μm resolution) was used for scanning. Surface maps were used to study retinal topography. Surface maps revealed manner and direction of epiretinal traction, pattern of attachment and blood vessel involvement. In 55.8% of eyes the membrane was globally adherent to the retina. There was a significant association (p = 0.02%) between pattern of membrane attachment and etiological classification of eyes. Posterior vitreous detachment (PVD) was associated with both groups, but no significant difference in between. SPECTRAL DOMAIN OCT ALLOWED BETTER CHARACTERIZATION OF ERM INCLUDING: visualization, extension, cleavage plane and zones with free edges. Surface maps revealed the topography of ERM and retina pathology. Idiopathic ERM are significantly associated with global pattern. PVD plays an important role in the pathogenesis of primary as well as secondary ERM.


Semiquantitative histochemical investigation of lysosomal enzyme activities in the aortic endothelial cells of spontaneously hypertensive rats.
In order to obtain information about changes in lysosomal enzyme activities in the aortic endothelial cells under hypertensive conditions, semiquantitative histochemical investigations of acid phosphatase (Ac-Pase) and N-acetyl-beta-glucosaminidase (NAGase) activities in the aorta of spontaneously hypertensive rats (SHR) were performed on 'Häutchen' monolayer preparations. The aortic endothelial cells in SHR showed increased Ac-Pase and NAGase activities as compared with those in control normotensive rats, and the activities tended to increase with advancing age. The degenerating process of endothelial cells expressed by lysosomal enzyme activity seems to be accelerated by hypertension. The increased lysosomal enzymes may participate in the further development of hypertensive vascular changes.


Evaluation of jojoba oil as a low-energy fat. 2. Intestinal transit time, stomach emptying and digestibility in short-term feeding studies in rats.
The influence of jojoba oil (JO) incorporation in the diet on stomach emptying and intestinal transit time, and the digestion and absorption of JO were investigated in short-term feeding studies in rats. The animals were fed purified diets containing 18% (w/w) fat, of which half consisted of a mixture of lard and sunflower seed oil (SF) supplemented with an equivalent amount of JO. The control animals were fed a mixture of lard and SF (18%). No treatment-related differences were observed in the rate of stomach emptying or the intestinal transit time. Comparative lipid analysis of lymph, intestinal content, intestinal mucosa and faeces indicated that most of the ingested JO was degraded and absorbed. Part of the JO was present as wax ester in the lymph. Hydrolysis of JO was much slower than that of triacylglycerols and continued in the alimentary tract beyond the small intestine due to bacterial processes. JO did not influence the absorption of the conventional fat.


The Novel H4R Antagonist 1-[(5-Chloro-2,3-Dihydro-1-Benzofuran-2-Yl)Methyl]-4-Methyl-Piperazine (LINS01007) Attenuates Several Symptoms in Murine Allergic Asthma.
Histamine is an important chemical transmitter involved in inflammatory processes, including asthma and other chronic inflammatory diseases. Its inflammatory effects involve mainly the histamine H4 receptor (H4R), whose role in several studies has already been demonstrated. Our group have explored the effects of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines as antagonists of H4R, and herein the compounds LINS01005 and LINS01007 were studied with more details, considering the different affinity profile on H4R and the anti-inflammatory potential of both compounds. We carried out a more focused evaluation of the modulatory effects of LINS01005 and LINS01007 in a murine asthma model. The compounds were given i.p. (1-7 mg/kg) to ovalbumin sensitized BALB/c male mice (12 weeks old) 30 min before the antigen challenging, and after 24 h the cell analysis from the bronchoalveolar lavage fluid (BALF) was performed. The lung tissue was used for evaluation by western blot (COX-2, 5-LO, NF-κB and STAT3 expressions) and histological analysis. Treatment with the more potent H4R antagonist LINS01007 significantly decreased the total cell count and eosinophils in BALF at lower doses when compared to LINS01005. The expression of COX-2, 5-LO, NF-κB and STAT3 in lung tissue was significantly reduced after treatment with LINS01007. Morphophysiological changes such as mucus and collagen production and airway wall thickening were significantly reduced after treatment with LINS01007. These results show important down regulatory effect of novel H4R antagonist (LINS01007) on allergic lung inflammation.


Esketamine opioid-free intravenous anesthesia versus opioid intravenous anesthesia in spontaneous ventilation video-assisted thoracic surgery: a randomized controlled trial.
Opioid-free anesthesia (OFA) provides adequate analgesia and can reduce postoperative opioid consumption, but its efficacy in spontaneous ventilation video-assisted thoracic surgery (SV-VATS) has not been demonstrated. We aimed to investigate the hypothesis that OFA could provide the same perioperative pain control as opioid anesthesia (OA), maintain safe and stable respiration and hemodynamics during surgery, and improve postoperative recovery. Sixty eligible patients (OFA group: n=30; OA group: n=30) treated between September 15, 2022, and December 15, 2022, at The First Hospital of Guangzhou Medical University were included. They were randomized to receive standard balanced OFA with esketamine or OA with remifentanil combined with sufentanil. The primary outcome was the pain numeric rating score (NRS) at postoperative 24 h, and the secondary outcomes were intraoperative respiratory and hemodynamic data, opioid consumption, vasoactive drug dosage, and recovery in the post-anesthesia care unit and ward. There was no significant difference in the postoperative pain scores and recovery quality between the two groups. The OFA group had a significantly lower dose of phenylephrine (P=0.001) and a lower incidence of hypotension (P=0.004) during surgery. The OFA group resumed spontaneous respiration faster (P<0.001) and had a higher quality of lung collapse (P=0.02). However, the total doses of propofol and dexmetomidine were higher (P=0.03 and P=0.02), and the time to consciousness was longer (P=0.039) in the OFA group. OFA provides the same level of postoperative pain control as OA, but it is more advantageous in maintaining circulatory and respiratory stability and improving the quality of pulmonary collapse in SV-VATS.


Downregulation of pyrroline-5-carboxylate reductase-2 induces the autophagy of melanoma cells via AMPK/mTOR pathway.
Melanoma is the most aggressive form of skin cancer and causes 50,000 deaths annually worldwide. The roles of proline-dependent process and autophagy have both been reported in studies on melanoma. In the present study, we focused on the effect of pyrroline-5-carboxylate reductase-2 (PYCR2) on inducing autophagy process in melanoma. The expression of PYCR2 was regulated by an RNAi technique, and the cell proliferation of A375 cell line was determined by methyl thiazolyl tetrazolium test; the effect of PYCR2 on the apoptosis process and AMPK/mTOR pathway was evaluated by flow cytometry assay and Western blot. It was found that silence of PYCR2 resulted in the decrease of proliferative ability and activation of AMPK/mTOR-induced autophagy of A375 cells. PYCR2 silencing also activated AMPK/mTOR pathway in another melanoma cell line, CHL-1. However, the overexpression of PYCR2 seemed to make no difference to the cell viability and targeted pathway. Our results offered a preliminary illustration on the mechanism of the PYCR2-dependent autophagy and showed that PYCR2 was a potential therapeutic target of melanoma.


Expression of CD34, VEGFR3 and eosinophil density in selected odontogenic tumors- a pilot study.
Limited statistically and clinically significant studies have been down on connective tissue factors in the odontogenic tumors. Therefore, the aim of this study was to determine the biological behavior of two selected epithelial odontogenic tumors (Ameloblastoma and Adenomatoid odontogenic tumor) by detecting CD34, VEGFR3 and eosinophil densities. In this cross-sectional study, paraffin blocks including 20 cases of ameloblastoma and 20 (AOT), were selected. Totally, 4 sections were prepared for hematoxylin-eosin, Congo red staining, immunohistochemistry with CD34 and VEGFR3. Expression of VEGFR3, CD34 and lymphatic, blood vessels and eosinophil densities was examined. The mean of blood, lymphatic vessels and eosinophils densities in ameloblastoma were 14.9 ± 6.4, 4.4 ± 2 and 3.2 ± 2.7, respectively; and in AOT, they were 8.9 ± 3.4, 3.6 ± 1.3 and 1.2 ± 07, respectively. There was a significant difference in eosinophils and blood vessels densities between the two lesions (p = 0.005; p = 0.003). By increasing the density of eosinophils, the density of the blood vessels increased in both lesions (r = 0.539, P = 0.001) There was no positive relationship between eosinophils and lymphatic vessels densities in the two above mentioned odontogenic lesions (p = 0.288, R = 0.191). It can be suggested that tumor angiogenesis and eosinophil densities may play a more effective role than lymphangiogenesis in local invasive behavior of ameloblastoma rather than AOT.


A Primer on Dose-Response Data Modeling in Radiation Therapy.
An overview of common approaches used to assess a dose response for radiation therapy-associated endpoints is presented, using lung toxicity data sets analyzed as a part of the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic effort as an example. Each component presented (eg, data-driven analysis, dose-response analysis, and calculating uncertainties on model prediction) is addressed using established approaches. Specifically, the maximum likelihood method was used to calculate best parameter values of the commonly used logistic model, the profile-likelihood to calculate confidence intervals on model parameters, and the likelihood ratio to determine whether the observed data fit is statistically significant. The bootstrap method was used to calculate confidence intervals for model predictions. Correlated behavior of model parameters and implication for interpreting dose response are discussed.


Automated assessment of Ki-67 in breast cancer: the utility of digital image analysis using virtual triple staining and whole slide imaging.
Precise evaluation of proliferative activity is essential for the stratified treatment of luminal-type breast cancer (BC). Immunohistochemical staining of Ki-67 has been widely used to determine proliferative activity and is recognised to be a useful prognostic marker. However, there remains discussion concerning the methodology. We aimed to develop an automated and reliable Ki-67 assessment approach for invasive BC. A retrospective study was designed to include two cohorts consisting of 152 and 261 consecutive patients with luminal-type BC. Representative tissue blocks following surgery were collected, and three serial sections were stained automatically with Ki-67, pan-cytokeratin and p63. The whole slides were scanned digitally and aligned using VirtualTripleStaining - an extension to the VirtualDoubleStaining™ technique provided by Visiopharm software. The aligned files underwent automated invasive cancer detection, hot-spot identification and Ki-67 counting. The automated scores showed a significant positive correlation with the pathologists' scores (r = 0.82, P < 0.0001). Among selected patients with curative surgery and standard adjuvant therapies (n = 130), the digitally assessed low Ki-67 group (<20%) demonstrated a significantly better prognosis (breast cancer-specific survival, P = 0.030; hazard ratio = 0.038) than the high Ki-67 group. Digital image analysis yielded similar results to the scores determined by experienced pathologists. The prognostic utility was verified in our cohort, and an automated process is expected to have high reproducibility. Although some pitfalls were confirmed and thus need to be monitored by laboratory staff, the application could be utilised for the assessment of BC.


The effect of positive and negative evaluation on state anxiety and repetitive negative thinking in social evaluative situations: An experimental study.
The Bivalent Fear of Evaluation (BFOE) Model suggests that fears of negative and positive evaluation are core cognitive vulnerability and maintenance factors for social anxiety disorder The aim of this study was to experimentally assess cognitive and emotional effects of positive and negative feedback in social anxiety. False positive or negative feedback (vs no feedback) was provided following a speech task to high and low socially anxious individuals to investigate impacts on state anxiety and repetitive negative thinking (N = 152, Mage = 22.13, 69 % female). Measures were completed prior to the speech and after the false feedback but prior to an anticipated discussion with the group about participants' feedback and performance. High socially anxious participants reporting higher state anxiety and repetitive negative thinking than low socially anxious participants. There were no feedback type by group interactions, indicating that high socially anxious individuals experienced heightened social anxiety and repetitive negative thinking regardless of feedback type (or the absence of feedback). Exploratory analyses revealed that state fear of negative evaluation but not state fear of positive evaluation uniquely predicted both outcomes. Implications for theory and clinical practice are discussed.


Acute changes in blood pressure in patients with neuroblastoma treated with ¹³¹I-metaiodobenzylguanidine (MIBG).
Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy for children with neuroblastoma. The aim of our study was to evaluate systematically the acute effects of (131)I-MIBG on blood pressure in patients with neuroblastoma and to identify possible predictors of hypertension. We conducted a retrospective chart review of neuroblastoma patients who were treated with (131)I-MIBG between January 1, 1999 and June 1, 2012 at the University of California, San Francisco. Clinical data for 172 patients with neuroblastoma, receiving 218 administrations of (131)I-MIBG, were collected. The primary endpoint was development of systolic blood pressure above the 95th percentile for age. Logistic regression with generalized estimating equations to account for multiple administrations in some subjects was used to identify bivariate and multivariate predictors of hypertension. Of the 218 administrations of (131)I-MIBG, 112 (51.3%) were associated with at least one episode of systolic hypertension during or after the (131)I-MIBG infusion. The majority of these acute elevations in blood pressure resolved within 48 hours of the infusion. Only six administrations in five patients required nifedipine administration to lower blood pressure. Younger age (P = 0.012), lower eGFR (P = 0.047), and elevated blood pressure measurements immediately before infusion began (P = 0.010) were all independently associated with risk of treatment-associated hypertension. Acute elevations in blood pressure are common after therapeutic doses of (131) I-MIBG. Elevations in blood pressure typically occur only within the first 48 hours after (131)I-MIBG administration. Blood pressure monitoring during this period of risk is recommended.


Therapeutic-oligonucleotides activated by nucleases (TOUCAN): A nanocarrier system for the specific delivery of clinical nucleoside analogues.
Nucleoside analogues have been in clinical use since 1960s and they are still used as the first therapeutic option for several cancers and viral infections, due to their high therapeutic efficacy. However, their wide clinical acceptance has been limited due to their high toxicity and severe side effects to patients. Herein, we report on a nanocarrier system that delivers nucleosides analogues in a target-specific manner, making nucleoside-based therapeutics safer and with the possibility to be used in other human conditions. This system, named, Therapeutic OligonUCleotides Activated by Nucleases" (TOUCAN) combines: i) the recognition power of oligonucleotides as substrates, ii) the use of nucleases as enzymatic biomarkers and iii) the clinical efficacy of nucleoside analogues, in a single approach. As a proof-of-concept, we report on a TOUCAN that is activated by a specific nuclease produced by bacteria and releases a therapeutic nucleoside, floxuridine. We demonstrate, for the first time, that, by incorporating a therapeutic nucleoside analogue into oligonucleotide probes, we can specifically inhibit bacterial growth in cultures. In this study, Staphylococcus aureus was selected as the targeted bacteria and the TOUCAN strategy successfully inhibited its growth with minimal inhibitory concentration (MIC) values ranging from 0.62 to 40 mg/L across all tested strains. Moreover, our results indicate that the intravenous administration of TOUCANs at a dose of 20 mg/kg over a 24-h period is a highly effective method for treating bacterial infections in a mouse model of pyomyositis. Importantly, no signs of toxicity were observed in our in vitro and in vivo studies. This work can significantly impact the current management of bacterial infections, laying the grounds for the development of a different class of antibiotics. Furthermore, it can provide a safer delivery platform for clinical nucleoside therapeutics in any human conditions, such as cancer and viral infection, where specific nuclease activity has been reported.


Quantification of peptide components in cinobufacini injection and toad skin by ultra-high-performance liquid chromatography/triple quadrupole mass spectrometry.
Cinobufacini injection is commonly used in the clinical treatment of tumors and hepatitis B, but the quality is uneven. Currently, the main focus of its quality assessment is on steroids and alkaloids. Based on a previous study, we screened four peptides with high reproducibility, responsiveness, and specificity. This research was the first to develop an ultra-high-performance liquid chromatography/triple quadrupole mass spectrometry approach for evaluating the quality of cinobufacini preparations from the peptide perspective. In this study, we have identified 230 peptides in cinobufacini injection by Q-Exactive mass spectrometry, which contains species-specific peptides. Then, we used ultra-high-performance liquid chromatography/triple quadrupole mass spectrometry to establish a quantitative method for species-specific peptides and carried out method validation. The result revealed that four peptides were linear in a specific range, and had great reproducibility, accuracy, and stability. Eventually, we evaluated the quality of eight batches of cinobufacini injections and 26 batches of toad skins using the total content of target peptides as the criterion. The outcomes demonstrated that the quality of cinobufacini injection is generally stable and the toad skin from Shandong is of the best quality. In conclusion, the quantitative approach that focuses on peptides will offer innovative perspectives on assessing the quality of cinobufacini preparations.


Comparison of three measurements on computed tomography for the prediction of less invasiveness in patients with clinical stage I non-small cell lung cancer.
A greater proportion of ground-glass opacity (GGO) is well known to be strongly associated with less invasive lung adenocarcinoma. Recently, the solid area diameter has also been reported to be a simple and better marker for the same purpose compared with the whole nodule diameter. From 1997 to 2009, 383 patients with clinical T1-2N0M0 non-small cell lung cancer (NSCLC) with a solid area of 3 cm or less underwent surgical resection, and their preoperative high-resolution computed tomographic images were preserved in Digital Imaging and Communications in Medicine format. Less invasive lung cancer was defined as having no vascular, lymphatic, or pleural invasion or lymph node metastasis. We compared the solid area and whole nodule diameters and proportion of GGO, with the objective of predicting less invasive lung cancer. Among the 383 patients, 187 were men, 335 had adenocarcinoma histologic type, 242 had less invasive lung cancer, and 43 experienced recurrence. Receiver operating characteristic (ROC) analysis to predict less invasive lung cancer showed that the area under the curve of proportion of GGO was the highest (0.848; 95% confidence interval [CI], 0.810-0.886), followed by the solid area diameter (0.785; 95% CI, 0.740-0.829), and then whole nodule diameter (0.621; 95% CI, 0.565-0.677). Multiple logistic regression analyses revealed that proportion of GGO was the only significant predictor of less invasive lung cancer. The proportion of GGO was also found to be a significant prognostic factor of disease-free survival (DFS) along with solid area diameter by multivariate analysis. Regardless of the solid area diameter, no patient with a greater proportion of GGO (> 50%) experienced recurrence. Proportion of GGO remains important for predicting less invasive lung cancer.


Quantitative variations of the isoforms in haptoglobin 1-2 and 2-2 individual phenotypes.
Haptoglobin is a hemoglobin-binding protein presenting in humans three distinct phenotypes (Hpt 1-1, Hpt 1-2, or Hpt 2-2). The Hpt 1-2 and Hpt 2-2 phenotypes are in turn represented by populations of isoforms. The relative amounts of the major isoforms of Hpt 1-2 and Hpt 2-2 were found to differ not only in different individuals, but also in the same individual before and after a physical effort. Exercise-dependent changes in the plasma concentrations of ascorbate, urate, alpha-tocopherol, retinol, and glutathione were also observed, but correlations between such changes and those of the amount for any isoform were not found. Samples of Hpt 1-2 or Hpt 2-2 were challenged with oxidants (H(2)O(2) with ferrous ions, spermine-NO, KO(2), and 3-morpholinosydnonimine), but the isoform levels were not altered. Hpt 2-2 isoforms were present in Hpt 1-2, as minor species. Furthermore, different isoforms exhibited different hemoglobin binding abilities. Thus, these parameters should also be taken into consideration in studies correlating Hpt phenotypes prevalence with pathologies or functional differences.


An evaluation of the TCu 380Ag and the Multiload Cu375.
The TCu 380Ag (Outokumpu Oy, Pori, Finland) and the Multiload Cu375 (Multilan, Organon, Oss, The Netherlands) were evaluated in 1477 women in a multicenter clinical trial. The intrauterine devices showed similar, low-event rates. Cumulative life-table pregnancy rates were less than 1.0, and continuation rates were approximately 90 per 100 women at 1 year after insertion. The risk of subsequent hospitalization or pelvic infection was low.


Quantification of 10,11-dihydro-10-hydroxy carbamazepine and 10,11-epoxycarbamazepine as the main by-products in the electrochemical degradation of carbamazepine.
Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs in Malaysia. It was detected frequently in wastewater. The electrochemical treatment process has been applied for the degradation of CBZ using graphite-PVC as an anode under these conditions: 0.5 g sodium chloride (NaCl)) as supporting electrolyte, 5 V and 0-60 min electrolysis time in 100 mL of solution. However, 10,11-dihydro10-hydroxy carbamazepine (HDX-CBZ) and 10,11-epoxycarbamazepine (EPX-CBZ) as the main by-product have been analysed and quantified using liquid chromatography-time of flight/mass spectrometry (LC-TOF/MS). Both by-products were analysed in positive ionization mode, and they were separated on a chromatographic C18 column (5 μm, 2 mm × 150 mm) at a flow rate of 0.3 mL/min. Solid-phase extraction (SPE) was applied as a pre-concentration step for the enhancement of the sensitivity and detectability for both HDX-CBZ and EPX-CBZ by-products. Methanol (MeOH) has been selected as the best elution solvent for both by-products compared to methyl tertiary butyl ether (MTBE) and acetone (AC). However, the recovery was 85% and 92% for HDX-CBZ and EPX-CBZ by-products, respectively. The limit of quantification (LOQ) was 0.588 and 0.109 µg/L for HDX-CBZ and EPX-CBZ by-products, respectively. After 20 min of electrolysis time, both by-products HDX-CBZ and EPX-CBZ appeared at maximum concentrations of 343 and 144 μg/L then they were decreased to 17.2 and 9.8 μg/L, respectively, after 40 min. At the end of electrochemical treatment, both by-products were completely eliminated after 60 min.


Evaluation of retention protocols among members of the American Association of Orthodontists in the United States.
Little research has been conducted to evaluate protocols and trends in orthodontic retention. The purpose of this study was to identify the general retention protocols used by orthodontists in the United States. Additionally, our goal was to identify trends in these orthodontic retention protocols by evaluating how they have changed over the past 5 years and how they might continue to change in the next 5 years. The study was conducted via a 36-question electronic survey (REDCap, Nashville, Tenn) with branching logic on certain questions. The survey was sent to all 9143 practicing members of the American Association of Orthodontists in the United States, and 1632 (18%) responded. Mean retention protocols of the surveyed population showed predominant use of Hawley or vacuum-formed retainers in the maxillary arch and fixed retention in the mandibular arch. For both arches, there is a current shift away from Hawley retainers and toward vacuum-formed retainers and fixed retention. Respondents who extract fewer teeth reported increased use of fixed retention in the maxillary (P = 0.041) and mandibular (P = 0.003) arches. Respondents who extract fewer teeth and use removable retainers were more likely to tell their patients to wear their retainers at night for the rest of their lives (P = 1.63 × 10(-6)).


Developing a digital assistive tool for dementia patients and their caregivers: A qualitative study on needs, potential functions, practical requirements, user acceptance, and ethical considerations.
Digital smartphone assistants for the care and support of people with dementia (PwD) have great potential due to the wide availability of smartphones and a growing number of users aged above 65. Research has mainly focused on the development of applications for only one user group (patients, caregivers, or relatives respectively), and with only one or a few functions included (Yousaf et al., 2020). A more integrative, multi-user, and multifunctional application would be beneficial because it could be adapted to the users' needs more flexibly. This qualitative interview study was the first step in a co-creative process with a user-centered approach aimed at developing a multifunctional digital assistant. Qualitative content analysis (Mayring, 2010) combining deductive and inductive techniques was applied to identify burdens, needs, functions, ethical considerations, and acceptance aspects. 14 semi-structured interviews were conducted with three participant groups (relatives of PwD; caregivers and nursing staff; psychologists). Interviews were conducted via video conferences due to Covid-19 restrictions. After the completion of all interviews, participants received several questionnaires on acceptance aspects (Technology Usage Inventory [TUI], acceptance rating of specific functions), and technological affinity (TA-EG questionnaire) via letter. Interviews were transcribed verbatim with the software MAXQDA. Coding was done by two independent researchers. A coding frame was generated using the interview guide as a theoretical basis and the collected data for building inductive categories. The coding frame was pilot-tested before the final analysis and intercoder reliability was sufficient (k=.81). Preliminary results showed that dealing with symptoms of dementia in everyday life was burdening. Emotional needs in patients and needs for additional care resources in relatives and caregivers were the most important unanswered needs. 53 functions were suggested in the areas: digital care, support, training, monitoring, navigation, leisure activities, and social contacts. Participants had ethical requirements (i.e. data protection, privacy, and autonomy) that if met, would enhance acceptance. Results on questionnaires showed positive attitudes towards, curiosity about, and no insecurity with regards to technology. The overall acceptability of suggested functions was high. Participants showed a large interest in the digital assistant. The importance of data protection was underlined.


Mobilization and methylation of mercury with sulfur addition in paddy soil: Implications for integrated water-sulfur management in controlling Hg accumulation in rice.
Sulfur-fertilizer is commonly applied in croplands and in immobilizing Hg in contaminated soil. However, there is still great uncertainty and controversy concerning Hg transportability and transformation when supplying sulfur in paddies with complex conditions. Herein, we explored the effect of adding sulfate in paddy soil at different rice growth stages on soil Hg release and MeHg accumulation in rice and uncovered the correlation between sulfur induced MeHg production and the dynamically changed soil Eh, dissolved Fe, and dissolved organic carbon (DOC). In specific, sulfate addition at early stages (flooding period) triggered the decrease of Eh and increase of DOC and dissolved Fe, which in turn promoted Hg release and favored MeHg generation (increased by 235.19-555.07% vs control). Interestingly, adding sulfate at late stages (drainage condition), as compared with that at early stages, alleviated Hg release and MeHg production accompanied by the increase of Eh and decrease of dissolved Fe and DOC. The microcosmic experiment further confirmed the reduction of sulfate to sulfide promoted the change of Eh, thereby stimulating HgS dissolution in soil extract. The results give clues on the rational application of sulfur-fertilizer and through the water-sulfur fertilizer management considering the correspondingly changed soil conditions to diminish Hg bioavailability and MeHg production in paddies and paddy-like environments.


Formation of reactive oxygen species in lung alveolar cells: effect of vitamin E deficiency.
Reactive oxygen species (ROS) play an important role in the pathogenesis of numerous pulmonary diseases. Various mainly membrane-bound ROS-generating processes exist in alveolar cells. Vitamin E (vit. E) is the most important lipophilic antioxidant. However, the significance of vit. E levels in alveolar cells for the regulation of ROS generation has not been investigated so far. We demonstrated here that feeding rats with vit. E-depleted nourishment for 5 weeks reduced the concentration of vit. E in alveolar type II cell preparations to one-fifth the amount of control animals. This reduction of vit. E levels was associated with an approximately threefold increase in ROS generation in type II pneumocytes, lymphocytes, and macrophages. The contribution of individual processes of ROS formation in control animals differed strongly among these three cell types. However, vit. E deficiency induced predominantly nonmitochondrial ROS formation in alveolar cells. Expression and NAD(P)H-oxidase activity in alveolar type II cell preparations was not affected by vit. E deficiency. Moreover, protein kinase C (PKC) also did not seem to be responsible for vit. E deficiency-induced ROS generation in alveolar cells. Alimentary vit. E supplementation for 2 days corrected the cellular vit. E concentration but failed to normalize ROS generation in alveolar cells. These data let us assume that alimentary vit. E deficiency caused a preferentially nonmitochondria-mediated increase of ROS formation in type II pneumocytes, macrophages, and lymphocytes. However, the short-term supplementation of vit. E does not reverse these effects.


Unfolding molecular switches for salt stress resilience in soybean: recent advances and prospects for salt-tolerant smart plant production.
The increasing sodium salts (NaCl, NaHCO3, NaSO4 etc.) in agricultural soil is a serious global concern for sustainable agricultural production and food security. Soybean is an important food crop, and their cultivation is severely challenged by high salt concentration in soils. Classical transgenic and innovative breeding technologies are immediately needed to engineer salt tolerant soybean plants. Additionally, unfolding the molecular switches and the key components of the soybean salt tolerance network are crucial for soybean salt tolerance improvement. Here we review our understandings of the core salt stress response mechanism in soybean. Recent findings described that salt stress sensing, signalling, ionic homeostasis (Na+/K+) and osmotic stress adjustment might be important in regulating the soybean salinity stress response. We also evaluated the importance of antiporters and transporters such as Arabidopsis K+ Transporter 1 (AKT1) potassium channel and the impact of epigenetic modification on soybean salt tolerance. We also review key phytohormones, and osmo-protectants and their role in salt tolerance in soybean. In addition, we discuss the progress of omics technologies for identifying salt stress responsive molecular switches and their targeted engineering for salt tolerance in soybean. This review summarizes recent progress in soybean salt stress functional genomics and way forward for molecular breeding for developing salt-tolerant soybean plant.


Sensory abnormalities in consecutive, unselected patients with central post-stroke pain.
This study examined the sensory abnormalities in an unselected, consecutive group of patients with central post-stroke pain (CPSP) surviving more than 1 year after stroke. The sensory examination included clinical examination and quantitative measures with detection and pain thresholds to heat and cold stimuli, argon laser, von Frey hair and determination of stimulus-response function in the 10-45 degrees C range. Sensory examination was in 11 identified CPSP patients (5 female, 6 male; aged 43-80 years) carried out in the painful area using the contralateral homologue area as reference. Pain rating was performed using the McGill Pain Questionnaire and a VAS scale. All patients had ischemic (MRI verified) infarction. Of the 11 patients with supratentorial lesions, 5 had thalamic lesions; in addition, 7 patients had lesions in the brain stem/cerebellum. Median present spontaneous pain intensity on the VAS scale was 3.3 (range: 0-7.7). All patients had pain in the body part with sensory abnormalities, which in 8 patients extended the area with pain. Warm detection threshold was higher in the pain area in all patients, and all except 1 patient had increased cold detection threshold. Cold and heat pain thresholds were raised as well, but to a lesser degree. Sensibility to touch (von Frey hairs) and pain (argon laser) were changed in only 4 and 3 patients, respectively. A stimulus-response curve in the 10-45 degrees C range showed different patterns compared to the non-affected side. A cold allodynia in the 10-45 degrees C range was present in the painful area in 6 (56%) of the patients. The results support the theory that damage to the spino-thalamo-cortical pathway is a necessary condition in CPSP. It is proposed that the spontaneous pain in CPSP is linked to hyperexitability or spontaneous discharges in thalamic or cortical neurons that have lost part of their normal input.


Detection of HER2/neu gene amplification in archival paraffin-embedded breast cancer tissues by fluorescence in situ hybridization.
We evaluated HER2/neu gene amplification by fluorescence in situ hybridization (FISH) in archival paraffin-embedded breast cancer tissues. Tumors from 63 human invasive breast cancers were categorized into two groups depending on whether the paraffin-embedded tissue blocks had been stored for more or less than 12 months duration. These were subjected to routine and modified FISH protocols. As microwave oven formalin fixation of tissues was carried out in the majority of the older archived specimens, the effect of this fixation method was also analyzed. FISH signals were obtained in all 13 archival specimens stored for less than 12 months. However, in 50 specimens stored for more than 12 months duration, the procedure was successful in only 10 specimens (20%), for which the pretreatment procedure had to be individually optimized for each specimen. There was no significant difference in the detection of FISH signals between microwave oven and routinely fixed specimens.


Clinical significance and prognostic value of PAX3 expression in human glioma.
The paired box 3 (PAX3), a crucial transcription factor, is normally expressed during embryonic development and is absent in normal adult human tissues. Deregulated expression of PAX3 has been observed in tumors like rhabdomyosarcoma and melanomas. To assess deregulated PAX3 expression in patients with gliomas, these samples from 57 glioma patients (13 grade I, 16 grade II, 14 grade III, and 14 grade IV tumors) and 10 normal brain specimens acquired from 10 patients undergoing surgery for epilepsy as control were obtained. PAX3 expression was measured by RT-PCR, Western blot, and immunohistochemistry. Survival analyses were performed using the Kaplan-Meier method. Association between PAX3 expression, clinicopathological characteristics, and patients' survival were analyzed by using SPSS 17.0. We found that the expression of PAX3 was upregulated in high-grade glioma tissues compared with that in low-grade and normal brain tissues, and increased with ascending tumor World Health Organization (WHO) grades (P = 0.001). The increased PAX3 expression in gliomas was significantly associated with higher WHO grade (P = 0.021) and poorer disease-specific survival of patients (P = 0.001). Our results suggested that PAX3 might be an intrinsic regulator of progression in glioma cells and it might serve as a prognostic factor for this dismal disease.