Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients.
Mutations in the PTPN11 gene are the main cause of Noonan syndrome (NS). The presence of some NS features is a frequent finding in children with idiopathic short stature (ISS). These children can represent the milder end of the NS clinical spectrum and PTPN11 is a good candidate for involvement in the pathogenesis of ISS. To evaluate the presence of mutations in PTPN11 in ISS children who presented NS-related signs and in well-characterized NS patients. We studied 50 ISS children who presented at least two NS-associated signs but did not fulfil the criteria for NS diagnosis. Forty-nine NS patients diagnosed by the criteria of van der Burgt et al. were used to assess the adequacy of these criteria to select patients for PTPN11 mutation screening. The coding region of PTPN11 was amplified by polymerase chain reaction (PCR), followed by direct sequencing. No mutations or polymorphisms were found in the coding region of the PTPN11 gene in ISS children. Nineteen of the 49 NS patients (39%) presented mutations in PTPN11. No single characteristic enabled us to distinguish between NS patients with or without PTPN11 mutations. Considering that no mutations were found in the present cohort with NS-related signs, it is unlikely that mutations would be found in unselected ISS children. The van der Burgt et al. criteria are adequate in attaining NS diagnosis and selecting patients for molecular studies. Mutations in the PTPN11 gene are commonly involved in the pathogenesis of NS but are not a common cause of ISS.


Quality of Life and Survivorship in Lymphoma.
With an increasing number of long-term lymphoma survivors, there has been emphasis on optimizing quality of life and identifying survivorship challenges. This review summarizes the latest advancements pertaining to health-related quality of life and survivorship in lymphoma. Quality of life can vary from diagnosis through survivorship though some physical, social, and emotional effects may be persistent. Incorporation of patient reported outcomes enables recognition of factors that significantly impact quality of life. A greater understanding of quality of life and survivorship issues has generated momentum for practice change, improving education, and designing behavior related interventions. Patients with lymphoma face many challenges as they navigate their cancer experience. There is a tremendous opportunity to build upon this work through well-designed prospective longitudinal studies aimed at identifying vulnerable patient groups and impactful points of intervention during survivorship.


Array comparative genomic hybridization characterization of prenatally detected de novo apparently balanced reciprocal translocations with or without genomic imbalance in other chromosomes.
We present our experience of array comparative genomic hybridization (aCGH) characterization of two cases of prenatally detected de novo simple and complex apparently balanced reciprocal translocations. Amniocentesis of the first case revealed a complex chromosome rearrangement and a karyotype of 46,XY,t(5;8;6)(q11.2;p23.1;q22.32)dn. aCGH of amniocytes revealed no genomic imbalance. Ultrasound findings were unremarkable. The pregnancy was carried to term, and pediatric follow-ups were normal at 3 months of age. Amniocentesis of the second case revealed a simple reciprocal translocation and a karyotype of 46,XY,t(3;11)(q14;q23)dn. aCGH of amniocytes revealed a 1.32-Mb microduplication in chromosome 2p12 [arr cgh 2p12 (75,245,747-76,563,965)×3] encompassing the genes of TACR1, FAM176A, MRPL19, and C2orf3. Ultrasound findings were unremarkable. The pregnancy was carried to term, and the pediatric follow-ups were normal at 8 months of age. In cases of prenatally detected de novo apparently balanced reciprocal translocations, cryptic intrachromosomal rearrangements may exist in addition to the cytogenetically visible structural chromosome aberrations. aCGH is useful not only in identifying the genomic imbalances at the breakpoints, but also in detecting unexpectedly complex rearrangements in other chromosomes.


Current status of ileorectal anastomosis for inflammatory bowel disease.
Between September 1959 and December 1986, a total of 210 patients in a consecutive series were operated on for inflammatory bowel disease. One hundred ten (66 percent) had ileorectal anastomosis performed. There were no postoperative deaths. There were six failures in 53 ileorectal anastomoses for ulcerative colitis (11 percent), and five failures (8 percent) in 61 for Crohn's disease. The overall failure rate was 11 in 110 (10 percent). Ileorectal anastomosis, in suitable patients, is still a viable operation in the late 1980s.


Reflections on the 24 years durability of an isolate tricuspid bovine pericardium IMC/Braile bioprosthesis.
We were challenged by the experience of one patient reoperation for a bioprosthetic bovine pericardium degenerative stenosis, 24 years after implantation. This bioprosthesis was implanted due to tricuspid valve bacterial staphylococcal endocarditis after septic abortion.


[Partial glansectomy by organsparing therapy of penile cancer].
The aim of the present research is to study the patients, having penile cancer diagnosis, treated at the Clinic of Urology, Medical University, Sofia, during the last 8 years. The study is focused on patients, undergoing T1 phase, treated through organsapring intervention partial glansectomia. From all 37 patients treated during the period from year 1998 to year 2005, 15 or 40% were in phase T1. By 7 patients or 19% were in phase T1 with infiltration of less of the half from Glans penis. Organsparing operation partiale glansectomy was undertaken for the patients in phase T1, with wite tomor surface. A total number of 15 patients treated in T1 phase have been studied. The following interventions were undertaken: glansectomia partialis in the case of 7 patients. The results were followed. The types of organsparing surgical interventions have been researched. The partial glansectomy as kind of organsparing treatment may be successfully applied to cases of penile cancer in T1 phase. The experience of other authors implemented organsparing treatment has been shared.


What makes community-based, multilevel physical activity promotion last? A systematic review with narrative synthesis on factors for sustainable implementation.
To follow the need for more research and strategies to enhance the knowledge of sustainable implementation, we examined cases of community-based, multilevel physical activity-related health promotion after initial funding has ceased and aimed to identify factors that influence their sustainable implementation. Five scientific databases (PubMed; Scopus; Ebsco Host with CINAHL, PsychInfo, and Sportdiscus; ProQuest and Web of Science) were systematically searched for relevant literature in December 2021. Three reviewers performed a title/abstract screening and independently screened the full texts of the remaining papers, followed by a quality assessment. A narrative synthesis method, including qualitative text analysis, was used to synthesise retrieved articles. As starting point, the framework of Schell et al. containing nine domains for sustainability capacity was used and new emerging themes were inductively added. The search revealed 270 potentially eligible articles out of 27,652 hits. After the systematic review process, 14 studies were included. In the synthesis, 14 factors influencing the sustainablity of community-based, multilevel physical activity-related health promotion were identified of which six are new factors compared to Schell et al. In particular, our findings bring forth a novel understanding of the importance of the factors 'Participation and Partnerships', 'Empowerment and Capacity Building' and 'Community Support'. A dynamic interplay and high connectedness between factors were visible. The identified factors can help establish a better understanding of sustainability processes within whole-system approaches intervening on multiple levels in the community with the aim of systems change. They are relevant for practitioners, researchers and policy makers alike. Future research should more closely examine based on further theoretical elaboration how an interplay between the factors can promote sustainability and which interdependencies are of particular importance in facilitating sustainable and equitable change.


Characterization of cys-loop receptor genes involved in inhibitory amine neurotransmission in parasitic and free living nematodes.
We have isolated two genes, Hco-lgc-53 and Hco-mod-1, from the parasitic nematode Haemonchus contortus, which are orthologs of previously characterized genes that encode dopamine and serotonin-gated chloride channels, respectively, in Caenorhabditis elegans. A search of transcriptome data for the filarial nematode parasites Loa loa, Brugia malayi, and Wucheria bancrofti revealed predicted coding sequences for orthologs of acetylcholine, serotonin and dopamine-gated chloride channels, which correspond to the C. elegans clades acc-1, mod-1 and ggr-3, respectively. Genome data for the more distantly related nematode parasite, Trichinella spiralis, contain genes predicted to encode members of the acc-1 clade only, but all three clades were absent from the trematode Schistosoma mansoni. Analysis of the ratio of non-synonymous to synonymous substitutions (ω) for receptor subunit sequences revealed strong selective constraint over the entire protein, consistent with the known highly conserved 3D structure of cys-loop receptors. This constraint was significantly greater for binding loop residues that are predicted to contact bound ligand and residues of the transmembrane domains. The substitution rate for ligand binding residues was significantly higher for branches leading to the acc-1 and mod-1 clades, where the convergent evolution for binding acetylcholine and serotonin, respectively, is thought to have occurred. Homology models of both Hco-MOD-1 and Hco-LGC-53 channels revealed the presence of binding structures typical of the cys-loop receptor family, including the presence of an aromatic box that is important for the formation of the binding pocket. Both receptors contain a tryptophan in loop C that appears to be a key residue important for the binding of amines to ligand-gated chloride channels. As additional ligand-gated chloride-channel sequences become available for a wider range of species the combination of molecular modeling and analysis of sequence evolution should provide an effective tool to understand the wide diversity of neurotransmitters that bind to this unique group of receptors.


Estimating the Burden of Child Undernutrition for Smaller Electoral Units in India.
Geographic targeting of public health interventions is needed in resource-constrained developing countries. To develop methods for estimating health and development indicators across micropolicy units, using assembly constituencies (ACs) in India as an example. This cross-sectional study included children younger than 5 years who participated in the fourth National Family and Health Survey (NFHS-4), conducted between January 2015 and December 2016. Participants lived in 36 states and union territories and 640 districts in India. Children who had valid weight and height measures were selected for stunting, underweight, and wasting analysis, and children between age 6 and 59 months with valid blood hemoglobin concentration levels were included in the anemia analysis sample. The analysis was performed between February 1 and August 15, 2020. A total of 3940 ACs were identified from the geographic location of primary sampling units in which the children's households were surveyed in NFHS-4. Stunting, underweight, and wasting were defined according to the World Health Organization Child Growth Standards. Anemia was defined as blood hemoglobin concentration less than 11.0 g/dL. The main analytic sample included 222 172 children (mean [SD] age, 30.03 [17.01] months; 114 902 [51.72%] boys) from 3940 ACs in the stunting, underweight, and wasting analysis and 215 593 children (mean [SD] age, 32.63 [15.47] months; 112 259 [52.07%] boys) from 3941 ACs in the anemia analysis. The burden of child undernutrition varied substantially across ACs: from 18.02% to 60.94% for stunting, with a median (IQR) of 35.56% (29.82%-42.42%); from 10.40% to 63.24% for underweight, with a median (IQR) of 32.82% (25.50%-40.96%); from 5.56% to 39.91% for wasting, with a median (IQR) of 19.91% (15.70%-24.27%); and from 18.63% to 83.05% for anemia, with a median (IQR) of 55.74% (48.41%-63.01%). The degree of inequality within states varied across states; those with high stunting, underweight, and wasting prevalence tended to have high levels of inequality. For example, Uttar Pradesh, Jharkhand, and Karnataka had high mean AC-level prevalence of child stunting (Uttar Pradesh, 45.29%; Jharkhand, 43.76%; Karnataka, 39.77%) and also large SDs (Uttar Pradesh, 6.90; Jharkhand, 6.02; Karnataka, 6.72). The Moran I indices ranged from 0.25 to 0.80, indicating varying levels of spatial autocorrelation in child undernutrition across the states in India. No substantial difference in AC-level child undernutrition prevalence was found after adjusting for possible random displacement of geographic location data. In this cross-sectional study, substantial inequality in child undernutrition was found across ACs in India, suggesting the importance of considering local electoral units in designing targeted interventions. The methods presented in this paper can be further applied to measuring health and development indicators in small electoral units for enhanced geographic precision of public health data in developing countries.


Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis.
Breast cancer is the second most common cause of central nervous system (CNS) metastases. Several risk factors for CNS metastases have been reported. The objective of the current study was to describe clinicopathologic characteristics and prognostic factors in breast cancer patients with CNS metastases. The authors retrospectively evaluated clinical data from 420 patients who had been diagnosed with breast cancer and CNS metastasis between 1994 and 2004 at the University of Texas M. D. Anderson Cancer Center. The median age of the patients at the time of diagnosis of breast cancer was 45 years (range, 25-77 years). Premenopausal and postmenopausal patients were distributed equally. Most patients had invasive ductal histology (91.2%), grade 3 tumors (81.4%) (using the modified Black nuclear grading system), T2 tumor classification (40.1%), and N1 lymph node status (59.7%) diagnosis. Forty percent of patients had estrogen receptor (ER)-positive disease, and 34% had progesterone receptor-positive disease. HER-2/neu status was recorded for only 248 patients, and 39% of the patients in that group had HER-2/neu-positive disease. The most common sites of first metastasis were liver, bone, and lung. CNS metastasis was the site of first recurrence in 53 patients (12%). In total, 329 patients had received either neoadjuvant treatment (113 patients) or adjuvant chemotherapy (216 patients). The majority of those patients (74.4%) had received anthracycline-based regimens. Metastasis was solitary in 111 patients (26.4%), and 29 patients had only leptomeningeal metastases. The median time from breast cancer diagnosis to CNS metastasis was 30.9 months (range, from -5 months to 216.7 months). The median follow-up after a diagnosis of CNS metastasis was 6 months (range, 7-95.9 months). In all, 359 patients died, and the overall median survival was 6.8 months. Only age at diagnosis and ER status were associated significantly with overall survival in the multivariate analysis. The current results indicated that the prognosis remains patients with breast cancer metastatic to the CNS. More effective treatment approaches are needed for patients with CNS metastases, even for those with favorable prognostic factors, such as ER-positive tumors or younger age.


Intraspecific variation, sex-biased dispersal and phylogeography of the eastern grey kangaroo (Macropus giganteus).
Genetic information has played an important role in the development of management units by focusing attention on the evolutionary properties and genetics of populations. Wildlife authorities cannot hope to manage species effectively without knowledge of geographical boundaries and demic structure. The present investigation provides an analysis of mitochondrial DNA and microsatellite data, which is used to infer both historical and contemporary patterns of population structuring and dispersal in the eastern grey kangaroo (Macropus giganteus) in Australia. The average level of genetic variation across sample locations was one of the highest observed for marsupials (h=0.95, HE=0.82). Contrary to ecological studies, both genic and genotypic analyses reveal weak genetic structure of populations, where high levels of dispersal may be inferred up to 230 km. The movement of individuals was predominantly male-biased (average Nem=22.61, average Nfm=2.73). However, neither sex showed significant isolation by distance. On a continental scale, there was strong genetic differentiation and phylogeographic distinction between southern (TAS, VIC and NSW) and northern (QLD) populations, indicating a current and/or historical restriction of gene flow. In addition, it is evident that northern populations are historically more recent, and were derived from a small number of southern founders. Phylogenetic comparisons between M. g. giganteus and M. g. tasmaniensis indicated that the current taxonomic status of these subspecies should be revised as there was a lack of genetic differentiation between the populations sampled.


Psychosocial Intervention Programs for Parents of Children with Cancer: A Systematic Review and Critical Comparison of Programs' Models and Development.
Intervention programs have been developed to help parents cope with their child's cancer. Despite some studies reporting a high level of evidence, it is unclear how these programs build on each other. Appraising models of change is critical to advance scientific knowledge and provide evidence-based interventions. This review aims to identify existing programs, explicitly formulate their underlying models, evaluate how they translate into concrete activities, as well as identify and discuss their development process. Eleven programs based on models of change from cognitive-behavioral, systemic and counselling theories were identified. Many models included a sound theoretical framework, targeted outcomes, as well as implementation strategies. In most cases, preliminary development studies were conducted, but details were rarely provided on how development stages informed the redesign of intervention programs. Acceptability and treatment fidelity were not available for one-third of the programs. Future reports should document the development and design redesign stages prior to conducting efficacy trials, as this step would provide crucial details to critically appraise programs.


Cultural niche construction with application to fertility control: A model for education and social transmission of contraceptive use.
The evolution of a cultural trait may be affected by niche construction, or changes in the selective environment of that trait due to the inheritance of other cultural traits that make up a cultural background. This study investigates the evolution of a cultural trait, such as the acceptance of the idea of contraception, that is both vertically and horizontally transmitted within a homogeneous social network. Individuals may conform to the norm, and adopters of the trait have fewer progeny than others. In addition, adoption of this trait is affected by a vertically transmitted aspect of the cultural background, such as the preference for high or low levels of education. Our model shows that such cultural niche construction can facilitate the spread of traits with low Darwinian fitness while providing an environment that counteracts conformity to norms. In addition, niche construction can facilitate the 'demographic transition' by making reduced fertility socially accepted.


A NMF based approach for integrating multiple data sources to predict HIV-1-human PPIs.
Predicting novel interactions between HIV-1 and human proteins contributes most promising area in HIV research. Prediction is generally guided by some classification and inference based methods using single biological source of information. In this article we have proposed a novel framework to predict protein-protein interactions (PPIs) between HIV-1 and human proteins by integrating multiple biological sources of information through non negative matrix factorization (NMF). For this purpose, the multiple data sets are converted to biological networks, which are then utilized to predict modules. These modules are subsequently combined into meta-modules by using NMF based clustering method. The integrated meta-modules are used to predict novel interactions between HIV-1 and human proteins. We have analyzed the significant GO terms and KEGG pathways in which the human proteins of the meta-modules participate. Moreover, the topological properties of human proteins involved in the meta modules are investigated. We have also performed statistical significance test to evaluate the predictions. Here, we propose a novel approach based on integration of different biological data sources, for predicting PPIs between HIV-1 and human proteins. Here, the integration is achieved through non negative matrix factorization (NMF) technique. Most of the predicted interactions are found to be well supported by the existing literature in PUBMED. Moreover, human proteins in the predicted set emerge as 'hubs' and 'bottlenecks' in the analysis. Low p-value in the significance test also suggests that the predictions are statistically significant.


Integrated fibrosis scoring by ultrasonography predicts the occurrence of hepatocellular carcinoma in patients with chronic hepatitis C virus infection.
This study was performed to elucidate whether evaluating the liver surface, edge, and texture by high-resolution ultrasonography is useful for predicting the occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-associated chronic liver diseases (CLDs) The integrated fibrosis stage (a comprehensive value of scores for liver edge, surface, and texture) of 337 patients with HCV-associated CLDs was evaluated, at entry, by ultrasonography (US), as a US score. The patients were followed up prospectively (mean observation period was 16.4 months; range 2.8-36.2 months) for the occurrence of HCC by US or helical CT at 3-month intervals. A total of 140 patients received interferon therapy, and the occurrence of HCC was compared between those with and without interferon therapy The annual incidence of HCC was 1.1, 5.5, and 10.2% in low, middle, and high US score groups, respectively. Univariate analysis showed that age, serum levels of total bilirubin, alpha-fetoprotein (AFP), platelet count, albumin, total cholesterol, and the US score were associated with HCC occurrence in the patients. A multivariate proportional hazard model revealed that only the middle and high US scores (p = 0.0922, hazard ratio 4.006, 95% CI 0.796-20.153 and p = 0.008, hazard ratio 7.991, 95% CI 1.721-37.10, respectively) and elevated AFP (p = 0.031, hazard ratio 2.774, CI 1.097-7.014) were independently associated with HCC occurrence. Our US scoring based on evaluation of the liver surface, edge, and texture was clearly and strongly associated with the occurrence of HCC in patients with HCV-associated CLDs, and with the higher occurrence rate of HCC in patients with higher US scores Thus, US is a good tool for evaluating the fibrosis stage of the liver, and may therefore be useful in designing an optimum follow-up interval for each patient with HCV-associated CLD.


Influence of algal community structure on denitrification rates in periphyton cultivated on artificial substrata.
We conducted a field survey of periphyton cultivated on benthic mesh installations in freshwater aquatic systems, including two constructed wetlands and a pond, and also studied periphyton grown on a benthic mesh in laboratory mesocosms. The objectives of this study were to (1) determine if periphyton cultivated on benthic mesh denitrifies at higher rates than the underlying sediments and (2) determine if denitrification rates within periphyton vary with characteristics such as algal and bacterial community structure and biomass. We measured denitrification potential rates of field and laboratory periphyton by the acetylene inhibition method. We characterized algal community composition by algal identification and bacterial community composition by terminal restriction fragment length polymorphisms. Periphyton collected on benthic mesh from our field sites denitrified at significantly higher rates than the underlying sediments, regardless of sampling site or season. Results from both our field survey and laboratory studies indicated a significant, positive correlation between diatom presence and denitrification rate. In our laboratory studies, we found that periphyton with the highest diatom abundance showed the highest denitrification rates as well as a distinct bacterial community composition. These results suggest a synergistic relationship between diatoms and denitrifying bacteria that warrants further study.


Reversal of sign of long spinal reflexes dependent on the phase of the step cycle in the high decerebrate cat.
Reversal of the sign of long ascending and descending spinal reflexes dependent on the phase of the step cycle has been shown in the high decerebrate cat. Electrical stimuli were applied to the skin over the dorsum of the metacarpals and metatarsals and the effects were recorded in the corresponding hindlimb or forelimb of the same side. Stimulation generally evoked an increase in activity of flexor or extensor muscles shortly before, and during, activity of the muscle. Inhibition of a muscle occurred when its activity overlapped with the activity of an antagonist muscle. From the latencies it was concluded that at least the early components of the long reflex responses are due to spinal mechanisms. In the stimulated limb the activity of flexor and extensor muscles was also modulated in a phase dependent manner. No consistent long spinal responses to skin stimulation were obtained in high spinal cats during stepping. Electrical stimulation of cutaneous nerve trunks in decerebrate preparations during stepping gave variable though phase dependent long spinal reflex effects.


Delayed infection with Parvimonas micra following spinal instrumentation.
Delayed-onset surgical site infections following spinal instrumentation are uncommon and often present with chronic pain and implant failure. Anaerobic organisms are rarely implicated and identified with difficulty in these infections. We report a case of vertebral osteomyelitis and epidural abscess due to Parvimonas micra, an anaerobic bacterium, six months following spinal instrumentation. Case Report. P. micra was identified from multiple intraoperative tissue and hardware specimens. With hardware explant and antibiotic therapy, the patient had a successful outcome. To our knowledge, this is the first report of a P. micra hardware-associated spinal infection.


Psychosocial consequences of potential overdiagnosis in prostate cancer a qualitative interview study.
Prostate cancer is a frequently diagnosed cancer and made up 6% of male cancer deaths globally in 2008. Its incidence varies more than 25-fold worldwide, which is primarily attributed to the implementation of the prostate-specific antigen (PSA) test in developed countries. To reduce harm of overdiagnosis, most international guidelines recommend surveillance programmes. However, this approach can entail negative psychosocial consequences from being under surveillance for an (over)diagnosed prostate cancer. To explore men's feelings and experiences in a surveillance programme. Qualitative study with Danish men diagnosed with asymptomatic prostate cancer Gleason score ≤ 6, who are in a surveillance programme. 12 semi-structured, individual interviews were conducted and analysed with systematic text condensation and selected theories. Most informants reported that they were astonished at the time of diagnosis. They were aware of the small likelihood of dying from cancer, but in some cases, the uncertainty created ambivalence between knowing and not knowing. The men expressed their risk awareness in different ways: a realization that life does not last forever, uncertainty towards the future, a feeling of powerlessness, and a need for control. The men in this study had substantial psychosocial consequences from being labelled with a cancer diagnosis. Bearing these men's high risk of overdiagnosis in mind, it is important to discuss whether the harms of this diagnosis outweigh the benefits. The psychosocial consequences of being in a prostate cancer surveillance programme should be explored further. KEY POINTS Current awareness: The number of men living with an asymptomatic prostate cancer has increased the last 20 years after the implementation of the PSA test. Main Statements: Men living with an asymptomatic, low-risk prostate cancer experience negative psychocosial consequences GPs should consider the possible negative psychosocial consequences in their decision-making of measuring the PSA level.


Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans.
The present experiments were designed to compare the understanding of the transcranial electric and magnetic stimulation of the human motorcortex. The spinal volleys evoked by single transcranial magnetic or electric stimulation over the cerebral motor cortex were recorded from a bipolar electrode inserted into the cervical epidural space of two conscious human subjects. These volleys were termed D- and I waves, according to their latency. Magnetic stimulation was performed with a figure-of-eight coil held over the right motor cortex at the optimum scalp position, in order to elicit motor responses in the contralateral FDI using two different orientations over the motor strip. The induced current flowed either in a postero-anterior or in a latero-medial direction. At active motor threshold intensity, the electric anodal stimulation evoked pure D activity. At this intensity, magnetic stimulation with the induced current flowing in a posterior-anterior direction evoked pure I1 activity. When a latero-medial induced current was used, magnetic stimulation evoked both D and I1 activity. Using electric anodal stimulation, at a stimulus intensity of 9% of the stimulator output above the active motor threshold (corresponding approximately to 1.5 active motor threshold), a small I1 wave appeared only in subject 1. Using magnetic stimulation with a posterior-anterior induced current, at a stimulus intensity of 21% of maximum stimulator output above the active motor threshold (corresponding approximately to 1.8 times threshold in subject 1 and to two times threshold in subject 2), a small D wave appeared in subject 1 but not in subject 2. Present results demonstrate that, in conscious humans at threshold intensities, electric stimulation evokes D waves and magnetic stimulation (with a posterior-anterior induced current) evokes I waves, while magnetic stimulation (with a latero-medial induced current) evokes both activities.


Factors that influence induction of gastroesophageal reflux in normal human subjects.
Findings from recent studies indicate that transient relaxation of the lower esophageal sphincter (LES) is an important contributory mechanism to spontaneous episodes of gastroesophageal reflux (GER) in normal subjects as well as in patients with reflux esophagitis. Our study aim was to evaluate the interrelationship between reduction of LES pressure and elevation of intraabdominal pressure in the induction of GER in healthy subjects. Seven volunteers were studied supine after gastric loading with 0.1 N HCl. A pH probe recorded acid GER. Leg raising (LR) or abdominal compression (AC) were used as stress maneuvers to increase intraabdominal pressure, either alone or in combination with stimuli that concurrently lowered LES pressure, namely multiple rapid swallows (RS) or intraesophageal balloon distention (BD). Each individual stimulus and stimulus combination was tested three times, giving a total of 24 test maneuvers per subject. The test maneuvers elicited 2-12 GERs in each subject. The GER incidence for single maneuvers was: AC, 0%; LR, 0%; RS, 19%; and BD, 24%. LR in combination with RS or BD did not increase the incidence of GER above that induced by RS or BD alone. In contrast, AC concurrent with RS and BD increased the incidence of GER to 52% and 81%, respectively. For all test conditions, a prerequisite for the occurrence of GER was a fall in LES pressure to a minimal value of 3 mm Hg or less. GER never occurred when LES pressure was greater than or equal to 4 mm Hg, even during intervals of increased intraabdominal pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Differential clinical features and stool findings in shigellosis and amoebic dysentery.
To obtain information that could assist the clinician to differentiate between shigellosis and amoebic dysentery, we compared clinical features and stool findings in 58 adult male patients in Bangladesh. Mean values indicated that patients with invasive amoebiasis were older and had a longer prehospital illness, a lower body weight, less frequent fever, a lower haematocrit and a higher white blood cell count than patients with shigellosis. The mean number of faecal leucocytes per mm3 was significantly higher in shigellosis than in amoebiasis (28,700 vs 10,300) and correlated with the estimated number of faecal leucocytes per microscopic high power field in a wet mount preparation. Patients with shigellosis more often had over 50 white blood cells per high power field. Although the mean stool pH in amoebiasis was lower than in shigellosis (6.26 vs 6.60), the difference was not statistically significant. Concentrations of stool electrolytes did not differ between the two diseases. These findings indicate that age, duration of illness, the presence of fever and the number of faecal leucocytes may help to differentiate between shigellosis and amoebic dysentery.


"Grumose degeneration" of the dentate nucleus. A light and electron microscopic study in progressive supranuclear palsy and dentatorubropallidoluysial atrophy.
So-called "grumose degeneration" (GD) of the dentate nucleus (DN) which is a unique alteration in progressive supranuclear palsy and dentatorubropallidoluysial atrophy was studied by light and electron microscope. Light microscopically, the presence of a large amount of eosinophilic granular and/or amorphous material around the neurons is the most conspicuous feature of GD. In addition, the number of neurons is decreased and some of them are swollen as with central chromatolysis. Electron microscopically, the granular and/or amorphous material mainly consists of the altered axon terminals of the Purkinje cells (Pax), which are relatively electron-dense and characteristically contain varying numbers of deformed lamellar bodies, highly electron-dense mitochondria and many vacuoles which are adherent to the astrocytic processes. GD is a unique histological change of both the chromatolytic DN neurons and the grumose appearance of the altered Pax. Possible mechanisms are discussed.


Fluorinated Aliphatic Diazirines: Preparation, Characterization, and Model Photolabeling Studies.
The previously unknown difluoromethyl diazirines and the previously neglected trifluoromethyl-aliphatic diazirines were synthesized and characterized. Model photolabeling experiments and biological studies showed that these compounds could indeed be used as photoaffinity labels.


Isolation and structural analysis of rat gastric mucus glycoprotein suggests a homogeneous protein backbone.
We isolated monomeric gastric mucus glycoprotein from the rat stomach by applying three successive CsCl-density-gradient steps in the continuous presence of guanidinium chloride. The rat gastric mucin was pure as compared with mucin isolated without the chaotropic reagent. In addition, the presence of guanidinium chloride resulted in a better preservation of the protein moiety. The purified mucin was fractionated according to buoyant density and chemically radiolabelled on tyrosine or cysteine residues and digested with specific proteinases. Analysis of mucin fractions of various densities gave identical peptide patterns, suggesting that the fractions contain a common protein backbone. Electron-microscopic images of the individual mucin molecules were recorded using rotary shadowing. They showed large filamentous molecules with a mean length of 208 nm that, after proteolytic digestion, yielded glycopeptides with a mean length of 149 nm. Heterogeneity in buoyant density and electrophoretic mobility is located in this large glycopeptide which remains after proteolytic digestion. Metabolic labelling of the mucin with [35 S]sulphate and [3H]galactose, followed by purification and proteolytic digestion, revealed that this glycopeptide accounts for most of the mass and contains relatively little protein, but probably all the oligosaccharides and sulphate. As this protein part is masked by the oligosaccharides, detailed study by the methods described was not possible. The results indicate that rat gastric mucin is homogeneous in a major part of the protein backbone and that the heterogeneity of the molecule originates most likely from differences in sulphate and/or sugar composition.


ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis.
The ARF and p53 tumor suppressors are thought to act in a linear pathway to prevent cellular transformation in response to various oncogenic signals. Here, we show that loss of p53 leads to an increase in ARF protein levels, which function to limit the proliferation and tumorigenicity of p53-deficient cells by inhibiting an IFN-β-STAT1-ISG15 signaling axis. Human triple-negative breast cancer (TNBC) tumor samples with coinactivation of p53 and ARF exhibit high expression of both STAT1 and ISG15, and TNBC cell lines are sensitive to STAT1 depletion. We propose that loss of p53 function and subsequent ARF induction creates a selective pressure to inactivate ARF and propose that tumors harboring coinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation.


Time dependence of response of transplanted mouse mammary tumors to single or split radiation doses.
The effect of single and different split radiation doses with varying rates and time intervals was investigated in an experimental system in vivo using second generation isotransplants of two mouse mammary carcinomas. The changes in the growth delay time (GDT) and tumor control rate (TCR) were analyzed, and explained by a dose dependence of the repair of sublethal radiation damage, reoxygenation and cellular repopulation in the tumors. A direct relationship was found between the size of the first of two dose fractions and the time interval between two exposures at which treatment with split doses is most effective in delaying or preventing tumor growth. Multiple exposures to unequal dose fractions are more effective than to equal fractions with the same total dose.


Large-scale analysis of cell cycle regulators in urothelial bladder cancer identifies p16 and p27 as potentially useful prognostic markers.
We investigated the value of multiple cell cycle markers for their prognostic impact on overall survival and recurrence-free survival in urothelial carcinoma (UC). A tissue microarray consisting of 99 UCs was evaluated for the expression of p53, p16, p21, p27, cyclin D1, cyclin E , Bcl-2, Ki-67 and PCNA. Statistical analysis was performed applying Kaplan-Meier and Cox regression models using receiver operator characteristic curves for determination of markers' cutoffs. Expression above the cutoffs of Ki-67, p53 and p27, particularly in high-grade and early-stage UC, was associated with worse overall survival, while expression of p16 indicated a better outcome in low-grade and low-stage tumors. Recurrence-free survival was better in patients with high-grade UC expressing PCNA, p16 and cyclin E, and low-grade UC expressing Bcl-2 above the cutoffs, but worse in all tumors with high Ki-67. Cell cycle deregulation in UC is complex and the prognostic value of the various involved proteins should be differentially regarded with respect to this complexity and other tumor characteristics such as grade and stage. Our results point towards the role of p16- and p27-associated pathways in tumor progression and indicate that, by using standardized approaches for tissue antigen expression, evaluation and cutoff determination, single potentially useful prognostic markers could be identified.


Identifying vulnerable populations to death and injuries from residential fires.
This study proposes and evaluates the theory that people who are susceptible to injury in residential fires are not susceptible to death in residential fires and vice versa. It is proposed that the population vulnerable to death in residential fires can be proxied by 'frailty', which is measured as age-gender adjusted fatality rates due to natural causes. This study uses an ecological approach and controls for exposure to estimate the vulnerability of different population groups to death and injury in residential fires. It allows fatalities and injuries to be estimated by different models. Frailty explains fire-related death in adults while not explaining injuries, which is consistent with the idea that deaths and injuries affect disjoint populations. Deaths and injuries in fire are drawn from different populations. People who are susceptible to dying in fires are unlikely to be injured in fires, and the people who are susceptible to injury are unlikely to die in fires.


Efficacy and safety of nonpreserved ketorolac ophthalmic solution in postoperative ocular pain following radial keratotomy.
To investigate the efficacy and safety of nonpreserved ketorolac tromethamine 0.5% ophthalmic solution in relieving pain following radial keratotomy (RK). Multicenter clinical trial. Topical ketorolac was compared with its vehicle in a double-masked, randomized, parallel-group study involving 170 RK patients. Patients were treated with nonpreserved ketorolac 0.5% ophthalmic solution or the vehicle 4 times daily beginning immediately after surgery and continuing for 3 days or until they no longer had ocular pain. At several intervals, patients treated with ketorolac reported significantly greater pain relief and less pain intensity than patients treated with the vehicle. The time required for patients to first report "complete relief" or "no pain" was shorter in the ketorolac than in the vehicle group (P < or = .006). Patients in the ketorolac group used less escape medication (acetaminophen) (P < or = .001) and had fewer sleep difficulties (P < or = .031), fewer symptoms of ocular discomfort (P < or = .028), and less difficulty performing activities of daily living (P = .048). Patients treated with ketorolac experienced the same low rate of treatment-related adverse events as those treated with the vehicle and exhibited the same improvement in visual acuity and manifest refraction. Nonpreserved ketorolac tromethamine 0.5% ophthalmic solution was significantly more effective than, and as safe as, the vehicle in alleviating the postoperative pain associated with RK. This resulted in significant improvements in patient quality of life and less need for oral analgesics, suggesting that topical ketorolac is an appropriate treatment option for ocular pain following RK.


Penetration of resin-based materials into initial erosion lesion: A confocal microscopic study.
The application of resin-based materials is an alternative of treatment for eroded lesions. Nevertheless, there are no studies about the penetration of these materials into eroded lesion, which might affect its adhesion. Therefore, this study evaluated the penetration of four resin-based materials, with and without enamel etching. By using an in vitro protocol, types of treatment were studied at five levels (AdheSE(®) , Tetric N-Bond(®) , Single Bond 2(®) , Helioseal Clear(®) , Icon(®) ) and types of enamel etching in two levels (with and without). Materials were stained with 0.02 mg/mL ethanolic solution of tetramethylrhodamine isothiocyanate. Bovine enamel samples (4 × 4 mm) were immersed in 0.01 M HCl, pH 2.3, for 30 seconds to produce initial eroded lesions. Afterward, the materials were applied on half of sample enamel surface following the manufacturer's instructions. On the other half of sample, the materials were applied without etching the enamel. Materials penetration into the enamel was assessed by Confocal Laser Scanning Microscopy on reflection and fluorescence modes. The penetration depth (PD) was measured using ImageJ software. Data were analyzed by two-way ANOVA and Tukey test (P < 0.05). Regardless of the material, etched enamel resulted in higher PD than non-etched (P < 0.05). Icon(®) showed the highest PD in enamel followed by Helioseal Clear(®) (P < 0.05), with significant difference between them (P < 0.05) and no difference was found among AdheSE(®) , Tetric N-Bond(®) , and Single Bond 2(®) (P > 0.05). It can be concluded that prior enamel etching increased the materials penetration into eroded enamel and the Icon(®) -infiltrant presented highest penetration.


Selegiline in Parkinson's disease.
Twenty patients with Parkinson's disease were treated with the MAO-B inhibitor selegiline (l-deprenyl) and placebo without levodopa (L-dopa) in a randomized double-blind clinical cross-over study to analyze relative importances of dopamine (DA) synthesis and metabolism. The daily dose of selegiline was gradually increased to a maximum of 30 mg in all patients. The clinical neurological disability (Columbia score) was about 10% less on selegiline (30 mg/day) than on placebo. This difference was neither statistically nor clinically significant. The results are compatible with the possibility that treatment with selegiline without concomitant L-dopa does not significantly increase DA concentration which remains low and is determined mainly by tyrosine hydroxylase activity. At low DA levels the DA re-uptake mechanism recaptures most of the released DA and DA deamination is of minor significance. The pathway of DA oxidation becomes more important only at higher DA concentrations, accomplished by bypassing the rate limiting step of tyrosine hydroxylation using L-dopa.


Novel electrochemical DNA hybridization biosensors for selective determination of silver ions.
In this work, novel electrochemical biosensors for Ag(+) determination based on Ag(+)-induced DNA hybridization, using Ethyl green (EG) as an electroactive label on the surface of bare carbon paste electrode (CPE) and gold nanoparticles-modified carbon paste electrode (GN-CPE) are reported. Two single-strand poly-C (100% cytosine bases) DNAs are used as oligonucleotide probe and target. In the presence of Ag(+), the target DNA with full cytosine-cytosine (C-C) mismatches could hybridize with the probe DNA by forming C-Ag(+)-C complex. The induced hybridization of the two oligonucleotides leads to the decrease in the reduction peak currents of EG, which could be used for electrochemical determination of Ag(+). This difference in the values of the reduction peak current of EG before and after DNA hybridization (∆I) was linear with the concentration of Ag(+) in the ranges from 3.0×10(-10) to 1.0×10(-9) mol L(-1) and 9.0×10(-11) to 1.0×10(-9) mol L(-1), for the biosensor and nanoparticles modified-biosensor, respectively. Calculated detection limits were 1.04×10(-10) and 2.64×10(-11) mol L(-1) for biosensor and nanoparticles modified-biosensor, respectively. The biosensors demonstrated good selectivity towards Ag(+) ions in the presence of some metal ions such as Pb(2+), Cu(2+), Ca(2+), Zn(2+), Fe(2+) and Hg(2+). The proposed biosensors were applied successfully to the voltammetric determination of Ag(+) in real samples.


The Bone Microenvironment Soil in Prostate Cancer Metastasis: An miRNA Approach.
Bone metastatic prostate cancer (PCa) is associated with a high risk of mortality. Changes in the expression pattern of miRNAs seem to be related to early aspects of prostate cancer, as well as its establishment and proliferation, including the necessary steps for metastasis. Here we compiled, for the first time, the important roles of miRNAs in the development, diagnosis, and treatment of bone metastasis, focusing on recent in vivo and in vitro studies. PCa exosomes are proven to promote metastasis-related events, such as osteoblast and osteoclast differentiation and proliferation. Aberrant miRNA expression in PCa may induce abnormal bone remodeling and support tumor development. Furthermore, miRNAs are capable of binding to multiple mRNA targets, a dynamic property that can be harnessed for the development of treatment tools, such as antagomiRs and miRNA mimics, which have emerged as promising candidates in PCa treatment. Finally, miRNAs may serve as noninvasive biomarkers, as they can be detected in tissue and bodily fluids, are highly stable, and show differential expression between nonmetastatic PCa and bone metastatic samples. Taken together, the findings underscore the importance of miRNA expression profiles and miRNA-based tools as rational technologies to increase the quality of life and longevity of patients.


Diffuse mesenteric amyloidosis: CT, sonographic, and pathologic findings.
We report an unusual case of diffuse infiltration of the mesentery by amyloidosis. The CT, sonographic, and operative findings mimicked abdominal carcinomatosis.


Weak localization and time reversal of ultrasound in a rotational flow.
A one-channel time-reversal (TR) experiment is performed inside a rough reverberating cavity in the presence of a rotational flow. The amplitude of the TR wave is plotted versus the distance between the TR channel and the initial source: when they coincide, it exhibits a "time-reversal enhancement" (TRE). With no flow, the TRE is the same as the coherent backscattering enhancement (CBE). But contrary to CBE, the TRE peak is shown to be insensitive to the breaking down of reciprocity due to the flow. This new effect of weak localization is sustained by a diagrammatic approach.


A Bayesian approach to the evaluation of comparisons of individually value-assigned reference materials.
Several recent international comparison studies used a relatively novel experimental design to evaluate the measurement capabilities of participating organizations. These studies compared the values assigned by each participant to one or more qualitatively similar materials with measurements made on all of the materials by one laboratory under repeatability conditions. A statistical model was then established relating the values to the repeatability measurements; the extent of agreement between the assigned value(s) and the consensus model reflected the participants' measurement capabilities. Since each participant used their own supplies, equipment, and methods to produce and value-assign their material(s), the agreement between the assigned value(s) and the model was a fairer reflection of their intrinsic capabilities than provided by studies that directly compared time- and material-constrained measurements on unknown samples prepared elsewhere. A new statistical procedure is presented for the analysis of such data. The procedure incorporates several novel concepts, most importantly a leave-one-out strategy for the estimation of the consensus value of the measurand, model fitting via Bayesian posterior probabilities, and posterior coverage probability calculation for the assigned 95% uncertainty intervals. The benefits of the new procedure are illustrated using data from the CCQM-K54 comparison of eight cylinders of n-hexane in methane.


Practical strategies for becoming a successful medical book author.
The authors, all senior editors in the Books Division of American Psychiatric Publishing, Inc., provide practical advice to authors who may be considering writing or editing a medical book. The authors summarize strategies for developing a book proposal and outline an approach to developing a focus for a book. They also list a number of common errors that authors frequently make when they develop a book proposal. The authors provide guidance on publishing research and discuss how authors can collaborate with a publisher's marketing department to publicize their book. By employing a systematic and well-considered approach to preparing a book proposal and writing or editing a book, authors may achieve professional success and personal satisfaction. Writing or editing a medical book requires a different series of steps than authoring a journal article.


A case of Creutzfeldt-Jacob disease with bilateral vocal fold abductor paralysis.
Bilateral vocal fold abductor paralysis was seen in a patient with Creutzfeldt-Jacob disease. After tracheotomy, the patient showed disappearance of reduced oxygen saturation with high-pitched inspiratory stridor and pulling phenomenon of the supraclavicular region and larynx. Electromyographic examinations of the intrinsic laryngeal muscles, including the thyroarytenoid and posterior cricoarytenoid muscles, demonstrated that there was no apparent action potential in those muscles during spontaneous respiratory movements, and there was no abnormal potential for those muscles at rest. By pushing the infrasternal region of the patient on the expiration, normal motor unit action potential could be seen in the posterior cricoarytenoid muscle on the next inspiration. Based on those findings, we concluded that bilateral vocal fold abductor paralysis in this case of Creutzfeldt-Jacob disease was not induced by disorders of the degeneration of motor nucleus in the ambiguus as in multiple system atrophy, but by a disorder of the upper motor neuron.


Child Development During the COVID-19 Pandemic Through a Life Course Theory Lens.
The COVID-19 global pandemic and the resulting economic, health, and educational disruptions have upset all aspects of young people's lives. The pandemic's reach will likely continue in the near term and as psychological and academic trajectories unfold over time. In this article, we draw on the central tenets of life course theory-intertwined developmental trajectories, linked lives, and stratification systems (Elder, 1998)-to inform understanding of potential adverse effects of the COVID-19 pandemic on children's and adolescents' adjustment and well-being, as well as mechanisms and processes that may buffer or exacerbate the pandemic's negative impact. We review empirical evidence on the impact of previous macro-level crises (e.g., the Great Recession) to illustrate how life course theory can aid developmental scientists in examining the effects of COVID-19 on children's development. We conclude with recommendations for research.


Imaging of HSV-tk Reporter gene expression: comparison between [18F]FEAU, [18F]FFEAU, and other imaging probes.
Herpes virus type 1 thymidine kinase (HSV1-tk) and the mutant HSV1-sr39tk are the 2 most widely used "reporter genes" for radiotracer-based imaging. Two pyrimidine nucleoside analogs, [18F]FEAU (1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-ethyluridine) and [18F]FFEAU (1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-(2-fluoroethyl)uridine), have generated recent interest as potential new probes for imaging HSV1-tk and HSV1-sr39tk gene expression. We compared [18F]FEAU and [18F]FFEAU with a series of other pyrimidine nucleoside derivatives (including 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-iodouridine [FIAU]) and with acycloguanosine analogs using a stable HSV1-tk transduced cell line (RG2TK+) and wild-type RG2 cells. The in vitro accumulation data and the calculated and normalized clearance constant, nKi, as well as sensitivity and selectivity indices indicated that 2 pyrimidine nucleoside probes, [18F]FEAU and [18F]FFEAU, had the best uptake characteristics. These probes were selected for further dynamic PET studies in nude rats bearing subcutaneous RG2TK+ and RG2 tumors. The 2-h postinjection [18F]FEAU uptake levels were 3.3% +/- 1.0% and 0.28% +/- 0.07% dose/cm3 in subcutaneous RG2TK+ and RG2 tumors, respectively, and 2.3% +/- 0.2% and 0.19% +/- 0.01% dose/cm3, respectively, for [18F]FFEAU. The corresponding RG2TK+/RG2 uptake ratios were 11.5 +/- 1.5 and 12.2 +/- 1.4, respectively. The inherent problem of comparing different radiolabeled pyrimidine nucleoside and guanosine-based probes for imaging HSV1-tk expression using different transduced cell lines and assay systems in the absence of an independent thymidine kinase-enzyme assay is discussed. For HSV1-tk reporter systems that require a 1- to 4-h PET paradigm, HSV1-tk-[18F]FEAU is the current top contender.


Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio.
The aim of this study was to examine whether the cytosolic NADPH/NADP+ ratio of beta cells serves as an amplifying signal in fuel-induced insulin secretion and whether such a function is mediated by cytosolic alpha-ketoglutarate. Pancreatic islets and islet cells were isolated from albino mice by collagenase digestion. Insulin secretion of incubated or perifused islets was measured by ELISA. The NADPH and NADP+ content of incubated islets was determined by enzymatic cycling. The cytosolic Ca2+ concentration ([Ca2+]c) in islets was measured by microfluorimetry and the activity of ATP-sensitive K+ channels in islet cells by patch-clamping. Both 30 mmol/l glucose and 10 mmol/l alpha-ketoisocaproate stimulated insulin secretion and elevated the NADPH/NADP+ ratio of islets preincubated in the absence of fuel. The increase in the NADPH/NADP+ ratio was abolished in the presence of 2.7 micromol/l glipizide (closing all ATP-sensitive K+ channels). However, alpha-ketoisocaproate, but not glucose, still stimulated insulin secretion. That glipizide did not inhibit alpha-ketoisocaproate-induced insulin secretion was not the result of elevated [Ca2+]c, as glucose caused a more marked [Ca2+]c increase. Insulin release triggered by glipizide alone was moderately amplified by dimethyl alpha-ketoglutarate (which is cleaved to produce cytosolic alpha-ketoglutarate), but there was no indication of a signal function of cytosolic alpha-ketoglutarate. The results strongly suggest that the NADPH/NADP+ ratio in the beta cell cytosol does not serve as an amplifying signal in fuel-induced insulin release. The study supports the view that amplification results from the intramitochondrial production of citrate by citrate synthase and from the associated export of citrate into the cytosol.


Microarray analysis of differentially expressed genes engaged in fruit development between table and wine grape.
Microarray analysis of genes can provide individual gene-expression profiles and new insights for elucidating biological mechanisms responsible for fruit development. To obtain an overall view on expression profiles of metabolism-related genes involved in fruit development of table and wine grapes, a microarray system comprising 15,403 ESTs was used to compare the expressed genes. The expression patterns from the microarray analysis were validated with quantitative real-time polymerase chain reaction analysis of 18 selected genes of interest. During the entire fruit development stage, 2,493 genes exhibited at least 2.0-fold differences in expression levels with 1,244 genes being up-regulated and 1,249 being down-regulated. Following gene ontology analysis, only 929 differentially expressed (including 403 up-regulated and 526 down-regulated) genes were annotated in table and wine grapes. These differentially expressed genes were found to be mainly involved in carbohydrate metabolism, biosynthesis of secondary metabolites as well as energy, lipid and amino acid metabolism via KEGG. Our results provide new insights into the molecular mechanisms and expression profiles of genes in the fruit development stage of table and wine grapes.


Design, synthesis, and evaluation of novelly substituted benzimidazole compounds as angiotensin II receptor antagonists.
5-Nitrobenzimidazole derivatives with varying substituents at 2-position have been designed, synthesized, and evaluated for angiotensin II antagonistic activity. A drug-receptor interaction model has been proposed.


Biodegradation of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) by Phanerochaete chrysosporium in the presence of Cd2.
Aerobic biodegradation of 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47) by Phanerochaete chrysosporium in the presence of Cd2+ was investigated in this study. The results showed that P. chrysosporium could effectively degrade BDE-47, and its extracellular enzyme played an important role in the process of decomposition. BDE-47 biodegradation by fungi was more tolerant than extracellular enzyme in the presence of Cd2+. Also, both of the activity of two typical enzymes, MnP and LiP, descended with ascended Cd2+ concentration. Based on the four mono-hydroxylated PBDEs (5-OH-BDE-47, 4'-OH-BDE-17, 6-OH-BDE-47, and 2'-OH-BDE-28) and two bromophenols (2,4-DBP, 4-BP) detected, three possible degradation pathways were proposed, inferring that BDE-47 was more easily to transform via hydroxylation. With addition of Cd2+, the types of degradation products did not change, merely a variation of the content of these products observed. Meanwhile, the major metabolites of BDE-47, bromophenol compounds, have been found to be transformed or even mineralized by P. chrysosporium quickly, which also helped better explain why the amounts of BDE-47 decomposed did not match with that of the metabolites detected.


Docking sites inside Cas9 for adenine base editing diversification and RNA off-target elimination.
Base editing tools with diversified editing scopes and minimized RNA off-target activities are required for broad applications. Nevertheless, current Streptococcus pyogenes Cas9 (SpCas9)-based adenine base editors (ABEs) with minimized RNA off-target activities display constrained editing scopes with efficient editing activities at positions 4-8. Here, functional ABE variants with diversified editing scopes and reduced RNA off-target activities are identified using domain insertion profiling inside SpCas9 and with different combinations of TadA variants. Engineered ABE variants in this study display narrowed, expanded or shifted editing scopes with efficient editing activities across protospacer positions 2-16. And when combined with deaminase engineering, the RNA off-target activities of engineered ABE variants are further minimized. Thus, domain insertion profiling provides a framework to improve and expand ABE toolkits, and its combination with other strategies for ABE engineering deserves comprehensive explorations in the future.


Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators.
Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients. We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA. Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses. Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.


A demonstration of the resolution of NMR imaging in biological systems.
A proton NMR imaging study of several fruit specimens demonstrates the integrity and resolution of this new imaging method.


Sophorolipid modification enables high reactivity and electron selectivity of nanoscale zerovalent iron toward hexavalent chromium.
Nanoscale zero-valent iron is considered to be a promising nanostructure for environmental remediation, while increasing the electron selectivity of nanoscale zerovalent iron (nZVI) during target contaminant removal is still a challenge (electron selectivity, defined as the percentage of electrons transferred to the target contaminants over the number of electrons donated by nZVI). In this study, the strategy for increasing the reactivity and electron selectivity of nZVI via sophorolipid (SL-nZVI) modification was proposed. The results showed that the removal efficiency and electron selectivity of SL-nZVI toward Cr(VI) was 99.99% and 56.30%, which was higher than that of nZVI (61.16%, 25.91%). Meanwhile, the particles were well characterized and the mechanism for enhanced reactivity and electron selectivity was investigated. Specially, both the morphology and BET specific surface area characterization suggested that stability against aggregation was higher in SL-nZVI nanoparticles than in nZVI. Besides, X-ray photoelectron spectroscopy (XPS), Tafel polarization curves, and Electrochemical impedance spectroscopy also indicated that the introduction of sophorolipid successfully prevent the nanoparticles from oxidation and benefit the electron transferring. In addition, a water contact angle test revealed that SL-nZVI nanoparticles were less hydrophilic (contact angle = 34.8°) than nZVI (contact angle = 23.9°). Therefore, in terms of reactivity, sophorolipid modification inhibited the aggregation of the nanoparticles and enhanced the electrical conductivity. For electron selectivity, the introduction of sophorolipid not only benefited Cr(VI) adsorption and the electron transfer from Fe0 to the surface-adsorbed Cr(VI) that followed but also reduced the possibility of side reactions between Fe0 and H2O. This study demonstrates that the introduction of sophorolipid is an effective strategy for developing a highly efficient nZVI-based nanocomposite system and highlights the potential role of sophorolipid in improving the electron selectivity of nZVI.


Brucella suis strain 2 vaccine is safe and protective against heterologous Brucella spp. infections.
Brucellosis is a wide spread zoonotic disease that causes abortion and infertility in mammals and leads to debilitating, febrile illness in humans. Brucella abortus, Brucella melitensis and Brucella suis are the major pathogenic species to humans. Vaccination with live attenuated B. suis strain 2 (S2) vaccine is an essential and critical component in the control of brucellosis in China. The S2 vaccine is very effective in preventing brucellosis in goats, sheep, cattle and swine. However, there are still debates outside of China whether the S2 vaccine is able to provide protection against heterologous virulent Brucella species. We investigated the residual virulence, immunogenicity and protective efficacy of the S2 vaccine in BALB/c mice by determining bacteria persistence in spleen, serum antibody response, cellular immune response and protection against a heterologous virulent challenge. The S2 vaccine was of low virulence as there were no bacteria recovered in spleen four weeks post vaccination. The vaccinated mice developed Brucella-specific IgG in 2-3 weeks, and a burst production of IFN-γ at one week as well as a two-fold increase in TNF-α production. The S2 vaccine protected mice from a virulent challenge by B. melitensis M28, B. abortus 2308 and B. suis S1330, and the S2 vaccinated mice did not develop any clinical signs or tissue damage. Our study demonstrated that the S2 vaccine is of low virulence, stimulates good humoral and cellular immunity and protects animals against infection by heterologous, virulent Brucella species.


Membrane specific carbonic anhydrase (CAIV) expression in human tissues.
Membrane-bound carbonic anhydrase IV (CAIV) expression has been evaluated in a range of fetal and adult human tissues and in cell culture. All tissues tested showed expression of CAIV, assessed by Western blotting, with a single immunodetected band at 55 kDa. The levels varied in fetal lung and liver during development and in various zones of the fetal brain. CAIV was clearly expressed in lung, pancreatic tumour and skin cell cultures.


The usefulness of microsurgical pedicle lengthening in free anterolateral thigh flaps.
A microsurgical pedicle-lengthening technique can be used when a pedicle length longer than that usually provided by an anterolateral thigh (ALT) flap is required. The purpose of this report is description of pedicle lengthening method from original pedicle length for free ALT flaps and presentation of the results of application of this technique in reconstruction from a series of cases. The microsurgical pedicle-lengthening procedure was used in 10 patients who received free ALT flaps from January 2012 to June 2015. The location of reconstruction was the heel in 3 patients, foot in 3 patients, flank in 2 patients, forehead in 1 patient, and lower leg in 1 patient. The technique was categorized as two distinct 2 types according to the branching pattern of the perforator. The transected segments of the extra vessel lengths were translocated anterogradely, and used to perform pedicle extensions. The average length of the original pedicle was 13.1 cm (range 10.1-16.4 cm), and the average gain in length using the pedicle-lengthening method was 6.5 cm (range 5.0-8.1 cm). All the flaps survived well postoperatively. Of the 10 patients, three experienced complications that included partial flap necrosis in one patient, wound dehiscence in one patient, and seroma in the third patient. No major complications occurred. The microsurgical pedicle-lengthening technique described here offers a solution for pedicles that are shorter than expected, with additional surgery required. This method may help overcome emergency situations that can arise during ALT flap surgery. © 2016 Wiley Periodicals, Inc. Microsurgery 36:559-566, 2016.


Transcriptome analysis of blastoderms exposed to prolonged egg storage and short periods of incubation during egg storage.
Cool temperature egg storage prior to incubation is a common practice in the broiler industry; however, prolonged egg storage causes increased embryonic mortality and decreased hatchability and growth in surviving chicks. Exposing eggs to short periods of incubation during egg storage (SPIDES) reduces the adverse consequences of prolonged storage. SPIDES increases blastodermal cell viability by reducing apoptosis, though the counteracting mechanisms are unclear. To define the impact of prolonged storage and SPIDES, transcriptome analysis compared gene expression from blastoderms isolated from eggs exposed to the following treatments: control (CR, stored at 17 °C for 4 days), prolonged storage (NSR, stored at 17 °C for 21 days), SPIDES (SR, stored at 17 °C for 21 days with SPIDES), and incubated control (C2, stored at 17 °C for 4 days followed by incubation to HH (Hamburger-Hamilton) stage 2, used as the ideal standard development) (n = 3/group). Data analysis was performed using the CLC Genomics Workbench platform. Functional annotation was performed using DAVID and QIAGEN Ingenuity Pathway Analysis. In total, 4726 DEGs (differentially expressed genes) were identified across all experimental group comparisons (q < 0.05, FPKM> 20, |fold change| > 1.5). DEGs common across experimental comparisons were involved in cellular homeostasis and cytoskeletal protein binding. The NSR group exhibited activation of ubiquitination, apoptotic, and cell senescence processes. The SR group showed activation of cell viability, division, and metabolic processes. Through comparison analysis, cellular respiration, tRNA charging, cell cycle control, and HMBG1 signaling pathways were significantly impacted by treatment and potential regulatory roles for ribosomal protein L23a (RPL23A) and MYC proto-oncogene, BHLH transcription factor (MYC) were identified. Prolonged egg storage (NSR) resulted in enriched cell stress and death pathways; while SPIDES (SR) resulted in enriched basic cell and anti-apoptotic pathways. New insights into DNA repair mechanisms, RNA processing, shifts in metabolism, and chromatin dynamics in relation to egg storage treatment were obtained through this study. Although egg storage protocols have been examined through targeted gene expression approaches, this study provided a global view of the extensive molecular networks affected by prolonged storage and SPIDES and helped to identify potential upstream regulators for future experiments to optimize egg storage parameters.


Parathyroid carcinoma presenting as normocalcemic hyperparathyroidism.
Parathyroid carcinoma (PC) is a rare malignancy, with an indolent but progressive course. Long-term survival is largely dependent on the extent of the primary surgical resection. Hence, pre- or intraoperative suspicion of malignancy is of great importance. We describe the case of a 62-year-old woman with a 2-year history of asthenia and mental depression. Her past medical history was significant for osteoporosis. A diagnosis of primary normocalcemic hyperparathyroidism was established and the patient underwent surgery. PC was suspected intraoperatively because of the size and appearance of the parathyroid mass (a grayish, lobulated 3.5 cm mass). Thus, aggressive surgery (en bloc resection) was performed, along with bilateral neck exploration. Pathological examination of the specimens confirmed the suspicion of PC, demonstrating vascular invasion and extracapsular infiltration into adjacent soft tissue. Immunohistochemical staining revealed an elevated Ki-67 score (8.43%; cut-off value 5%). The mean area of silver-stained nucleolar organizer regions (AgNOR) was high (4.972 μm(2)), indicating an elevated proliferation rate. Serum calcium and parathyroid hormone levels normalized postoperatively, and the patient's 5-year outcome was good. The present case provides evidence that parathyroid malignancy cannot be excluded a priori based on normocalcemic hyperparathyroidism, emphasizing the variability in clinical presentation. Moreover, Ki-67 expression and AgNOR analysis confirmed their additional value in complementing the histological evaluation of a parathyroid malignant mass.


Discovery of novel antibody-drug conjugates bearing tissue protease specific linker with both anti-angiogenic and strong cytotoxic effects.
Bevacizumab is an FDA-approved class of monoclonal antibodies used to inhibit angiogenesis and promote normalization of blood vessels. It is usually combined with chemotherapeutic agents to treat a variety of solid tumors. However, the whole-body toxicities and toxicity associated with chemotherapy greatly limit the clinical use of this combination therapy. Antibody-drug conjugates (ADCs) couple monoclonal antibodies to cytotoxic molecules via a linker, utilizing the high specificity of monoclonal antibodies to tumor surface antigens to act as a "biological missile" to deliver chemotherapeutic drugs to the tumor site. Herein, we designed a bevacizumab-based ADC, Bevacizumab Vedotin, conjugating bevacizumab to the microtubulin inhibitor MMAE via a tissue protease-specific linker. Biological studies showed strong stability and good tumor cell targeting of our constructed ADCs; rapid drug release was achieved in the presence of exogenous histone protease B. In addition, Bevacizumab Vedotin exhibited good anti-proliferative, apoptosis-promoting and cell cycle-stalling effects on glioma (U87), hepatocellular carcinoma (HepG2), and breast cancer (MCF-7) cell lines. Further in vitro assays demonstrated the enhanced anti-migration activity against MCF-7, potent anti-angiogenic effects, and blockade of the VEGF/VEGFR pathway of Bevacizumab Vedotin.


Detection of beta-catenin mutations in paraffin-embedded sporadic desmoid-type fibromatosis by mutation-specific restriction enzyme digestion (MSRED): an ancillary diagnostic tool.
Desmoid-type fibromatosis is a locally aggressive deep soft tissue tumor. Some cases are associated with adenosis polyposis coli germline mutations whereas others harbor somatic beta-catenin point mutations mainly in exon 3, codons 41 and 45. These mutations result in stabilization of beta-catenin, and activation of the Wnt signaling pathway. The aim of this study was to determine the specificity and sensitivity of these 3 most common beta-catenin mutations in the diagnosis of desmoid-type fibromatosis using paraffin-embedded material. The results were compared with nuclear expression of beta-catenin. Mutation-specific restriction enzyme digestion methodology was employed to detect the 3 mutations. One hundred and thirty-three cases were analyzed, including 76 desmoid-type, and 18 superficial fibromatosis, in addition to a further 39 fibromatosis mimics. A restriction site was present for analysis of the codon 41 mutation. Mismatch primers were designed for the codon 45 mutations. Mutations were detected in 66 cases (87%) of 76 desmoid-type fibromatosis (71 extra-abdominal). Of these, 34 (45%) were in codon 45 (TCT>TTT), 27 (35%) in codon 41 (ACC>GCC), and 5 (7%) in codon 45 (TCT>CCT). No mutations were detected in the other lesions studied. All desmoid-type fibromatosis cases and 72% of the mimics tested showed nuclear positivity for beta-catenin indicating immunohistochemistry is a sensitive but not a specific test for desmoid-type fibromatosis. In contrast, to date, beta-catenin mutations have not been detected in any lesions which mimic desmoid-type fibromatosis. Mutation-specific restriction enzyme digestion, a simple and efficient means of detecting the common beta-catenin mutations in desmoid-type fibromatosis, complements light microscopy in reaching a diagnosis.


In vitro comparison of the radiopacity of cavity lining materials with human dental structures.
To compare the optical densities (OD) of calcium hydroxide (CH) and glass ionomer cement with the same thicknesses of the dental structures. Eighteen specimens of each material, with thicknesses of 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 mm were made in a Teflon matrix. To compare the radiopacity of the materials with the dental structures, dental cuts of the first molars, increasing in thickness from 0.5 to 3.0 mm, were obtained. To standardize the radiographs, a transparent acrylic matrix (Standardizing Device) was developed and used. Thirty radiographs were taken, five for each tested material. Statistical analysis (Two-way ANOVA - Bonferroni, P < 0.05) demonstrated that when the materials were compared, there was statistically significant difference between the ODs, only for the thickness of 1.0 mm (P < 0.05). The thickness of the material contributed to its radiopacity, and these materials had to be used in a thickness between 1.5 and 2.0 mm.


Safety of biologics: elaboration and validation of a questionnaire assessing patients' self-care safety skills: the BioSecure questionnaire. An initiative of the French Rheumatology Society Therapeutic Education section.
Biologics are known to entail specific risks (e.g. infections). Patients should possess self-care safety skills to develop appropriate behaviors in situations of risks (e.g. fever). To date, there is no adequate tool to assess these skills. To elaborate a questionnaire to measure knowledge and skills regarding safety issues, for patients treated by biologics. Three-step process. (1) A steering group of 10 rheumatologists, one pharmacist and two allied health professionals elaborated an exhaustive list of safety skills. Through a 3-round Delphi process involving the steering group, 14 patients on biologics and 14 other allied health professionals, the list of skills was reduced. (2) A corresponding series of questions and of clinical situations with multiple-choice answers were designed. (3) Preliminary validation was performed against the physician's opinion on skills, and reliability was assessed. The list includes 24 skills e.g. how to deal with fever, planned surgery, dental care, travel, minor traumas, and immunizations. A 55-question questionnaire was constructed. Preliminary validation (62 patients) showed the questionnaire was filled in 10 minutes (median) and correlated to the physician's opinion of skills (R=0.47, P<0.0001) but not to disease status or disease duration. The median score was 75% (range 20%-96%). The questionnaire was reliable: intraclass correlation coefficient, 0.83 (95% CI: 0.63-0.93). A simple (multiple-choice questionnaire) and valid tool investigating a core set of safety skills has been developed. This tool could be useful to detect further educational needs regarding biologics safety, and to assess the efficacy of oriented educational interventions.


EEG-based BCI Dataset of Semantic Concepts for Imagination and Perception Tasks.
Electroencephalography (EEG) is a widely-used neuroimaging technique in Brain Computer Interfaces (BCIs) due to its non-invasive nature, accessibility and high temporal resolution. A range of input representations has been explored for BCIs. The same semantic meaning can be conveyed in different representations, such as visual (orthographic and pictorial) and auditory (spoken words). These stimuli representations can be either imagined or perceived by the BCI user. In particular, there is a scarcity of existing open source EEG datasets for imagined visual content, and to our knowledge there are no open source EEG datasets for semantics captured through multiple sensory modalities for both perceived and imagined content. Here we present an open source multisensory imagination and perception dataset, with twelve participants, acquired with a 124 EEG channel system. The aim is for the dataset to be open for purposes such as BCI related decoding and for better understanding the neural mechanisms behind perception, imagination and across the sensory modalities when the semantic category is held constant.


The histopathology of experimental spinal cord trauma. The effect of systemic blood pressure.
The early sequential histopathological alterations following a concussive paraplegic injury to the posterior thoracic spinal cord in cats were studied. The lack of significant progression of hemorrhages over a 4-hour period after injury indicates that most hemorrhages probably occur within the first hour. The marked enhancement or retardation of hemorrhages in the post-injury period, when the blood pressure was increased or decreased, respectively, demonstrates the loss of autoregulation of spinal cord vasculature at the trauma site after a concussive paraplegic injury. Progressive edema formation was evident over a 4-hour period following injury, and it could be enhanced or retarded by elevation or reduction of the systemic blood pressure.


Neurosarcoidosis: Analysis of a series of 20 patients.
Neurosarcoidosis is a rare complication of sarcoidosis. There are small series on the condition and very few from Spain. We conducted a retrospective study of neurosarcoidosis in Virgen de la Victoria Hospital over the last 10 years. the medical records of patients diagnosed with sarcoidosis in our setting in the last 10 years were reviewed. One hundred twenty patients with sarcoidosis, 20 patients with probable neurosarcoidosis: 30% at the beginning of the illness, 55% later, 15% had isolated neurosarcoidosis. Forty percent had polyneuropathy, 15% cranial neuropathy, 15% myopathy, 10% hemispheric symptoms. OTHERS: headache, myelitis, seizures, confusional syndrome. They were treated with steroids, some of them with immunosuppressive treatment. Seventy-two percent improved or were stabilized. Therefore, neurosarcoidosis prevalence in our hospital was 11%, similar to other published series, with similar features, but polyneuropathy was more frequent. Early diagnosis is very important as prognosis is favourable with treatment.


Inhibitory effect of gentamicin on gluconeogenesis from pyruvate, propionate, and lactate in isolated rabbit kidney-cortex tubules.
The effect of gentamicin on glucose production in isolated rabbit renal tubules was studied with lactate, propionate, malate, 2-oxoglutarate, and succinate as substrates. This antibiotic at 5 mM concentration inhibited gluconeogenesis from lactate by about 60% and that from either pyruvate or propionate by about 30%. In contrast, it did not alter the rate of glucose formation from other substrates studied. The rate of gluconeogenesis was higher at 1 mM propionate than at increasing concentrations of this substrate and was stimulated in the presence of 1 mM carnitine. However, the addition of carnitine did not affect the degree of inhibition of glucose formation by gentamicin. Since the mitochondrial free coenzyme A level was significantly lower in the presence of 10 than 1 mM propionate and increased on the addition of carnitine to the reaction medium, the inhibitory effect of propionate concentrations above 1 mM on gluconeogenesis in rabbit renal tubules may be due to a depletion of the free mitochondrial coenzyme A level, resulting in an inhibition of the mitochondrial coenzyme A-dependent reactions. In intact rabbit kidney cortex mitochondria incubated in State 4 as well as in Triton X-100-treated mitochondria, 5 mM gentamicin inhibited by about 30-40% the incorporation of 14CO2 into both pyruvate and propionate. The results indicate that the inhibitory effect of gentamicin on glucose formation in isolated kidney tubules incubated with lactate, pyruvate, or propionate is likely due to a decrease of the rate of carboxylation reactions.


Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women.
Increased plasma total homocysteine (tHcy) is a risk factor for vascular disease and adverse pregnancy outcomes. Health authorities recommend periconceptional supplementation with 400 micro g folic acid to prevent neural tube defects. Several countries have implemented food fortification with folic acid. However, excessive intake of folic acid could mask an undiagnosed vitamin B-12 deficiency. The biologically active [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) may be an alternative to folic acid because it is unlikely to mask vitamin B-12 deficiency symptoms. We compared the tHcy-lowering potential of 2 dosages of [6S]-5-MTHF with that of 400 micro g folic acid during 24 wk of supplementation. In this double-blind, randomized, controlled intervention trial, 144 female participants were supplemented daily with 400 micro g folic acid, 416 micro g [6S]-5-MTHF, 208 micro g [6S]-5-MTHF, or placebo. Concentrations of tHcy and plasma folate were measured at baseline and at 4-wk intervals. After supplementation, there was a significant interaction between time and treatment with respect to changes in tHcy and plasma folate (both P < 0.001 by two-factor repeated-measures analysis of variance). The decrease in tHcy did not differ significantly between the 3 supplemented groups (P > 0.05; Tukey's post hoc test). The increase in plasma folate in the group receiving 208 micro g [6S]-5-MTHF was significantly lower than that in the groups receiving 400 micro g folic acid (P < 0.001) or 416 micro g [6S]-5-MTHF (P < 0.05). [6S]-5-MTHF was shown to be an adequate alternative to folic acid in reducing tHcy concentrations. Supplementation with 416 micro g [6S]-5-MTHF was no more effective than that with 208 micro g [6S]-5-MTHF.


Host immune response in renal cell cancer: interleukin-4 (IL-4) and IL-10 mRNA are frequently detected in freshly collected tumor-infiltrating lymphocytes.
Human renal cell cancer (RCC) is clearly responsive to immunotherapy. Clinical responses may be mediated by "non-specific" (e.g. natural killer, NK, cells) or "specific" MHC-class-I-restricted tumor-specific CD8+ T lymphocytes. Typically RCC progresses, however, despite significant infiltration of various lymphoid cells. We examined freshly isolated RCC tumor-infiltrating lymphocytes (TIL) derived from seven RCC patients for cytokine expression by the polymerase chain reaction (PCR). Established RCC tumor cell lines derived from these RCC patients were negative for interleukin-2 (IL-2), IL-4, IL-10, and interferon gamma and found to be positive for tumor necrosis factor alpha (TNF alpha), IL-6, IL-1 beta, granulocyte/macrophage-colony-stimulating factor (GM-CSF), and transforming growth factor beta 1 (TGF beta 1) message as detected by PCR. An identical pattern of cytokine mRNA expression was identified in other long-term RCC lines and in normal human kidney cells upon culture, but not in two Wilms tumor cell lines tested. Short-term-, and long-term-established RCC lines, but not Wilms tumor lines, secreted substantial levels of GM-CSF, TNF alpha, IL-1 beta, and IL-6 as detected by enzyme-linked immunosorbent assay. Both RCC lines and Wilms tumor lines secreted TGF beta 1. In comparison, normal kidney cells secreted IL-6 and GM-CSF, but not IL-1 beta, or TFG beta 1 under identical in vitro cell culture conditions. We applied PCR-based methods to characterize the cytokine mRNA expression pattern in immune cells infiltrating into renal cell cancer without the need for expansion of such effector cells in vitro. Examining freshly collected RCC TIL by PCR from patients with primary cell cell cancer, we could demonstrate that such cells, but not lympho-mononuclear cells harvested from normal human kidney tissue, typically exhibit IL-4 and IL-10 mRNA expression.


Ultrafine ferroferric oxide nanoparticles embedded into mesoporous carbon nanotubes for lithium ion batteries.
An effective one-pot hydrothermal method for in situ filling of multi-wall carbon nanotubes (CNT, diameter of 20-40 nm, length of 30-100 μm) with ultrafine ferroferric oxide (Fe3O4) nanoparticles (8-10 nm) has been demonstrated. The synthesized Fe3O4@CNT exhibited a mesoporous texture with a specific surface area of 109.4 m(2) g(-1). The loading of CNT, in terms of the weight ratio of Fe3O4 nanoparticles, can reach as high as 66.5 wt%. Compared to the conventional method of using a Al2O3 membrane as template to fill CNT with iron oxides nanoparticles, our strategy is facile, effective, low cost and easy to scale up to large scale production (~1.42 g per one-pot). When evaluated for lithium storage at 1.0 C (1 C = 928 mA g(-1)), the mesoporous Fe3O4@CNT can retain at 358.9 mAh g(-1) after 60 cycles. Even when cycled at high rate of 20 C, high capacity of 275.2 mAh g(-1) could still be achieved. At high rate (10 C) and long life cycling (500 cycles), the cells still exhibit a good capacity of 137.5 mAhg(-1).


Lignosulfonate as reinforcement in polyvinyl alcohol film: Mechanical properties and interaction analysis.
Recently, there has been a growing research interest on renewable composite due to sustainability concerns. This work demonstrated the possibility of using eucalyptus lignosulfonate calcium (HLS) particles as reinforcement in polyvinyl alcohol (PVA) matrix. 41% and 384.7% improvement of pure PVA tensile strength and Young's modulus were achieved with incorporation of 5 wt% HLS. The above results were ascribed to specific intermolecular interactions between HLS and PVA, suggested by the increasing PVA glass transition and crystalline relaxations temperature, depression of melting point with HLS incorporation. Moreover, this interaction was quantitatively determined by q value of -62.4±10.0 in Kwei equation. Additionally, the remarkable red shift of wavenumber corresponding to hydroxyl group also indicated the formation of strong hydrogen bond in HLS/PVA blend. SEM characterization confirmed that HLS/PVA blends are at least miscible.


A cost-effective chart review sampling design to account for phenotyping error in electronic health records (EHR) data.
Electronic health records (EHR) are commonly used for the identification of novel risk factors for disease, often referred to as an association study. A major challenge to EHR-based association studies is phenotyping error in EHR-derived outcomes. A manual chart review of phenotypes is necessary for unbiased evaluation of risk factor associations. However, this process is time-consuming and expensive. The objective of this paper is to develop an outcome-dependent sampling approach for designing manual chart review, where EHR-derived phenotypes can be used to guide the selection of charts to be reviewed in order to maximize statistical efficiency in the subsequent estimation of risk factor associations. After applying outcome-dependent sampling, an augmented estimator can be constructed by optimally combining the chart-reviewed phenotypes from the selected patients with the error-prone EHR-derived phenotype. We conducted simulation studies to evaluate the proposed method and applied our method to data on colon cancer recurrence in a cohort of patients treated for a primary colon cancer in the Kaiser Permanente Washington (KPW) healthcare system. Simulations verify the coverage probability of the proposed method and show that, when disease prevalence is less than 30%, the proposed method has smaller variance than an existing method where the validation set for chart review is uniformly sampled. In addition, from design perspective, the proposed method is able to achieve the same statistical power with 50% fewer charts to be validated than the uniform sampling method, thus, leading to a substantial efficiency gain in chart review. These findings were also confirmed by the application of the competing methods to the KPW colon cancer data. Our simulation studies and analysis of data from KPW demonstrate that, compared to an existing uniform sampling method, the proposed outcome-dependent method can lead to a more efficient chart review sampling design and unbiased association estimates with higher statistical efficiency. The proposed method not only optimally combines phenotypes from chart review with EHR-derived phenotypes but also suggests an efficient design for conducting chart review, with the goal of improving the efficiency of estimated risk factor associations using EHR data.


Modeling Human Cytomegalovirus-Induced Microcephaly in Human iPSC-Derived Brain Organoids.
Although congenital infection by human cytomegalovirus (HCMV) is well recognized as a leading cause of neurodevelopmental defects, HCMV neuropathogenesis remains poorly understood. A major challenge for investigating HCMV-induced abnormal brain development is the strict CMV species specificity, which prevents the use of animal models to directly study brain defects caused by HCMV. We show that infection of human-induced pluripotent-stem-cell-derived brain organoids by a "clinical-like" HCMV strain results in reduced brain organoid growth, impaired formation of cortical layers, and abnormal calcium signaling and neural network activity. Moreover, we show that the impeded brain organoid development caused by HCMV can be prevented by neutralizing antibodies (NAbs) that recognize the HCMV pentamer complex. These results demonstrate in a three-dimensional cellular biosystem that HCMV can impair the development and function of the human brain and provide insights into the potential capacity of NAbs to mitigate brain defects resulted from HCMV infection.


Differences in embryogenesis of epispadias, exstrophy-epispadias complex and hypospadias.
Minor variants of a spectrum of anomalies are usually more common than the major variants. Penile epispadias is rare compared with the relatively more common exstrophy-epispadias complex, but it has been assumed that the former is simply a lesser form of the latter. This assumption is challenged and an alternative explanation is proposed for the embryogenesis of isolated epispadias. Descriptions of the normal and abnormal development of the cloaca, the cloacal membrane, the external genitalia, the pubis, and in particular the tail were studied. The tail was found to begin its elongation at about 21 days of development, when it overlies the cloacal membrane; it then impacts upon the body stalk and turns aside to lie upon the ventral abdominal wall. By 8 weeks all 10 tail segments have undergone apoptosis. The tail may briefly compress and separate the merging second sacral pair of mesodermal streams that sever the cloacal-allantoic connection and form part of the phallus. These streams then come together to form the phallus behind the allantoic connection which then lies on the dorsal slope of the epispadiac penis. If the compression by the tail occurs after the first paired streams have met and formed the penis, the next pair that form the inner genital folds and penile urethra may be held apart by compression of the tail creating extreme forms of hypospadias on the ventral slope of the penis. This tail compression theory may explain the rarity of epispadias compared to the relatively more common exstrophy-epispadias complex.