Spontaneous immune responses to sporadic tumors: tumor-promoting, tumor-protective or both?
Cancer cells cannot develop into invasive cancers without interactions with cells and soluble mediators present in the tumor microenvironment. Accumulating evidence indicates that the immune system is a critical determinant of malignant outgrowth; however, the tumor-modulating effects of spontaneous immune responses towards nascent malignancies are rather paradoxical. Both cancer-protective and cancer-promoting features of the immune system have been described. This review will discuss the role of the dynamic inflammatory tumor microenvironment during cancer development and progression, and will focus on the intriguing question: "Do malignancies develop in spite of-or because of-spontaneous immune responses?" Special emphasis will be put on recent progress in our understanding of the immune system's double-edged sword function during de novo carcinogenesis.


Molecular mechanism of the spider toxin κ-LhTx-I acting on the bacterial voltage-gated sodium channel NaChBac.
The bacterial sodium channel NaChBac is the prokaryotic prototype for the eukaryotic NaV and CaV channels, which could be used as a relatively simple model to study their structure-function relationships. However, few modulators of NaChBac have been reported thus far, and the pharmacology of NaChBac remains to be investigated. In the present study, we show that the spider toxin κ-LhTx-1, an antagonist of the KV4 family potassium channels, potently inhibits NaChBac with an IC50 of 491.0 ± 61.7 nM. Kinetics analysis revealed that κ-LhTx-1 inhibits NaChBac by impeding the voltage-sensor activation. Site-directed mutagenesis confirmed that phenylalanine-103 (F103) in the S3-S4 extracellular loop of NaChBac was critical for interacting with κ-LhTx-1. Molecular docking predicts the binding interface between κ-LhTx-1 and NaChBac and highlights a dominant hydrophobic interaction between W27 in κ-LhTx-1 and F103 in NaChBac that stabilizes the interface. In contrast, κ-LhTx-1 showed weak activity on the mammalian NaV channels, with 10 µM toxin slightly inhibiting the peak currents of NaV1.2-1.9 subtypes. Taken together, our study shows that κ-LhTx-1 inhibits the bacterial sodium channel, NaChBac, using a voltage-sensor trapping mechanism similar to mammalian NaV site 4 toxins. κ-LhTx-1 could be used as a ligand to study the toxin-channel interactions in the native membrane environments, given that the NaChBac structure was successfully resolved in a nanodisc.


Nest defense in the face of cuckoldry: evolutionary rather than facultative adaptation to chronic paternity loss.
Raising unrelated offspring is typically wasteful of parental resources and so individuals are expected to reduce or maintain low levels of parental effort when their parentage is low. This can involve facultative, flexible adjustments of parental care to cues of lost parentage in the current brood, stabilizing selection for a low level of paternal investment, or an evolutionary reduction in parental investment in response to chronically low parentage. We studied parental care in Variabilichromis moorii, a socially monogamous, biparental cichlid fish, whose mating system is characterized by frequent cuckoldry and whose primary form of parental care is offspring defense. We combine field observations with genetic parentage analyses to show that while both parents defend their nest against intruding con- and hetero-specifics, males and females may do so for different reasons. Males in the study group (30 breeding pairs) sired 0-100% (median 83%) of the fry in their nests. Males defended less against immediate threats to the offspring, and more against threats to their territories, which are essential for the males' future reproductive success. Males also showed no clear relationship between their share of defense and their paternity of the brood. Females, on the other hand, were related to nearly all the offspring under their care, and defended almost equally against all types of threats. Overall, males contributed less to defense than females and we suggest that this asymmetry is the result of an evolutionary response by males to chronically high paternity loss in this species. Although most males in the current study group achieved high parentage in their nests, the average paternity in V. moorii, sampled across multiple seasons, is only about 55%. We highlight the importance and complexity of studying nest defense as a form of parental care in systems where defense may serve not only to protect current offspring, but also to ensure future reproductive success by maintaining a territory.


Practical forensic use of kinship determination using high-density SNP profiling based on a microarray platform, focusing on low-quantity DNA.
Instead of traditional short tandem repeat (STR) profiling, the genetic genealogy method, which uses hundreds of thousands of single nucleotide polymorphisms (SNPs) spread across genome-wide, has emerged as a powerful kinship determination tool and recently attracted great attention in forensic genetics. In this study, we explored the tolerance and viability of kinship discrimination based on a high-density SNP profile for forensic DNA, especially focusing on low-quantity DNA. Using the Affymetrix Genome-Wide Human SNP Array 6.0 platform (Thermo Fisher Scientific), the influence of low-quantity DNA on SNP genotype determination was evaluated. The low-quantity DNA samples failed once every few samples, the generated SNP profile had low data quality. Our investigation revealed that the SNP profile with low data quality contained many genotyping errors in which the SNP genotype changed from homozygote to heterozygote. The kinship discrimination analysis using KING software was directly influenced by these genotyping errors, which was confirmed that some unrelated pairs were mis-specified as 4th-degree relatives. We confirmed that the false heterozygous SNPs resulted in an inflation of kinship coefficient and a decrease of non-shared allele between a tested pair. To eliminate the influence of these genotyping errors and acquire an accurate kinship discrimination result, we developed a novel method to select only the robust SNPs, which stably give the genotype determination with high accuracy even in SNP profiles with low data quality. The application of our novel method led to the improved results of kinship discrimination up to the same level as in the SNP profile with high data quality. In addition, this study demonstrated the advantage of kinship analysis using a high-density SNP profile in the forensic field. It is well known that likelihood ratio calculation based on autosomal STR profile, which is the most commonly applied approach, has difficulty in gaining true kinship analysis results, especially when the relationship between the tested two individuals is more biologically distant. We showed the kinship discrimination analysis with a high-density SNP profile is more suitable for the case without close relatives, using the real case data. Although further study with larger samples will be necessary, this study indicated that practical forensic use of kinship determination with a high-density SNP profile would bring benefits to the forensic field.


Temozolomide and oral VP-16 for children and young adults with recurrent or treatment-induced malignant gliomas.
Children and young adults with recurrent or treatment-induced malignant gliomas have limited responses to temozolomide or oral VP-16 when either is administered as a single agent. We postulated that a combination of these two drugs for patients with recurrent or treatment-induced malignant gliomas might result in better and more prolonged responses. A retrospective analysis was performed on patients treated with the combination of temozolomide and VP-16. Eleven patients with recurrent or treatment-induced malignant gliomas were treated with varying combinations of temozolomide (150-210 mg/m2/d for 5 days) and oral VP-16 (50 mg/m2/d for 4-12 days). Responses were assessed by MRI scan, and data on clinical course and toxicity were retrospectively obtained from the medical record. The median age of the 11 patients was 17 years (range 5-23 years). Diagnoses included recurrent brain stem glioma (2), recurrent anaplastic astrocytoma (2), and glioblastoma (7) (3 treatment-induced, 2 malignant transformations of lower grade tumors, 1 recurrence, and 1 second tumor arising 10 months after diagnosis of medulloblastoma). All 11 patients had received radiotherapy (including 4 who received craniospinal radiation), and 7 had prior chemotherapy. Nine patients were treated at first recurrence, two at second recurrence. One patient had a complete response (CR), six had partial responses (PR), and four had progressive disease (PD). The median progression-free survival for the seven responding patients was 6 months (range 4-15+ months). There was one grade 4 neutropenia, but no other grade 3 or 4 toxicities. These data suggest there is activity of temozolomide in combination with oral VP-16 for children and young adults with recurrent malignant gliomas.


ln vitro inhibition of beta-hematin formation and in vivo effects of Diospyros mespiliformis and Mondia whitei methanol extracts on chloroquine-susceptible Plasmodium berghei-induced malaria in mice.
This study was carried out to investigate antiplasmodial activities of Diospyros mespiliformis (DM) and Mondia whitei (MW) in Plasmodium berghei-infected mice. Air-dried stem of DM and root of MW were soaked in methanol, decanted and concentrated to give extracts. Parts of these extracts were partitioned successively to give dichloromethane, ethylacetate and methanol fractions. Mice (18 ± 3 g) were infected with Plasmodium berghei-infected erythrocytes from a donor mouse and were treated with the extracts, while the drug control group received 10 mg/kg body weight of artesunate and the parasitized control received the vehicle (5% v/v DMSO). Percentage parasitemia and clearance were estimated from thin films of blood smear. Hematological parameters were determined using standard methods. Both extracts were also tested on in vitro inhibition of β-hematin formation. Results showed that DM had the least percentage parasitemia (0.67%) and highest percentage parasite clearance (84.7%) while the MW had 0.89% percentage parasitemia and 79.7% clearance at the highest dose used after the seventh day relative to untreated control. The cell free antiplasmodial activity of the fractions and extracts of both DM and MW revealed that DM significantly inhibited β-hematin formation than MW. The packed cell volume, white blood cell count, Lymphocyte, Eosinophil, Monocyte and Neutrophil significantly increased in the treated groups compared with the control. The results showed that the DM had higher antiplasmodial activity.


Engineering C4 photosynthetic regulatory networks.
C4 photosynthesis is a complex metabolic pathway responsible for carbon fixation in major feed, food and bioenergy crops. Although many enzymes driving this pathway have been identified, regulatory mechanisms underlying this system remain elusive. C4 photosynthesis contributes to photosynthetic efficiency in major bioenergy crops such as sugarcane, Miscanthus, switchgrass, maize and sorghum, and international efforts are underway to engineer C4 photosynthesis into C3 crops. A fundamental understanding of the C4 network is thus needed. New experimental and informatics methods can facilitate the accumulation and analysis of high-throughput data to define components of the C4 system. The use of new model plants, closely related to C4 crops, will also contribute to our understanding of the mechanisms that regulate this complex and important pathway.


Nausea and Vomiting After Laparoscopic Cholecystectomy: Analysis of Predictive Factors.
The purpose of this study was to identify the factors predictive of postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy. This is a descriptive, cross-sectional study. In total, 172 patients completed the study. "The Questionnaire Form," "Visual Analog Scale," "Nausea Scale," and "Anxiety Specific to Surgery Questionnaire" created by the researchers were used for data collection. At the second postoperative hour, 55.8% of the patients had nausea, 20.3% had vomiting and 75% had severe pain. The severity of nausea, vomiting, and pain decreased with time. Age, gender, smoking, motion sickness, postoperative pain, opioid use, preoperative fasting time, time of first postoperative fluid intake and preoperative anxiety score were found to be among the factors predictive of PONV (P < .05). High rates of postoperative nausea and vomiting were recorded. The factors predictive of PONV can be evaluated in the preoperative period, and PONV can be controlled with early interventions and treatment of patients in the risk group.


Volvulus caused by a free intraperitoneal staple after laparoscopic appendectomy: A case report.
Laparoscopic appendectomies are routinely performed using linear staplers. Few case reports have discussed complications from free intraperitoneal staples after appendectomy. We present the first case of a volvulus caused by a free staple that subsequently required bowel resection. A 27-year-old female underwent laparoscopic appendectomy for uncomplicated appendicitis. The base of the appendix was divided using a laparoscopic gastrointestinal anastomosis (GIA) stapler and the mesoappendix was divided using a LigaSure device. The patient was discharged the following day. Eight days later, the patient returned to the emergency department with severe abdominal pain, emesis, and peritoneal signs. Computed tomography (CT) showed significant pneumoperitoneum and nonspecific small bowel edema. Exploratory laparotomy was performed revealing a necrotic small bowel segment from a malformed, free staple caught on the peritoneum of the small bowel mesentery causing a closed loop obstruction. After reduction and detorsion, the small bowel segment was not viable and required resection. She was discharged on postoperative day four with no additional perioperative complications. Mechanical staplers are commonly used in laparoscopic appendectomy and free intraperitoneal staples are generally considered inert. A high index of suspicion should be maintained for the early postoperative appendectomy patient with obstructive symptoms. Inspection of the staple line, choosing the appropriate staple size and cartridge, and removing free malformed staples if seen should be employed during appendectomy to prevent rare but devastating complications.


Selective inhibition of PKR improves vascular inflammation and remodelling in high fructose treated primary vascular smooth muscle cells.
Double-stranded RNA dependent protein kinase (PKR) is reported to play a critical role in the pathogenesis of diabetes and associated vascular complications. Increased PKR activity is observed in metabolic disorders. Increased PKR activity is reported to induce inflammation and oxidative stress. Inflammation and oxidative stress are implicated in the pathogenesis of vascular disease. There are no studies done so far about the role of PKR in vascular smooth muscle cells (VSMCs) and the underlying molecular mechanism. Thus the aim of the present study is to investigate the role of PKR in high fructose treated VSMCs. Moreover, a selective PKR inhibitor, imoxin (C16) was used to investigate the underlying molecular mechanism. VSMCs were isolated by enzymatic digestion method from thoracic aorta of rats and incubated with high fructose (HF) and PKR inhibitor. Immunocytochemistry and Western blotting were performed for PKR and its downstream markers of inflammation, apoptosis and phenotypic transition (AGEs, MMP-9, and ERK1/2). Oxidative stress was measured using flow cytometry. Cellular hypertrophy and proliferative index were determined by haematoxylin and eosin staining, MTT assay, BrdU labelling assay and agarose gel electrophoresis. Scratch test was done for migratory behaviour. Alizarin red staining was performed for assessing vascular calcification. Mitochondrial membrane potential and chromatin condensation was determined by rhodamine 6G and DAPI staining. PKR expression was significantly increased in HF treated VSMCs which was accompanied by increase in levels of gene markers of inflammation, oxidative stress and apoptosis. Moreover, increase in cellular proliferation, phenotypic switch and decrease in membrane potential was observed in HF treated VSMCs. All these effects of HF were attenuated by selective PKR inhibitor, imoxin (C16). In conclusion PKR activation plays an important role in the pathogenesis of vascular inflammation and remodelling, and therapeutically targeting PKR could be an effective approach to treat the abnormalities associated with vascular complications.


GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.
The GODDESS© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients' lives. This study evaluated GODDESS©'s cross-sectional and longitudinal measurement properties. The Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS©'s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items. DeFi participants (N = 142) had a median age of 34 years (range: 18-76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach's α > 0.70) and test-retest reliability (intra-class correlation coefficient > 0.85). GODDESS© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening. GODDESS© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses. NCT03785964; December 24, 2018.


Evaluation of online interprofessional simulation workshops for obstetric and neonatal emergencies.
To explore student perceptions of learning and interprofessional aspects of obstetric and neonatal emergencies through online simulation-based workshops. This qualitative study was conducted at Monash University, Australia. Data were obtained from six separate online Obstetric Neonatal Emergency Simulation workshops held between May 2020 and August 2021. A total of 385 students attended and were invited to participate in the study by completing an online survey two-three weeks later. Of the attendees, 144 students completed the survey (95 medical, 45 midwifery), equating to a response rate of 37%. Survey responses were downloaded from online survey platform and separated into medical and midwifery responses. Thematic analysis of data was performed using a coding framework, resulting in development of themes and subthemes. Main themes were adaptability, connectivism, preparedness for practice, experiential learning, learning through modelling and dynamics of online interaction. Students reported that online workshop was a useful alternative method to experience simulation-based learning, increase their readiness for clinical practice and foster positive interprofessional relationships. Consistent with existing literature evaluating similar in-person programs, midwifery students were most interested in interprofessional interaction (predominant theme: dynamics of online interaction), whilst medical students were more concerned with developing clinical skills (predominant themes: learning through modelling, experiential learning). Online learning may be a useful and convenient way of delivering interprofessional simulation-based education during the pandemic, in remote areas and as an adjunct to in-person teaching. Future studies should evaluate the impact of online learning with a mixed methods study and in comparison, to in-person programs.


Tumour-infiltrating lymphocytes in primary melanoma: functional consequences of differential IL-2 receptor expression.
Tumour-infiltrating lymphocytes (TIL) have been isolated from early primary melanoma (Clark level III) and expanded in vitro using culture conditions with low concentrations of IL-2 (50 U/ml). Immediately after isolation TIL consisted of mainly CD3+ T cells, and the portion of CD56+ natural killer (NK) cells was below 20%. Fresh TIL cultures could be distinguished by CD25 expression since some contained up to 33%, others less than 5% CD25+ cells. These showed differences in subsequent development during in vitro expansion. CD25-expressing cultures remained stable in their phenotype, whereas the second TIL type showed major changes: CD3 (ca 70-30%) expression decrease, CD25 (ca 5-35%) and CD56 (ca 15-55%) expression increase. The TIL type, which remained dominated by CD3+ T cells, killed autologous tumour cells efficiently (51Cr-release greater than 30% at a E/T ratio of 20:1), which could be blocked by MoAbs against MHC class I molecules. In contrast, the other TIL type exhibited weak cytotoxicity (less than 17% 51Cr-release at an E/T ratio of 20:1) against the autologous tumour. Therefore, the expression of CD25 on freshly isolated TIL is a good marker for tumour specificity of in vitro expanded TIL.


Inhibition evaluation of ABC powder in aluminum dust explosion.
To investigate the inhibition effect of ABC powder for 5 μm and 30 μm aluminum dust explosions, a standard 20 L spherical chamber was employed to determine the explosion severity of Al/ABC mixtures and the MIC (minimum inerting concentration) of ABC powder. Results showed that the MIC increased as the concentration of aluminum dust increased. Meanwhile, the MIC decreased with the declining particle diameter of ABC but increased with the reducing diameter of the aluminum particles. SEEP (suppressant enhanced explosion parameter) phenomenon was observed when the concentration of ABC powder was low. To reveal the enhancement mechanism of ABC powder, explosion severity of NH3 and Al/NH3 mixture was also determined. Results showed that the explosion severity of aluminum dust was significantly enhanced by adding NH3. Scanning electron microscopy showed that the particles of the explosion residues of Al/NH3 mixture and Al/ABC mixture were significantly larger than those of pure aluminum explosion residues. X-ray photoelectron spectroscopy revealed that the major explosion products of Al/NH3 mixture was Al2O3. Explosion products of Al/ABC mixture were mainly comprised of Al2O3 and P2O5. The inhibition mechanism of aluminum dust explosion by ABC powder was summarized systematically based on these results.


Investigating 3He diffusion NMR in the lungs using finite difference simulations and in vivo PGSE experiments.
Finite difference simulations have been used to model (3)He gas diffusion in simulated lung tissue. The technique has the advantage that a wide range of structural models and diffusion-sensitizing gradient waveforms can be investigated, for which analytical methods would otherwise be virtually impossible. Results from simulations and in vivo pulsed-gradient-spin-echo (PGSE) experiments show that the apparent diffusion coefficient (ADC) is a function of diffusion time and gradient strength, and suggests diffusion is locally anisotropic. The simulations have been compared to recent work on an analytical model that characterizes lung tissue as a series of independent cylinders. The results presented may have clinical implications for (3)He ADC measurements in assessing lung diseases such as chronic-obstructive-pulmonary-disease.


Altered tissue repair in hevin-null mice: inhibition of fibroblast migration by a matricellular SPARC homolog.
Matricellular proteins such as hevin, secreted protein acidic and rich in cysteine, and thrombospondin-2 play an important role during tissue repair through their influence on fundamental cellular activities such as adhesion, migration, proliferation, and extracellular matrix synthesis/reorganization. We have investigated the role played by hevin during excisional and incisional cutaneous wound repair in hevin-null mice. Hevin-null animals both close and heal their skin wounds faster than wild-type animals, as evidenced by enhanced macrophage infiltration of wound beds at early time points, the earlier appearance of mature extracellular matrix, and the overall higher maturity score. In addition, fibrovascular invasion of polyvinyl alcohol sponges was more robust in hevin-null mice, a result indicating that differences in cell migration might underlie the observed alterations in wound repair. Experiments in vitro showed that hevin induced the deadhesion and inhibited the migration of primary dermal fibroblasts in a Rac-1-dependent manner. These findings indicate that the differences in wound repair between hevin-null and wild-type animals can be attributed in part to the deadhesive function of hevin and reduced cell migration within dermal wound beds in which this protein is expressed.


Cloning and characterization of chloroplast and cytosolic forms of cyclophilin from Arabidopsis thaliana.
Cyclophilin (CyP), a protein with peptidyl-prolyl cis-trans isomerase (rotamase) activity, is the specific cellular target of cyclosporin A. We have isolated cDNA clones of two genes (designated ROC1 and ROC4) encoding CyP homologs from Arabidopsis thaliana (L.). The protein products of these genes are distinct from a previously identified Arabidopsis CyP. ROC1 is expressed in all tested plant organs and encodes a protein which is highly similar to previously described cytosolic CyP isoforms of other plants. In contrast, ROC4 is expressed only in photosynthetic organs and encodes a protein which includes an amino-terminal extension with properties of known chloroplast transit peptides. In vitro import experiments using the putative precursor protein to ROC4 showed that the protein is imported into chloroplasts where it is processed to the predicted mature size. Rotamase assays and immunoblot analysis of subcellular fractions indicate the presence of a CyP isoform in the stroma of chloroplasts but not in the thylakoid membranes or thylakoid lumen. Together, these data show that ROC4 is a novel CyP isoform which is located in the stroma of chloroplasts. In vitro chloroplast import of precursors of other chloroplast proteins was unaffected by concentrations of cyclosporin A which completely inhibit rotamase activity of chloroplast stromal CyP. Thus, this activity is not essential for protein import into chloroplasts.


Identification of a null allele in genetic tests for bovine leukocyte adhesion deficiency in Pakistani Bos indicus × Bos taurus cattle.
Two clinically healthy mature Pakistani Bos indicus × Bos taurus cattle were genotyped as homozygous affected for the lethal immunodeficiency disorder bovine leukocyte adhesion deficiency (BLAD) using previously described PCR-RFLP based DNA tests which was confirmed by sequencing. Sequencing of Bos taurus and B. indicus × B. taurus genomic DNA surrounding the disease causing mutation (c.383A > G) in the ITGB2 gene identified numerous variations in exonic and intronic regions within and between species, including substantial variation in primer annealing sites for three PCR-RFLP tests for one of the B. indicus allelic variants. These variations in the primer annealing sites resulted in a null allele in the DNA tests causing the misdiagnosis of some heterozygous B. taurus × B. indicus cattle to be classified as homozygous affected. New primers were designed and a modified test was developed which simultaneously identified the disease mutation and the Pakistani B. indicus allelic variant associated with the null allele in the previous test.


Ocular motility disorders following coronavirus disease-19 vaccination.
To describe clinical manifestations and short-term prognosis of ocular motility disorders following coronavirus disease-2019 (COVID-19) vaccination. Ocular motility disorders were diagnosed by clinical assessment, high-resolution magnetic resonance imaging, and laboratory testing. Clinical manifestations, short-term prognosis, and rate of complete recovery were analyzed. Sixty-three patients (37 males, 26 females) with a mean age of 61.6 ± 13.3 years (range, 22-81 years) were included in this study. Among 61 applicable patients with sufficient information regarding medical histories, 38 (62.3%) had one or more significant underlying past medical histories including vasculopathic risk factors. The interval between initial symptoms and vaccination was 8.6 ± 8.2 (range, 0-28) days. Forty-two (66.7%), 14 (22.2%), and 7 (11.1%) patients developed symptoms after the first, second, and third vaccinations, respectively. One case of internuclear ophthalmoplegia, 52 cases of cranial nerve palsy, two cases of myasthenia gravis, six cases of orbital diseases (such as myositis, thyroid eye disease, and IgG-related orbital myopathy), and two cases of comitant vertical strabismus with acute onset diplopia were found. Among 42 patients with follow-up data (duration: 62.1 ± 40.3 days), complete improvement, partial improvement, no improvement, and exacerbation were shown in 20, 15, 3, and 4 patients, respectively. This study provided various clinical features of ocular motility disorders following COVID-19 vaccination. The majority of cases had a mild clinical course while some cases showed a progressive nature. Close follow-up and further studies are needed to elucidate the underlying mechanisms and long-term prognosis.


Considerations in the Diagnosis and Management of Pediatric Patients With Favorable Histology Wilms Tumor Who Present With Only Pulmonary Nodules.
More than 70% of children with stage IV, favorable histology (FH) Wilms tumor will be relapse-free survivors 16 years after diagnosis. Successful treatment generally includes whole lung radiation therapy and doxorubicin. Such therapy is associated with adverse, long-term effects, including impaired pulmonary function, congestive heart failure, and second malignant neoplasms, especially breast cancer. Cooperative groups have adopted a risk-based approach to the treatment of these patients. It is important to recall the good overall prognosis for this group before recommendations for intensification are made based on preliminary data and in the absence of histological confirmation of persistent malignant disease.


Role of renal Na+,K(+)-ATPase in the regulation of sodium excretion under normal conditions and in acute congestive heart failure.
Cardiac glycosides have traditionally been used as inotropic agents in the treatment of congestive heart failure (CHF). The renal actions of cardiac glycosides independent of inotropic effects are not characterized. The presence of endogenous digitalis-like factors (EDLFs) with characteristic Na+,K(+)-ATPase activity has been postulated in volume-expanded states such as CHF, and recent studies have demonstrated that at least one EDLF shares structural homology with ouabain. This study was undertaken to evaluate the renal actions of ouabain in normal dogs and those with CHF. After surgical preparation, normal dogs (n = 6) and dogs in pacing-induced CHF (n = 6) received intrarenal ouabain in sequential doses of 0.167 micrograms/kg/min, 0.334 micrograms/kg/min, and 0.668 micrograms/kg/min. Hemodynamics and renal function were evaluated during the infusion. There was no change in heart rate or mean arterial pressure during the infusion compared with baseline in both groups. Sodium excretion and urine volume significantly increased in both groups. Plasma renin activity, activated by the onset of pacing in the CHF group, was inhibited by the administration of intrarenal ouabain in this group only. These studies demonstrate that ouabain has diuretic and natriuretic actions independent of cardiac hemodynamics that are preserved in CHF. Furthermore, intrarenal ouabain suppresses activation of renin in CHF.


Nano-TiO(2)-flavin adenine dinucleotide film redox processes in contact to humidified gas | salt electrolyte.
Redox processes in nano-TiO(2)-flavin adenine dinucleotide (TiO(2)-FAD) layer-by-layer assembled films on ITO substrate electrodes are investigated and compared in contact to aqueous electrolyte media (for dilute and saturated electrolyte) and in contact to solid humidified salt electrolyte (for extreme salt levels and different types of salts). Under these unusual conditions an aqueous microphase present at the gas | salt | electrode interface allows voltammograms to be obtained and redox processes to be analysed. It is demonstrated that the 2-electron 2-proton reduction of FAD can be used as reporter redox system to determine local pH at the electrode | gas | salt interface as pH 15, 12, 7 for contacts to K(3)PO(4), K(2)HPO(4), and KH(2)PO(4), respectively. Exposure to gases such as carbon dioxide is shown to lead to unexpected changes in surface pH. In the future, bio-electrochemical microphase processes under halophilic conditions could be useful for air-quality and rapid gas sensing devices.


Adoption, Infertility, and Love Affirmed.
A nurse describes the emotional journey of getting pregnant and giving birth after the experiences of adoption and infertility.


Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria.
The genus Propionibacterium is composed of dairy and cutaneous bacteria which produce short-chain fatty acids (SCFA), mainly propionate and acetate, by fermentation. Here, we show that P. acidipropionici and freudenreichii, two species which can survive in the human intestine, can kill two human colorectal carcinoma cell lines by apoptosis. Propionate and acetate were identified as the major cytotoxic components secreted by the bacteria. Bacterial culture supernatants as well as pure SCFA induced typical signs of apoptosis including a loss of mitochondrial transmembrane potential, the generation of reactive oxygen species, caspase-3 processing, and nuclear chromatin condensation. The oncoprotein Bcl-2, which is known to prevent apoptosis via mitochondrial effects, and the cytomegalovirus-encoded protein vMIA, which inhibits apoptosis and interacts with the mitochondrial adenine nucleotide translocator (ANT), both inhibited cell death induced by propionibacterial SCFA, suggesting that mitochondria and ANT are involved in the cell death pathway. Accordingly, propionate and acetate induced mitochondrial swelling when added to purified mitochondria in vitro. Moreover, they specifically permeabi-lize proteoliposomes containing ANT, indicating that ANT can be a critical target in SCFA-induced apoptosis. We suggest that propionibacteria could constitute probiotics efficient in digestive cancer prophylaxis via their ability to produce apoptosis-inducing SCFA.


Heart extension of an intravenous leiomyomatosis.
Intravenous leiomyomatosis is a rare growth pattern of benign uterine leiomyomas. Approximately 300 cases of intravenous leiomyomatosis have been reported in the English literature; however, there have only been a few in radiology journals. Even more rare is its extension through the inferior vena cava and heart chambers. Radiologic diagnosis can be challenging, as it is often difficult to differentiate it from other entities. We present a case of a 45-year-old woman with a cardiac extension of an intravenous leiomyomatosis and discuss the cross-sectional imaging appearance of this entity as well as the differential diagnosis.


SHISA5/SCOTIN restrains spontaneous autophagy induction by blocking contact between the ERES and phagophores.
ATG2: autophagy related 2; BECN1: beclin 1; COPII: coat protein II; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; ERES: ER exit site(s); GFP: green fluorescent protein; H89: H-89 dihydrochloride hydrate; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NS5A: nonstructural protein 5A; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PLA: proximity ligation assay; PtdIns3P: phosphatidylionositol-3-phosphate; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RFP: red fluorescent protein; RPS6KB1/S6K: ribosomal protein S6 kinase B1; SBP: streptavidin binding protein; SEC16A: SEC16 homolog A, endoplasmic reticulum export factor; SEC31A: SEC31 homolog A, COPII coat complex component; siRNA: small interfering RNA; Str: streptavidin; ULK1: unc-51-like autophagy activating kinase 1; VSVG: vesicular stomatitis virus glycoprotein; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild type.


Cysteinyl leukotrienes mediate the response of submucosal ganglia from rat colon to bradykinin.
The aim of the present study was to find out the mechanism by which the inflammatory mediator, bradykinin, induces an increase of the cytosolic Ca(2+) concentration ([Ca(2+)](i)) in enteric neurons. For this purpose, ganglia in the isolated submucosa from rat colon were loaded with the Ca(2+)-sensitive dye, fura-2, and were exposed to bradykinin (2·10(-8)mol/l). Under control conditions, the kinin evoked a transient increase in [Ca(2+)](i). Preincubation with quinacrine or arachidonyltrifluoromethylketone (AACOCF(3)), i.e. blockers of cytosolic phospholipase A(2), prevented the raise of [Ca(2+)](i). This inhibition was mimicked by 5,8,11,14-eicosatetrayonic acid (ETYA), an inhibitor of cyclooxygenases as well as lipoxygenases, and by BWA4C, a selective inhibitor of lipoxygenases, whereas indomethacin was ineffective, suggesting the mediation of the kinin response by a lipoxygenase metabolite. Indeed, a leukotriene, leukotriene D(4) (LTD(4)), mimicked the effect of bradykinin. The LTD(4) receptor blocker, MK-571, inhibited the increase in [Ca(2+)](i) evoked by LTD(4) and by bradykinin. Consequently, bradykinin receptors in submucosal ganglia from rat colon are coupled to a stimulation of phospholipase A(2), the release of arachidonic acid and the production of LTD(4), which seems to be finally responsible for the change in the cytosolic Ca(2+) concentration.


Treatment of patients with carcinoma of the thyroid invading the airway.
To determine if complete resection (vs incomplete resection) improved survival of patients with thyroid carcinoma invading the airway. Retrospective, nonrandomized end point study. Tertiary care referral centers. All patients who had invasion of the airway by thyroid carcinoma and underwent some type of surgical resection. Surgical resection. Survival. Complete resection showed significantly better survival than incomplete resection (P = .0136). Complete resection of thyroid carcinoma invading the airway offers improved survival compared with incomplete resection.


A validated model for individualized prediction of pregnancy outcome in woman after fresh cycle of Day 5 single blastocyst transfer.
The association between the embryo quality, clinical characteristics, miRNAs (secreted by blastocysts in the culture medium) and pregnancy outcomes has been well-established. Studies on prediction models for pregnancy outcome, using clinical characteristics and miRNA expression, are limited. We aimed to establish the prediction model for prediction of pregnancy outcome of woman after a fresh cycle of Day 5 single blastocyst transfer (Day 5 SBT) based on clinical data and miRNA expression. A total of 86 women, 50 with successful pregnancy and 36 with pregnancy failure after fresh cycle of Day 5 SBT, were enrolled in this study. All samples were divided into training set and test set (3:1). Based on clinical index statistics of enrolled population and miRNA expression, the prediction model was constructed, followed by validation of the prediction model. Four clinical indicators, female age, sperm DNA fragmentation index, anti-mullerian hormone, estradiol, can be used as independent predictors of pregnancy failure after fresh cycle of Day 5 SBT. Three miRNAs (hsa-miR-199a-3p, hsa-miR-199a-5p and hsa-miR-99a-5p) had a potential diagnostic value for pregnancy failure after Day 5 SBT. The predictive effect of model combining 4 clinical indicators and 3 miRNAs (area under the receiver operating characteristic curve, AUC = 0.853) was better than models combining single 4 clinical indicators (AUC = 0.755) or 3 miRNAs (AUC = 0.713). Based on 4 clinical indicators and 3 miRNAs, a novel model to predict pregnancy outcome in woman after fresh cycle of Day 5 SBT has been developed and validated. The predictive model may be valuable for clinicians to make the optimal clinical decision and patient selection.


NCX2 Regulates Intracellular Calcium Homeostasis and Translocation of HIF-1α into the Nucleus to Inhibit Glioma Invasion.
Glioma is the most common tumor of the central nervous system, and its poor prognosis can be linked to hypoxia and gene inactivation. Na+/Ca2+ exchanger 2 (NCX2) is expressed only in the normal brain and not in other tissues or glioma. We constructed a hypoxic microenvironment to more accurately understand the effect of NCX2 in glioma. Our previous experiments confirmed that NCX2 inhibited the growth of U87 cells in nude mice, indicating that NCX2 is a potential tumor suppressor gene. Malignant tumor cells are often exposed to an anoxic environment. To more accurately understand the effect of NCX2 in glioma, we constructed a hypoxic microenvironment. To detect the localization of NCX2 in transfected U87 cells, immunofluorescence was used. We tested the function of NCX2 in glioma, i.e., how it contributes to the cytosolic Ca2+ homeostasis by X-Rhod-1. We tested the cell proliferation of NCX2 in glioma in hypoxic using Cell counting kit-8 (CCK8). Cell migration and invasion were evaluated in 24-well transwell matrigel-coated or non-matrigel-coated in hypoxia. NCX2 promoted the proliferation of U87 cells in the hypoxic microenvironment. It inhibited the invasion and migration abilities of U87 cells. We demonstrated that NCX2 was located on the cell membrane and that it reduced intracellular Ca2+ levels and reactivated P53 and PTEN. We further demonstrated that NCX2 impaired cell invasion through the HIF-1α pathway in glioma. The results indicated that NCX2 plays a key role in glioma formation and tumor invasion functionality.


Hearing versus Listening: Attention to Speech and Its Role in Language Acquisition in Deaf Infants with Cochlear Implants.
The advent of cochlear implantation has provided thousands of deaf infants and children access to speech and the opportunity to learn spoken language. Whether or not deaf infants successfully learn spoken language after implantation may depend in part on the extent to which they listen to speech rather than just hear it. We explore this question by examining the role that attention to speech plays in early language development according to a prominent model of infant speech perception - Jusczyk's WRAPSA model - and by reviewing the kinds of speech input that maintains normal-hearing infants' attention. We then review recent findings suggesting that cochlear-implanted infants' attention to speech is reduced compared to normal-hearing infants and that speech input to these infants differs from input to infants with normal hearing. Finally, we discuss possible roles attention to speech may play on deaf children's language acquisition after cochlear implantation in light of these findings and predictions from Jusczyk's WRAPSA model.


Hypermethylation and prognostic implication of Syk gene in human colorectal cancer.
The study was aimed to investigate the relationship between hypermethylation of Syk gene and clinicopathological characteristics and long-term outcomes in colorectal cancer. The effect of Syk on cell proliferation and invasion ability was also assessed. Methylation and expression status of Syk were explored in CRC tissues and cell lines by MSP, qRT-PCR and western blot assay. The effects of Syk overexpression on tumorigenesis were studied by in vitro assay. The correlation between Syk methylation and clinical relevance in CRC patients was also analyzed. Syk methylation was found 48.6 % in CRC tissue samples and 57.1 % in cell lines, respectively. The loss of Syk expression could be restored by demethylation agent. Overexpression of Syk in CRC cell inhibited cell proliferation (p < 0.01) and invasion (p < 0.01). The methylation of Syk was significantly associated with histological grade (p = 0.002), lymph node status (p < 0.001) and TNM stage (p < 0.001). Five-year overall survival in methylated Syk group was significantly lower than that in unmethylated Syk group (59 vs. 80 %, p < 0.001). Multivariate analysis demonstrated that Syk methylation was an independent prognostic factor for overall survival. Syk is identified as a potential tumor suppressor in CRC progression. Syk methylation is correlated with poor overall survival, which acts as an independent prognostic indicator of CRC.


Salivary response to esophageal acid in normal subjects and patients with reflux esophagitis.
We studied the effect of esophageal acid perfusion on salivation in patients with reflux esophagitis and in normal subjects. Serial 10-min saliva collections were obtained by expectoration during perfusion of the esophagus with water, and then 0.1 N HCl (pH 1.2) for 50 min or 0.01 N HCl (pH 2.1) for 120 min. Within 1-5 min of beginning 0.1 N HCl perfusion, all 8 patients with esophagitis developed heartburn accompanied by an increase in saliva flow. By the time the severity of heartburn required discontinuation of HCl perfusion (10-40 min), saliva flow had increased nearly fourfold. With 0.1 N HCl perfusion, 8 of 10 volunteers developed mild heartburn after 22 +/- 3 min (mean +/- SE), whereas 0.01 N HCl induced heartburn in 6 of 10 volunteers after 57 +/- 12 min of perfusion. Saliva flow increased concurrently with the onset of heartburn and doubled in those volunteers who developed heartburn. Saliva flow did not change in those volunteers who were without heartburn. We conclude that esophageal acid perfusion unaccompanied by heartburn does not affect salivation. However, saliva flow increases concurrently with the onset of heartburn, a phenomenon called "water brash" when clinically evident. The increased saliva flow that accompanies heartburn may act as an endogenous antacid that serves as a protective response to symptomatic gastroesophageal reflux.


Gastrointestinal malignancies and cardiovascular diseases--non-negligible comorbidity in an era of multi-antithrombotic drug use.
Nowadays, antiplatelet and anticoagulant drug medications are indicated in patients with a variety of cardiovascular disorders, such as atrial fibrillation, coronary artery disease, and peripheral artery disease. Among cardiology patients, regardless of gastrointestinal (GI) protection, we do not infrequently encounter those patients who have signs and symptoms that are suggestive of GI tract problems. We should bear in mind that such GI signs and symptoms may be attributed to GI cancers, as well as to benign or clinically insignificant lesions. Several clinical studies have shown, albeit controversially that the predictive value of positive fecal occult blood for colorectal malignant neoplasm may not be lower in patients taking antithrombotic medication. In addition, it has been shown that in patients taking antithrombotic drug(s), diagnosed colorectal malignancies are in a relatively earlier phase, suggesting that antithrombotic drugs may facilitate the detection of otherwise unrecognized cancers. The possibility also exists that certain cardiovascular disease may be associated with a higher risk of GI malignant neoplasms. There has been no established evidence concerning whether more aggressive GI tract screening will reduce the probability of cancer death in cardiology patients; nevertheless, GI tract lesions should not be overlooked among cardiology patients, especially when unexplained anemia, gastrointestinal symptoms, or positive fecal occult blood test is present, and GI tract screening should be performed with appropriate timing.


Psychiatric diagnoses and psychosocial needs of outpatient deaf children and adolescents.
Deaf youth may be more vulnerable to psychiatric disorders but very little research data is available. The current study identified prevalence rates of psychiatric disorders and examined the psychosocial needs and strengths of deaf youth aged 4-17 receiving specialized outpatient mental health services for the deaf. Compared to hearing peers, deaf youth had greater rates of attention deficit hyperactivity disorder, conduct, autism-spectrum and bipolar disorders and spent three times longer in treatment than their hearing peers. In the deaf subsample, moderate-severe risk was found in social functioning (33.3 %) and suicidal behavior (14 %). Deaf youth had moderate to severe impairment in social relationships (54.8 %), school functioning (42.9 %). Over one-third of deaf youth had impaired family relationships, living situation, communication, judgment and physical health. Deaf youth present with higher rates of certain clinical disorders and have deficits in multiple life domains that may impact functioning and create a longer treatment course.


Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer.
The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes, NSD1, HDAC10, KRT24, ACACA and TP63 were selected based on specific criteria relevant for hereditary CRC genes. Gene sequencing was performed in 736 patients with familial/early onset CRC or polyposis without germline pathogenic variants in known genes. Twelve (predicted) damaging variants in 18 patients were identified. A gene-based burden test in 1596 familial/early-onset CRC patients, 271 polyposis patients, 543 TCGA CRC patients and >134,000 controls (gnomAD, non-cancer), revealed no clear association with CRC for any of the studied genes. Nevertheless, (non-significant) over-representation of disruptive variants in NSD1, KRT24 and ACACA in CRC patients compared to controls was observed. A somatic second hit was identified in one of 20 tumors tested, corresponding to an NSD1 carrier. In conclusion, most genes identified through the ALFRED in silico method were not relevant for CRC predisposition, although a possible association was detected for NSD1, KRT24 and ACACA.


Clinical and economic burden of bacteremia due to multidrug-resistant organisms in Korea: a prospective case control study.
The socioeconomic and clinical burden of multidrug-resistant organisms (MDRO), including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant Acinetobacter baumannii (MRAB), multidrug-resistant Pseudomonas aeruginosa (MRPA), and carbapenem-resistant Enterobacteriaceae (CRE) have not yet been adequately addressed. We prospectively searched for MDRO bacteremia cases with matched controls from 10 hospitals across Korea during a 6-month period in 2017. Patients were classified into the MDRO, susceptible organism, and no-infection groups. The corresponding susceptible or no-infection controls had been selected according to predefined criteria. We collected clinical information and estimated the total additional medical cost due to MDRO infections using the multistate model. During the 6-month period, a total of 486 MDRO bacteremia cases (260, 87, 18, 20, and 101 cases of MRSA, MRAB, MRPA, CRE, and VRE, respectively) were identified. The 90-d mortality rates were 30.4%, 63.2%, 16.7%, 55.0%, and 47.5%, respectively. The additional costs caused by bacteremia were $15 768, $35 682, $39 908, $72 051, and $33 662 per MDRO type, respectively. Based on these 6-month data, the estimated annual number of bacteremia cases due to these five MDRO in Korea were 7979 (4070, 1396, 218, 461, and 1834 cases, respectively). Overall, this caused an estimated 3280 (1237, 882, 36, 254, and 871, respectively) deaths and cost $294 505 002 ($84 707 359, $74 387 364, $10 344 370, $45 850 215, and $79 215 694, respectively) (range $170,627,020-$416,094,679) in socioeconomic loss. A tremendous clinical and economic burden is caused by MDRO bacteremia compared with antibiotic-susceptible and no-infection groups. Substantial investment and efforts by related government agencies and medical staffs are needed.


Simultaneous measurement of the amount of muscle recession and transposition. A new caliper.
A Castroviejo caliper was modified, adding another caliper to one arm to be able to measure contemporaneously the amount of muscle recession and transposition.


Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab.
One of the hallmarks of cancer immunotherapy is the long duration of responses, evident with cytokines like interleukin-2 or a variety of cancer vaccines. However, there is limited information available on very long term outcomes of patients treated with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies. Tremelimumab is an anti-CTLA-4 antibody of immunoglobulin G2 (IgG2) isotype initially tested in patients with advanced melanoma over 12 years ago. We reviewed the outcomes of patients with advanced melanoma enrolled in four phase 1 and 2 tremelimumab trials at two sites to determine response rates and long-term survival. A total of 143 patients were enrolled at two institutions from 2002 to 2008. Tremelimumab administration varied between a single dose of 0.01 mg/kg and 15 mg/kg every 3 months. Median overall survival was 13 months (95% confidence interval (CI), 10-16.6), ranging from less than a month to 12+ years. An objective response rate of 15.6% was observed, with median duration of response of 6.5 years, range of 3-136+ months. The Kaplan-Meier estimated 5 year survival rate was 20% (95% CI, 13-26%), with 10 and 12.5 year survival rates of 16% (95% CI, 9-23%). CTLA-4 blockade with tremelimumab can lead to very long duration of objective anti-tumour responses beyond 12 years.


Vitamin D protects human melanocytes against oxidative damage by activation of Wnt/β-catenin signaling.
Vitamin D analogs have been widely utilized for the treatment of vitiligo, but the molecular mechanism underlying their pharmacological effects (especially their antioxidant properties) has not yet been investigated. We evaluated the relationship between serum vitamin D level and oxidative damage severity in vitiligo patients, and investigated the molecular mechanism of vitamin D in protecting melanocytes against oxidative stress. Serum levels of 25-hydroxyvitamin D and malondialdehyde (MDA) were first measured in patients. A variety of in vitro experiments such as intracellular reactive oxygen species (ROS), cellular viability, migration, and apoptotic assays were then performed to detect the effects of vitamin D or β-catenin silencing on H2O2-treated melanocytes. Expression of Wnt/β-catenin, Nrf2, apoptotic, and MITF pathways was finally examined using quantitative real-time PCR and western blot. In this study, we initially found that vitamin D insufficiency was closely associated with the severity of oxidative stress in vitiligo patients. Using ex vivo cell models, we further showed that vitamin D positively modulated β-catenin signaling at both translational and posttranslational levels in melanocytes under oxidative stress. Like WNT agonists, vitamin D significantly inhibited ROS accumulation and cell apoptosis in H2O2-treated melanocytes and promoted their proliferative and migratory activity, while the protective effects of vitamin D against oxidative stress were abolished by β-catenin silencing in melanocytes. Furthermore, β-catenin deficiency also blocked the activation of Nrf2 and MITF as well as the inhibition of apoptosis induced by vitamin D. Taken together, vitamin D insufficiency was associated with severity of oxidative stress in vitiligo patients. Our work also provides new insights into the mechanism of vitamin D against vitiligo, in which vitamin D protects melanocytes against oxidative stress by activating Wnt/β-catenin signaling.


Internet-Based Patient Education Prior to Colonoscopy: Prospective, Observational Study of a Single Center's Implementation, with Objective Assessment of Bowel Preparation Quality and Patient Satisfaction.
Nonpharmacologic factors, including patient education, affect bowel preparation for colonoscopy. Optimal cleansing increases quality and reduces repeat procedures. This study prospectively analyzes use of an individualized online patient education module in place of traditional patient education. To determine the effectiveness of online education for patients, measured by the proportion achieving sufficient bowel preparation. Secondary measures include assessment of patient satisfaction. Prospective, single-center, observational study. Adults aged 19 years and over, with an e-mail account, scheduled for nonurgent colonoscopy, with English proficiency (or someone who could translate for them) were recruited. Demographics and objective bowel preparation quality were collected. Patient satisfaction was assessed via survey to assess clarity and usefulness of the module. Nine hundred consecutive patients completed the study. 84.6% of patients achieved adequate bowel preparation as measured by Boston bowel preparation score ≥ 6 and 90.1% scored adequately using Ottawa bowel preparation score ≤7. 94.2% and 92.1% of patients rated the web-education module as 'very useful' and 'very clear', respectively (≥8/10 on respective scales). Our analysis suggests that internet-based patient education prior to colonoscopy is a viable option and achieves adequate bowel preparation. Preparation quality is comparable to previously published trials. Included patients found the process clear and useful. Pragmatic benefits of a web-based protocol such as time and cost savings were not formally assessed but may contribute to greater satisfaction for endoscopists and patients.


Repair of the established post traumatic boutonnière deformity.
A technique is described for the repair of the chronic, post traumatic, uncomplicated boutonnière deformity which has given consistently good results. The fundamental steps are: Mobilisation and reefing of the lengthened middle slip; Kirschner wire fixation of the proximal joint in full extension and replacement of the mobilised lateral slips with the distal joint flexed approximately 45 degrees.


Human Papillomavirus vaccine coverage among female students in Brunei Darussalam: results from the first 4 years of the national school-based vaccination programme.
Human Papillomavirus (HPV) is the leading cause of cervical cancer. HPV vaccination among girls (ages 9-14) is an effective way to prevent infection. Since 2012, Brunei Darussalam has implemented the National School-based HPV Vaccination programme which aims to vaccinate all female school students of 10-17 years old. This study was conducted to calculate and descriptively compare the coverage rates of all private and government secondary school students at both national and district levels, along with the parental consent rate. HPV vaccination records of all female students between January 2012 and December 2015 were retrospectively extracted from the School Health Services, Ministry of Health. Descriptive statistics were used to report the overall and annual vaccination coverage rate (by district, class year, nationality and type of school) and parental consent rate. A total of 27,178 female students were recorded during the study period, with an overall complete dose coverage rate of 85.8% (95% CI: 85.4%, 86.2%) and 90.8% (95% CI: 90.4%, 91.2%) for all and Bruneian female students, respectively. A similar trend could be observed each year, where there is a decrease in the coverage rate from the first, second and complete doses. Brunei-Muara had the lowest vaccination coverage and parental consent rates among the country's four districts. We also observed higher HPV vaccination coverage rate for government students. Parental consent rate of Bruneian students were considerably higher than that of non-Bruneian students. Overall, the national school-based vaccination programme has achieved a high complete dose coverage rate in its first 4 years of implementation. Issues identified for this programme are vaccine cost and difficulty to reach students who have missed their scheduled vaccination in schools. The programme can be further improved by identifying other barriers of accepting and completing their HPV vaccine dose schedule.


Age-dependent differences in nicotine reward and withdrawal in female mice.
Adolescent smoking is an increasing epidemic in the US. Research has shown that the commencement of smoking at a young age increases addiction and decreases the probability of successful cessation; however, limited work has focused on nicotine dependence in the female. The goal of the present study was to identify the biological and behavioral factors that may contribute to nicotine's increased abuse liability in female adolescents using animal models of nicotine dependence. Early adolescent (PND 28) and adult (PND 70) female mice were compared in various aspects of nicotine dependence using reward and withdrawal models following sub-chronic nicotine exposure. Furthermore, in vivo acute sensitivity and tolerance to nicotine were examined. In the conditioned place preference model, adolescents demonstrated a significant preference at 0.5 mg/kg nicotine, an inactive dose in adults. Adults found higher doses (0.7 and 1.0 mg/kg) of nicotine to elicit rewarding effects. Furthermore, adolescents displayed increased physical, but not affective, withdrawal signs in three models. Upon acute exposure to nicotine, adolescent mice showed increased sensitivity in an analgesic measure as well as hypothermia. After chronic nicotine exposure, both adults and adolescents displayed tolerance to nicotine with adolescents having a lower degree of tolerance to changes in body temperature. These data indicate that differences in nicotine's rewarding and aversive effects may contribute to variations in certain components of nicotine dependence between adult and adolescent female mice. Furthermore, this implies that smoking cessation therapies may not be equally effective across all ages.


Trace elements in commonly used medicinal plants from Varna region, Bulgaria.
In this study, we assessed the concentrations of some trace and toxic elements (Cd, Pb, Zn, Cu, Ni, Cr, Fe, and Mn) in traditionally used wild medicinal plants: chamomile (Matricaria chamomilla), white yarrow (Achillea millefolium), linden (Tilia sp.), and elder (Sambucus nigra L.) collected from urban and rural region near Varna, Bulgaria. Concentrations of examined elements were determined by inductively coupled plasma-optical emission spectrometry (ICP-OES) after sample mineralization. The samples were digested with concentrated nitric acid in a microwave system. Mean element levels in medicinal herbs were established in decreasing order as follows: Fe > Mn > Zn ≈ Cu > Pb > Ni > Cr > Cd. The content of toxic elements in medicinal herbs was found significantly higher in areas with intensive traffic compared with a suburban area. Instead discrimination between metal content in rural and urban samples was confirmed by PCA. Concentrations of toxic elements Cd and Pb in all plant species from the rural region were found in the range from not detected to 0.08 and 0.796 ng/kg, respectively and were below the permissible limit of the WHO.


Analysis of risk factors affecting olfactory dysfunction in patients with chronic rhinosinusitis: Highlighting the role of metabolic syndrome.
This study aims to evaluate the relationship between chronic sinusitis (CRS) and metabolic syndrome (MS) in a Chinese population and to explore the risk factors for olfactory dysfunction in patients with CRS. A total of 387 CRS patients were enrolled. Olfactory function was assessed by the Sniffin' Sticks 12-item test and MS was diagnosed according to the guidelines. Logistic regression analysis was performed on CRS patients to screen independent risk factors of olfactory dysfunction, adjusted for confounding factors. Among 387 patients, average age of visit and duration of onset were 48.7 years and 1.8 years, respectively. The prevalence of MS was 15.0%. CRS patients with MS were more likely to be older (51.2 vs. 46.8, p = .004), predominantly male (p < .001) and have a higher proportion of olfactory dysfunction (62.1% vs. 44.1%, p = .018) than those without MS. In multivariate logistic regression analysis, MS was associated with olfactory dysfunction in CRS patients (OR: 2.06, 95% CI: 1.14-3.72, p = .016). This association remained significant after controlling for confounding factors. In addition, nasal polyps (OR: 13.41, 95% CI: 8.11-22.17, p < .001) and allergic rhinitis (OR: 3.16, 95% CI: 1.67-5.99, p < .001) were also risk factors for olfactory dysfunction after adjusting for confounding factors. MS is associated with olfactory dysfunction in patients with CRS. MS, nasal polyps, and allergic rhinitis are risk factors for olfactory dysfunction in CRS patients. IV.


Plastid-produced interorgannellar stress signal MEcPP potentiates induction of the unfolded protein response in endoplasmic reticulum.
Cellular homeostasis in response to internal and external stimuli requires a tightly coordinated interorgannellar communication network. We recently identified methylerythritol cyclodiphosphate (MEcPP) as a novel stress-specific retrograde signaling metabolite that accumulates in response to environmental perturbations to relay information from plastids to the nucleus. We now demonstrate, using a combination of transcriptome and proteome profiling approaches, that mutant plants (ceh1) with high endogenous levels of MEcPP display increased transcript and protein levels for a subset of the core unfolded protein response (UPR) genes. The UPR is an adaptive cellular response conserved throughout eukaryotes to stress conditions that perturb the endoplasmic reticulum (ER) homeostasis. Our results suggest that MEcPP directly triggers the UPR. Exogenous treatment with MEcPP induces the rapid and transient induction of both the unspliced and spliced forms of the UPR gene bZIP60. Moreover, compared with the parent background (P), ceh1 mutants are less sensitive to the ER-stress-inducing agent tunicamycin (Tm). P and ceh1 plants treated with Tm display similar UPR transcript profiles, suggesting that although MEcPP accumulation causes partial induction of selected UPR genes, full induction is triggered by accumulation of misfolded proteins. This finding refines our perspective of interorgannellar communication by providing a link between a plastidial retrograde signaling molecule and its targeted ensemble of UPR components in ER.


Regional Differences in School-Based Physical Therapy Practice for Students Who Made Progress on 2 Outcome Measures.
This study examined whether regional differences exist in the provision of school-based physical therapy services for students who achieved positive progress and explored relationships between student outcomes and school-based physical therapy. Physical therapists developed student goals using Goal Attainment Scaling (GAS) and administered the School Function Assessment (SFA). Therapists documented activities, interventions, and type of service delivery provided weekly. Students were assigned to regions for analysis. Student GAS goal attainment and progress on the SFA did not vary significantly among regions. The dosage of school-based physical therapy services, interventions, and activities varied. There were regional differences that did not impact goal achievement. Further research is needed to identify the most efficient and effective interventions and dosage to support student outcomes.


Migraine and tension-type headache among undergraduate medical, dental and pharmaceutical students of University of Aleppo: a cross-sectional study.
Headache disorders are among the most common 10 causes of disability worldwide according to the global burden of disease survey 2010. Headache is also wildly common among universities students when compared with other populations. The purpose of this study is to assess headache prevalence among Aleppo University medical, dental and pharmaceutical undergraduate students. A questionnaire-based cross-sectional study was conducted among medical, dental and pharmaceutical students at Aleppo University, Syria. We determined the type of headache according to the International Classification of Headache Disorder-III. The total number of participants was 2068. A χ2 test was used to evaluate the association between the categorical outcomes. P<0.05 was considered significant. Out of 2068 participants, 1604 (77.6%) were medical students, 205 (9.9%) were dental students and 259 (12.5%) were pharmaceutical students. The effect on daily activities was higher in chronic tension headache (96.7%) and migraine without aura (94.6%) than migraine with aura (91.3) and episodic tension headache (85.1%). Out of 1191 who had a headache, only 188 (15.9%) had a medical consultation. There was no a statistically significant difference in prevalence of tension headache and migraine according to faculties. There was a statistically significant difference in patients with migraine according to academic year, living with family and smoking. The effect on daily activities was higher in chronic tension-type headache and migraine without aura. There is a significant lack of medical consultation among students and most of them took over the counter analgesics depending on personal choice.


Alterations in energy status by menadione metabolism in hepatocytes isolated from fasted and fed rats.
The biochemical mechanism of cytotoxicity, induced by the quinoid compound 2-methyl 1,4-naphthoquinone (menadione), was investigated in hepatocytes freshly isolated from fasted and fed rats. Hepatocytes from fasted rats were significantly more vulnerable to the toxicity of menadione than hepatocytes from fed rats. Menadione (150 microM) induced a 50% loss of viability of cells (LT50) from fasted rats after 55 min of incubation, whereas a LT50 of 80 min was observed after exposure of hepatocytes from fed rats to menadione. Glutathione and NADPH levels were rapidly depleted by menadione metabolism. This depletion was sustained during the incubation period. No significant differences were found in the time course and extent of the menadione-induced glutathione and NADPH depletion in hepatocytes of both nutritional states. Menadione also affected the energy status of the hepatocytes. The ATP content of cells from fasted rats decreased to 50% (AT50) within 18 min of exposure to menadione, whereas a 50% loss of ATP content of hepatocytes from fed rats was reached at 65 min. In contrast to depletion of glutathione and NADPH, the time course and extent of menadione-induced ATP depletion correlated well with the time of onset and rate of cell killing. Our results suggest that menadione metabolism may interfere with both mitochondrial and glycolytic ATP production. Depletion of ATP might be a critical step in menadione-induced cytotoxicity.


The effect of topical tranexamic acid on post-rhinoplasty periorbital ecchymosis and eyelid edema.
This study aimed to examine the effectiveness of topical tranexamic acid application in overcoming the periorbital ecchymosis and eyelid edema in patients who have undergone open technique rhinoplasty. Fifty patients were included in the study and divided into two groups: those who were applied topical tranexamic acid and those who were not (control). In the tranexamic acid group, tranexamic acid-soaked pledgets were placed under the skin flap in a way that both sides can reach the osteotomy area and left for 5 minutes. In the control group, isotonic saline-soaked pledgets were placed under the skin flap in the same way and left for 5 minutes. Digital photographs were obtained on postoperative day 1, 3 and 7. Eyelid edema and periorbital ecchymosis were scored by two different examiners and averaged for comparison. The edema that developed in the patients who applied tranexamic acid was significantly less than in the control group on the postoperative day 1. There was no difference between the two groups on postoperative day 3 and 7. The ecchymosis developed in patients who applied tranexamic acid was significantly less than in the control group on all days. Topical tranexamic acid applied to the surgical field immediately after osteotomy in rhinoplasty surgery reduces the development of postoperative periorbital ecchymosis. In addition, the topical tranexamic acid application also reduces the development of eyelid edema in the early postoperative period.


Aortic dissection after stent dilatation for coarctation of the aorta: a case report and literature review.
A case of stenting for native coarctation is described in a 65-year-old female with a fatal dissection after implantation. The histology of the aorta in coarctation and in the elderly is described. The experience of stenting in older patients is reviewed and discussed.


Selective excision of 5-carboxylcytosine by a thymine DNA glycosylase mutant.
The mammalian thymine DNA glycosylase (TDG) excises the mismatched base, uracil, thymine or 5-hydroxymethyluracil (5hmU), as well as removes 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) when paired with a guanine. In the previously solved structure of TDG in complex with DNA containing 5caC, the side chain of asparagine 157 (N157) contacts the 5-carboxyl moiety of 5caC via a weak hydrogen bond. We examined the role of N157 in recognition of 5caC by mutagenesis. The asparagine-to-alanine (N157A) mutant has no detectable base excision activity for a G:T mismatch, and its excision activity is reduced for other substrates including G:5caC. Unexpectedly, the asparagine-to-aspartate (N157D) mutant has a comparable base excision rate for G:5caC substrate to that of wild type, but it only has residual activity for G:U and no detectable activity for other substrates. We further show that the N157D mutant has higher activity for 5caC at a lower pH (6.0), suggesting that increased protonation of the carboxylate of 5caC and the aspartate facilitates base excision. The N157D mutant remains highly specific for 5caC even in the presence of large excess of genomic DNA, a property that can potentially be used for mapping the very low amount of 5caC in genomes.


Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis.
Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-gamma and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-gamma and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-alpha, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.


Basic trauma life support.
The impact of traumatic injuries on modern society in terms of morbidity, mortality, and economic cost is enormous. Studies have shown that both advanced life support skills and rapid stabilization and transport of the trauma victim have a beneficial effect on the patient's ultimate outcome. The Basic Trauma Life Support (BTLS) course was designed to provide pre-hospital care providers with the skills necessary to provide a thorough assessment, initial resuscitation, and rapid transportation of the trauma victim. Early studies suggest that the material is easily learned by prehospital care providers and that the on-scene time for trauma cases is reduced following training in BTLS. More widespread training in BTLS may have a significant effect on the mortality and morbidity associated with traumatic injuries.


Anti-sense RNA efficiently inhibits formation of the 10 kd polypeptide of photosystem II in transgenic potato plants: analysis of the role of the 10 kd protein.
A chimeric gene encoding an anti-sense RNA of the 10 kd protein of the water-splitting apparatus of photosystem II of higher plants under the control of the CaMV 35S promoter was introduced into potato using Agrobacterium based vectors. The expression of the anti-sense RNA led to a significant reduction of the amounts of the 10 kd protein and RNA in a number of transgenic plants. In three out of 36 plants tested, the level of the 10 kd protein was only up to 1-3% compared with the wild-type control. The drastic reduction of the 10 kd protein did not influence the accumulation of other photosystem II associated polypeptides at both the RNA and protein level. Furthermore no phenotypic differences were observed between potato plants expressing wild-type and drastically reduced levels of the 10 kd protein with respect to growth rate, habitus or ultrastructure of the chloroplasts. Measurements of the relaxation of the flash-induced enhancement in the fluorescence quantum yield as determined in intact leaves and the rates and characteristic oscillation pattern of O2 evolution as determined in isolated thylakoid samples however, show that the elimination of the 10 kd protein on the one hand retards reoxidation of QA- and on the other hand introduces a general disorder into the PSII complex.


Meandering right pulmonary vein associated with severe and progressive "idiopathic-like" pulmonary hypertensive vascular disease.
Congenital anomalies of the pulmonary veins are rare. Meandering right pulmonary vein, considered a part of the Scimitar syndrome spectrum, is often an incidental finding during chest imaging. We present the case of a 4-year-old girl diagnosed with meandering pulmonary vein, who developed pulmonary hypertensive disease with an aggressive course, in spite of absence of hypoxia or elevated pulmonary wedge pressure.


Fetal transient clitoromegaly and transient hypertrophy of the labia minora in early and mid pregnancy.
The purpose of this study was to describe a series of cases of transient changes in the female fetal external genitalia. In our practice area, most pregnant women usually undergo a detailed sonographic survey of all fetal organs, including the external genitalia in early and mid pregnancy. During the study period (1987-2010), 62,145 consecutive pregnant women were scanned. We detected 4 fetuses with an isolated finding of clitoromegaly at 15 to 16 weeks' gestation, which disappeared at 22 to 26 weeks. Maternal hormonal study results were normal. There was 1 case of clitoromegaly and a cloacal anomaly at 15 weeks' gestation, in which the clitoris retuned to a normal size at 22 weeks. In addition, there were 3 cases of hypertrophy of the labia minora in early pregnancy, which disappeared at 26 to 32 weeks. All fetuses in these series had a normal XX karyotype and normal external genitalia at birth. Transient changes in the appearance of the fetal external genitalia may occur in chromosomally normal female fetuses.


Leukocytes Crossing the Endothelium: A Matter of Communication.
Leukocytes cross the endothelial vessel wall in a process called transendothelial migration (TEM). The purpose of leukocyte TEM is to clear the causing agents of inflammation in underlying tissues, for example, bacteria and viruses. During TEM, endothelial cells initiate signals that attract and guide leukocytes to sites of tissue damage. Leukocytes react by attaching to these sites and signal their readiness to move back to endothelial cells. Endothelial cells in turn respond by facilitating the passage of leukocytes while retaining overall integrity. In this review, we present recent findings in the field and we have endeavored to synthesize a coherent picture of the intricate interplay between endothelial cells and leukocytes during TEM.


The action of rat cytosol enzymes on some methylated nucleic acid components produced by the carcinogenic N-nitroso compounds.
The stabilities of several alkylated nucleic acid components have been examined in the presence of cytosol extracts from a variety of rat tissues. An activity capable of demethylating O6-methyldeoxyguanosine was readily detectable in all tissues examined; arranged in approximate order of decreasing specific activity these are as follows: small intestine, spleen, kidney, lung, liver, skin, heart and brain. The in vitro requirements for the activity derived from liver and the observations that O6-methylguanine and its deoxynucleoside 5'-monophosphate are insensitive to the action of these extracts suggests that this activity may be due to an enzyme which resembles adenosine deaminase. In contrast to the ready degradation of O6-methyldeoxyguanosine the corresponding ethyl derivative was degraded very much more slowly but there was no evidence for other activities against the O4- and O2-methyldeoxythymidines. Similarly, no demethylation of the N-substituted deoxynucleosides, 3-methyldeoxycytidine 3-methldeoxythymidine, 1-methyldeoxyadenosine and 7-methyldeoxyguanosine, was detected.


Spinal cord compression in mycosis fungoides.
Symptomatic involvement of the central nervous system (CNS) with mycosis fungoides is rare, and usually characterized by involvement of meninges. We describe a patient with long-standing mycosis fungoides who developed acute spinal cord compression. Since tumor-related spinal cord compression requires early intervention for a successful outcome, it should be recognized as an additional form of CNS mycosis fungoides.


Diaphragmatic crus lipoma: a case report.
Diaphragmatic crus lipoma is a very rare entity. In this case report, smooth, rounded masses of diaphragmatic lipoma, incidentally observed in a 37-year-old female on routine abdominal computed tomographic scanning is presented.


Morphine-enhanced apoptosis in selective brain regions of neonatal rats.
Prolonged neonatal opioid exposure has been associated with: antinociceptive tolerance, long-term neurodevelopmental delay, cognitive, and motor impairment. Morphine has also been shown to induce apoptotic cell death in vitro studies, but its in vivo effect in developing rat brain is unknown. Thus, we hypothesized that prolongued morphine administration in neonatal rats in a model of antinociceptive tolerance and dependence is associated with increased neuroapoptosis. We analyzed neonatal rats from the following groups (1) naïve group (n=6); (2) control group (normal saline (NS), n=5), and (3) morphine group (n=8). Morphine sulfate or equal volume of NS was injected subcutaneously twice daily for 6½ days starting on postnatal day (PD) 1. Development of antinociceptive tolerance was previously confirmed by Hot Plate test on the 7th day. Evidence of neuronal and glial apoptosis was determined by cleaved caspase-3 immunofluorescence combined with specific markers. At PD7, morphine administration after 6½ days significantly increased the density of apoptotic cells in the cortex and amygdala, but not in the hippocampus, hypothalamus, or periaqueductal gray. Apoptotic cells exhibited morphology analogous to neurons. Irrespective of the treatment, only a very few individual microglia but not astrocytes were caspase-3 positive. In summary, repeated morphine administration in neonatal rats (PD1-7) is associated with increased supraspinal apoptosis in distinct anatomical regions known to be important for sensory (cortex) and emotional memory processing (amygdala). Brain regions important for learning (hippocampus), and autonomic and nociceptive processing (hypothalamus and periaqueductal gray) were not affected. Lack of widespread glial apoptosis or robust glial activation following repeated morphine administration suggests that glia might not be affected by chronic morphine at this early age. Future studies should investigate long-term behavioral sequelae of demonstrated enhanced apoptosis associated with prolonged morphine administration in a neonatal rat model.


Remote infarct of the temporal lobe with coexistent hippocampal sclerosis in mesial temporal lobe epilepsy.
In patients undergoing surgery for temporal lobe epilepsy, hippocampal sclerosis remains the most commonly observed pathology. In addition to hippocampal sclerosis, 5% to 30% of these resections on magnetic resonance imaging contain a second independently epileptogenic lesion, commonly referred to as dual pathology. A second etiology of seizure activity, as seen in dual pathology, may serve as an important cause of treatment failure in striving for post-operative seizure control. Dual pathology, consisting of hippocampal sclerosis and a remote infarct of the adjacent cortex, has been rarely reported. Cases of pathologically confirmed hippocampal sclerosis diagnosed between January 2000 and December 2012 (n = 349) were reviewed, and 7 cases of coexistent infarct (2%) formed the study group. Seven individuals (mean age, 29years; range, 5-47 years) with a mean epilepsy duration of 12.5years (3.3-25 years) and a mean pre-surgery frequency of 15 seizures per week (range, 0.5-56 seizures/week) were followed up postoperatively for a mean duration of 64months (range, 3-137 months). Pathologically, the most common form of hippocampal sclerosis observed was International League against Epilepsy type Ib or severe variant (n = 4). Four of the six individuals with post-surgery follow-up were seizure free at last encounter. The reported incidence of dual pathology, including hippocampal sclerosis and remote infarct, is low (2% in the present study) but may indicate a slightly increased risk of developing hippocampal sclerosis in the setting of a remote infarct. Surgical intervention for such cases anecdotally appears effective in achieving seizure control.


Preeclampsia and human reproduction. An essay of a long term reflection.
Hypertensive disorders of pregnancy (HDP: pregnancy-induced hypertension, preeclampsia, eclampsia) affect approximately 10% of human births. Women are at increased risk for HDP during their first conception; and/or when the conception is with a new partner (new paternity); when conception occurs very shortly after the beginning of their sexual relationship. A primary cause of preeclampsia is the defect of the normal human-specific deep endovascular invasion of trophoblast, which is a consequence of the nutritional demands of growth of the human fetal brain. The occurrence of preeclampsia represents a reproductive disadvantage unique to humans compared with other mammals. As such, it may have played a significant role in shaping human reproduction and, therefore, human sexuality. This deep implantation/preeclampsia phenomenon may explain many anthropological mysteries of human sexuality that do not exist in other mammalian species (and primates). These include: very low fertility rate, concealed ovulation, all year long 'apparent-waste-of-efficiency' sexuality, absence of sperm competition in human females at the time of conception, and the unexplained testicle size in human males compared with relevant primates. Further, this deep trophoblastic implantation (and its failure in preeclampsia) in humans might be a decisive condition of hominization between great apes and all the other Homo genuses. This frontier might even have occurred inside these Homo lineages: because of their relatively small brains, the first species of Homo might not have presented the deep trophoblastic invasion described in Homo sapiens.


Flow dependency and off-line measurement of exhaled NO in children.
Levels of exhaled nitric oxide (eNO) are flow-dependent, and the choice of an optimal flow rate for off-line and on-line eNO measurement has raised much debate. Recently, a flow rate of 50 ml/s was recommended, but children younger than 5-6 years are not capable of stabilizing their expiratory flow at low flow rates. The power of off-line eNO values to discriminate between normal and atopic children was therefore evaluated at different exhalation flow rates. At flow rates of both 8.3 ml/s and of 350 ml/s, children (8-12 years) sensitive to house dust mite have two-fold higher eNO values (p < 0.001) as compared with children lacking such a sensitivity. The power of eNO to discriminate between normal and atopic subjects was similar at the two flow rates (no difference in AUC of receiver operation curves, p = 0.89). All children from 4.5 to 5 years of age (n = 29) could perform a single off-line exhalation manoeuvre at high (>350 ml/s) but not at low (8.3 ml/s) flow rates. At high exhalation flow rate, eNO was 7.1 +/- 2.4 (mean +/- SD) median, 6.5 p.p.b. with a mean variation coefficient of 5.5%. Depending on their developmental level, about half of the younger children (35-46 months of age) could perform an off-line exhalation manoeuvre at high flow rate with good reproducibility (mean variation coefficient of 6.6%). It is concluded that an exhalation flow rate of 350 ml/s is feasible to determine off-line eNO-values in children from 3.5 years of age, and that this high flow rate does not compromise the power of eNO to detect allergic disease.


The Impact of Thyroid Function and TPOAb in the First Trimester on Pregnancy Outcomes: A Retrospective Study in Peking.
The impact of mild TSH elevation (2.5-4.08 mIU/L) on pregnancy outcomes is unclear. The treatment strategy for mild TSH elevation is dependent on thyroid peroxidase antibody (TPOAb) status according to the guidelines. To assess the effects of mild thyroid dysfunction combined with TPOAb status in the first trimester on pregnancy outcomes and the impact of levothyroxine (L-T4) treatment on pregnancy outcomes. The study retrospectively evaluated 3562 pregnant women. A total of 3296 untreated women were divided into 4 subgroups: group A: 4.08 < TSH <10 mIU/L, TPOAb+/-; group B: 2.5 < TSH ≤ 4.08 mIU/L, TPOAb+; group C: 2.5 < TSH ≤ 4.08 mIU/L, TPOAb-; and group D: 0.23 ≤ TSH ≤ 2.5 mIU/L, TPOAb+/-. The other 266 women with L-T4 treatment were divided into TSH 4.08 to 10 mIU/L and 2.5 to 4.08 mIU/L subgroups. The study was conducted at Peking University First Hospital in China. A total of 3562 pregnant women were evaluated. The incidence of pregnancy outcomes in the untreated subgroups (groups A-D) and treated subgroups were measured. Miscarriage and maternal composite outcome risks were 3.53 (1.85-6.75) and 2.19 (1.26-3.81) times greater in group A; 1.58 (1.17-2.13) and 1.27 (1.04-1.54) times greater in group C than in group D. L-T4 improved the miscarriage risk in the TSH 4.08 to 10 and 2.5 to 4.08 mIU/L groups but doubled the risk of gestational diabetes mellitus in the TSH 2.5 to 4.08 mIU/L treated group compared with the untreated group. TSH 2.5 to 4.08 mIU/L combined with TPOAb- during early pregnancy was associated with miscarriages and maternal composite outcomes. The advantages and disadvantages of L-T4 administration in TSH 2.5 to 4.08 mIU/L pregnant women remain uncertain.


Oxygenated functional group-driven spontaneous fabrication of Pd nanoparticles decorated porous carbon nanosheets for electrocatalytic hydrodechlorination of 4-chlorophenol.
Researchers have been committed to reducing the hazardous pollutants by developing efficient catalysts while ignoring the pollution caused by the use of toxic surface capping agents, reductants and/or organic solvents in the catalyst preparation process. To alleviate such problems, we here report a novel one-step oxygenated functional group-driven electroless deposition strategy to synthesize clean and uniformly distributed Pd nanoparticles (NPs) using porous carbon nanosheets (PCN) as both substrates and reducing agents. It is observed that the oxygenated functional groups enriched PCN possesses a low work function and allows the spontaneous reduction of PdCl42- ions to Pd NPs deposited on the PCN support (Pd/PCN). The particle size of Pd NPs can be flexibly modulated by simply controlling the immersing time and thereby their maximum catalytic performances can be achieved. Specifically, the optimal Pd/PCN-08 with a Pd loading of 3.0 wt% shows an excellent activity with a turnover frequency of 0.38 min-1 for electrocatalytic hydrodechlorination (ECH) of 4-chlorophenol (4-CP), superior to the previously reported materials. The stability of Pd/PCN-08 for 4-CP ECH is impressive in repetitive cycles. This work proposes a facile and efficient strategy to synthesize high-performance catalysts for detoxifying the hazardous organic pollutants.


Variability of subfoveal choroidal thickness measurements in patients with age-related macular degeneration and central serous chorioretinopathy.
To evaluate the variability in subfoveal choroidal thickness measurements in patients with age-related macular degeneration (AMD) and central serous chorioretinopathy using enhanced depth imaging optical coherence tomography (EDI-OCT). One hundred and sixty eyes of 160 patients who were diagnosed with early AMD (N=40), exudative AMD (N=40), polypoidal choroidal vasculopathy (PCV, N=40), or central serous chorioretinopathy (CSC, N=40) were included in this retrospective observational study. In addition, we included 40 normal eyes of 40 subjects. Subfoveal choroidal thickness was measured manually by two masked observers based on EDI-OCT images. The correlation of choroidal thickness with the absolute value of the difference in the choroidal thickness measurement was estimated for all 200 eyes. Intraobserver and interobserver coefficients of repeatability (CRs) were calculated. There was a significant positive correlation between subfoveal choroidal thickness and both intraobserver (P<0.001) and interobserver (P<0.001) difference in choroidal thickness measurements. The mean intraobserver CRs in nonexudative AMD, exudative AMD, PCV, CSC, and normal eyes were ~15-21, 23-29, 24-35, 32-38, and 19-25 μm, respectively. The mean interobserver CRs were ~24-28, 30-36, 39-45, 46-57, and 26-35 μm, respectively. Relatively great measurement variability should be considered when investigating eyes with pathologic conditions related to a thick choroid, including PCV or CSC.


Higher concentration of 25-hydroxycholesterol in treatment-naïve patients with type 2 diabetes compared to healthy individuals.
Oxysterols are cholesterol oxidation derivatives with diverse biological activities. However, little is known about the oxysterol levels in treatment-naïve patients with type 2 diabetes. We utilized gas chromatography-mass spectrometry to investigate the potential association between oxysterol concentrations and type 2 diabetes and atherosclerosis in treatment-naïve patients diagnosed with type 2 diabetes. This case-control study enrolled 53 eligible patients with type 2 diabetes and 50 healthy volunteers. We compared serum oxysterol concentrations between the two groups; we examined the correlation between the oxysterol concentrations and the carotid plaque score in the type 2 diabetes group. Univariate analysis revealed significant differences in the concentrations of oxysterols (i.e., cholesterol-5α, 6α-epoxide; cholesterol-5β, 6β-epoxide; 7β-hydroxycholesterol; and 25-hydroxycholesterol [25-HC]) and other cardiovascular risk factors between the two groups. The 25-HC concentration was almost twofold greater in the type 2 diabetes group than in the healthy volunteers (median [interquartile range]: 8.52 [6.37-11.26] vs. 4.58 [3.45-5.44] ng/mL). After adjusting for multiple covariates, such as age, body mass index, mean arterial pressure, and triglyceride, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels, only the concentration of 25-HC showed a significant association with type 2 diabetes. However, the univariate analysis failed to demonstrate any significant correlation between oxysterol concentrations and the carotid plaque score among individuals with type 2 diabetes. The levels of various oxysterols differ between treatment-naïve patients with type 2 diabetes and healthy individuals; the 25-HC level differs the most prominently.


Reply to Kalfert, D. Comment on "Zwierz et al. The Long-Term Effects of 12-Week Intranasal Steroid Therapy on Adenoid Size, Its Mucus Coverage and Otitis Media with Effusion: A Cohort Study in Preschool Children. J. Clin. Med. 2022, 11, 507".
We wish to thank the author for raising the issues of how we performed the adenoid size classification and why we did not classify the condition of the nasopharyngeal orifice of the Eustachian tube [...].