Alterations of the p16/MTS1-tumor suppressor gene in gastric cancer.
Deletions, mutations and the functional inactivation of tumor suppressor gene p16 are involved in the genesis of different neoplasias. Little is known about the role of p16 gene alterations in the genesis of gastric carcinomas. This study aimed to detect genetic alterations of the p16 gene in gastric carcinomas. We analyzed p16 gene mutations and the frequency of loss of heterozygosity (LOH) at the p16 locus in 43 gastric carcinomas. PCR-SSCP analysis of exons 1 and 2 revealed only one gene mutation in a carcinoma of the diffuse type. Besides carcinomas of the diffuse, intestinal and the mixed type, we also investigated a small-cell primary gastric carcinoma, which was the only one to show a deletion in the p16 gene. LOH analysis was performed using two polymorphic markers located near the p16 gene (D9S171, D9S162) and a sequence-tagged-site marker (c5.1). Allelic loss was noted in two carcinomas of the diffuse type and in one carcinoma of the intestinal type. Allelic instabilities were found in one tumor of the intestinal type and diffuse type each. Although only five of 43 (11.6%) gastric carcinomas had p16 alterations, tumors of the diffuse type tend to show a higher number of genetic alterations near the p16 locus.


Synthesis of single-stranded hybridization probes from reusable DNA templates bound to solid support.
A convenient and rapid technique for preparing radiolabeled single-stranded DNA hybridization probes has been developed. Single-stranded recombinant M13 phage DNA containing the mRNA strand of a cloned cDNA is bound to diazobenzyloxymethyl-cellulose in a manner that permits the synthesis of a complementary DNA using reverse transcriptase and primed with either oligo(dT) or the M13 single-stranded primer. A procedural advantage is that after synthesis the unincorporated radiolabeled nucleotides are washed away easily, and the radiolabeled single-stranded DNA probe is eluted with formamide, ready for use. To limit the DNA copy to the insert, a preliminary synthesis reaction is performed with unlabeled nucleotides, primer, and enzyme, followed by digestion of the reaction mix with a restriction endonuclease that recognizes a unique site in the recombinant immediately upstream of the cDNA insert. After elution of the unlabeled synthesized complementary DNA, a second synthesis reaction yields highly radiolabeled single-stranded DNA that extends only the length of the mRNA insert. A major advantage is that the restriction enzyme-cleaved, cellulose-bound template can be stored and reused repeatedly.


Imaging of the pediatric airway using optical coherence tomography.
Optical coherence tomography (OCT) is an imaging modality that uses a broadband light source to produce high-resolution cross-sectional images in living tissue (8-20 microm). A prospective study of normal, benign, and pathologic tissues in the pediatric airway was conducted to assess the utility of OCT technology in characterizing the microanatomy of the pediatric upper aerodigestive tract in vivo. Prospective clinical trial. Fifteen patients from 1 to 17 years of age underwent surgical endoscopy and OCT for various airway disorders. OCT imaging was performed at a frame rate of 1 Hz using a 1.3-microm broadband light source to produce images 1.6 x 6 mm in vertical and horizontal dimensions. The epithelium, lamina propria, and unique tissue microstructures were visualized and then measured using digital micrometry. Direct comparison of OCT images with endoscopic photography was performed. Systematic imaging of the oral cavity, oropharynx, hypopharynx, and larynx was performed in all 15 patients. Normal microstructures identified included papillae, ducts, glands, and vessels, whereas pathologic conditions included distinct zones of mature scar, granulation tissue, edema, ulceration, and papillomatosis. Endoscopic photographs were well correlated with OCT images. OCT is capable of obtaining high-resolution microanatomy images of pediatric airway in vivo tissue. OCT clearly identifies the epithelium and lamina propria while providing detailed structural information on normal and diseased tissues. OCT is a promising emerging imaging modality for use in current pediatric patient populations.


High prevalence of reduced fertility and use of assisted reproductive technology in a German cohort of patients with peripartum cardiomyopathy.
Over the past decades the use of assisted reproduction technology (ART) increased worldwide. ARTs are associated with an elevated risk for cardiovascular complications. However, a potential relation between subfertility/ARTs and the heart disease peripartum cardiomyopathy (PPCM) has not been systematically analyzed yet. A retrospective cohort study was carried out, including n = 111 PPCM patients from the German PPCM registry. Data from PPCM patients were compared to those from postpartum women in the German general population. The prevalence of reported subfertility was high among PPCM patients (30%; 33/111). Most of the subfertile PPCM patients (55%; 18/33) obtained vitro fertilizations (IVF) or intracytoplasmic sperm injections (ICSI). PPCM patients were older (p < 0.0001), the percentage of born infants conceived by IVF/ICSI was higher (p < 0.0001) with a higher multiple birth (p < 0.0001), C-section (p < 0.0001) and preeclampsia rate (p < 0.0001), compared to postpartum women. The cardiac outcome was comparable between subfertile and fertile PPCM patients. Whole exome sequencing in a subset of n = 15 subfertile PPCM patients revealed that 33% (5/15) carried pathogenic or likely pathogenic gene variants associated with cardiomyopathies and/or cancer predisposition syndrome. Subfertility occurred frequently among PPCM patients and was associated with increased age, hormonal disorders, higher twin pregnancy rate and high prevalence of pathogenic gene variants suggesting a causal relationship between subfertility and PPCM. Although this study found no evidence that the ART treatment per se increases the risk for PPCM or the risk for an adverse outcome, women with subfertility should be closely monitored for signs of peripartum heart failure.


Should psychomotor disturbance be an essential criterion for a DSM-5 diagnosis of melancholia?
The CORE measure has proved useful in rating observed psychomotor disturbance (PMD), which has been held to be a key feature of melancholic depression. However, studies have shown a substantial percentage of subjects fulfilling DSM criteria for melancholia do not have observable PMD. A semi-structured interview schedule was used in assessing and diagnosing depressed older patients. DSM-IV diagnoses were made, and the CORE measure was used to rate PMD. Comparisons were made between melancholia inpatients who scored low and those scoring high on the CORE in relation to presentation and pattern of symptoms. Of 32 inpatients with melancholia, 10 scored 0-7, 8 scored 8-10, and 14 scored 15 or more on the CORE. Thirty-two inpatients with psychotic depression scored 13 or more. High-CORE participants manifested unvarying depression more often than did low-CORE participants, and were less likely to state that stress precipitated their depressive episode. High-CORE melancholia cases appear to have more in common with psychotic depression than do low-CORE cases. Designation of observable PMD as an essential criterion in making a diagnosis of melancholia could increase the utility of the DSM classification in relation to treatment planning.


Biomonitoring the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in hair: impact of exposure, hair pigmentation, and cytochrome P450 1A2 phenotype.
Hair is a promising tissue to assess exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogen formed in cooked meats. However, an understanding of how dietary exposure to PhIP, cytochrome P450 1A2 activity-a key enzyme involved in PhIP metabolism, and hair pigmentation affect the level of PhIP accrued in hair is required to determine the reliability of the PhIP hair level as a biomarker of exposure to this carcinogen. We examined the impact of PhIP exposure, cytochrome P450 1A2 activity, and hair pigmentation on the levels of PhIP accumulated in the hair of volunteers on a 4-week semicontrolled diet of cooked meat containing known quantities of PhIP. The amount of PhIP in hair increased, on average, 15-fold in light- and dark-haired individuals during consumption of cooked meat. PhIP levels in hair were correlated to PhIP intake (ρ = 0.53; P < 0.001), and the relationship was strengthened when PhIP levels were normalized for the melanin content of hair (ρ = 0.71; P < 0.001). However, PhIP accrual in hair was not correlated to cytochrome P450 1A2 activity, as assessed by the caffeine test, or to the levels of unmetabolized PhIP in urine or to the metabolic ratio of the major urinary metabolite N(2)-(β-1-glucosiduronyl-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine to unmetabolized PhIP. The use of the PhIP hair biomarker should take hair pigmentation into account for accurate exposure assessment of PhIP. PhIP hair levels can serve as a biomarker in epidemiologic studies investigating the association of heterocyclic aromatic amine (HAA), cooked meat, and cancer risk.


Isolation of spontaneous and interferon inducible natural killer like cells from human colonic mucosa: lysis of lymphoid and autologous epithelial target cells.
Viable mononuclear and epithelial cells were dispersed from human colonic tissue by treatment with collagenase and ethylene diamino-tetra acetate (EDTA) and separated by centrifugal elutriation. Using a single cell cytotoxic assay, functional endogenous and interferon responsive mononuclear cytotoxic cells were detected. Compared to peripheral blood lymphocyte associated killer cells that had been exposed to similar treatment, these colonic killer cells demonstrated lower efficiency cytotoxicity of Molt-4 target cells. Furthermore, inefficient, but interferon responsive cytotoxic cells were present which bound and lysed freshly isolated autologous epithelial cells. The cytotoxicity of these colonic mononuclear natural killer (NK) like cells appeared specific in that cells bound but did not lyse NK resistant Raji cells, even after interferon activation.


Thoracic actinomycosis.
Thoracic actinomycosis is a disease that is difficult to diagnose because its appearance varies from similarities with bronchogenic carcinoma to pneumonitis-like tuberculosis infections. Therefore the majority of patients undergo operations for diagnosis. We had seven patients with thoracic actinomycosis which were not diagnosed before operation. Between July 1990 and November 1997, seven patients with thoracic actinomycosis were diagnosed after thoracotomy in our centre. They all had non-specific symptoms and radiographic findings, so we failed to diagnose the disease during preoperative examinations. Therefore they all underwent thoracotomy for diagnosis. Four patients were operated because of suspicion of malignancy, two patients were operated because of pulmonary infiltration and abscess formation and one patient because of undiagnosed pulmonary infiltration. Lobectomy was performed in five of them because of destroyed lobes, and wedge resection was performed in two patients. In two patients the disease was diagnosed by fresh smears obtained from specimens in the course of operation and confirmed histopathologically and in the others histopathologically in the postoperative period. Three major complications, acute renal failure, empyema and persistent air leakage developed in three cases after the operations. Bronchopleural fistula was found in only one of them and the patient died because of uncontrolled infection and sepsis on the 26th postoperative day. All of the other six cases are still alive. We did not observe any other problem in their long-term follow-up. All patients regularly took 20 million units/day of intravenous crystalline penicillin G when they were in the hospital. After that, antibiotic treatment was completed up to 2 months with procaine penicillin. Sometimes diagnosis of the actinomycosis of the lung is very difficult although it is an infection. In that case thoracotomy is needed for the diagnosis and sometimes for the treatment. In some cases because of the irreversible parenchymal change resective surgery may be needed. Actinomyces israelii infections should be suspected of in chronic infiltrative, nodular, cavitary process and tumour-like mass lesions besides other most probable causes. After diagnosed, it is treated using penicillin chemotherapy at least for 2 months.


Eukaryotic gene prediction using GeneMark.hmm-E and GeneMark-ES.
This unit describes how to use the gene-finding programs GeneMark.hmm-E and GeneMark-ES for finding protein-coding genes in the genomic DNA of eukaryotic organisms. These bioinformatics tools have been demonstrated to have state-of-the-art accuracy for many fungal, plant, and animal genomes, and have frequently been used for gene annotation in novel genomic sequences. An additional advantage of GeneMark-ES is that the problem of algorithm parameterization is solved automatically, with parameters estimated by iterative self-training (unsupervised training).


Infraorbital pigmented skin. Preliminary observations of laser therapy.
The presence of infraobital dark skin, often known as dark circles under the eyes, is a frequent cosmetic concern. There has been little reported on therapy of this condition. One group of patients was determined to have dermal melanin deposition, which we treated with a Q-switched ruby laser. Our study evaluated the clinical and histological appearance of infraobital skin pigment in 17 patients with dermal melanin deposition treated with a Q-switched ruby laser. Seventeen patients with melanin deposition were treated with the Q-switched ruby laser (694 nm) with a pulse width of 28 nanoseconds and fluences of 7.5 J/cm2. Response to treatment was assessed by an independent investigator with patient and photograph evaluation. Skin Biopsies were obtained in nine of the 17 patients. Of those patients treated with one Q-switched ruby session, 23.5% achieved a greater than 50% response. Of those treated twice, 88.9% achieved greater than 50% response. In postreatment skin biopsies there was reduction of dermal melanin deposition. Patients with infraobital pigmented skin due to dermal melanin deposition may be considered candidates for Q-switched Ruby laser treatment.


Lurbinectedin: an FDA-approved inducer of immunogenic cell death for the treatment of small-cell lung cancer.
Lurbinectedin is a DNA-binding inhibitor of transcription that potently induces immunogenic cell death (ICD). In June 2020, the Federal Drug Administration (FDA) approved lurbinectedin for the salvage treatment of small-cell lung cancer that has relapsed from platinum compound-based first-line chemotherapy. Thus, the clinical activity of lurbinectedin may originate, at least in part, from the induction of ICD.


Serum Gamma Glutamyl transferase is a predictor of recurrence after R0 hepatectomy for patients with colorectal cancer liver metastases.
Gamma glutamyl-transpeptidase (GGT) has been shown as a prognostic marker in many cancers. The aim of this study was to explore whether serum GGT could predict tumor recurrence in patients with liver-confined colorectal cancer liver metastases (CRCLM) undergoing R0 resection. We reviewed patients who had underwent liver surgery for CRCLM. Patients with liver-only metastases that underwent R0 resection were included. Pre-operative serum GGT were classified into either high or low using a cut-off value of 33 U/L for female and 51 U/L for male. Relapse-free survival (RFS) was compared in relation to GGT and other clinicopathological factors. Of the 350 patients included, 108 (30.9%) had a high serum GGT. Patients with metachronous liver metastases, number of metastases ⩾2, size of the largest metastasis ⩾3 cm, or a history of neoadjuvant chemotherapy had a higher GGT level (p = 0.001, 0.027, 0.001, and 0.002, respectively). In survival analyses, patients with a high GGT had a shorter RFS than those with a low GGT, with a median RFS of 11.8 versus 30.3 months (p < 0.001). RFS was also associated with the number of metastases, size of the largest metastasis and the delivery of neoadjuvant chemotherapy. In multivariate analysis, GGT remained an independent prognostic factor of RFS. Our study demonstrates that the serum GGT level before liver surgery is an adverse prognostic factor of RFS for patients with liver-confined CRCLM.


Studies on glycosphingolipids of fresh-water bivalves. IV. Structure of a branched globoside containing mannose from spermatozoa of the fresh-water bivalve, Hyriopsis schlegelii.
1. A second novel globoside, provisionally named Lipid II in the previous study, was obtained from spermatozoa of the fresh-water bivalve, Hyriopsis schlegelii. The structure of this globoside was established by the results of partial acid hydrolysis, methylation studies, and oxidation with chromium trioxide. 2. The structure was shown to be GlcNAcbeta(1 leads to 2)Manbeta(1 leads to 3)[Xylbeta(1 leads to 2)]Manbeta(1 leads to 4)Glcbeta-(1 leads to 1)-ceramide. It is structurally related to the previously described globoside (Lipid I), except that a branched xylose is linked to the heterooligo saccharide chain of the latter lipid. 3. The predominant fatty acids were palmitic and stearic acids, and octadeca-4-sphingenine was the principal base, amounting to 70% of the total. The fatty acid and long-chain base compositions show nearly the same distribution in both of these globosides.


A subset of interneurons required for Drosophila larval locomotion.
Efforts to define the neural circuits generating locomotor behavior have produced an initial understanding of some of the components within the spinal cord, as well as a basic understanding of several invertebrate motor pattern generators. However, how these circuits are assembled during development is poorly understood. We are defining the neural circuit that generates larval locomotion in the genetically tractable fruit fly Drosophila melanogaster to study locomotor circuit development. Forward larval locomotion involves a stereotyped posterior-to-anterior segmental translocation of body wall muscle contraction and is generated by a relatively small number of identified muscles, motor and sensory neurons, plus an unknown number of the ~270 bilaterally-paired interneurons per segment of the 1st instar larva. To begin identifying the relevant interneurons, we have conditionally inactivated synaptic transmission of interneuron subsets and assayed for the effects on locomotion. From this screen we have identified a subset of 25 interneurons per hemisegment, called the lateral locomotor neurons (LLNs), that are required for locomotion. Both inactivation and constitutive activation of the LLNs disrupt locomotion, indicating that patterned output of the LLNs is required. By expressing a calcium indicator in the LLNs, we found that they display a posterior-to-anterior wave of activity within the CNS corresponding to the segmental translocation of the muscle contraction wave. Identification of the LLNs represents the first step toward elucidating the circuit generating larval locomotion.


Large-scale serosurveillance of COVID-19 in Japan: Acquisition of neutralizing antibodies for Delta but not for Omicron and requirement of booster vaccination to overcome the Omicron's outbreak.
Continuous appearance of SARS-CoV-2 variants and mass vaccination have been intricately influencing on the COVID-19 situation. To elucidate the current status in Japan, we analyzed totally 2,000 sera in August (n = 1,000) and December (n = 1,000) 2021 collected from individuals who underwent a health check-up. The anti-N seropositive rate were 2.1% and 3.9% in August and December 2021, respectively, demonstrating a Delta variant endemic during that time; it was approximately twofold higher than the rate based on the PCR-based diagnosis. The anti-S seropositive rate was 38.7% in August and it reached 90.8% in December, in concordance with the vaccination rate in Japan. In the December cohort, 78.7% of the sera showed neutralizing activity against the Delta variant, whereas that against the Omicron was much lower at 36.6%. These analyses revealed that effective immunity against the Delta variant was established in December 2021, however, prompt three-dose vaccination is needed to overcome Omicron's outbreak.


Incidence of Altered Sensation after Mandibular Premolar and Molar Periapical Surgery.
Altered sensation is a rare but disturbing adverse event after mandibular premolar and molar periapical surgery procedures, and its incidence is not known. The aim of this study was to determine the incidence of altered sensation after periapical surgery procedures in mandibular premolars and molars. This retrospective study includes patients who received periapical surgery in endodontic clinics of a university hospital in the United States. Data were obtained by review of the records for patients who met the inclusion criteria, and statistical analysis of possible predictive factors was performed using the 2-tailed Fisher exact test (α = 0.05). Sixty-two patients (63 teeth, 13 premolars and 50 molars) met the inclusion and exclusion criteria and were analyzed in the study. The first follow-up visit occurred 3 to 37 days after surgery. Altered sensation was observed in 9 patients. Observation of altered sensation was significantly higher (odds ratio = 7.19) after premolar surgeries (5/13) compared with molar surgeries (4/50). Despite the limited size and retrospective nature of this study, it was concluded that the incidence of altered sensation after periapical surgery appears to be relatively high (14%), with a higher incidence found in premolars compared with molars.


Effect of a factor VIII concentrate on type IIB von Willebrand's disease-associated thrombocytopenia presenting during pregnancy in identical twin mothers.
Marked thrombocytopenia developed during pregnancy in both identical twins mothers who had systemic lupus erythematosus (SLE) and also type IIB von Willebrand's disease (vWD). The proband's platelet count decreased in the third trimester of pregnancy. Large-dose gamma-globulin and prednisolone treatments were performed because of the suspicion of immune thrombocytopenic reaction associated with SLE. These treatments were not effective. Her platelet count returned to the normal range immediately after delivery. Postpartum examinations revealed the decreased ristocetin cofactor activity and the deficiency of large von Willebrand factor (vWF) multimers in preserved plasma samples from the third trimester. These abnormal findings improved after delivery. Investigation of family members revealed that the proband had inherited type IIB vWD from her mother. The other twin, who was also under treatment for SLE, became pregnant about 1 year after delivery in the proband and followed almost the same course as that observed in the proband. As bleeding tendency was observed a few days before delivery, a factor VIII concentrate (Haemate P) was administered to compete with her variant vWF. This concentrate could prevent the further decrease in her platelet count, thereby correcting the hemorrhagic tendency. It seems evident that factor VII concentrate would be effective in treating thrombocytopenia associated with type IIB vWD.


Multi-view graph embedding clustering network: Joint self-supervision and block diagonal representation.
Multi-view clustering has become an active topic in artificial intelligence. Yet, similar investigation for graph-structured data clustering has been absent so far. To fill this gap, we present a Multi-View Graph embedding Clustering network (MVGC). Specifically, unlike traditional multi-view construction methods, which are only suitable to describe Euclidean structure data, we leverage Euler transform to augment the node attribute, as a new view descriptor, for non-Euclidean structure data. Meanwhile, we impose block diagonal representation constraint, which is measured by the ℓ1,2-norm, on self-expression coefficient matrix to well explore the cluster structure. By doing so, the learned view-consensus coefficient matrix well encodes the discriminative information. Moreover, we make use of the learned clustering labels to guide the learnings of node representation and coefficient matrix, where the latter is used in turn to conduct the subsequent clustering. In this way, clustering and representation learning are seamlessly connected, with the aim to achieve better clustering performance. Extensive experimental results indicate that MVGC is superior to 11 state-of-the-art methods on four benchmark datasets. In particular, MVGC achieves an Accuracy of 96.17% (53.31%) on the ACM (IMDB) dataset, which is an up to 2.85% (1.97%) clustering performance improvement compared with the strongest baseline.


The role of speed of processing, inhibitory mechanisms, and presentation order in trail-making test performance.
The roles of speed of processing, inhibition, and presentation order in the Trail Making Test (TMT) performance were examined. One-hundred ten undergraduates performed the TMT (1/2 received order Part A-Part B, 1/2 received order Part B-Part A) and also completed computerized tests of inhibitory functioning and speed of processing. Neither speed of processing nor inhibitory functioning affected TMT performance. However, order of presentation significantly affected TMT performance. Presentation order is an important variable to consider in TMT performance.


Transcriptome analysis reveals complex response of the medicinal/ornamental halophyte Iris halophila Pall. to high environmental salinity.
The remediation and subsequent use of saline-alkaline land are of great significance to ecological environment construction and sustainable agricultural development. Iris halophila Pall. is a salt-tolerant medicinal and ornamental plant, which has good application prospects in the ecological construction of saline-alkaline land; therefore, study of the molecular mechanisms of salt tolerance in I. halophila has important theoretical and practical value. To evaluate the molecular mechanism of the response of I. halophila to salt toxicity, I. halophila seedlings were treated with salt (300 mM NaCl) and subjected to deep RNA sequencing. The clean reads were obtained and assembled into 297,188 unigenes. Among them, 1120 and 100 salt-responsive genes were identified in I. halophila shoots and roots, respectively. Among them, the key flavonoid and lignin biosynthetic genes, hormone signaling genes, sodium/potassium ion transporter genes, and transcription factors were analyzed and summarized. Quantitative reverse-transcription PCR analysis strengthened the reliability of the RNA sequencing results. This work provides an overview of the transcriptomic responses to salt toxicity in I. halophila and identifies the responsive genes that may contribute to its reduced salt toxicity. These results lay an important foundation for further study of the molecular mechanisms of salt tolerance in I. halophila and related species.


Simulated electronic health documentation: A cross-sectional exploration of factors influencing nursing students' intention to use.
The aim of this study was to investigate factors influencing nursing students' intention to use a simulated web-application 'Integrated Nursing Education System' for practicing electronic health documentation. The cross-sectional study was conducted at a Malaysian University that provides undergraduate nursing degree program. A total of 133 undergraduate nursing students in their year 2 to year 4 of the program were recruited. They had accessed the simulated web-application as part of the teaching-learning activities during the academic year 2016/2017. Technology Acceptance Model was used to guide the study. Validated questionnaires were used to measure the students' perceived ease of use, perceived usefulness, attitudes and intention to use the application. Data collection was done at the end of the semester. Data analysis was done using SPSS (19.0) and AMOS (23.0). Perceived usefulness was the most influential factor of the students' intention to use the simulated web-application. Perceived ease of use influenced their perceived usefulness significantly. Nurse educators should explain the usefulness of the simulated web-application before assigning students to access it to practice electronic health documentation. The availability of a stable internet access and IT support is important to influence students' perceived ease of use and intention to use the application.


Mechano-responsive fluorescent polydiacetylene-based materials: towards quantification of shearing stress at the nanoscale.
An OFF to ON mechano-responsive fluorescent polydiacetylene derivative has been prepared by photopolymerisation of a diacetylene covalently linked to a tetrazine fluorophore. This system has been studied at the nanoscale and shows a fluorescence emission intensity that increases with the intensity of the mechanical stimulation in the 20-200 nN range.


Increased serum gastrin concentrations and gastric acid hyposecretion in the immediate newborn period.
Thirty-two infants and their mothers were studied to determine the source of elevated serum gastrin concentrations in umbilical blood and to learn whether neonates hypersecreted acid in response to hypergastrinemia. Gastrin concentrations in the umbilical artery and vein were similar. Both were significantly higher than maternal gastrin concentrations. No significant amount of gastrin could be measured in placental extracts. These results suggest that the increased neonatal gastrin concentrations were fetal in origin. Continuous basal acid secretory studies done for 4 hr in 32 infants and for 8 hr in 9 infants demonstrated hyposecretion of gastric acid for the first 5 hr of life. Acid secretion from hour 6 to 8 was similar to that in older children. Increased gastrin levels were still present at hour 8 and were associated with normal gastric acid secretion.


Radiotherapy alone or combined with neck dissection for T1-T2 carcinoma of the pyriform sinus: an alternative to conservation surgery.
We present our experience with irradiation alone or combined with neck dissection for AJCC T1-T2 pyriform sinus carcinoma and compare our results to those obtained with conservation surgery. Seventy-three patients were treated between 1964 and 1990. All patients had a minimum of 2 years of follow-up; no patient was lost to follow-up. The 5-year rates of local control and ultimate local control were, for Stage T1 (17 patients), 88% and 94%; and for Stage T2 (56 patients), 79% and 91%. Patients with T2 lesions had a significantly higher rate of local control after twice-daily, compared with once-daily, irradiation (p = .04). However, a multivariate analysis of various parameters revealed that none of the variables tested significantly influenced this end point: vocal cord mobility (p = .15), once- vs. twice-daily fractionation (p = .33), T1 vs. T2 (p = .32), apex invasion (p = .58), and pretreatment CT scan (p = .67). Local control with laryngeal voice preservation was obtained in 88% of patients with T1 cancers and 80% of those with T2 cancers. Ultimate control above the clavicles at 5 years according to AJCC stage was as follows: I and II, 100%; III, 78%; IVA, 75%; and IVB, 60%. The probability of cause-specific survival at 5 years was as follows: I and II, 100%; III, 83%; and IVA and IVB, 51%. Overall, nine patients (12%) developed severe complications, one of which was fatal. Compared with available data from series using conservation surgery, radiotherapy alone or followed by neck dissection results in similar rates of local control and survival with a significantly lower risk of fatal complications.


Apoplexy in Richard Bright's (1789-1858) reports of medical cases.
This study examines Bright's cases in the section on pressure in Volume II of his Reports of Medical Cases of intracranial hemorrhages, cerebral congestion, and the "effusion of serum," which Bright regarded as causes of apoplexy. He arranged the cases of intracranial hemorrhages in such a way that it became possible to recognize the differences in the symptomatology of what is currently known as subarachnoid, subdural, and extradural bleeding and of intracerebral hemorrhages. The value of these reports rests mainly on the accurate documentation of the symptomatology of his cases and detailed autopsy reports, some accompanied by intricate illustrations. Bright's contributions to the notion of cerebral localizations and accounts of neurological conditions that were new or not well known at the time enhance the merit of this part of his Reports.


Danggui Shaoyaosan attenuates doxorubicin induced Nephrotic Syndrome through regulating on PI3K/Akt Pathway.
The study aimed to explore the role and the underlying mechanism of Danggui Shaoyaosan (DSS) in nephrotic syndrome (NS). NS rat model was induced by doxorubicin injection twice. After DSS treatment, inflammation and oxidative stress index were detected via ELISA. Western blot was used for the protein detection. Go and KEGG analysis was applied to evaluate target gene and signaling of DSS. MCP-5 cell was applied for the cell rescue experiments and mechanism exploration. The 24 h urine protein levels of NS rats increased significantly, which was reduced by DSS treatment in a concentration-dependent manner. After DSS treatment, levels of BUN, SCr, TG and TC were also decreased, and serum ALB and TP levels were increased in rats. GO and KEGG pathway enrichment identified PI3K-Akt to be the candidate signaling of DSS in the treatment of NS, which was activated in NS rats. The recuse experiments in MCP-5 demonstrated that IGF-1, the agonist of PI3K/AKT, abolished the beneficial role of DSS in podocyte cell viability, apoptosis, inflammation and oxidative stress. In conclusion, DSS exerts a protective role against the development of NS. The mechanism is related to the improvement of podocyte injury and the inhibition of PI3K/Akt pathway-related proteins.


UV-light promoted formation of boron nitride-fullerene composite and its photodegradation performance for antibiotics under visible light irradiation.
A series of C60/BN composites have been synthesized, which can efficiently photodegrade TC under visible-light irradiation. Compared with C60/BN-D6 and C60/BN-V6 synthesized under dark and visible-light irradiation, C60/BN-U6 synthesized under UV-light irradiation has the largest adsorption and photodegradation performance for TC under visible-light irradiation. FTIR and XPS characterizations suggest that C60/BN composite is most likely the charge transfer composite, in which C60 acts as electron acceptor and BN acts as electron donor. UV-light has the best promotion effect for the formation of C60/BN. The adsorption quantity of TC by C60/BN-U6 is 2.77 times higher than that of BN (131.05 mg g-1 vs. 47.27 mg g-1), being due to that C60/BN-U6 has higher surface area than BN (135.7 m2 g-1 vs. 18.8 m2 g-1). The photodegradation of C60/BN-U6 for TC follows Z-scheme heterojunction mechanism, as well as the photo-induced ·O2- and h+ are the dominant photoactive species. Quantitative structure-activity relationship (QSAR) method is applied to evaluate the toxicity of TC and its photodegradation intermediates. The photodegradation rate of C60/BN-U6 for TC is 19.19 times, 10.06 times, 5.83 times, 2.73 times and 1.84 times higher than that of TiO2 (P25), g-C3N4, BNPA, BCNPA, and BN/TiO2, respectively, implying that C60/BN-U is a good metal-free photocatalyst.


A TCR-like antibody against a proinsulin-containing fusion peptide ameliorates type 1 diabetes in NOD mice.
Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing β cells. The response of autoreactive T cells to β cell antigens plays a central role in the development of T1D. Recently, fusion peptides composed by insulin C-peptide fragments and other proteins were reported as β cell target antigens for diabetogenic CD4+ T cells in non-obese diabetic (NOD) mice. In this study, we generated a T cell-receptor (TCR)-like monoclonal antibody (mAb) against a fusion peptide bound to major histocompatibility complex (MHC) class II component to elucidate the function of the fusion peptides in T1D. In addition, we developed a novel NFAT-GFP TCR reporter system to evaluate the TCR-like mAb. The NFAT-GFP reporter T cells expressing the diabetogenic TCR were specifically activated by the fusion peptide presented on the MHC class II molecules. By using the NFAT-GFP reporter T cells, we showed that the TCR-like mAb blocks the diabetogenic T cell response against the fusion peptide presented on the MHC class II molecules. Furthermore, the development of T1D was ameliorated when pre-diabetic NOD mice were treated with this mAb. These findings suggest that NFAT-GFP reporter T cells are useful to assess the function of specific TCR and the recognition of fusion peptides by T cells is crucial for the pathogenesis of T1D.


Validation of the 33-item Hypomania Checklist (HCL-33) in screening adolescents with bipolar disorder.
Adolescents with bipolar disorder (BD) are often misdiagnosed with major depressive disorder (MDD), which delays the introduction of appropriate treatment resulting in adverse outcomes. This study examined the psychometric properties of the 33-item Hypomania Checklist (HCL-33) and its accuracy to distinguish BD from MDD in adolescents. A total of 248 participants (171 MDD and 77 BD patients) were recruited from a university-affiliated hospital in China. Depression was measured with the Hamilton Depression Rating Scale. All participants completed the assessment with the HCL-33. A two-factor structure was found for the HCL-33, which explained 30.2% of the total variance. The internal consistency and split half reliability of the total scale were acceptable. The optimal cut-off value of 18 generated sensitivity of 0.52 and specificity of 0.73 for distinguishing BD from MDD. The HCL-33 seems to be a useful screening instrument to distinguish BD from depressed adolescents. However, considering certain less than robust psychometric properties, the HCL-33 needs to be modified and further refined for adolescent patients.


Defining the duration of the dispensation of oral anticoagulants in administrative healthcare databases.
In clinical practice, warfarin therapy requires frequent dose adjustments. In pharmacy claims, the days supplied value may not reflect the true duration of warfarin dispensation. This may affect the measures of association comparing the safety of direct oral anticoagulants (DOACs) versus warfarin. Using Quebec healthcare administrative databases, we formed a cohort of 55 230 patients newly treated with oral anticoagulants between 2010 and 2016. The duration of dispensations was defined using two approaches: the recorded days supplied value, and the longitudinal coverage approximation (data-driven) that may account for individual variation in drug usage patterns. Propensity scores adjusted Cox proportional hazards regression models were used to estimate the hazard ratio (HR) of major bleeding with dabigatran or rivaroxaban versus warfarin. Using the days supplied, the mean (and standard deviation) dispensation durations for dabigatran, rivaroxaban, and warfarin were 19 (15), 19 (14), and 13 (12) days, respectively. Using the data-driven approach, the durations were 20 (16), 19 (15), and 15 (16) days, respectively. The choice of the approach had no impact on the HR estimates. In our settings, the data-driven approach closely approximated the recorded days supplied value for the standard dose therapies such as dabigatran and rivaroxaban. For warfarin, the data-driven approach captured more variability in the duration of dispensations compared to the days supplied value, which may better reflect the true drug-taking behavior of warfarin. Both approaches may provide valid estimates when comparing the safety of DOACs versus warfarin.


Antibody studies in the Kuru region. Immunological epidemiology of population groups in and adjacent to the Kuru region in Papua New Guinea. I. Enteroviruses.
A serological survey is reported for antibodies to Coxsackie, ECHO and polioviruses on sera collected in the kuru region of Papua New Guinea during earliest European contacts with kuru-affected and control populations through the period of highest kuru incidence. The results are discussed in the light of increasing European contact over the period of investigation. Suggestions are made concerning possible immunization programs with polioviruses.


Femtosecond laser-assisted cataract surgery in a spherophakic lens: An unusual case report.
Spherophakia is a rare diagnosis which is often associated with a shallow anterior chamber, angle-closure glaucoma, lens subluxation, and lenticular myopia. When cataracts occur with subluxation of the lens, vision is often markedly affected. This often presents surgeons with a unique challenge of maintaining good visual outcomes while minimizing potential complications. A 48-year-old female was referred for ophthalmological assessment due to decreased vision in the left eye. In the left eye, the best-corrected visual acuity at distance was 20/125 with manifest refraction of -6.5D + (-0.75) D × 118°. The slit lamp examination showed iridodonesis and a significant nuclear cataract (C3N3) with tremor in the left eye. After pupil dilation, a subluxated lens, weak zonules, and "fake golden ring" within the lens was noted. Due to the patient's symptoms, examination results, she was diagnosed with cataract, subluxation of the lens and spherophakia in left eye. The patient underwent an uneventful femtosecond laser-assisted cataract surgery (Alcon Fort Worth, TX). The laser was able to perform a circular free-floating anterior capsulotomy and easy lens fragmentation. There were no postoperative complications. At 3 months postoperatively, the uncorrected visual acuity was 20/25, and the manifest refraction was -0.25 D - 0.75 D × 148° with the corrected distance visual acuity of 20/16. Femtosecond laser-assisted cataract surgery is an effective approach for cataract surgery in patients with subluxated and spherophakic lenses, with the benefits of causing minimal further zonular damage and easy lens fragmentation.


The effects of mutating Tyr9 and Arg15 on the structure, stability, conformational dynamics and mechanism of GSTA3-3.
Glutathione S-transferase A3-3 is the most catalytically efficient steroid isomerase enzyme known in humans, transforming Δ5-androstene-3-17-dione into Δ4-androstene-3-17-dione. GSTA3-3 catalyzes this reaction with ten-fold greater efficiency than GSTA1-1, its closest competitor in the Alpha class of GSTs. In order to examine the differences between Alpha class GSTs and to better elucidate the mechanism of GSTA3-3 the roles of Tyr9 and Arg15 were examined. Tyr9 is the major catalytic residue of Alpha class GSTs and Arg15 is proposed to be catalytically important to GSTA3-3 but never before experimentally examined. While the structure and stability of the Alpha class enzymes are highly comparable, subtle differences at the G-site of the enzymes account for GSTA3-3 having a ten-fold greater affinity for the substrate GSH. Y9F and R15L mutations, singly or together, have no effect on the structure and stability of GSTA3-3 (the same effect they have on GSTA1-1) despite the R15L mutation removing an interdomain salt-bridge at the active site. Hydrogen-deuterium exchange mass spectrometry also revealed that neither mutation had a significant effect on the conformational dynamics of GSTA3-3. The R15L and Y9F mutations are equally important to the specific activity of the steroid isomerase reaction; however, Arg15 is more important for lowering the pKa of GSH. Lowering the pKa of GSH being how GSTs catalyze their reactions. Additionally, there is evidence to suggest that Arg15 is integral to allowing GSTA3-3 to differentiate between Δ5-androstene-3-17-dione and Δ4-androstene-3-17-dione, indicating that Arg15 is a more important active-site residue than previously known.


Intra-operative correction of acidosis, coagulopathy and hypothermia in combat casualties with severe haemorrhagic shock.
We assessed acidosis, coagulopathy and hypothermia, before and after surgery in 51 combat troops operated on for severe blast injury. Patients were transfused a median (IQR [range]) of 27 (17-38 [5-84]) units of red cell concentrate, 27 (16-38 [4-83]) units of plasma, 2.0 (0.5-3.5 [0-13.0]) units of cryoprecipitate and 4 (2-6 [0-17]) pools of platelets. The pH, base excess, prothrombin time and temperature increased: from 7.19 (7.10-7.29 [6.50-7.49]) to 7.45 (7.40-7.51 [7.15-7.62]); from -9.0 (-13.5 to -4.5 [-28 to -2]) mmol.l⁻¹ to 4.5 (1.0-8.0 [-7 to +11]) mmol.l⁻¹; from 18 (15-21 [9-24]) s to 14 (11-18 [9-21]) s; and from 36.1 (35.1-37.1 [33.0-38.1]) °C to 37.4 (37.0-37.9 [36.0-38.0]) °C, respectively. Contemporary intra-operative resuscitation strategies can normalise the physiological derangements caused by haemorrhagic shock.


CX3CR1 polymorphisms and the risk of age-related macular degeneration.
Age-related macular degeneration (AMD), a most common eye disease, can lead to irreversible visual impairment. Age, genetic and environmental factors have been implicated in AMD. Chemokine (C-X3-C motif) receptor 1 (CX3CR1) gene polymorphisms could influence the susceptibility of AMD. We tested the association between AMD and single nocleotide polymorphisms (SNPs) of CX3CR1 gene (rs3732378 and rs3732379) in 102 cases and 115 controls from China. Genotypes were determined by MassArray genotyping assay method. Association between CX3CR1 gene polymorphisms and AMD were examined by χ(2) test and logistic regression. Genotype distribution of CX3CR1 gene polymorphisms were in accordance with HWE examination. No obvious differences were observed in the genotypes of rs3732378 polymorphism between case and control groups (P>0.05), but A allele of it could increase the risk of AMD (P=0.025, OR=2.391, 95% CI=1.092-5.237). Both TT genotype and T allele of rs3732379 were significantly associated with the susceptibility of AMD (P=8.663, OR=8.663, 95% CI=1.044-71.874; P=0.021, OR=2.076, 95% CI=1.104-3.903). Age, gender and smoking status were used as common confounders to adjust the association between CX3CR1 gene polymorphism and AMD risk. Then we found that rs3732378 had no obvious association with AMD susceptibility. TT genotype of rs3732379 related to the occurrence of AMD, but the association was not significant (P=0.050, OR=8.274, 95% CI=1.002-69.963). T allele of rs3732379 might increase the susceptibility of AMD (P=0.029, OR=2.033, 95% CI=1.077-3.838). T allele of rs3732379 might have a positive association with the susceptibility of AMD.


Surgical correction of nipple hypertrophy in male gynecomastia: case report.
We report a case of nipple hypertrophy in male gynecomastia. By raising 4 small quadrant flaps on the areolar-nipple junction, we were able to do an appropriate core excision of the gynecomastia and hypertrophied nipple--and closure of the flaps produced a small simulated nipple.


Green Synthesized Silver Nanoparticles: A Potential Antibacterial Agent, Antioxidant, and Colorimetric Nanoprobe for the Detection of Hg2+ Ions.
Silver nanoparticles (AgNPs) prepared by green synthesis have a lot of potentials in various fields. Among them, as an antioxidant, antibacterial agent, and nanoprobe for the colorimetric detection of mercury (Hg2+) ions is thought to be the most important. The antibacterial, antioxidant, and colorimetric sensing potential of the greenly produced AgNPs utilizing Piper chaba stem extract are all predicted in this investigation. By using the disc diffusion method, the antibacterial activity of greenly produced AgNPs are assessed, and the findings are measured from the zone of inhibition (ZOI). It is revealed that the Staphylococcus aureus, Micrococcus spp., Escherichia coli, and Pseudomonas aeruginosa bacterial strains are significantly resisted by the greenly produced AgNPs. The antioxidant activity test of AgNPs reveals a considerable impact on free radical scavenging having the inhibitory concentration (IC 50) is 1.13 mL (equivalent to 0.45 mg mL-1). Also, with a low limit of detection of 28 ppm, the resulting AgNPs are used as highly selective and economical colorimetric sensors for Hg2+ detection. The study's findings support the hypothesis that Piper chaba stems can serve as a source for the production of AgNPs with high antibacterial and antioxidant activity and usefulness for simple colorimetric readings of Hg2+.


Propagation effects of current and conductance noise in a model neuron with subthreshold oscillations.
We have examined the effects of current and conductance noise in a single-neuron model which can generate a variety of physiologically important impulse patterns. Current noise enters the membrane equation directly while conductance noise is propagated through the activation variables. Additive Gaussian white noise which is implemented as conductance noise appears in the voltage equations as an additive and a multiplicative term. Moreover, the originally white noise is turned into colored noise. The noise correlation time is a function of the system's control parameters which may explain the different effects of current and conductance noise in different dynamic states. We have found the most significant, qualitative differences between different noise implementations in a pacemaker-like, tonic firing regime at the transition to chaotic burst discharges. This reflects a dynamic state of high physiological relevance.


The Alcohol Hangover Research Group: Ten Years of Progress in Research on the Causes, Consequences, and Treatment of the Alcohol Hangover.
The alcohol hangover is defined as the combination of negative mental and physical symptoms, which can be experienced after a single episode of alcohol consumption, starting when blood alcohol concentration (BAC) approaches zero. Here, we present the book "The alcohol hangover: causes, consequences, and treatment", written to celebrate the 10th anniversary of the Alcohol Hangover Research Group (AHRG), summarizing recent advances in the field of alcohol hangover research.


National and subnational survey on diabetes burden and quality of care index in Iran: a systematic analysis of the global burden of disease study 1990-2019.
Diabetes care is one of the major healthcare problems . This study aimed to introduce a recently-developed Quality of Care Index (QCI) for type 2 diabetes and utilized it to compare different genders, age groups, and Iranian provinces. From the Global Burden of Disease 1990-2019 database, we obtained primary epidemiologic measures and combined them to build four secondary indices, all indicating the quality of care provided to patients. We utilized the principal component analysis (PCA) method to calculate the substantial component named QCI (with a scale of 0-100). Gender inequality was shown by the gender disparity ratio (GDR), defining female to male QCI. National QCI ranged from 43.0 in 1990 to 38.6 in 2019. By excluding the more frequent outlier province; Tehran as the Capital of Iran, the QCI score reached 50.27 in 2019. The GDR decreased from 1.04 to 0.95. QCI indicated rather more favorable conditions in Iranian provinces with a higher socio-demographic index (SDI). Conversely, provinces with a lower SDI had worse QCI. In 2019, Tehran, the capital of Iran, with the highest (58.5), and South Khorasan with the lowest QCIs (0.4) were the two Iranian provinces' extremes. Moreover, the elderly QCI improved in 2019. During 1990-2019, there are remarkable disparities between Iran's provinces, genders and age groups. The equitable and widespread provision of facilities should be considered along with the decentralization of healthcare resources. The online version contains supplementary material available at 10.1007/s40200-022-01108-x.


Untargeted metabolite profiling of serum in rats exposed to pyrraline.
Pyrraline, one of advanced glycation end-products, is formed in advanced Maillard reactions. It was reported that the presence of pyrraline was tested to be associated with nephropathy and diabetes. Pyrraline might result in potential health risks because many modern diets are heat processed. In the study, an integrated metabolomics by ultra-high-performance liquid chromatography with mass spectrometry was used to evaluate the effects of pyrraline on metabolism in rats. Thirty-two metabolites were identified as differential metabolites. Linolenic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arachidonic acid metabolism, tyrosine metabolism and glycerophospholipid metabolism were the main perturbed networks in this pathological process. Differential metabolites and metabolic pathways we found give new insights into studying the toxic molecular mechanisms of pyrraline. The online version contains supplementary material available at 10.1007/s10068-023-01256-7.


[Red cell distribution width in the prognosis of surgical correction of congenital heart diseases].
To evaluate the capacity of red cell distribution width (RDW) to predict mortality in children undergoing cardiovascular surgery at the Fundación Hospital Infantil Napoleón Franco Pareja, in Colombia. Retrospective cross-sectional analytical study that included 45 individuals aged 0 to 17 years operated for congenital heart disease. The RACHS-1 (Risk Adjustment in Congenital Heart Surgery) scale and laboratory variables including the RDW were applied. The association between RDW and mortality was determined by ROC curve analysis and Spearman's rho correlation. An RDW greater than 15.52% represented 1.6 times more risk, compared to individuals below that value (95% confidence interval: 1.01-2.6; p = 0.034). The RDW values did not correlate with days of hospital stay or complications. The preoperative RDW and RACHS-1 score were significantly higher in the mortality group. The relationship between presurgical RDW and the RACHS-1 score was significant. In our study, the preoperative RDW had moderate power to discriminate perioperative mortality in the surgical correction of congenital heart disease. More studies with a larger sample size are required.


The effect of adjuvants added to local anaesthetics for single-injection upper extremity peripheral regional anaesthesia: A systematic review with network meta-analysis of randomised trials.
Peripheral regional anaesthesia is frequently used for upper extremity surgery. To prolong the duration of analgesia, adjuvants can be added to single-injection local anaesthetics. Despite attempts to compare several adjuvants in pairwise meta-analyses, a comprehensive comparison is still missing. The objective of this network meta-analysis was to determine the effectiveness of adjuvants in upper extremity peripheral nerve blocks. A systematic review of randomised controlled trials with network meta-analyses. A literature search in Embase, CENTRAL, MEDLINE and Web of Science was performed up to March 2023. Randomised trials comparing different adjuvants injected perineurally in peripheral upper extremity nerve blocks were eligible. Frequentist network meta-analysis was conducted using a random effects model with physiological saline as the comparator. The primary endpoint was the ratio of means (ROM) of the duration of analgesia. The review included 242 randomised controlled trials with a total of 17 391 patients. Twenty-eight adjuvants were compared in the largest networks. Most network estimations consisted of a high proportion of direct evidence. Fourteen adjuvants increased the duration of analgesia significantly by the following factors, ROM [95% confidence interval (CI)]: dexamethasone 1.95 (1.79 to 2.13), buprenorphine 1.83 (1.51 to 2.24), butorphanol 1.84 (1.41 to 2.39), potassium chloride 1.89 (1.15 to 3.11), dexmedetomidine 1.70 (1.59 to 1.81), sufentanil 1.70 (1.27 to 2.29), ketorolac 1.68 (1.24 to 2.27), midazolam 1.55 (1.24 to 1.94), tramadol 1.52 (1.32 to 1.75), nalbuphine 1.50 (1.30 to 1.72), morphine 1.43 (1.09 to 1.88), magnesium sulfate 1.42 (1.20 to 1.67), clonidine 1.36 (1.24 to 1.50) and fentanyl 1.23 (1.08 to 1.40). Inconsistency in network meta-analysis was substantial. Overall side effect rates were low with all adjuvants. The best interventions to prolong the duration of analgesia were dexamethasone, followed by dexmedetomidine, opioids, electrolytes, ketorolac and midazolam. There are general concerns about the quality of underlying studies and the risk of publication bias. PROSPERO 2018 CRD42018115722.


Male and female blastocysts: any difference other than the sex?
Is there any imbalance in the sex ratio at the blastocyst stage of human embryos? And what is the sex ratio in euploid, transferred, implanted blastocysts and at birth? Embryos from 646 women undergoing 921 preimplantation genetic testing for aneuploidy (PGT-A) cycles from September 2017 to February 2020 were included. Data from the chromosomal constitution of 2637 biopsied blastocysts were retrospectively analysed. Trophectoderm samples were analysed by next-generation sequencing. Embryos were categorized as euploid, mosaic or aneuploid. A total of 548 blastocysts diagnosed as euploid were warmed and transferred in a subsequent single-embryo transfer cycle. The blastocyst sex ratio was skewed in favour of male sex with 53.1% (1401/2637) of blastocysts diagnosed as male and 46.9% (1236/2637) as female (sex ratio 1.13, 95% confidence interval [CI] 1.05-1.22). Following biopsy and PGT-A, 41.2% (1086/2637) of blastocysts were classified as euploid, 7.7% (202/2637) as mosaic and 51.2% (1349/2637) as aneuploid. More chromosome euploidy was observed among female than male blastocysts (adjusted odds ratio 1.29, 95% CI 1.08-1.55) after adjusting for female age, male age and gonadotrophin dose. Euploid blastocysts were comparable between the sexes (sex ratio 0.99, 95% CI 0.88-1.11). No significant differences were observed between the sexes in implantation (sex ratio 0.86, 95% CI 0.68-1.08), miscarriage (sex ratio 1, 95% CI 0.51-1.97) or live birth rate (sex ratio 0.85, 95% CI 0.66-1.08). More male than female embryos develop to the blastocyst stage. Male blastocysts exhibit a higher aneuploidy rate. The capacity to implant and lead to a live birth is similar between the sexes.


Fabrication of mechanically improved hydrogels using a movable cross-linker based on vinyl modified polyrotaxane.
This manuscript describes the preparation of new slide-ring gels by using a polyrotaxane as a cross-linker.


The room temperature potentiometry of xanthine oxidase. pH-dependent redox behavior of the flavin, molybdenum, and iron-sulfur centers.
A series of potentiometric titrations of xanthine oxidase have been performed at room temperature in the pH range 6.1-9.9. Reduction of the two Fe/S centers was monitored by CD, and that of the FAD and Mo center by EPR. The Fe/S centers behave as centers having a protonable group whose pKa changes with reduction state (E = -344 mV, pKo = 6.4, and pKr = 8.1 for Fe/S I; E = -249 mV, pKo = 6.4, and pKr = 8.0 for Fe/S II). The flavin and the two types of molybdenum centers show varying behavior, but, in all cases, electron addition is accompanied by protonation. The sequence for FAD is reduction, protonation, reduction, protonation with E1 = -398 mV, E2 = -240 mV, pK1 = 9.5, pK2 = 7.4. For "rapid" molybdenum, the sequence is protonation, reduction, protonation, reduction with E1 = -369 mV, E2 = -301 mV, pK1 = 7.9, pK2 = 8.4; and for slow molybdenum, protonation, reduction, protonation with E1 = 320 mV, E2 = -477 mV, pK1 = 7.5, pK2 = 9.5. Comparison to data obtained previously at cryogenic temperatures (Cammack, R., Barber, M. J., and Bray, R. C. (1976) Biochem. J. 157, 469-468 and Barber, M. J., and Seigel, L. M. (1982) in Flavins and Flavoproteins (Massey, V., and Williams, C. H., eds) pp. 796-804, Elsevier/North-Holland, New York) showed the centers to have significant temperature dependence, which calls for a re-evaluation of conclusions reached using cryogenic techniques (e.g. rapid-freeze). The optical absorbance characteristics of the enzyme were also investigated and a possible absorbance for molybdenum was suggested.


Investigation of maximum mouth opening in terms of age, weight, height and body mass index in Turkish adult population.
Maximum mouth opening (MMO) is an important finding in the detection of many diseases and conditions.The aim of this study is to determine the relationship of MMO level with age, gender, weight, height, BMI variables in adult individuals. A total of 1582 participants, 806 women and 756 men, between the ages of 18-85 were included in the study. MMO, age, gender, weight, height and BMI values of the participants were recorded. Among the 1582 participants included in the study, the MMO value of men was 44.2 mm, while it was 40.29 mm in women. The MMO value of men was found to be higher than that of women (p < .05). A correlation was observed between MMO and height (p < .05). In the study, a correlation was observed between MMO and height. The MMO value was found to be higher in men.


Dietary Peptides from Phaseolus vulgaris L. Reduced AOM/DSS-Induced Colitis-Associated Colon Carcinogenesis in Balb/c Mice.
The aim was to evaluate the antineoplastic potential of a previously characterized peptide extract from the non-digestible fraction of common bean cv. Azufrado Higuera (AH) and its most abundant pure peptide GLTSK, in an azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colon carcinogenesis Balb/c mice model. The healthy control (C-) had no induction and no treatment, and the induced control (C+) had induction but no treatment. Groups AH and GLTSK were administered 50 mg/kg-bw of AH or GLTSK, respectively. The administration of AH and GLTSK decreased (p < 0.05) the disease activity index (DAI) compared to C+ (5.8, 9.1, 11.8, respectively). Furthermore, AH reduced the number of evident neoplasms compared to group C+ (1.8, 5.9 neoplasms/mice, respectively). The results suggest that peptides from common bean cv. Azufrado Higuera could prevent colitis-associated colon carcinogenesis.


Next-generation sequencing and bioinformatics to identify genetic causes of malignant hyperthermia.
Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous exons, and they reportedly only account for 50-70% of known MH patients. Next-generation sequencing (NGS) technology and bioinformatics could help delineate the genetic diagnosis of MH and several MH-like clinical presentations. We established a capture-based targeted NGS sequencing framework to examine the whole genomic regions of RYR1, CACNA1S and the 16.6 Kb mitochondrial genome, as well as 12 other genes related to excitation-contraction coupling and/or skeletal muscle calcium homeostasis. We applied bioinformatics analyses to the variants identified in this study and also to the 48 documented RYR1 pathogenic variants. The causative variants were identified in seven of the eight (87.5%) MH families, but in none of the 10 individuals classified as either normal controls (N = 2) or patients displaying MH-like clinical features later found to be caused by other etiologies (N = 8). We showed that RYR1 c.1565A>G (p.Tyr522Cys)(rs118192162) could be a genetic hot spot in the Taiwanese population. Bioinformatics analyses demonstrated low population frequencies and predicted damaging effects from all known pathogenic RYR1 variants. We estimated that more than one in 1149 individuals worldwide carry MH pathogenic variants at RYR1. NGS and bioinformatics are sensitive and specific tools to examine RYR1 and CACNA1S for the genetic diagnosis of MH. Pathogenic variants in RYR1 can be found in the majority of MH patients in Taiwan.


Parsonage Turner syndrome after cervical trauma and COVID-19 infection: a case report and review of the literature.
Parsonage Turner syndrome is an uncommon condition characterized by acute onset shoulder pain, followed by neurologic deficits such as weakness and paresthesia. It is a condition that is thought to be immune-mediated, and triggered by several recognized factors such as trauma, surgery, infections, and immunizations. Upper extremity Parsonage Turner syndrome may affect any distribution of the brachial plexus and most commonly presents unilaterally. Clinical history and examination are the basis of diagnosis, although electrodiagnostic studies may be important for confirmation. Magnetic resonance and ultrasonographic studies have also been effectively used in the diagnosis of Parsonage Turner syndrome. The case herein presents a patient with multiple possible triggers of Parsonage Turner syndrome. We present a case of 62-year-old Caucasian male with bilateral radicular pain and weakness in the upper extremities after cervical spine surgery for a fracture in a patient that was infected with COVID-19. The patient underwent electrodiagnostic testing, as well as ultrasonographic studies that demonstrated Parsonage Turner syndrome. A literature review on Parsonage Turner syndrome associated with trauma, surgery and COVID-19 was also performed. Most cases of Parsonage Turner syndrome have a known associated risk factor. The patient in this report is unique in that they had several known risk factors for Parsonage Turner syndrome simultaneously. For timely and accurate diagnosis, it is important to consider the potential triggers of Parsonage Turner syndrome including trauma, surgery and viral illnesses such as COVID-19.


Triphenyltin alters androgen metabolism in the sea urchin Paracentrotus lividus.
Androgen metabolism (androstenedione and testosterone) has been assessed in the digestive tube and gonads of the echinoderm Paracentrotus lividus exposed to different concentrations of the biocide triphenyltin (TPT) in a semi-static water regime for 4 weeks. Key enzymatic activities involved in both synthesis and metabolism of androgens, namely 17beta-hydroxysteroid dehydrogenases (17beta-HSDs), 3beta-HSDs, 5alpha-reductases, P450-aromatase, palmitoyl-CoA:testosterone acyltransferases (ATAT) and testosterone sulfotransferases (SULT), were investigated in digestive tube and/or gonads of control and TPT-exposed specimens in an attempt to see whether androgen metabolism was altered by exposure. In agreement with previous data for vertebrates, exposure to TPT led to a concentration dependent decrease of P450-aromatase that was statistically significant at the highest TPT concentration tested (225ng/L). Additionally, increased metabolism of testosterone to form dihydrotestosterone (DHT) and 5alpha-androstane-3beta,17beta-diol was observed, suggesting increased 5alpha-reductase activity in the gonads of TPT-exposed individuals. Interestingly, exposure to TPT induced testosterone conjugating activities in organisms exposed to medium (SULT) and high (ATAT and SULT) TPT concentrations. Despite the changes of androgen metabolizing enzymes, testosterone levels in gonads remained rather stable. In contrast, an increase in testosterone and a concomitant decrease in estradiol were observed in the coelomic fluid of TPT-exposed organisms. Overall, the data indicate the ability of TPT to modulate androgen metabolism and circulating steroid levels in P. lividus and suggest the existence of regulatory mechanisms to maintain stable endogenous levels of testosterone in gonads. This study also contributes to a better knowledge of echinoderm endocrinology.


Cost improvement program generates major savings.
The rationale and components of a model for containing and reducing costs are described in this article. The project-oriented program, which uses cross-functional teams as well as individual participants, encourages employees to be aware of the need for cost effective performance.


Striatum-specific expression of Cre recombinase using the Gpr88 promoter in mice.
We generated a transgenic (Tg) mouse line expressing Cre recombinase under the control of the Gpr88 promoter within a bacterial artificial chromosome clone. We crossed the established Tg mice with reporter mice (CAG-CAT-Z Tg), which express Escherichia coli lacZ in response to Cre-mediated excision of the loxP-flanked chloramphenicol acetyltransferase gene, and examined the Cre activity in the Tg mouse brains by assessing β-galactosidase activity. Cre activity was specifically detected in the caudate-putamen, nucleus accumbens, and olfactory tubercle of the Gpr88-Cre Tg mouse brain. Medium spiny neurons within the caudate-putamen exhibited Cre activity. Thus, Gpr88-Cre Tg mice could be a useful tool for analyzing the function of the basal ganglia by using Cre/loxP systems.


Evaluation of low-dose propofol preadministration to attenuate vascular pain during induction of anesthesia.
To determine whether a small dose of propofol before induction decreases pain with injection using two different formulas of propofol-10% long-chain triglycerides (LCT) and medium-chain triglycerides (MCT) and LCT. Prospective, randomized, comparative study. University-affiliated hospital. 200 ASA physical status I and II patients. Group A (LCT control) and group B (MCT/LCT control) were first preadministered normal saline plus Intralipid (Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan) as a placebo, whereas group C (LCT study) and group D (MCT/LCT study) received each formulation of propofol 0.1 mg/kg before induction. After three minutes, groups A and C received LCT propofol two mg/kg for induction. Groups B and D received LCT/MCT propofol in the same manner. Pain was evaluated blindly at the time of both preadministration and induction, using a 4-point scale: 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain. 36 (72%) LCT and 31 (62%) LCT/MCT control group patients (groups A and B) had pain. Pretreatment with propofol (groups C and D) attenuated the frequency of pain significantly in 21 (42%) and 24 (48%) patients at induction, respectively. Long-chain triglyceride and LCT/MCT propofol, 0.1 mg/kg administration before induction, resulted in attenuated pain at an induction dose of propofol.


Correlative analyses of notch signaling with resveratrol-induced differentiation and apoptosis of human medulloblastoma cells.
Altered Notch signaling seems linked with medulloblastoma (MB) formation and resveratrol exhibits anti-medulloblastoma effects. However, the influence of resveratrol in Notch signaling of MB cells has not been described. This issue was addressed here by checking Notch1 and Notch2 statuses in three MB cell lines with and without resveratrol treatment. Notch1 and Notch2 were detected in the cytoplasm of three cell lines under normal condition, which were up-regulated by resveratrol along with differentiation, apoptosis and enhanced Hes1 nuclear translocation. Nevertheless, blockage of Notch enzymatic cleavage with gamma-seacretase inhibitors, DAPT and L-685,458, neither interrupted resveratrol-caused cellular events nor affected MB cell growth. These results demonstrate that Notch signaling has little relevance with resveratrol-induced differentiation and apoptosis and may not be a universal critical factor of MB cells.


Influence of homozygosity for methionine at codon 129 of the human prion gene on the onset of neurological and hepatic symptoms in Wilson disease.
The clinical heterogeneity of Wilson disease expression cannot be fully explained by the various mutations of the Wilson disease gene. The prion-related protein (PrP) has been shown to bind copper in vitro and might therefore influence Wilson disease. To examine the effect of the PrP polymorphism at codon 129, resulting in either methionine or valine (M129V), on the clinical phenotype of patients with Wilson disease. Retrospective cross-sectional study at a university hospital. A total of 134 patients were grouped according to their PrP M129V genotypes and initial clinical symptoms (hepatic vs neurological). The onset of symptoms was significantly delayed in patients homozygous for the 129M allele as compared with patients with at least 1 V allele (mean +/- SD age, 20.90 +/- 11.9 years vs 15.5 +/- 7.6 years; P = .003). No significant correlation was found when analyzing the impact of the PrP M129V genotype on the clinical symptoms at initial manifestation (hepatic vs neurological; P = .44). This study shows for the first time, to our knowledge, that the human PrP polymorphism M129V influences the onset of symptoms in patients with the copper storage disorder Wilson disease.


Age structure landscapes emerge from the equilibrium between aging and rejuvenation in bacterial populations.
The physiological asymmetry between daughters of a mother bacterium is produced by the inheritance of either old poles, carrying non-genetic damage, or newly synthesized poles. However, as bacteria display long-term growth stability leading to physiological immortality, there is controversy on whether asymmetry corresponds to aging. Here we show that deterministic age structure landscapes emerge from physiologically immortal bacterial lineages. Through single-cell microscopy and microfluidic techniques, we demonstrate that aging and rejuvenating bacterial lineages reach two distinct states of growth equilibria. These equilibria display stabilizing properties, which we quantified according to the compensatory trajectories of continuous lineages throughout generations. Finally, we show that the physiological asymmetry between aging and rejuvenating lineages produces complex age structure landscapes, resulting in a deterministic phenotypic heterogeneity that is neither an artifact of starvation nor a product of extrinsic damage. These findings indicate that physiological immortality and cellular aging can both be manifested in single celled organisms.


Complete Pathologic Response to Pembrolizumab and Axitinib in a Patient With Sarcomatoid RCC and Ocrelizumab-Treated Multiple Sclerosis.
Non-clear cell renal cell carcinoma (RCC) is a heterogeneous disease. We report a case of sarcomatoid non-clear cell RCC in a patient with underlying multiple sclerosis (MS) on immunosuppression with a complete pathologic response to pembrolizumab and axitinib. Comprehensive genomic profiling revealed pathogenic mutations in SETD2 and TP53 with high RNA expression levels of immune checkpoint proteins. Our case illustrates the importance of treatment selection based on presence of sarcomatoid features, underlying autoimmune disease, and genomic profiling.


A covariance structure analysis of flicker sensitivity.
We tested whether linear structural models of the mechanisms underlying flicker sensitivity could reproduce the variance-covariance matrix of temporal contrast sensitivity data. Monocular sensitivities to frequencies between 2.5 and 45 Hz were measured for 124 subjects, ages 18-88 yr. Exploratory factor analyses revealed that both a two-mechanism and a three-mechanism model could adequately account for the data. Furthermore, confirmatory factor analyses and full structural equation models, using age as an explanatory variable, supported both models, with the three-factor model giving a somewhat better representation of the data. Parsimony favors the two-mechanism model. But patterns of loss associated with pre-exudative age-related maculopathy are more easily understood in terms of three underlying mechanisms.


Dispersive liquid-liquid microextraction followed by high-performance liquid chromatography for determination of benzoate and sorbate in yogurt drinks and method optimization by central composite design.
A new method based on dispersive liquid-liquid microextraction (DLLME) followed by high-performance liquid chromatography (HPLC) for determination of benzoate and sorbate salts in yogurt drinks was developed. The effective parameters in DLLME process, including volume of extraction and disperser solvents, pH and salt effect, were optimized using response surface methodology (RSM) based on central composite design. The yogurt drink samples were extracted using NaOH and Carrez solutions (potassium hexaferrocyanide and zinc acetate) were used for sedimentation of proteins. For DLLME, a mixture of extraction solvent (1-octanol) and disperser solvent (ethanol) was rapidly injected into the sample solution by syringe and cloudy solution is formed. Subsequently, the upper 1-octanol layer was analyzed by HPLC. The detection limits for benzoate and sorbate were 0.06 ng mL(-1) and 0.15 ng mL(-1), respectively. The relative standard deviations (RSD) for seven analyses were 4.96% for benzoate and 4.58% for sorbate. The proposed method demonstrated good linearity and high enrichment factor. A clean separation and good chromatogram is readily achieved without the presence of matrix interference. A comparison of this method with previous methods demonstrated that the proposed method is an accurate, rapid and reliable sample-pretreatment method that gives very good enrichment factors and detection limits for extracting and determining sorbate and benzoate in yogurt drink samples.


Fully robotic total gastrectomy with D2 lymphadenectomy for gastric cancer.
Robotic surgery with technical advantages was shown to make complex maneuvers easier and more precise for gastric surgery [1]. This video demonstrates our technique on robotic total gastrectomy with the da Vinci Xi platform for gastric cancer. 68-year-old female was presented with persistent epigastric abdominal pain and underwent upper endoscopy showed ulcerated mass extended from the cardia to the lesser curvature. Histopathology showed gastric adenocarcinoma. After patient received neoadjuvant chemotherapy, decision was made to proceed with surgery. Initially, greater curvature dissection was started by division of the gastrocolic ligament with entering the lesser sac with monopolar scissors and bipolar forceps. The right gastroomental vessels were identified and divided at their root along with lymph nodes. After ligation of the right gastric vessels, dissection was extended to retrieve lymph nodes around the left gastric vessels. Duodenum was circumferentially dissected and transected 2 cm distal to the pylorus. Subsequently, extended lymphadenectomy was started with suprapancreatic lymph node dissection to retrieve lymph nodes around the common hepatic artery and celiac axis. Spleen-preserving dissection of the lymphatic tissue of the distal splenic artery and the splenic hilum was performed. The distal esophagus was divided with robotic stapler. Fully robotic end-to-side esophagojejunal anastomosis was constructed. For the reconstruction of gastrointestinal continuity after total gastrectomy, side-to-side jejuno-jejunal anastomosis was performed. Total operative time was 5 hours and estimated blood loss was 20 cc. Totally robotic gastrectomy with D2-lymphadenectomy is a safe technique for gastric cancer and provides intracorporeal suturing in reconstructing the anatomy.


Prevalence and determinants of hypertension in the adult Inuit population of Nunavik (northern Quebec, Canada).
To assess the prevalence of arterial hypertension among Inuit adults living in Nunavik (northern Quebec, Canada) in 2017 and identify its sociodemographic and lifestyle determinants. We used data obtained from 1177 Inuit adults aged ≥ 18 years who participated in the cross-sectional Qanuilirpitaa? Nunavik Inuit Health Survey during late summer-early fall of 2017. Resting blood pressure (BP) and anthropometric characteristics were measured during a clinical session, while sociodemographic characteristics and lifestyle habits were documented using validated questionnaires. Information on current medication was retrieved from medical files. Sex-stratified population-weighted log-binomial regressions were conducted to identify determinants of hypertension, adjusting for potential confounders. Hypertension (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mmHg or taking antihypertensive medication) was present in 23% of the adult population and was more frequent in men than women (29% vs. 18%). About a third of hypertensive individuals (34%) were taking antihypertensive medication. These estimates are prone to biases due to the relatively low participation rate (37%). As expected, the prevalence of hypertension increased with age, but values were surprisingly elevated in 18 to 29-year-old men and women (18% and 8%, respectively) compared with 20 to 39-year-old adults of the general Canadian population (3% in both sexes, according to data from the Canadian Health Measures Survey, 2012-2015). Hypertension was associated with obesity and alcohol consumption in both men and women, and with higher socioeconomic status among men. This survey revealed a high prevalence of hypertension among young Nunavimmiut adults in 2017 and the need to improve hypertension diagnosis and treatment in the region. Curbing obesity and alcohol consumption, two actionable determinants of hypertension, will require improving food security and addressing the consequences of historical trauma linked to colonization.


Organochlorine pesticides and PCBs (including dl-PCBs) in human milk samples collected from multiparae from Croatia and comparison with primiparae.
This study investigated the levels of 20 congeners of polychlorinated biphenyls (PCBs), including toxic dioxin-like PCBs and 7 organochlorine pesticides (OCPs) in 33 human milk samples collected in 2011 from multiparae living in Zadar, Croatia. Concentrations of ∑PCBs, ∑DDTs, ∑HCHs and HCB in samples ranged from 11.7 to 146.3, 8.7 to 89.2, 0.9 to 28.4, and <LOD to 8.0ngg(-1) milk fat, respectively. PCB congeners -153, -138, -180 and -170 dominated in the PCB profiles, while p,ṕ-DDE was the most abundant OCP. PCB-126 was the most abundant non-ortho PCB, while among mono-ortho PCBs, the congeners -118, -105 and -156 equally contributed to the mono-ortho PCB fraction. TEQs for dl-PCBs ranged between 0 and 13.3pgg(-1) milk fat. The calculated estimated daily intakes for all compound groups were below the tolerable daily intake indicating no risk for breastfed infants. A comparison of our results with our previous study on primiparae revealed that the concentrations of the main contaminant groups are lower in the milk of multiparae, with the exception of toxic mono-ortho PCBs whose concentrations and TEQ remained similar among the groups, and HCB whose concentrations were found to be higher in multiparae. Concentrations of PCBs and OCPs found in the samples from this study did not exceed those from other parts of the world. This study revealed that there are differences in contaminant concentrations depending on the mothers' parity and that this fact should be taken into account when risk assessment studies are conducted.


Integrin-linked kinase regulates oligodendrocyte cytoskeleton, growth cone, and adhesion dynamics.
Integrin-linked kinase (ILK), a focal adhesion protein, brokers the link between cytoskeleton, cell membrane, and extracellular environment. Here, we demonstrate a role for ILK in laminin-2-mediated adhesion in primary murine oligodendrocytes (OLs) - with ILK loss leading to severe defects in process branching and outgrowth. These defects were partially recovered when the ILK-depleted OLs were instead grown on the non-integrin-activating substrate poly-l-lysine. Intriguingly, ILK loss on the neutral poly-l-lysine substrate led to swelling at the tips of OL processes, which we identified as enlarged growth cones. Employing the bloated ILK-depleted growth cones as template, we demonstrate the appearance of distinct cytoskeletal domains within OL growth cones bearing classic neuronal growth cone architecture. Further, microtubule organization was severely perturbed following ILK loss, with centripetal microtubule looping and failure to bundle occurring in a laminin-2-independent manner. Together, our work highlights differences in specific aspects of OL biology as driven by laminin-2-dependent or independent ILK governed mechanisms. We also reinforce the idea of OLs as growth cone bearing cells and describe the neuronal-like cytoskeleton therein. Finally, we demonstrate a role for ILK in OL growth cone maturation through microtubule regulation, the loss of which translates to decreased process length and myelin production capacity. We describe herein how different substrates fundamentally alter the oligodendrocyte's response to loss of integrin-linked kinase (ILK). On laminin-2 (Ln-2), ILK-depleted oligodendrocytes appear stunted and malformed, while on the non-integrin-activating substrate PLL branching and membrane formation are restored. We also reinforce the idea of oligodendrocytes as growth cone-bearing cells, detailing the growth cone's cytoskeletal architecture. Strikingly, loss of ILK on poly-l-lysine leads to growth cone swelling, the structure's size and motility rendered less dynamic. Together, our work helps reconcile the phenotypic discrepancy between ILK loss in vitro and in vivo, informs on the oligodendrocyte's growth cone, and ascribes a role for ILK in growth cone dynamics.


[Cytology and immunophenotype features of hairy cell leukemia: 6 cases].
Hairy cell leukemia is a rare lymphoproliferative disorder. with cytological and immunophenotypic features. We report 6 cases of hairy cell leukemia diagnosed in the Biological Department of Hematology at the Aziza Othmana Hospital of Tunis. Hairy cells was observed in blood smears of 5 cases. Flow cytometry analysis shown monoclonal a monoclonal population B while gatinting on the expression of the CD19 and SSC signal. The positivity of the CD103 is noted in 5 cases and the CD11c signal is intense in all the cases. Immunophenotype is of great interest in the diagnosis of hairy cell leukemia.


A novel concept for the treatment of couperosis based on nanocrystals in combination with solid lipid nanoparticles (SLN).
For the post laser treatment of couperosis a new dermal formulation was developed combining three actives: vitamin K1, A1 and rutin, where both vitamins were incorporated into solid lipid nanoparticles (SLN) and the poorly soluble antioxidant rutin formulated as nanocrystal. All three formulations were stable over 6 months either on their own or after their incorporation into a hydrogel. Vitamin A1 at 0.3% in emulsions shows local skin irritation due to very rapid release. By forming SLN, prolonged release with less irritation potential but deeper penetration was achieved in porcine ear skin. Due to the nanosized rutin, the new hydrogel showed clearly increased antioxidant activity, representing a stronger protection potential against reactive oxygen species (ROS), compared to marketed anti-redness products with rutin as raw drug powder or water-soluble derivative. In addition, rutin nanocrystals showed up to 5 times pronounced penetration compared to μm-sized raw drug powder. The orientating in-vivo case study revealed a three to six times faster recovery after laser treatment of couperosis by twice daily application of the new hydrogel, regarding scabbed-over areas and erythema. Continued use of the new gel also showed preventive properties against recurrences of veins for at least 8 month.


Alleviation of osteoarthritis by intra-articular transplantation of circulating mesenchymal stem cells.
This study aimed to evaluate the efficacy of intra-articular delivery of peripheral blood derived mesenchymal stromal cells (PB-MSCs) on the progression of trauma-induced osteoarthritis (OA) in mice. Adult male C57BL/6J mice subjected to destabilization of the medial meniscus surgeries (DMM) were randomly divided into four groups: sham surgery group; vehicle control group (treated with saline), PBMSC-treated group, or adipose tissue derived MSCs (AD-MSC)-treated group (n = 4 per group). PB-MSCs and AD-MSCs were harvested and cultured following previously established protocols, and pre-labeled with BrdU for 48 h before transplantation. PB-MSCs or AD-MSCs (5 × 105 cells/mouse; passage 3-5) were intra-articular injected into the right knee joints thrice post-surgery. The mice were euthanized at 8 weeks post-surgery and knee joint samples were collected for micro-CT and histological examinations. PB-MSCs administration significantly reduced subchondral bone volume comparing to the vehicle control group. Safranin O staining showed that PB-MSCs treatment ameliorated degeneration of articular cartilage, which was comparable to AD-MSCs treatment. The expression of catabolic marker MMP13 was significantly reduced in articular cartilage of the PB-MSCs treated group comparing to that of the vehicle control group. Co-expression of BrdU and Sox9 indicated that injected PB-MSCs differentiated in chondrocytes in situ, along with reduced levels of IL-6 within peripheral sera of PB-MSCs- and AD-MSCs-treated mice. Therefore, administration of PB-MSCs or AD-MSCs attenuated trauma-induced OA progression through inhibiting cartilage degradation and inflammation. PB-MSCs are ideal cell source for treating cartilage-associated diseases.


The deubiquitylase Ubp15 couples transcription to mRNA export.
Nuclear export of messenger RNAs (mRNAs) is intimately coupled to their synthesis. pre-mRNAs assemble into dynamic ribonucleoparticles as they are being transcribed, processed, and exported. The role of ubiquitylation in this process is increasingly recognized but, while a few E3 ligases have been shown to regulate nuclear export, evidence for deubiquitylases is currently lacking. Here we identified deubiquitylase Ubp15 as a regulator of nuclear export in Saccharomyces cerevisiae. Ubp15 interacts with both RNA polymerase II and the nuclear pore complex, and its deletion reverts the nuclear export defect of E3 ligase Rsp5 mutants. The deletion of UBP15 leads to hyper-ubiquitylation of the main nuclear export receptor Mex67 and affects its association with THO, a complex coupling transcription to mRNA processing and involved in the recruitment of mRNA export factors to nascent transcripts. Collectively, our data support a role for Ubp15 in coupling transcription to mRNA export.


Temporal expression of CD44 during embryonic chick limb development and modulation of its expression with retinoic acid.
Hyaluronan-cell interactions are initiated co-ordinately with mesenchymal condensation during chondrogenic differentiation in the limb bud. Hyaluronan is responsible for the retention and organization of proteoglycan within the cartilage matrix. Hyaluronan-CD44 binding also retains proteoglycan aggregates to the chondrocyte plasma membrane. A sequence for CD44 protein in chick has recently been reported, but never evaluated in chick chondrocytes. Total RNA was isolated from embryonic chick limb buds, stages 18, 19, 24, 25 and 30. Using semi-quantitative RT-PCR, expression of aggrecan, this chick CD44 orthologue and GAPDH mRNA was analyzed. Aggrecan expression was detected at all stages, but was increased at stage 30. CD44 mRNA was detected at extremely low levels at stage 18 to higher levels in the latter stages. Thus, the temporal expression of CD44 mRNA correlated with the onset of pre-cartilage condensation. The full-length chick chondrocyte CD44 cDNA was obtained following RT-PCR using RNA derived from tibial chondrocytes from stage 37 chick embryos. The nucleotide sequence was used to generate an amino acid sequence and analyses revealed homologies of 44.4% with mouse, 47.8% with bovine and 46.3% with human CD44. Tibial chondrocytes were cultured in the presence or absence of retinoic acid for 36 or 72 h. By RT-PCR, expression of aggrecan and the CD44 mRNA by chick chondrocytes was decreased after retinoic acid treatment, while GAPDH expression showed no change. As expected, control chondrocytes exhibited a round morphology while retinoic acid-treated chondrocytes were elongated. The retinoic acid-treated chondrocytes also exhibited reduced hyaluronan binding. This functional assay indicates a role for a CD44 receptor in matrix retention by chick chondrocytes.


Ex vivo pretreatment of human vessels with siRNA nanoparticles provides protein silencing in endothelial cells.
Human endothelial cells are initiators and targets of the rejection response. Pre-operative modification of endothelial cells by small interfering RNA transfection could shape the nature of the host response post-transplantation. Ablation of endothelial cell class II major histocompatibility complex molecules by small interfering RNA targeting of class II transactivator can reduce the capacity of human endothelial cells to recruit and activate alloreactive T cells. Here, we report the development of small interfering RNA-releasing poly(amine-co-ester) nanoparticles, distinguished by their high content of a hydrophobic lactone. We show that a single transfection of small interfering RNA targeting class II transactivator attenuates major histocompatibility complex class II expression on endothelial cells for at least 4 to 6 weeks after transplantation into immunodeficient mouse hosts. Furthermore, silencing of major histocompatibility complex class II reduces allogeneic T-cell responses in vitro and in vivo. These data suggest that poly(amine-co-ester) nanoparticles, potentially administered during ex vivo normothermic machine perfusion of human organs, could be used to modify endothelial cells with a sustained effect after transplantation.The use of gene silencing techniques in the treatment of post-transplantation host rejection is not long lasting and can have systemic effects. Here, the authors utilize a nanocarrier for siRNA for treatment of arteries ex vivo prior to implantation subsequently attenuating immune reaction in vivo.


Uptake of long acting reversible contraception following integrated couples HIV and fertility goal-based family planning counselling in Catholic and non-Catholic, urban and rural government health centers in Kigali, Rwanda.
When integrated with couples' voluntary HIV counselling and testing (CVCT), family planning including long acting reversible contraceptives (LARC) addresses prongs one and two of prevention of mother-to-child transmission (PMTCT). In this observational study, we enrolled equal numbers of HIV concordant and discordant couples in four rural and four urban clinics, with two Catholic and two non-Catholic clinics in each area. Eligible couples were fertile, not already using a LARC method, and wished to limit or delay fertility for at least 2 years. We provided CVCT and fertility goal-based family planning counselling with the offer of LARC and conducted multivariate analysis of clinic, couple, and individual predictors of LARC uptake. Of 1290 couples enrolled, 960 (74%) selected LARC: Jadelle 5-year implant (37%), Implanon 3-year implant (26%), or copper intrauterine device (IUD) (11%). Uptake was higher in non-Catholic clinics (85% vs. 63% in Catholic clinics, p < 0.0001), in urban clinics (82% vs. 67% in rural clinics, p < 0.0001), and in HIV concordant couples (79% vs. 70% of discordant couples, p = .0005). Religion of the couple was unrelated to clinic religious affiliation, and uptake was highest among Catholics (80%) and lowest among Protestants (70%) who were predominantly Pentecostal. In multivariable analysis, urban location and non-Catholic clinic affiliation, Catholic religion of woman or couple, younger age of men, lower educational level of both partners, non-use of condoms or injectable contraception at enrollment, prior discussion of LARC by the couple, and women not having concerns about negative side effects of implant were associated with LARC uptake. Fertility goal-based LARC recommendations combined with couples' HIV counselling and testing resulted in a high uptake of LARC methods, even among discordant couples using condoms for HIV prevention, in Catholic clinics, and in rural populations. This model successfully integrates prevention of HIV and unplanned pregnancy.


Compliance with Evidence-Based Guidelines in Acute Pancreatitis: an Audit of Practices in University of Toronto Hospitals.
Despite existing evidence-based practice guidelines for the management of acute pancreatitis, clinical compliance with recommendations is poor. We conducted a retrospective review of 248 patients admitted between 2010 and 2012 with acute pancreatitis at eight University of Toronto affiliated hospitals. We included all patients admitted to ICU (52) and 25 ward patients from each site (196). Management was compared with the most current evidence used in the Best Practice in General Surgery Management of Acute Pancreatitis Guideline. Fifty-six patients (22.6 %) had only serum lipase tested for biochemical diagnosis. Admission ultrasound was performed in 174 (70.2 %) patients, with 69 (27.8 %) undergoing ultrasound and CT. Of non-ICU patients, 158 (80.6 %) were maintained nil per os, and only 18 (34.6 %) ICU patients received enteral nutrition, commencing an average 7.5 days post-admission. Fifty (25.5 %) non-ICU patients and 25 (48.1 %) ICU patients received prophylactic antibiotics. Only 24 patients (22.6 %) with gallstone pancreatitis underwent index admission cholecystectomy. ERCP with sphincterotomy was under-utilized among patients with biliary obstruction (16 [31 %]) and candidates for prophylactic sphincterotomy (18 [22 %]). Discrepancies exist between the most current evidence and clinical practice within the University of Toronto hospitals. A guideline, knowledge translation strategy, and assessment of barriers to clinical uptake are required to change current clinical practice.