Pharmacokinetics and population pharmacodynamic analysis of lanreotide Autogel.
Somatostatin analogs are the first-line medical therapy for acromegaly, and the treatment of this disease has been simplified by the development of extended-release formulations of these analogs. Lanreotide is a somatostatin analog that is available either as the microparticle formulation, requiring 7- to 14-day dosing, or as the aqueous Autogel formulation, requiring 28-day dosing. This study investigated the pharmacokinetics and pharmacodynamics of lanreotide. Patients with acromegaly were given 5 injections of lanreotide microparticles, 30 mg, followed by 3 injections of lanreotide Autogel, at doses of 60, 90, or 120 mg every 28 days. The study was extended to a further 12 injections of lanreotide Autogel with dose titration. A total of 144 patients were recruited; 130 received 3 injections of lanreotide Autogel, and 130 completed the extension phase. Average minimum lanreotide concentrations (Cmin) at steady state were 1.949 +/- 0.619, 2.685 +/- 0.783, and 3.575 +/- 1.271 ng/mL for 60, 90, and 120 mg of lanreotide Autogel, respectively, showing a dose-proportional increase. Population pharmacodynamic analysis showed that the relationship between either formulation of lanreotide and serum growth hormone (GH) concentrations was best described using an inhibitory maximum response (Emax) model that allowed for the possibility of an incomplete inhibition of GH. Lanreotide elicited a maximum reduction in GH of 82%. Because patients were already being treated, baseline GH (E0) was estimated, and the value of 8.63 ng/mL was in agreement with the inclusion criteria of GH 10 ng/mL or less. The effectiveness of treatment was demonstrated by the median serum concentration of lanreotide, 1.13 ng/mL, required to lower GH to 2.5 ng/mL or less. The serum concentration that elicited half of the Emax (EC50) was estimated as 0.206 ng/mL, showing a high sensitivity to lanreotide, with a predictably high interpatient variability of 200.75% reflecting the range of dosing regimens needed to control GH.


Selectivity in an encapsulated cycloaddition reaction.
A 1,3-dipolar cycloaddition takes place within a reversibly formed, self-assembled capsule. The reaction proceeds through an unsymmetrically loaded encapsulation complex with absolute regioselectivity.


Inhibitory effects of ethanol extract from Radix Ophiopogon japonicus on venous thrombosis linked with its endothelium-protective and anti-adhesive activities.
The in-vivo inhibitory effects of the ethanol extract of Radix Ophiopogon japonicus (ROJ-ext) on venous thrombosis were studied in mouse and rat models and in-vitro endothelial cell-protective and anti-adhesive activities were observed in ECV304 cells injured by sodium dithionite and HL-60 adhesion to ECV304 cells injured by TNF-alpha. The in-vivo results showed that ROJ-ext significantly inhibited venous thrombosis induced by tight ligation of the inferior vena cava for 6 h in mice and for 24 h in rats by once oral administration at doses of 12.5 and 25 mg/kg. Meanwhile, ROJ-ext had no obvious effect on some coagulation parameters, which was different from warfarin, which remarkably prolonged activated partial thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT) in rats at the same time. Histological analysis under light microscope and scanning electron microscope (SEM) of inferior vena cava indicated that ROJ-ext could protect endothelial cells from anoxic injury and alleviate inflammatory changes in the vein wall. On the other hand, the in-vitro studies approved that ROJ-ext significantly enhanced viability of ECV304 cells injured by sodium dithionite at the concentrations of 0.1, 1.0 and 10 mug/ml when given before and after the anoxic induction. Meanwhile, ROJ-ext remarkably inhibited adhesion of HL-60 cells to ECV304 cells injured by rh TNF-alpha at above concentrations in a dose-dependent manner. The findings of this study showed that ethanol extract of Radix Ophiopogon japonicus (ROJ-ext) inhibited venous thrombosis, which linked with its endothelial cell-protective and anti-adhesive activities. This lends scientific support to the therapeutic use of the plant for thrombotic diseases.


A case of long-term survival treated with three metastasectomies and two subsequent adjuvant nivolumab therapies for recurrent malignant melanoma of the esophagus.
The treatment strategy for metastatic lesions of primary malignant melanoma of the esophagus (PMME) is currently determined on a case-by-case basis, based on the National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma. The NCCN guidelines state that resection should be considered in patients with resectable metastatic recurrence. Herein, we report a case of long-term survival treated with three metastasectomies and two subsequent adjuvant nivolumab therapies for the metastatic recurrence of PMME. A 65-year-old female patient with PMME underwent thoracoscopic subtotal esophagectomy, gastric tube reconstruction via the posterior mediastinal route, and cervical esophagogastric anastomosis. Histopathological examination of the resected specimen revealed that the tumor was PMME with tumor invasion into the muscularis propria and no lymph node metastasis. At the age of 68 years, she developed intestinal invagination due to jejunal metastasis of malignant melanoma and underwent resection of the jejunum. Histopathological examination of the resected specimen revealed two metastases of malignant melanoma in the jejunum and one metastasis to the mesenteric lymph node. At the age of 75 years, a recurrence of malignant melanoma was found in the cervical esophagus. She underwent thoracoscopic mobilization of the gastric tube and esophagus followed by cervical esophagectomy and reconstruction with a free jejunum flap. She received 24 courses of nivolumab therapy for 1 year as a postoperative adjuvant therapy. Subsequently, at the age of 78 years, an enlarged left cervical lymph node and a mass in the right lower lobe of the lung were found. She underwent left cervical lymph node dissection and thoracoscopic wedge resection of the right lung. Histopathological examination of the resected specimens revealed that both tumors were metastases of malignant melanoma. At age 79 years, she received eight courses of nivolumab therapy as a second postoperative adjuvant therapy, with no sign of recurrence in a 9-month follow-up period after the third metastasectomy. In cases of metastatic recurrence of PMME, aggressive resection of oligometastasis with postoperative adjuvant nivolumab therapy may result in long-term survival.


Deep-supercooling for extended preservation of adipose-derived stem cells.
Cell preservation is an enabling technology for widespread distribution and applications of mammalian cells. Traditional cryopreservation via slow-freezing or vitrification provides long-term storage but requires cytotoxic cryoprotectants (CPA) and tedious CPA loading/unloading, cooling, and recovering procedures. Hypothermic storage around 0-4 °C is an alternative method but only works for a short period due to its high storage temperatures. Here, we report on the deep-supercooling (DSC) preservation of human adipose-derived stem cells at deep subzero temperatures without freezing for extended storage. Enabled by surface sealing with an immiscible oil phase, cell suspension can be preserved in a liquid state at -13 °C and -16 °C for 7 days with high cell viability, retention of stemness, attachment, and multilineage differentiation capacities. These results demonstrate that DSC is an improved short-term preservation approach to provide off-the-shelf cell sources for booming cell-based medicine and bioengineering.


Chronic myelomonocytic leukemia: 2013 update on diagnosis, risk stratification, and management.
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that is classified as a myelodysplastic/myeloproliferative neoplasm by the 2008 World Health Organization classification of hematopoietic tumors. It is characterized by absolute monocytosis (>1 × 10⁹/L) in the peripheral blood that persists for at least 3 months. The diagnosis of CMML rests on a combination of morphologic, histopathologic and chromosomal abnormalities in the bone marrow. It is important to exclude other myeloproliferative neoplasms and infectious/autoimmune conditions that can cause monocytosis. Several CMML-specific prognostic models incorporating novel mutations have been recently reported. The Mayo prognostic model classified CMML patients into three risk groups based on: increased absolute monocyte count, presence of circulating blasts, hemoglobin <10 gm/dL and platelets <100 × 10⁹/L. The median survival was 32 months, 18.5 months and 10 months in the low, intermediate, and high-risk groups, respectively. The Groupe Francophone des (GFM) score segregated CMML patients into three risk groups based on: age >65 years, WBC >15 × 10⁹/L, anemia, platelets <100 × 10⁹/L, and ASXL1 mutation status. After a median follow-up of 2.5 years, survival ranged from not reached in the low-risk group to 14.4 months in the high-risk group. The Food and Drug Administration has approved azacitidine and decitabine for the treatment of patients with CMML. An allogeneic stem cell transplant can potentially offer a curative option to a subset of CMML patients. It is hoped that with the discovery of several novel mutations, targeted therapies will become available in the near future.


Ensuring access to post-cancer breast reconstructions: COVID-19 lessons from the Dutch Breast Implant Registry.
COVID-19 has impacted breast implant surgery for oncological and non-oncological patients worldwide. This population-based study aimed to evaluate the impact of the COVID-19 pandemic on access to reconstructive and cosmetic breast implant surgery in the Netherlands using real-world data to describe trends, and to identify lessons to prevent future capacity problems within (inter)national healthcare. This longitudinal study included patients undergoing breast implant surgery from the mandatory nationwide Dutch Breast Implant Registry. For 2020, the first COVID-19 wave, intermediate period, and second wave were defined. We compared data from during the pandemic to a pre-pandemic (2019) reference year, assessing differences in the number of registered breast implants, and patient and surgery-related characteristics. A total of 34133 breast implants (17459 patients) were included. Compared to 2019, fewer implants were registered for post-cancer (n=484; -14.7%), cosmetic (n=480; -3.6%), and gender-affirming indications (n=104; -38.0%) during 2020. Fewer implants were registered in academic (n=196; -22.0%) and regional hospitals (n=1591; -16.5%), but more in private clinics (n=725; +10.1%). After the first wave, up to twice as many implants were registered in private clinics compared to 2019. No differences were found in characteristics of patients undergoing surgery in 2020 versus 2019. Hospital-based reconstructive and gender-affirming surgery were heavily impacted during the pandemic, while private-clinic-based cosmetic surgery quickly recovered. These outcomes are useful to fuel discussions about how healthcare could be reorganized in times of capacity problems. We suggest exploring options to deploy private clinics for ambulatory surgery aiming to keep hospital capacity available for acutely ill patients.


Persistence of recipient lymphocytes in NOD mice after irradiation and bone marrow transplantation.
The non-obese diabetic (NOD) mouse is a unique and invaluable model of autoimmune disease, in particular type 1 diabetes. Bone marrow transplantation as a therapy for type 1 diabetes has been explored in NOD mice. NOD mice require higher doses of conditioning irradiation for successful allogeneic bone marrow transplantation, suggesting that NOD hematopoietic cells are radioresistant compared to those of other mouse strains. However, studies of hematopoietic reconstitution in NOD mice are hampered by the lack of mice bearing a suitable cell-surface marker that would allow transferred cells or their progeny to be distinguished. In order to monitor hematopoietic reconstitution in NOD mice we generated congenic NOD mice that carry the alternative allelic form of the pan-leukocyte alloantigen CD45. Following irradiation and congenic bone marrow transplantation, we found that the myeloid lineage was rapidly reconstituted by cells of donor origin but substantial numbers of recipient T lymphocytes persisted even after supra-lethal irradiation. This indicates that radiation resistance in the NOD hematopoietic compartment is a property primarily of mature T lymphocytes.


Differential analysis of bactericidal systems of blood serum with recombinant luminescent Escherichia coli and Bacillus subtilis strains.
Luminescence intensity of recombinant Escherichia coli and Bacillus subtilis strains with cloned luxCD(AB)E genes of the natural luminescent microorganism Photobacterium leiognathi was studied under the influence of 30 individual samples of human blood serum of different component composition. A relationship was found between the level of residual bioluminescence and degree of the bactericidal effect. Moreover, the inhibition of E. coli lux+ luminescence was shown to be related to activity of the complement-lysozyme system. The reaction of B. subtilis lux+ primarily depended on the presence of β-lysin in the blood serum. These data provide an experimental substantiation of a new method of differential analysis of humoral factors of nonspecific innate immunity with recombinant luminescent bacteria.


A Normative Brain MRI Database of Neurotypical Participants from 5 to 90 Years of Age.
Brain magnetic resonance imaging (MRI) studies of clinical populations often require comparison to a normative 'control' cohort, usually of similar age/sex, scanned with the same protocol. The goal here was to create a normative brain MRI database of common quantitative methods to be used in comparisons with a variety of neurological disorders across the lifespan. 378 neurotypical controls (aged 5-90 years; median 31 years; 216 females, 162 males) completed brain MRI, cognitive testing, clinical assessment, and a demographics questionnaire. In addition, this large normative sample will yield novel insight into healthy brain development and aging.


Sex-linked differences in developmental potential of single blastomeres from in vitro-fertilized 2-cell stage mouse embryos.
Single blastomeres were isolated from 2-cell mouse embryos and analyzed for their sex using the partially deleted Y chromosome as a marker. Sex identification of 83% of the embryos was achieved with conventionally Giemsa-stained chromosome preparations. The other half-embryos were cultured individually and were transferred to pseudopregnant recipient females. The implantation rate was significantly higher in the male half-embryos. Although 6% of the half-embryos were male. The male half-embryos contained more blastomeres in the blastocyst stage than female ones. These facts suggests that the potential for the development of male half-embryos into fetuses is different from that of female half-embryos.


Prospective study of the association between abandoned dwellings and testosterone level on the development of behaviors leading to cannabis use disorder in boys.
The role of testosterone in the development of behaviors presaging cannabis use and subsequently cannabis use disorder was investigated in a prospective study of 208 boys. It was theorized that adverse neighborhood correlates with testosterone level that in turn potentiates behaviors predisposing to cannabis consumption and subsequently diagnosis of cannabis use disorder. Proportion of boarded-up dwellings in the 1990 census tract and testosterone level were recorded at baseline (ages 10-12), followed by assessments of assaultiveness and testosterone level (ages 12-14), social dominance/norm-violating behavior (SDNVB) (age 16), cannabis use (age 19), and cannabis use disorder (age 22). Percent of vacant dwellings correlates with testosterone level that in turn predicts assaultive behavior sequentially leading to SDNVB, cannabis use, and cannabis use disorder. Externalizing behaviors and cannabis use disorder are not directly predicted by neighborhood quality. Elevated testosterone level intermediates the association between neighborhood adversity and aggressive socially deviant behaviors presaging cannabis use and cannabis use disorder.


Skeletal scintigraphy for the diagnosis of malignant metastatic disease to the bones.
The use of skeletal scintigraphy for the detection of metastatic disease of the bone is reviewed. The review is based on published data for sensitivity, specificity, yield and prognostic value. The analysis, and interpretation of published data is complicated by the variation in criteria. It appears nonetheless, that for a number of tumors the relative (in comparison with other methods) and absolute (based on outcome prediction) sensitivity is high. For certain tumors in early stages, and in asymptomatic patients the yield (of positive studies) is low, even when the prognostic value is high. Those factors should be weighed with the availability of therapeutic options to determine the clinical efficacy of skeletal scintigraphy.


The effects of human myelin basic protein (HMBP) on the bioelectrical activity of the frog spinal cord.
The effects of human myelin basic protein (HMBP) and its individual microheterogeneous components on the electrical activity of the frog spinal cord are compared with those of bovine MBP (BMBP) and glutamate (Glu). HMBP causes a dose-dependent depolarization of the ventral (VR) and dorsal (DR) roots with a reduction of the evoked root potentials. The amplitude of the depolarization induced by 0.01 mM HMBP corresponds to that observed with application of 1 mM Glu. A weaker depolarization persists during blockade of synaptic transmission by MgSO4 or tetrodotoxin, suggesting a direct depolarizing effect on motoneurones and primary afferents. HMBP causes a long-lasting tachyphylaxis. The individual microheterogeneous components of HMBP (peaks 1, 2 and 3), and a mixture of smaller myelin basic proteins elicit similar responses, whereas BMBP and its microheterogeneous components are slightly less active.


Genome analyses reveal population structure and a purple stigma color gene candidate in finger millet.
Finger millet is a key food security crop widely grown in eastern Africa, India and Nepal. Long considered a 'poor man's crop', finger millet has regained attention over the past decade for its climate resilience and the nutritional qualities of its grain. To bring finger millet breeding into the 21st century, here we present the assembly and annotation of a chromosome-scale reference genome. We show that this ~1.3 million years old allotetraploid has a high level of homoeologous gene retention and lacks subgenome dominance. Population structure is mainly driven by the differential presence of large wild segments in the pericentromeric regions of several chromosomes. Trait mapping, followed by variant analysis of gene candidates, reveals that loss of purple coloration of anthers and stigma is associated with loss-of-function mutations in the finger millet orthologs of the maize R1/B1 and Arabidopsis GL3/EGL3 anthocyanin regulatory genes. Proanthocyanidin production in seed is not affected by these gene knockouts.


Assessing and Raising Concerns About Duplicate Publication, Authorship Transgressions and Data Errors in a Body of Preclinical Research.
Authorship transgressions, duplicate data reporting and reporting/data errors compromise the integrity of biomedical publications. Using a standardized template, we raised concerns with journals about each of these characteristics in 33 pairs of publications originating from 15 preclinical (animal) trials reported by a group of researchers. The outcomes of interest were journal responses, including time to acknowledgement of concerns, time to decision, content of decision letter, and disposition of publications at 1 year. Authorship transgressions affected 27/36 (75%) publications. The median proportion of duplicate data within pairs of publications was 45% (interquartile range 29-57). Data/reporting discrepancies [median 3 (1-5)] were present in 28/33 (85%) pairs. Journals acknowledged receipt of concerns for 53% and 94% of publications by 1 month and 9 months, respectively. After 1 year, journals had communicated decisions for 16/36 (44%) publications. None of the decision letters specifically addressed each of the concerns raised. Decisions were no action, correction and retraction for 9, 3 and 4 publications, respectively: the amounts of duplicate data reporting and data/reporting discrepancies were similar irrespective of journal decision. Authorship transgressions affected 6/9 (67%) publications for which no action was decided. Journal responses to concerns about duplicate publication, authorship transgressions, and data/reporting discrepancies were slow, opaque and inconsistent.


Effect of specific training course for competency in professional oral hygiene care in the intensive care unit: a quasi-experimental study for developing a standardized learning curve.
The development of evidence-based training standards can help improve the quality of educational programs for novice intensive care unit (ICU) nurses. This study was conducted to assess the application of a training course on competency development of nurses in relation to oral hygiene care in ICU patients and to develop a checklist for evaluating the competence performance. In addition, to achieve a certain level of oral hygiene competence, as well as to assess the relative importance of predicting factors and learning competency patterns in oral hygiene care, we used standard learning curve. This quasi-experimental study with time series design was conducted on newly registered ICU nurses of a teaching hospital affiliated with Tehran University of Medical Sciences, Iran, between 2016 and 2018. In the first phase of this study, we designed a checklist to assess nurses' professional competence in oral hygiene care in three stages: before, during, and after care. Then, in the second phase, the level of competence of nurses in repeated times of oral hygiene care was determined based on checklist items and recorded in the learning curve. The greatest increase of oral hygiene care competency due to repetition was observed in the first and fourth times of repetition in comparison to the subsequent and previous steps. In the linear regression model, demographic variables predicted 12-19% of changes related to skill scores in repetitions. According to the learning curve, newly registered ICU nurses can reach an acceptable competency after 6 repetitions of oral hygiene care.


Hepatic hydatidosis that debuts with a direct rupture to the pleural cavity.
We present the case of a patient with pain in the right hypochondrium, dyspnea, deterioration of his general condition and a positive anti-Echinoccocus antibodies test. Ultrasound and thoraco-abdominal computed tomography (CT) demonstrated a complex hepatic cystic lesion with a transdiaphragmatic fistulous tract trajectory, directed to the pleural space. The lesion was compatible with a complicated hydatid cyst with direct rupture to the pleural cavity. Treatment with albendazole prior to surgery was started.


Development of a novel predictive model for a successful stone removal after flexible ureteroscopic lithotripsy based on ipsilateral renal function: a single-centre, retrospective cohort study in China.
The aims of this study were to investigate the effect of preoperative ipsilateral renal function on the success of kidney stone removal with flexible ureteroscopic lithotripsy and to develop a predictive model based on the results. Retrospective cohort study. Data from the 2001-2012 period were collected from the electronic records of West China Hospital, Sichuan University. 576 patients who underwent flexible ureteroscopic lithotripsy were included in the study. Stone-free rate (SFR) after the procedures. In patients with suspected impaired kidney function, the overall SFR was 70.1%. Stone volume (OR 1.46; 95% CI 1.18 to 1.80), lower calyx stones (OR 1.80; 95% CI 1.22 to 2.65), age (OR 1.02; 95% CI 1.00 to 1.04), body mass index (OR 1.10; 95% CI 1.04 to 1.17) and estimated glomerular filtration rate of the affected kidney (OR 0.95; 95% CI 0.94 to 0.97) were identified as independent predictors of SFR. Lasso regression selected the same five predictors as those identified by univariate and multivariate logistic regression analyses, thus verifying our model. The mean area under the curve, based on 1000 iterations and 10-fold validation, was 0.715 (95% CI 0.714 to 0.716). The Hodges-Lehmann test and calibration curve analysis revealed no significant mismatch between the prediction model and the retrospective cohort. Ipsilateral renal function may be a novel independent risk factor for kidney stone removal with flexible ureteroscopic lithotripsy. A novel nomogram for predicting SFR that uses stone volume, lower calyx stones, age, body mass index and estimated glomerular filtration rate was developed, but remains to be externally validated.


Teamwork, communication and resident leadership at resident-attended, neonatal delivery room resuscitations.
Determine if a NICU resident delivery room (DR) skills educational curriculum is associated with changes in neonatal resuscitation team characteristics, including teamwork, communication and leadership. This prospective, observational study of resident-attended neonatal resuscitations utilized team questionnaire, video assessment and chart review. Each resident NICU block included a curriculum consisting of two educational programs focusing on NRP knowledge and skills with additional emphasis on teamwork and communication strategies. Ninety-nine resuscitations met inclusion criteria. Comparing behaviors at the beginning versus end of a NICU block, residents demonstrated increased frequency of initiating leadership (31% vs. 93%, p < 0.001) and maintaining leadership (19% vs. 79%, p < 0.001) at low-risk, resident-attended DR resuscitations. Overall measurements of teamwork and communication were unchanged. A NICU DR skills educational curriculum is associated with increased resident leadership at low-risk DR resuscitations over the course of NICU blocks, without compromising measurements of teamwork or communication.


The prognostic value of arginase-1 and glypican-3 expression levels in patients after surgical intrahepatic cholangiocarcinoma resection.
The aim of this study was to investigate the prognostic value of arginase-1 (Arg-1) and glypican-3 (GPC-3) in patients with intrahepatic cholangiocarcinoma (ICC). Two hundred and thirty-seven patients with ICC were included in this study. All patients had undergone radical surgery and had complete clinical information. Immunohistochemistry was used to assess the levels of Arg-1 and GPC-3 in ICC tissues. Univariate and multivariate analyses were conducted to identify independent risk factors in ICC. The relationship between Arg-1 and GPC-3 levels and patient survival was determined using the Kaplan-Meier method. High Arg-1 and GPC-3 expression levels were associated with poor prognosis in patients with ICC, and they could be as new prognostic biomarkers in ICC. Arg-1 and GPC-3 can serve as independent prognostic biomarkers in ICC.


Evolutionary flux of potentially bldA-dependent Streptomyces genes containing the rare leucine codon TTA.
Previous studies have shown that one of the six leucine codons, UUA, is rare in Streptomyces, and that, while the gene for the UUA-specific tRNA, bldA, can generally be inactivated in diverse streptomycetes without impairing vegetative growth, bldA mutants are typically defective in reproductive aerial growth and in antibiotic production. Here, four complete genome sequences and 143 gene clusters for antibiotic biosynthesis from diverse streptomycetes were analysed in order to evaluate the evolution and function of genes whose possession of TTA codons makes them dependent on bldA. It was deduced that the last common ancestor of the four sequenced genomes, possibly 220 million years ago, already possessed the bldA system, together with perhaps 200 TTA-containing target genes. Some 33 of these genes are retained by the modern descendants, though only three of them retain a TTA in all occurrences. Nearly all of these 33, as well as many of the TTA-containing genes with orthologues in two or three of the four genomes, have the same location on the chromosomes as in their common ancestor. However, the majority of TTA-containing genes (61% overall in the four genomes) are species-specific, and were probably acquired by comparatively recent horizontal gene transfer. Most of these genes are of unknown function, and it is likely that many of them confer specialised ecological benefits. On the other hand, one class of species-specific, functionally recognisable, horizontally acquired genes--the gene clusters for antibiotic production--very often contain TTA codons; and nearly half of them have TTA codons in their pathway-specific regulatory genes.


Redox regulation in the lens.
The high content of glutathione (GSH) in the lens is believed to protect thiols in structural proteins and enzymes for proper biological functions. The lens has both biosynthetic and regenerating systems for GSH to maintain its large pool size. However, ageing lenses or lenses under oxidative stress show an extensively diminished size of GSH pool with some protein thiols being S-thiolated by oxidized non-protein thiols to form protein-thiol mixed disulfides, either as protein-S-S-glutathione (PSSG) or protein-S-S-cysteine (PSSC) or protein-S-S-gamma-glutamylcysteine. It was shown in an H(2)O(2)-induced cataract model that PSSG formation precedes a cascade of events before cataract formation, starting with protein disulfide crosslinks, protein solubility loss and high molecular weight aggregation. Furthermore, this early oxidative damage in protein thiols can be spontaneously reversed in H(2)O(2) pretreated lenses if the oxidant is removed in time. This dethiolation process appears to have mediated through a redox-regulating enzyme, thioltransferase (TTase), which is ubiquitously present in microbial, plant and animal tissues, including the lens. The GSH-dependent, low molecular weight (11.8 kDa) cytosolic enzyme plays an important role in oxidative defense and can modulate key metabolic enzymes in the glycolytic pathway. The enzyme repairs oxidatively damaged proteins/enzymes through its unique catalytic site with a vicinal cysteine moiety, which can specifically dethiolate protein-S-S-glutathione and restore protein free SH groups for proper enzymatic or protein functions. Most importantly, it has been demonstrated that thioltransferase has a remarkable resistance to oxidation (H(2)O(2)) in cultured human and rabbit lens epithelial cells under oxidative stress conditions when other oxidation defense systems of GSH peroxidase and GSH reductase are severely inactivated. A second repair enzyme, thioredoxin (TRx), which is NADPH-dependent, is widely found in many lower and higher life forms of life. It can dethiolate protein disulfides and thus is an extremely important regulator for redox homeostasis in the cells. Thioredoxin has been recently found in the lens and has been shown to participate in the repair process of oxidatively damaged lens proteins/enzymes. These two enzymes may work synergistically to regulate and repair thiols in lens proteins and enzymes, keeping a balanced redox potential to maintain the function of the lens.


[Construction of plasmids expressing hepatitis E virus antigen fragments and their combinations].
Several different regions of the HEV antigen were expressed in Escherichia coli and their immunological characteristics were simply evaluated. Three coding sequences of immunodominant antigenic regions in structural protein of the hepatitis E virus (ORF2.1: 6287-6403nt, ORF2.2: 6743-7126nt, ORF3: full length of ORF3) were amplified by RT-PCR from the fecal supernatants of macaques experimentally infected with HEV. These three fragments were inserted into the pThioHisC expression vector separately or fused in line by (Gly)n short arms. After identified by DNA sequence analysis, these six recombinant plasmids were transformed into Escherichia coli, and immunology characteristics of expressed antigen fragments were evaluated by Western blotting. All six genes were successfully expressed in Escherichia coli. Western blotting assay showed that the recombinant proteins specifically reacted with the serum antibody from hepatitis E patient in various degrees. Artificial antigen based on strung epitopes provides a promising strategy for detection and prevention of HEV infection.


[Dementia].
A female tends to suffer from dementia and dementia is thought as a disease with sex difference clearly. A female has the longer life, so it has been thought that a female prevalence rate is higher than a man seemingly. However, even if sex difference was considered, it was demonstrated clearly in recent years that a female suffer from dementia with high frequencies. Now, it isn't clear yet why such sex difference exists. The strongest hypothesis may be influence by sex hormones, and role of androgen as well as estrogen is pointed out. Now, 15% of more than 65 years old suffer from dementia. Dementia is thought as a common disease". More than 65-year-old elderly people don' t want to suffer from dementia. Although many people have such great interest of dementia, they do not find the early stage symptom of dementia. Forgetfulness is often overlooked and early detection isn't done. There are many diseases which lead to dementia, but Alzheimer-type dementia accounts for the most part of dementia. Alzheimer-type dementia can be treated by medicines, therefore early detection and an early stage check are necessary. I explain how do general physicians notice dementia in their outpatient clinic and diagnose and treat.


Soluble suppression of tumorigenicity 2 (sST2) for predicting disease severity or mortality outcomes in cardiovascular diseases: A systematic review and meta-analysis.
Soluble suppression of tumorigenicity 2 (sST2) is a member of the interleukin-1 receptor family. It is raised in various cardiovascular diseases, but its value in predicting disease severity or mortality outcomes has been controversial. Therefore, we conducted a systematic review and meta-analysis to determine whether sST2 levels differed between survivors and non-survivors of patients with cardiovascular diseases, and whether elevated sST2 levels correlated with adverse outcomes. PubMed and Embase were searched until 23rd June 2021 for studies that evaluated the relationship between sST2 levels and cardiovascular disease severity or mortality. A total of 707 entries were retrieved from both databases, of which 14 studies were included in the final meta-analysis. In acute heart failure, sST2 levels did not differ between survivors and non-survivors (mean difference [MD]: 24.2 ± 13.0 ng/ml; P = 0.06; I 2: 95%). Elevated sST2 levels tend to be associated with increased mortality risk (hazard ratio [HR]: 1.12, 95 %CI: 0.99-1.27, P = 0.07; I 2: 88%). In chronic heart failure, sST2 levels were higher in non-survivors than in survivors (MD: 0.19 ± 0.04 ng/ml; P = 0.001; I 2: 0%) and elevated levels were associated with increased mortality risk (HR: 1.64, 95% CI: 1.27-2.12, P < 0.001; I 2: 82%). sST2 levels were significantly higher in severe disease compared to less severe disease (MD: 1.56 ± 0.46 ng/ml; P = 0.001; I 2: 98%). Finally, in stable coronary artery disease, sST2 levels were higher in non-survivors than survivors (MD: 3.0 ± 1.1 ng/ml; P = 0.005; I 2: 80%) and elevated levels were significantly associated with increased mortality risk (HR: 1.32, 95% CI: 1.04-1.68, P < 0.05; I 2: 57%). sST2 significantly predicts disease severity and mortality in cardiovascular disease and is a good predictor of mortality in patients with stable coronary artery disease and chronic heart failure.


Compensatory expressive behavior for facial paralysis: adaptation to congenital or acquired disability.
Although there has been little research on the adaptive behavior of people with congenital compared to acquired disability, there is reason to predict that people with congenital conditions may be better adapted because they have lived with their conditions for their entire lives (Smart, 2008). We examined whether people with congenital facial paralysis (FP), compared to people with acquired FP, compensate more for impoverished facial expression by using alternative channels of expression (i.e., voice and body). Participants with congenital (n = 13) and acquired (n = 14) FP were videotaped while recalling emotional events. Expressive verbal behavior was measured using the Linguistic Inquiry Word Count (Pennebaker, Booth, & Francis, 2007). Nonverbal behavior and FP severity were rated by trained coders. People with congenital FP, compared to acquired FP, used more compensatory expressive verbal and nonverbal behavior in their language, voices, and bodies. The extent of FP severity had little effect on compensatory expressivity. This study provides the first behavioral evidence that people with congenital FP use more adaptations to express themselves than people with acquired FP. These behaviors could inform social functioning interventions for people with FP.


Human splenic marginal zone B cells lack expression of activation-induced cytidine deaminase.
It has been speculated that somatic hypermutation of rearranged immunoglobulin variable (V) region genes does not only take place in the germinal center (GC) microenvironment, but also in the marginal zone (MZ) of the spleen, and that human peripheral blood IgM-positive B cells with somatically mutated V region genes may derive from mutating MZ B cells. As somatic hypermutation is strictly dependent on the enzyme activation-induced cytidine deaminase (AID), we used an AID-specific monoclonal antibody that is suitable for immunohistochemical staining to analyze human splenic MZ cells for AID expression. Analysis of tissue sections from 29 spleens revealed only very rare MZ cells (approx. 0.05%) showing AID staining, whereas in 25 of the spleen samples strong AID staining of GC B cells was observed. Thus, there are virtually no AID-expressing MZ B cells, indicating that somatic hypermutation does not take place at a significant level in the MZ. Consequently, it appears unlikely that the somatically mutated IgM B cells are generated in the splenic MZ. Moreover, the lack of AID-positive MZ B cells questions the recent speculation that B cell chronic lymphocytic leukemias with mutated V genes are derived from mutating MZ B cells.


Lobular Neoplasia.
Lobular neoplasia (LN) is a term that describes atypical epithelial lesions originating in the terminal duct-lobular unit (TDLU) of the breast, including atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS). LN is both a risk factor and nonobligate precursor to invasive breast cancer. A diagnosis of LCIS is associated with a 7-to-10-fold increased risk of breast cancer compared with the general population. When classic LN is diagnosed on a core needle biopsy (CNB), the patient may proceed with either increased screening or excisional biopsy of the lesion. Physicians should counsel patients diagnosed with LN on the risk of developing invasive carcinoma and inform them of the current screening and chemoprevention recommendations to reduce risk.


Structural and stability characteristics of a monothiol glutaredoxin: glutaredoxin-like protein 1 from Plasmodium falciparum.
Recently discovered monothiol glutaredoxins with CXXS-active site sequence share a common structural motif and biochemical mechanism of action and are involved in multiple cellular functions. Here we report first studies on the structural and stability characterization of a monothiol glutaredoxin, in particular--PfGLP1. Our results demonstrate that in the native conformation, the enzyme has a compact core structure with a relatively flexible N-terminal portion having an open configuration. Comparative functional studies with the full-length and N-terminal truncated protein demonstrate that the flexible N-terminal portion does not play any significant role in functional activity of the protein. In contrast to other Grxs, PfGLP1 does not contain a Fe-S cluster. The pH dependent studies demonstrate that the protein is resistant to alkaline pH but highly sensitive to acidic pH and undergoes significant unfolding between pH 4 and 5. However, acidic conditions also do not induce complete unfolding of the enzyme. The protein is stabilized with a conformational free energy of about 3.2+/-0.1 kcal mol(-1). The protein is a highly cooperative molecule as during denaturant-induced equilibrium unfolding a simultaneous unfolding of the protein without stabilization of any partially folded intermediate is observed.


Measures Matter: The Local Exposure/Isolation (LEx/Is) Metrics and Relationships between Local-Level Segregation and Breast Cancer Survival.
Background: The Black-to-White disparity in breast cancer survival is increasing, and racial residential segregation is a potential driver for this trend. However, study findings have been mixed, and no study has comprehensively compared the effectiveness of different local-level segregation metrics in explaining cancer survival.Methods: We proposed a set of new local segregation metrics named local exposure and isolation (LEx/Is) and compared our new local isolation metric with two related metrics, the location quotient (LQ) and the index of concentration at extremes (ICE), across the 102 largest U.S. metropolitan areas. Then, using case data from the Milwaukee, WI, metropolitan area, we used proportional hazards models to explore associations between segregation and breast cancer survival.Results: Across the 102 metropolitan areas, the new local isolation metric was less skewed than the LQ or ICE. Across all races, Hispanic isolation was associated with poorer all-cause survival, and Hispanic LQ and Hispanic-White ICE were found to be associated with poorer survival for both breast cancer-specific and all-cause mortality. For Black patients, Black LQ was associated with lower all-cause mortality and Black local isolation was associated with reduced all-cause and breast cancer-specific mortality. ICE was found to suffer from high multicollinearity.Conclusions: Local segregation is associated with breast cancer survival, but associations varied based on patient race and metric employed.Impact: We highlight how selection of a segregation measure can alter study findings. These relationships need to be validated in other geographic areas. Cancer Epidemiol Biomarkers Prev; 26(4); 516-24. ©2017 AACRSee all the articles in this CEBP Focus section, "Geospatial Approaches to Cancer Control and Population Sciences."


Visualization of the thoracic duct by lymphoscintigraphy.
Imaging of the thoracic duct is usually performed by radiological lymphography. However, this procedure, which uses an oil based dye injected directly into the lymph channels, has some adverse effects. In this paper we note that lymphoscintigraphy, a physiological and non invasive method, may visualize thoracic duct abnormalities, and might be particularly useful when radiological lymphography is contraindicated.


Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes.
Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy. ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]). In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P<0.001). An increase in plasma ADMA of 0.1 micromol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P<0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml.min(-1).1.73 m(-2)) (P<0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P>0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05). Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.


Drought response of a native and introduced Hawaiian grass.
The alien grass, Pennisetum setaceum, dominates many of the lowland arid regions that once supported native Heteropogon contortus grassland on the island of Hawaii. Response to drought in a glasshouse was compared between these C4 grasses to test if success as an invader is related to drought tolerance or plasticity for traits that confer drought tolerance. Pennisetum produced 51% more total biomass, allocated 49% more biomass to leaves, and had higher net photosynthetic rates (P n) on a leaf area basis than Heteropogon. Plants of both species under drought produced less total biomass and increased their allocation to roots compared to well-watered plants, but there was no difference between the two species in the magnitude of these responses. The decline in P n with decreasing leaf water potential (ψ1) was greater for Pennisetum compared to Heteropogon. Plasticity in the response of P n to ψ1, osmotic potentials, and the water potentials at turgor loss in response to drought were not different between the two species. Stomata were more responsive to Δw in Heteropogon than in Pennisetum and for well-watered plants compared to droughted plants. Plasticity for the stomatal response to Δw, however, was not different between the species. There was no evidence that the alien, Pennisetum, had greater plasticity for traits related to drought tolerance compared to the native, Heteropogon. Higher P n and greater biomass allocation to leaves resulted in greater growth for Pennisetum compared to Heteropogon and may explain the success of Pennisetum as an invader of lowland arid zones on Hawaii.


BODIPY-Ethynylestradiol molecular rotors as fluorescent viscosity probes in endoplasmic reticulum.
Due to their capability for sensing changes in viscosity, fluorescent molecular rotors (FMRs) have emerged as potential tools to develop several promising viscosity probes; most of them, however, localize non-selectively within cells, precluding changes in the viscosity of specific cellular microdomains to be studied by these means. Following previous reports on enhanced fluorophore uptake efficiency and selectivity by incorporation of biological submolecular fragments, here we report two potential BODIPY FMRs based on an ethynylestradiol spindle, a non-cytotoxic semisynthetic estrogen well recognized by human cells. A critical evaluation of the potential of these fluorophores for being employed as FMRs is presented, including the photophysical characterization of the probes, SXRD studies and TD-DFT computations, as well as confocal microscopy imaging in MCF-7 (breast cancer) cells.


Significant expression of G-CSF-induced gene-1 (GIG-1) protein in myeloid cells and NK cells.
The granulocyte colony-stimulating factor (G-CSF)-induced gene, GIG-1, was originally cloned from G-CSF-stimulated bone marrow mononuclear cells obtained from a patient with chronic myelogenous leukemia (CML). We have characterized the GIG-1 gene and its protein product. Expression of GIG-1 mRNA was elevated by treatment with G-CSF in normal bone marrow mononuclear cells, as well as in some cases of blast cells obtained from patients with acute myelogenous leukemia (AML) and CML. Western blot analysis with anti-GIG-1 peptide antiserum showed the molecular mass of GIG-1 product was about 17 kDa. Immunostaining of the hematopoietic cells demonstrated that GIG-1 product was mainly localized to the cytoplasm of both myeloid and natural killer (NK) cells. These results suggested that GIG-1 protein is an integral component that is accumulated during the differentiation of myeloid cells toward the stage of mature neutrophils. Expression of GIG-1 gene in mature neutrophils was tightly regulated and reactivation of GIG-1 gene by G-CSF in mature neutrophils may represent a compensation process for the protein lost through the activation of these cells, thus implying an important role for this protein in host defense mechanisms.


Exploring the efficacy and contribution of Dupilumab in asthma management.
IgG4 monoclonal antibody Dupilumab binds to the alpha chain (IL4R) of both types of the ligand-binding domains (IL4R/ IL13R1; equally IL4 and IL13 specific) of the IL-4 receptor. The current focus on precision medicine techniques to blocking pathways implicated in allergy disorders is crucial to the development of Dupilumab and broadening its therapeutic uses. Our review describes how the IL-4R complexes signaling pathway works, explores the probable mechanisms of Dupilumab activity and addresses its clinical usefulness and safety in asthma. The FDA (Food and Drug Administration) already licences it to treat Alzheimer's disease and moderate-to-severe asthma, and it has shown highly significant results in the management of chronic rhinosinusitis and Eosinophilic esophagitis (EoE). Previous investigations and clinical trials undertaken by various pharmaceutical firms are examined in this review article to assess the existing literature fully. The discovery of Dupilumab and the expanding range of therapeutic uses are pertinent to the current focus on precision medicine methods to blocking asthma-related pathways.


Pseudoaneurysm of the uterine artery with presentation of haematuria; a rare case report.
Pseudoaneurysm of the uterine artery is a condition in which extra luminal collection of blood with a turbulent flow that communicates with flowing blood of uterine artery through a defect in its arterial wall. As per literature uterine artery pseudoaneurysm is a very rare condition and its incidence is 2-3/1000 deliveries. Clinical diagnosis is very challenging and in the index case haematuria was the presenting complaint which in fact is the extremely rare presenting complaint. Angioembolization is the ideal treatment modality for such a rare condition. A 25-year old female presented in a shock state with history of massive haematuria two months after delivering a baby. She was resuscitated with fluid, blood and blood products. A computed tomography angiogram was done which showed a large pseudoaneurysm of the left uterine artery so consequently angioembolization was done with n-butyl cyanoacrylate (NBCA) and lipoid mixture. Serial assessment of biochemical and clinical parameters depicted improvement in the clinical status of the patient. She was doing well at 6 months of follow up. A post-partum massive haematuria could be due to pseudo aneurysm of uterine artery. The presentation of haematuria may occur due to communication of aneurysm with urinary bladder and which further get ruptured. Aggressive resuscitation and angioembolization of the pseudoaneurysm is employed to treat such patients. Pseudoaneurysm of uterine artery is rare condition which may present as haematuria. Once clinical diagnosis is suspected it's better to first resuscitate and plan for angioembolization for better outcome.


Accuracy of preoperative studies in staging nonseminomatous germ cell testicular tumors.
The preoperative staging procedures used in 45 patients with surgical Stage I and Stage II nonseminomatous germ cell tumors of the testis were analyzed retrospectively. Our results indicate that gallium-67-citrate scan and supraclavicular lymph node biopsy add little information in the routine preoperative evaluation of these patients. Bipedal lymphangiography, in our experience, was no more accurate than excretory urograms in selecting patients with retroperitoneal disease and in addition provides no information regarding the status of the upper urinary tract. Thus, we suggest that physical examination, excretory urography, chest x-ray film, whole lung tomography, serum tumor markers, and liver scan provide sufficient information to proceed with surgical treatment when appropriate.


Incentive moderates the impact of implicit anger vs. sadness cues on effort-related cardiac response.
This experiment investigated the combined effect of implicit affect and monetary success incentive on effort-related cardiac response in a 2 (Affect Prime: anger vs. sadness)×2 (Incentive: low vs. high) between-person design. Sixty-two participants were exposed to affect primes during an objectively difficult short-term memory task. As predicted, by our theorizing about affect primes' systematic impact on subjectively experienced task demand and corresponding effort mobilization, sadness primes led to a weak cardiac pre-ejection period (PEP) response when incentive was low (disengagement), but to a very strong PEP response when incentive was high (high effort). PEP responses were moderate in the anger-prime conditions (low effort). HR responses largely corresponded to those of PEP. The results demonstrate for the first time that high incentive can compensate the effort mobilization deficit of individuals who process sadness primes during a difficult task.


Fasting and Fasting Mimicking Diets in Obesity and Cardiometabolic Disease Prevention and Treatment.
Worldwide obesity has risen to record levels generating a major risk factor for metabolic syndrome, diabetes, hypertension, and cardiovascular disease as well as cancer and neurodegenerative diseases. Here we discuss the impact of obesity on lifespan and cardiometabolic disease in mice and humans and how different types of fasting can help prevent and treat them. We argue that specific types of fasting regimens which are associated with low burden, high long-term compliance and safety, can reduce obesity and other disease risk factors, lower morbidity and extend healthspan.


Influence of response-time limits on automated hearing threshold determination.
In automated hearing threshold determination procedures, prespecified response- time limits can be applied to evaluate whether a stimulus was truly heard by checking whether the test subject reacts to the onset and the offset of the stimuli within given time intervals. The influence of different response-time limits on the threshold of normal-hearing test subjects was investigated. Two-stage hearing threshold level measurements applying the ISO 8253-1 (2010) bracketing procedure were performed. Pre-tests at 125 Hz and 1000 Hz were carried out with maximum accepted response times of 600 ms, 1000 ms, and 1200 ms. Subsequently, thresholds were measured at the seven octaves between 125 Hz and 8000 Hz with maximum accepted response times of 600 ms and 1000 ms. 15 test subjects in pre-tests, 25 test subjects in the main study. Threshold levels determined with a maximum accepted response time of 1000 ms are 2.6 dB lower than those obtained with a maximum accepted response time of 600 ms (95% CI -1.6 dB to 6.9 dB). The threshold shift was similar at all frequencies. Based on this study, response-time limits after both stimulus onset and offset of at least 1000 ms are recommended.


Immunohistochemical Analysis of Sox17 Associated Pathway in Brain Arteriovenous Malformations.
Sox17 has emerged as an important factor in vascular remodeling because of the potential linkage with Wnt/β-catenin, Notch, and the inflammatory pathway. Brain arteriovenous malformation (BAVM), as an angiogenic and inflammatory disorder, might possess an aberrant regulation of the Sox17 associated pathway. We sought to investigate the expression of the Sox17 associated pathway in BAVMs. Using immunohistochemical methods, 16 paraffin specimens of BAVM nidus were analyzed. Specimens were obtained from patients during surgical procedures. Expression of Sox17, Hey1, and β-catenin was observed in all specimens. Large veins possessed a distinct pattern of expression; thick-walled veins had a stronger intensity, whereas thin-walled veins had a weaker intensity, of Sox17, Hey1, and β-catenin (P < 0.001). Thick-walled veins also had a higher expression of Sox17, Hey1, and β-catenin compared with large arteries (P < 0.05). Hey1 and β-catenin expression was also higher in thick-walled veins compared with brain microvessels (P < 0.01). In addition, the difference in expression of the Sox17 associated pathway (Hey1 and β-catenin) was observed in medium and small arteries compared with large arteries in BAVM nidus and brain microvessels (P < 0.01). The Sox17 associated pathway was activated in the BAVM nidus. Our results indicate that arterial identity is gained in thick-walled veins; this might reflect the process of arterialization of the veins as a result of hemodynamic stress. In addition, high expression of the Sox17 associated pathway in medium and small arteries indicates that BAVM vessels are intrinsically active.


Steroids in the treatment of retroperitoneal fibrosis.
Two cases of retroperitoneal fibrosis with asynchronous bilateral hydronephrosis are reported. One case was managed initially by unilateral ureterolysis. Subsequent contralateral disease was treated with a 6-week course of oral steroids alone with resolution of the bilateral hydronephrosis for 10 years. The other case was treated with unilateral renal exploration. Subsequent contralateral and residual ipsilateral disease was treated similarly with steroids and 7 months later there was resolution of bilateral hydronephrosis.


Pharmacokinetic-directed high-dose busulfan combined with cyclophosphamide and etoposide results in predictable drug levels and durable long-term survival in lymphoma patients undergoing autologous stem cell transplantation.
The clinical advantage of pharmacokinetic (PK)-directed-based dosing on intravenous (i.v.) versus oral busulfan-related toxicity and survival remains unclear. We performed a retrospective cohort study of sequential cohorts of patients comparing PK-directed oral and i.v. busulfan-based conditioning regimens in lymphoma patients undergoing autologous hematopoietic cell transplantation (ASCT). Patients received oral (n = 95), every 6 hours i.v. (IV16, n = 113), or once-daily i.v. (IV4, n = 86) busulfan, cyclophosphamide, and etoposide. PK-directed dosing was performed to achieve a predefined target area under the curve (AUC) of 20,000 μM-min (range: 18,400-21,600 μM-min). PK-directed dose adjustments markedly reduced the number of patients in the oral group with total AUC higher than the targeted AUC range, and reduced the variations of total AUC values in all patient groups. One hundred-day mortality was 2.1%, 3.6%, and 3.5% for oral, IV16, and IV4 cohorts, respectively. Five-year overall survival (OS) was 57% (95% confidence interval [CI] 45%-66%) and 64% (95% CI 53%-73%) for patients who received oral and i.v. busulfan, respectively. Both multivariable and instrumental variable analyses indicated the route of delivery had no significant impact on OS, whereas refractory disease and age ≥55 were significantly associated with poorer OS. In lymphoma patients undergoing ASCT, PK-directed i.v. or oral busulfan-based conditioning regimens have comparable toxicity and OS.


The view from two worlds: The convergence of social network reports between mental health clients and their ties.
Traditionally, concerns with the similarities and discrepancies between the reports of persons (or focal respondents) and their collaterals (or network ties/respondents) about the former's social support network is framed as a methodological concern. As individuals experience the devastating effects of illness, and especially as their cognitive capabilities or social perceptions may be impaired by mental health problems, these listings are seen as potentially problematic. While we share this concern, we expand the investigation of the comparison of network ties from focal and network respondents to consider the nature of differences. Using data from Wave I of the Indianapolis Network Mental Health Study, we target the "health matters" network of individuals making their first major contact with the city's largest public and voluntary facilities. Overall, we find that the networks on which "first timers" rely to discuss health matters are small, with both focal and network respondents mentioning four individuals on average. The overlap in ties mentioned is just over 2 people (or 56 percent), on average, and differ with regard to the number of friends and health care professionals mentioned. Ironically, listings are more accurate for focal respondents who have more serious mental illnesses or larger networks. The extent of overlap is lower for women focal respondents than men. In sum, while convergence is in a range considered acceptable in network studies, the substantive nature of discrepancies have interesting and important theoretical and clinical implications.


Early-life stress affects peripheral, blood-brain barrier, and brain responses to immune challenge in juvenile and adult rats.
Early-life stress (ELS) may affect brain maturation and neuroimmune interactions and, consequently, the inflammatory response to subsequent environmental factors later in life. Recently, the coexistence of blood-brain barrier (BBB) dysfunction and inflammation has been implicated in the etiology and progression of mental and/or neurodegenerative diseases. There are sex differences in the prevalence and outcomes of these disorders. The number of studies reporting the effects of ELS and sex on BBB functioning and neuroinflammatory processes in response to immune challenge is very limited, and the data are inconsistent. In the present study, we examined whether ELS, based on the maternal separation (MS) paradigm in rats, can condition male and female subjects to subsequent lipopolysaccharide (LPS)-induced immune challenge in juvenility or adulthood. Twenty-four hours after acute LPS injection, serum proinflammatory cytokines were measured, and BBB permeability in the medial prefrontal cortex (mPFC) and hippocampus (HP) was evaluated. Additionally, the mRNA expression of neuroinflammatory markers and BBB-related genes was also studied. We found that a single LPS challenge induced a proinflammatory response both in the periphery and in the mPFC and HP and increased BBB permeability in a sex-dependent fashion. Moreover, MS enhanced the neuroinflammatory response to LPS challenge in males (especially juveniles), whereas MS females showed no difference or a blunted central response to LPS compared with control females, mainly during adulthood. These results suggest that ELS may precondition individuals to subsequent environmental factors later in life in a sex-specific manner and potentially determine their susceptibility or resilience to mental and/or neurodegenerative diseases.


Inclusion body myositis: from genetics to clinical trials.
Inclusion body myositis (IBM) belongs to the group of idiopathic inflammatory myopathies and is characterized by a slowly progressive disease course with asymmetric muscle weakness of predominantly the finger flexors and knee extensors. The disease leads to severe disability and most patients lose ambulation due to lack of curative or disease-modifying treatment options. Despite some genes reported to be associated with hereditary IBM (a distinct group of conditions), data on the genetic susceptibility of sporadic IBM are very limited. This review gives an overview of the disease and focuses on the current genetic knowledge and potential therapeutic implications.


Temperature, water, and PAR influences on predicted and measured productivity of Agave deserti at various elevations.
To measure productivity of Agave deserti over its elevational range in the northwestern Sonoran Desert, leaf unfolding from its basal rosette was monitored on groups of 10 plants at 13 sites. Based on data from an intermediate elevation (840 m), leaf unfolding proved to be highly correlated (r 2=0.88) with an environmental productivity index (EPI) formed as the product of indices for water status, temperature, and photosynthetically active radiation (PAR); each of these latter indices indicated the fraction of maximum net CO2 uptake expected for that parameter based on laboratory measurements of gas exchange and field microclimatic data. At 840 m, the main environmental variable influencing leaf unfolding for A. deserti over a 2-y period was soil water potential. On steep slopes, however, leaf unfolding during the winter ranged from 0.7 leaves per 10 plants for north-facing slopes to 7.3 for south-facing slopes, reflecting the importance of PAR. Summer and winter rainfall increased 3-fold from elevations of 300 m to 1,200 m. Temperatures were more optimal for net CO2 uptake at high elevations in the summer and at low elevations in the winter. Hence EPI increased with elevation in the summer but was maximal at an intermediate elevation in the winter. Moreover, measured leaf unfolding in both the summer and the winter closely followed the changes in EPI with elevation, indicating that productivity could be closely predicted for A. deserti based on physiological CO2 responses and changes in environmental conditions with elevation.


On-chip protein sample desalting and preparation for direct coupling with electrospray ionization mass spectrometry.
A membrane-based desalting step integrated in a MS microchip is presented: drugs, peptides and proteins are adsorbed on a hydrophobic poly(vinylidene difluoride) membrane, which allows the washing out of salts. The integration with microfluidics permits a controlled elution of analytes from the membrane and their direct mass spectrometric analysis by electrospray ionisation MS. The desalting process is demonstrated with picomole amounts of propanolol, insulin and cytochrome c. Moreover, this stop-and-go desalting process is tolerant to high concentrations of urea, and to the presence of reductants such as dithiothreitol. This particular feature allowed the chemical tagging of cysteines in beta-lactoglobulin A with iodoacetamide. Finally, the integration of chemical tagging, on-chip desalting and MS microchip paves the way for the development of high-throughput analytical procedure for structural proteomics.


Structural analysis of the C-terminal region of chicken gizzard desmin.
The C-terminal sequence of chicken gizzard desmin has been examined by computer programs based on Chou-Fasman prediction of secondary structure, auto-correlation and Fourier analysis of hydrophobic residue distribution, and cross-correlation analysis of acidic and basic residues. These analyses indicate that, although parts of the desmin sequence are alpha-helical, the helical regions may not be as extensive as predicted previously. Detailed analysis of the distribution of the charged residues in the desmin sequence strongly suggests that it cannot form a tropomyosin-like coiled-coil double-helix because of the almost complete absence of stabilizing salt-bridge interactions between proximal pairs of acidic and basic residues. Although the desmin sequence does contain the tropomyosin-like hydrophobic residue distribution, differences exist in the overall distributions of hydrophobes, with clusters of these residues being found in certain regions of the desmin sequence. Analyses of the sequences of porcine desmin and vimentin reveal very similar structural characteristics for these molecules, although vimentin is predicted to have a different structure at its C-terminus.


Cardiovascular effects of amitriptyline in anaesthetized dogs.
1. The effect of amitriptyline on cardiovascular variables has been studied in anaesthetized dogs. 2. In small doses (0.25 mg/dg) amitryptyline caused small increases in heart rates, contractility, blood pressure, coronary blood flow and aortic flow. 3. Large doses produced initial depressant effects on myocardial reflex rises in these and rate and blood pressure, which were followed by secondary reflex rises in these measurements. 4. The depressant effects were dose-related and were accompanied by marked increases in coronary flow and smaller increases in ortic flow. 5. The secondary reflex rises in cardiac parameters were abolished by propranolol and that of the blood pressure was much reduced.


Bispectral analysis of the rat EEG during various vigilance states.
Bispectra were computed to detect phase coupling in the cortical and hippocampal EEG of the rat during various vigilance states. For EEG's recorded from the hippocampus, significant phase coupling was obtained during REM sleep between the frequency components (6-8 Hz) associated with theta rhythm.


Correction: Letrozole vs. Placebo Pretreatment in the Medical Management of First Trimester Missed Miscarriage: a Randomized Controlled Trial.
[This corrects the article DOI: 10.1055/s-0043-122499.].


Early Postoperative Albumin Administration Contributes to Morbidity After the Fontan Operation.
The Fontan operation has low mortality, but is associated with significant postoperative morbidity, including prolonged chest tube output (PCTO), which is associated with prolonged hospital length of stay (PLOS). We sought to identify variables present early in the clinical course that could predict patients at high risk for PCTO and PLOS. Retrospective data were collected on 84 Fontan (extracardiac conduit) operations from 1/2008 to 12/2013 at a single institution. PCTO was defined as ≥8 days (>75th percentile); PLOS was defined as ≥12 days postoperatively (>75th percentile). Multivariate regression was used to determine covariates associated with PCTO and PLOS. Median age was 3.5 years (IQR 3-5); weight was 14.5 kg (IQR 13-17). There was no mortality. LOS was 9 days (IQR 3-11), and duration of chest tube drainage 6 days (IQR 5-8) at 15 ml/kg/day (IQR 9-20). In univariate analysis, only systemic right ventricle, 24-h 5 % albumin administration, 24-h fluid balance, and 12-h inotrope score were associated with PCTO. In multivariate analysis, only 5 % albumin administration in first 24 h (p < 0.001) and PCTO were independently associated with PLOS. ROC curve analysis showed patients receiving >25 ml/kg of 5 % albumin in first 24-h predicted PLOS (94 % specificity, 93 % sensitivity, AUC = 0.95, p < 0.001). Increased colloid in the first 24-h post-CPB strongly predicts PCTO and PLOS after Fontan operation, potentially providing an early identification of a cohort with unfavorable Fontan physiology. A better understanding of the role of colloid resuscitation after Fontan is necessary, and efforts to reduce perioperative colloid administration could decrease hospital morbidity.


Characterization of orexins (hypocretins) and melanin-concentrating hormone in genetically obese mice.
Orexins (hypocretins) and the melanin-concentrating hormone (MCH) are neuropeptides localized to the lateral hypothalamic area and are potential regulators of energy homeostasis. Using highly sensitive radioimmunoassay for orexins and MCH, we determined their contents in the lateral hypothalamus (LH) of genetically obese ob/ob and db/db mice and their controls, C57BL/6J and C57BL/KSJ. The orexin contents in the lateral hypothalamus significantly increased in the ob/ob mice, whereas the orexin contents significantly decreased in the db/db mice. Mature orexin-A and -B peptides were the major endogenous orexin molecules in the lateral hypothalamus. Conversely, the MCH contents in the lateral hypothalamus of both obese mice increased compared to the control mice. MCH contents in the lateral hypothalamus were two- to five-fold higher than that of orexin contents. These results suggest that the regulatory mechanism of orexin and MCH may be different in the genetically obese mice.


Long-term prognostic scores may underestimate the risk of death in patients with heart failure with reduced ejection fraction in whom red cell distribution width is elevated.
Risk prediction in patients with heart failure with reduced ejection fraction (HFrEF) is one of the key challenges for clinicians. Novel biomarkers aggregating several important pathophysiological pathways may modify the diagnostic discrimination of validated scores. The red cell distribution width (RDW) is a cheap and easily available measure of anisocytosis, and was shown to have a strong independent prognostic power in short- and medium‑term prognosis in HFrEF. Our aim was to assess the prognostic power of RDW in optimally treated chronic HFrEF, and to investigate whether different RDW may impact the prognostic accuracy of validated long‑term scores in HFrEF. The study included 551 patients at a median (interquartile range [IQR]) age of 54 (47-59) years, of whom 86.6% were men. The patients represented the median New York Heart Association class III (IQR, II-III), and ischemic etiology occurred in 56.6% of the cases. In all patients, RDW as a coefficient of variation was calculated, along with Meta‑Analysis Global Group in Chronic Heart Failure Score (MAGGIC‑HF) and Seattle Heart Failure Survival Model (SHFSM). The patients were followed for 5 years and all‑cause mortality was assessed. We recorded 166 (30.1%) and 225 (40.8%) deaths at 3 and 5 years, respectively. Scores based on MAGGIC‑HF and SHFSM algorithms for the respective prediction of 3- and 5‑year mortality were calculated for each patient and compared with the observed mortality. There was a significant underestimation of mortality in the patients with RDW above 15.4% (reference values, 11.5%-14.5%), while in those with lower RDW SHFSM overestimated the actual risk. The excess mortality in the higher RDW group was confirmed by the Hosmer-Lemeshow statistic. The RDW has a strong prognostic value in chronic HFrEF, independently of the risk assessed by the MAGGIC‑HF or the SHFSM score.


Ablative-Transarterial Radioembolization resulting in complete histopathological response of hepatocellular carcinoma in the resected liver specimen after salvage hepatectomy.
Hepatocellular carcinoma (HCC) is a common disease. Many patients at the time of diagnosis of HCC are in advanced stages and cannot benefit from curative treatment. Palliative treatments remain the only treatment option. Advances in palliative treatment can occasionally downstage HCC and induce enough liver hypertrophy to allow salvage hepatectomy to be performed on patients with initially unresectable HCC. We herein present a patient who underwent salvage hepatectomy after successful Ablative-Transarterial Radioembolization (A-TARE) with complete histopathologic response in the resected liver specimen. A 67-year old obese patient presented with a 9.7 cm HCC at liver segment 8, with local tumour extension to involve segments 4,5 and 7. Initial workup suggested the tumour to be unresectable. A-TARE with yttrium-90 microspheres was given. Further workup 4 months after A-TARE showed the tumour to be downstaged with adequate hypertrophy of future liver remnant. Salvage hepatectomy became possible and the patient underwent salvage trisectionectomy 5 months after A-TARE. He recovered uneventfully from the operation. Histopathological examination of the resected liver specimen showed no viable tumour cells inside a fibrous mass which corresponded to the radiologic residual tumour. Salvage hepatectomy should be offered to patients after tumour downstaging with A-TARE as viable malignant cells are likely to persist. Complete response with no viable tumour cells in the resected liver specimen, to our knowledge, has never been reported in literature. A-TARE was able to induce complete histopathological response in a patient who initially presented with a large and unresectable HCC mass.


Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid.
In the elderly, cerebral ischemia (CI) occurs in the presence of high levels of amyloid. Neuroinflammation plays a critical role in the pathophysiology of Alzheimer's disease and CI. This study examined infarct size, neuroinflammation, and cognitive deficits over time in rat models of Alzheimer's disease and CI. beta-amyloid toxicity was modeled using bilateral intracerebroventricular injections of beta-amyloid 25 to 35 peptides. CI was modeled using unilateral injections of the potent vasoconstrictor, endothelin-1, into the striatum. Infarct volumes were higher in the presence of amyloid and compared with the CI model alone. In the CI model alone, the infarct volume was significantly smaller 28 days after surgery compared with 7 days after surgery. However, when Alzheimer's disease and CI models were combined, the infarct volume was significantly larger 28 days after surgery compared with 7 days after surgery. The neuroinflammation in the region of the infarct was also significantly increased. The Barnes circular platform test showed time-dependent increases in memory and learning deficits in the beta-amyloid-treated rats that were even greater when beta-amyloid treatment was combined with CI. CI in the presence of high levels of amyloid results in progressive increases in infarct size, neuroinflammation, and cognitive deficits.


Are yellow-brownish opacities in hypomineralized teeth more prone to breakage than white-creamy ones? A systematic review.
To evaluate all the available evidence assessing if in hypomineralized teeth, yellow-brownish opacities are more prone to post-eruptive breakdown (PEB) compared to white-creamy opacities. Observational studies that evaluated the occurrence of PEB in hypomineralized teeth were considered for inclusion. Electronic searches were performed up to January 2022 in MedLine, LILACS, BBO, Cochrane Library, Web of Science, Scopus, and EMBASE. Neither publication date nor language restrictions were imposed to the searches. Two researchers independently performed the study selection, data extraction, and quality assessment of the included studies according to the Newcastle-Ottawa Scale (NOS). Datasets from studies were grouped for narrative synthesis based on the severity of the PEB (enamel or dentin), type of tooth (molar or incisor), unit of analysis (subject or tooth or tooth surface), and follow-up period (in months). The certainty of evidence was evaluated using the GRADE approach. Nine studies were included, five cohort and three cross-sectional. All studies assessed the opacities and PEB by visual examination and diagnosed MIH according to EAPD criteria. In the cohort studies, considering all follow-up periods (ranging from 6 to 36 months), dark opacities fractured more than light opacities, at both enamel and enamel/dentin levels, and molars fractured more than incisors. In two out of three cross-sectional studies, dark opacities also fractured more than light opacities, but the deep of the PEB (enamel or dentin breakdown) or the type of tooth (molar or incisor) was not considered in the analysis. Although it seems plausible to state that darker demarcated opacities in MIH patients broke more often than light ones, based on this systematic review of the literature, the certainty of the available evidence about this association is still very low. More reliable and valid research is still necessary to support any future recommendation that MIH children who present yellow-brownish opacities should be monitored at shorter intervals compared to those who present only white-creamy opacities.


Using Stem Cells to Treat Diabetes-Induced Infertility.
Diabetes is one of the main causes of infertility, which impacts the quality of life of couples. These reproductive complications are important issues for all clinicians. The strategies for the treatment of diabetes-induced infertility are limited with the high cost and unsatisfied results. Due to the multi-directional differentiation potential and self-renewal ability of stem cells, these cells have emerged as attractive therapeutic agents in many diseases, including diabetes mellitus. We reviewed the current knowledge on the best available evidence regarding the role of stem cell transplantation in reproductive complications of diabetes.


A closer look at the current knowledge and prospects of artificial intelligence integration in dentistry practice: A cross-sectional study.
Healthcare professionals have expressed worries about using AI, while others anticipate more work opportunities in the future and better patient care. Integrating AI into practice will directly impact dentistry practice. The purpose of the study is to evaluate organizational readiness, knowledge, attitude, and willingness to integrate AI into dentistry practice. a cross-sectional exploratory study of dentists, academic faculty and students who practice and study dentistry in UAE. Participants were invited to participate in a previously validated survey used to collect participants' demographics, knowledge, perceptions, and organizational readiness. One hundred thirty-four responded to the survey with a response rate was 78% from the invited group. Results showed excitement to implement AI in practice accompanied by medium to high knowledge and a lack of education and training programs. As a result, organizations were not well prepared and had to ensure readiness for AI implementation. An effort to ensure professional and student readiness will improve AI integration in practice. In addition, dental professional societies and educational institutions must collaborate to develop proper training programs for dentists to close the knowledge gap.


Epidemiology of metabolic syndrome and its components in Chinese patients with a range of thyroid-stimulating hormone concentrations.
To investigate the relationship between thyroid stimulating hormone (TSH) concentration and the risks of developing metabolic syndrome and its components. A total of 10,140 residents of the Yunyan district of Guiyang (Guizhou, China) who were ≥40 years old were selected by cluster random sampling between May and August 2011, of whom 5692 were eligible. TSH concentration and indices of metabolic syndrome were documented at baseline and 3 years later. Participants were allocated to a euthyroid (TSH 0.55-4.78 mIU/L) or high TSH concentration (TSH >4.78 mIU/L) group. Patients with overt hypothyroidism or were undergoing treatment for hypothyroidism were excluded. The crude and adjusted prevalences of metabolic syndrome were 39.9% and 33.9% in the euthyroid group and 44.3% and 37.5% in the high TSH group, respectively. Binary logistic regression analysis revealed a positive correlation between a high TSH concentration at baseline and the cumulative incidence of metabolic syndrome during follow up. High TSH is associated with a higher risk of developing metabolic syndrome or one of its components; therefore, people with a high TSH concentration should be screened regularly to permit the early identification of metabolic syndrome and followed up thoroughly.


Effects of cytokine gene therapy on particulate-induced inflammation in the murine air pouch.
Retroviral vectors encoding the human IL-1 antagonist (IL-1Ra) gene and the human tumor necrosis factor soluble receptor (sTNF-R) gene were investigated using an in vivo model of the inflammatory response to orthopedic wear debris. Air pouches established in BALB/c mice were injected with polymethylmethacrylate (PMMA) particles to provoke an inflammatory reaction, and infected with retroviral vectors expressing IL-1Ra, sTNF-R or a LacZ marker gene. Pouch membranes and fluids were harvested after 48 or 72 hours for analyses. Positive PCR reactions for Neo genes were observed specifically in DNA extracted from the membrane of retroviral-infected pouches. ELISA assays revealed the presence of human IL-1 Ra in pouch fluid from DFG-IRAP-Neo transduced mice, but not control animals. Histological evaluation indicated that the IL-1Ra gene transfer was associated with markedly decreased inflammation in the model, with resolution of the edematous phase of the reaction, decreased pouch fluid accumulation, and lowered macrophage influx. The data suggest that the air pouch model represents a useful tool to evaluate gene therapy, and demonstrate that IL-1Ra gene therapy may be an appropriate therapeutic approach to inflammation.


Domain inhibitory and bacteriostatic activities of the five-domain Kazal-type serine proteinase inhibitor from black tiger shrimp Penaeus monodon.
Serine proteinase inhibitors (SPIs) in multi-cellular organisms are important modulators of proteinase activities in various biological processes. A five-domain Kazal-type SPI SPIPm2 from the black tiger shrimp Penaeus monodon is presumably involved in innate immune response. The SPIPm2 with the domain P1 residues T, A, E, K and E was isolated from the hemocyte cDNA libraries and found to strongly inhibit subtilisin and elastase, and weakly inhibit trypsin. To unravel further the inhibitory activity of each domain, we subcloned, over-expressed and purified each individual SPI domain. Their inhibitory specificities against trypsin, subtilisin and elastase were determined. Domain 1 was found to be inactive. Domains 2, 3 and 5 inhibited subtilisin. Domain 2 inhibited also elastase. Domain 4 weakly inhibited subtilisin and trypsin. The intact SPIPm2 inhibitor was found to possess bacteriostatic activity against the Bacillus subtilis but not the Bacillus megaterium, Staphylococcus aureus, Vibrio harveyi 639 and Escherichia coli JM109. Domains 2, 4 and 5 contributed to this bacteriostatic activity.


Development of simulated-gas standards.
Multigamma simulated-gas standards were developed for monitoring the surrounding air at nuclear power plants by several commercial firms and laboratories. The main advantages of our simulated-gas standard consist of the easy preparation, gravimetrically spiking the matrix with a standardised multigamma radioactive solution. and that it does not require to be tested against actual gas standards. Self-attenuation correction factors for low gamma-ray energies were calculated. Original studies about the stability of the adherence of the dried radioactive residue to the matrix are presented and discussed.


Classification and Epidemiology of Sleep Disorders in Children and Adolescents.
Sleep disturbances are common in children and adolescents but still remain unrecognized and undertreated. Several classification systems of sleep disorders are available, which include recent attempts to develop more specific nosologic categories that reflect developmental aspects of sleep. The prevalence of sleep disorders has been studied across various samples of healthy, typically developing children and those with special medical, psychiatric, and neurodevelopmental needs. Sleep disorders are highly prevalent in children and adolescents with psychiatric disorders, making it important for mental health professionals to be aware of sleep problems and to address them in the context of psychiatric comorbidities.


Audit of paediatric residents' medical records.
The quality of the information contained in a medical record is dependent on the knowledge and skills of the doctor. The auditing of medical records is one of the items included in the competency evaluation of residents at the Department of Pediatrics, Prince of Songkla University (PSU), Thailand. To determine the percentages of 'not met' and 'not acceptable' charts written by residents, which parts of the residents' writing required improvement and associated factors. The charts of four newly admitted cases at each ward were selected non-randomly by attending staff for bi-weekly audit. The audit form comprised 15 components, with each component scored as 'met' or 'not met'. Medical records with more than two 'not met' items were categorised as 'not acceptable'. From September 2012 to October 2013, a total 506 in-patient medical records written by PSU paediatric residents were reviewed. The components identified as having the highest rates of 'not acceptable' completion were 'initial investigations' (5.3%), 'summary of investigations' (4.5%) and 'progression of clinical conditions' (4.3%). The reasons for a 'not acceptable' evaluation were 'incomplete documentation' (65.0%), 'lack of follow-up' (26.7%) and 'incorrect clinical reasoning' (8.3%). Using logistic regression analysis, the charts of patients from the chronic illness wards were found to be most significantly associated with the 'not acceptable' rating. Residents need skills and knowledge when completing patient records CONCLUSIONS: Residents need skills and knowledge when completing patient records, and attending staff should be aware that it is their responsibility to ensure that residents complete documentation fully and correctly.


Evaluation of transferrin-polyethylenimine conjugate for targeted gene delivery.
With the aim to improve the specificity and to reduce the cytotoxicity of polyethylenimine (PEI), we have synthesized the conjugates of the branched PEI (25 kDa) with transferrin. The transferrin-PEI (TP) conjugates with five compositions were synthesized using periodate oxidation method and confirmed by FT-IR spectroscopy and gel permeation chromatography. The free amine contents of TP conjugates, which were able to condense and deliver DNA, increased as the amount of PEI increased. TP/DNA polyplexes were characterized by measuring gel electrophoresis, ethidium bromide fluorescence quenching, particle size and zeta potential of complexes. Complete complexation of the polyplexes was observed above the N/P ratio of 5 in TP/ DNA, and above 3 in PEI/DNA, respectively. The zeta potential of the complexes decreased as the amount of transferrin in TP conjugates increased. Transfection efficiency of TP conjugates was evaluated in HeLa cell and Jurkat cell systems. Among the five compositions of TP conjugates, TP-2 system mediated a higher beta-galactosidase gene expression than PEI system in Jurkat cell which was known to express elevated numbers of transferrin receptors. From the results of the cell viability based on MTT assay, TP conjugates showed lower cytotoxicity compared with the PEI system. We expect that the TP conjugate can be used efficiently as a nonviral gene delivery vector.


Parental unemployment: a ticking time bomb for children's adverse childhood experiences.
Parental unemployment poses a significant threat to the well-being and development of children, acting as a ticking time bomb that can trigger adverse childhood experiences. To defuse this time bomb, comprehensive support systems must be in place, including financial assistance, emotional support, educational resources and social integration programmes.


[Neuronal apoptosis following cerebral ischemia. Basis, physiopathology and treatment strategies].
Neuronal injury following cardiac arrest (global cerebral ischaemia) and stroke (focal cerebral ischaemia) is one of the major causes of the high morbidity and mortality associated with these pathological events. One of the major characteristics of this kind of neuronal injury is delayed neuronal degeneration. An increasing body of evidence indicates that apoptosis (programmed cell death) is involved in this process after global and focal cerebral ischaemia. In contrast to necrosis, which is primarily characterised by cellular metabolism failure and loss of membrane integrity, apoptosis represents a pattern of cell death in which an active energy-dependent cell death programme is initiated without any concomitant inflammatory reaction. Based on the knowledge that apoptosis plays a major role in delayed neuronal death following cerebral ischaemia, a variety of new neuroprotective therapeutic strategies have emerged (e.g. caspase inhibitors, viral anti-apoptotic proteins, modulation of systemic anti- and pro-apoptotic protein expression and death receptor antagonists). Many of these are still being experimentally evaluated. Relevant anti-apoptotic and neuroprotective therapeutic strategies could be introduced into clinical practice in the near future. The field of anaesthesiology will benefit from these important developments. New therapeutic opportunities might also become available in emergency medicine and critical care medicine. This article reviews the molecular basis of apoptosis and its physiological and pathophysiological relevance. The mechanisms of delayed neuronal death following focal and global cerebral ischaemia are presented with particular emphasis on the role of apoptosis. Based on this, possible future therapeutic interventions are highlighted and discussed.


Neighborhood cohesion and psychological distress across race and sexual orientation.
We investigate the association neighborhood cohesion, as source of social support, has with psychological distress among white, Black, and Latinx lesbian, gay, and bisexual (LGB) individuals, compared to heterosexual individuals in the United States. We estimate zero-order multinomial logistic regression models to assess the likelihood of moderate and severe psychological distress among respondents. In the models accounting for neighborhood cohesion and all other covariates, white, Black, and Latinx lesbian, gay, and bisexual individuals are more likely to meet the criteria for moderate and severe psychological distress than non-LGB people. Neighborhood cohesion has differing impact on psychological distress outcomes by racial/ethnic-sexual orientation groups, but in general provides a greater magnitude of protection against moderate psychological distress for non-LGB groups and a greater magnitude of protection against severe psychological distress for LGB groups.


Role of acetaldehyde in the ethanol-induced impairment of glycoprotein metabolism in rat liver slices.
The mechanism responsible for ethanol-induced changes in the glycosylation of proteins was investigated in rat liver slices. Ethanol (5 to 50 mM) decreased [1-14C]glucosamine and [14C]leucine incorporation into total liver and microsomal proteins and greatly inhibited incorporation into medium (secretory) proteins. Pyrazole prevented the inhibition of glycoprotein synthesis by ethanol. Additions of methylene blue or pyruvate, which corrected the disordered redox state caused by ethanol oxidation, did not reverse the inhibitory effects of ethanol on glycosylation. Sorbitol, which mimics ethanol in generating reducing equivalents in the hepatocyte, also inhibited glycosylation; however, fructose, the immediate oxidation product of sorbitol, similarly inhibited glycoprotein synthesis without altering the redox state. When low levels of acetaldehyde (0.12 to 0.70 mM) were maintained in the medium by means of infusion, a significant inhibition of glycoprotein synthesis was observed. Acetate did not impair glycosylation. These data suggest that the ethanol-induced impairment of glycoprotein synthesis and secretion is a consequence of ethanol metabolism and further suggest that this inhibition is attributable to acetaldehyde formation rather than to the altered redox state resulting from ethanol oxidation.


Function tests on the neuroendocrine hypothalamo-pituitary system following acute midbrain syndrome, with special reference to computertomographical and magnetic resonance imaging results.
Seventeen patients underwent a neuroendocrinological function test at a mean 6.3 years following a severe craniocerebral trauma (CCT) accompanied by midbrain syndrome. An insulin hypoglycaemia test (IHT) and the combined pituitary anterior lobe test (CPALT) were applied. Whereas the IHT as maximum stimulator of the hypothalamo-pituitary system (HPS) showed an adequate reserve capacity, the CPALT yielded a partial limitation of the secretion dynamic in the somatotropic, adrenocorticotropic axis as well as a dysfunction in the FSH secretion. Neuroradiological tests could not establish substantial injury in the regio hypothalamica in any patient.


The value of clinical symptoms in the diagnosis of urinary incontinence in the female.
In a study of 566 patients with urinary incontinence the presenting symptom or combination of symptoms were shown to have limited diagnostic predictive value as measured by urodynamic diagnostic criteria.


Young children's spontaneous inspection of negative instances in a search task.
Forty children 1 1/2 to 3 1/2 years of age searched for stickers that were hidden underneath two discretely different classes of objects embedded in arrays containing several classes. The paper focuses on a previously unobserved strategy that appeared at 3 1/2. Whereas the younger children searched underneath those objects that looked like the objects the children knew had stickers, the 3 1/2-year-olds systematically explored not only the objects that did, but also the objects that did not, have stickers. Eight adults performed similarly to the 3 1/2-year-olds. Analyses of developmental trends in the data and the observation of individual children performing the tasks suggest that the children's increased inspection of the negative objects was not merely the result of a random or more exhaustive search. The children appear to have been attempting to determine which kinds of choices were the wrong ones. The attempt to define and delimit negative cases is a central aspect of reflective thought.