WDR74 serves as a novel therapeutic target by its oncogenic role in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most refractory human malignancies. WD repeat-containing protein 74 (WDR74) is involved in the tumorigenesis of various cancers, however, its clinical implications and biological function in HCC have yet to be clearly determined. Bioinformatics analysis was conducted using various databases, including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and UALCAN. The expression of WDR74 was confirmed in HCC tumor samples and the corresponding adjacent nontumor samples by qRT-PCR, western blot and immunohistochemistry. Functional enrichment analysis was used for the biological function prediction. In vitro experiments were performed to determine the effects of WDR74 on HCC cell proliferation. Our findings revealed that WDR74 was markedly upregulated in HCC tissues. Increased WDR74 expression had an unfavorable overall survival (OS). Multivariate Cox regression analysis demonstrated that WDR74 was an independent prognostic factor for OS in patients with HCC. Functional enrichment analysis suggested a significant correlation with cytokine-cytokine receptor interaction pathway in both TCGA-LIHC and GSE112790 datasets. Gene set enrichment analysis showed that WDR74 is probably involved in several pathways, such as MYC targets, ribosome, translation, and cell cycle. Finally, WDR74 knockdown reduced HCC cell proliferation by restraining the G1/S cell cycle transition and inducing apoptosis. The current study demonstrates that elevated WDR74 expression is linked to an accelerated rate of tumor cell proliferation and is indicative of a poorer outcome in patients with HCC. Therefore, WDR74 could be used as a reliable prognostic biomarker and is a potential therapeutic target for HCC.


Effects of prenatal exposure to cancer treatment on neurocognitive development, a review.
Due to the increasing incidence of cancer during pregnancy, the need to better understand long-term outcome after prenatal exposure to chemo- and/or radiotherapy has become more urgent. This manuscript focuses on the neurocognitive development after prenatal exposure to cancer treatment. We will review possible pathways for brain damage that could explain the subtle changes in neurocognition and behavior found after in utero exposure to cancer treatment. Contrary to radiation, which has a direct effect on the developing nervous system, chemotherapy has to pass the placental and blood brain barrier to reach the fetal brain. However, there are also indirect effects such as inflammation and oxidative stress. Furthermore, the indirect effects of the cancer itself and its treatment, e.g., poor maternal nutrition and high maternal stress, as well as prematurity, can be related to cognitive impairment. Although the available evidence suggests that cancer treatment can be administered during pregnancy without jeopardizing the fetal chances, larger numbers and longer follow up of these children are needed.


[Transfection of human hepatic stimulator substance gene could protect BEL-7402 cells against hepatotoxins].
To investigate protective effects of hHSS transfection against CCl4 or H2O2. cDNA coding for hHSS was constructed into eukaryotic vector of pcDNA3.1 and transfected into BEL-7402 hepatoma cells. The expression of hHSS was analyzed with Northern blot. The growth of the hepatoma cells was remarkably enhanced 24 to 144h after hHSS gene transfection, which suggesting hHSS gene expression could stimulate cells activity. Meantime, incubation of both wild-type and vector-transfected as well as hHSS-transfected cells with CCl4 or H2O2 resulted in severe damage as marked by cell mortality and the rate of apoptosis. However, it appeared that the transfection of hHSS enabled the hepatoma cells to raise obvious resistance against CCl4 and H2O2 injury. Compared the vector cells to the vector-transfected cells, apoptosis ratio were (32.44+/-0.52)% and (25.60+/-0.66)% in which treated with CCl4, while (47.78+/-0.45)% and (37.40+/-0.69)% in which treated with H2O2, t value is 16.82 and 25.20, P<0.01. MAPK phosphorylation was also activated after HSS transfected. The function of hHSS gene expression could be related to proliferation of cell and protection against free radical damage.


Torilin ameliorates type II collagen-induced arthritis in mouse model of rheumatoid arthritis.
Advancements in rheumatoid-arthritis-(RA) therapies have shown considerable progresses in the comprehension of disease. However, the development of new potential agents with relative safety and efficacy continues and natural compounds have been considered as alternatives to identify new entities. Since previous in-vivo data and our in-vitro findings showed that torilin has a strong anti-inflammatory property, we further investigated its effect against collagen-induced-arthritis-(CIA) in mice. CIA-induced DBA/1J mice were treated with torilin or methotrexate (MTX) for 5-weeks. Arthritis severity was evaluated by arthritic score and joint histopathology. Draining lymph node (dLN), joint and peripheral-blood mononuclear-cell (PBMC) counts, and activation/localization of T-/B-lymphocytes, dendritic cells (DCs) and neutrophils were examined by FACS analysis. Serum anti-type-II-collagen-(CII) antibody levels and cultured-splenocyte and serum cytokines were also evaluated. Torilin markedly reduced CIA-induced arthritic score, histopathology and leukocyte counts. Besides, torilin suppressed CIA-activated T-cells including CD3+, CD3+/CD69+, CD8+, CD4+ and CD4+/CD25+ in dLNs or joints. It also modified CD19+ or CD20+/CD23+ (B-cells), MHCII+/CD11c+ (DCs) and Gr-1+/CD11b+ (neutrophil) subpopulations. It further depressed total anti-CII-IgG, anti-CII-IgG1 and anti-CII-IgG2a antibody productions. Moreover, while IFN-γ and IL-10 were not affected, torilin suppressed CIA-induced serum TNF-α, IL-1β and IL-6 levels. Interestingly, torilin also blocked IFN-γ, IL-17 and IL-6 cytokines while it did not affect IL-10 but enhanced IL-4 in splenocytes. These results show that torilin attenuated arthritis severity, modified leukocyte activations in dLNs or joints, and restored serum and splenocyte cytokine imbalances. Torilin may have immunomodulatory and anti-inflammatory properties with the capacity to ameliorate the inflammatory response in CIA-mice.


Temporal synchrony and audiovisual integration of speech and object stimuli in autism.
Individuals with Autism Spectrum Disorders (ASD) have been shown to have multisensory integration deficits, which may lead to problems perceiving complex, multisensory environments. For example, understanding audiovisual speech requires integration of visual information from the lips and face with auditory information from the voice, and audiovisual speech integration deficits can lead to impaired understanding and comprehension. While there is strong evidence for an audiovisual speech integration impairment in ASD, it is unclear whether this impairment is due to low level perceptual processes that affect all types of audiovisual integration or if it is specific to speech processing. Here, we measure audiovisual integration of basic speech (i.e., consonant-vowel utterances) and object stimuli (i.e., a bouncing ball) in adolescents with ASD and well-matched controls. We calculate a temporal window of integration (TWI) using each individual's ability to identify which of two videos (one temporally aligned and one misaligned) matches auditory stimuli. The TWI measures tolerance for temporal asynchrony between the auditory and visual streams, and is an important feature of audiovisual perception. While controls showed similar tolerance of asynchrony for the simple speech and object stimuli, individuals with ASD did not. Specifically, individuals with ASD showed less tolerance of asynchrony for speech stimuli compared to object stimuli. In individuals with ASD, decreased tolerance for asynchrony in speech stimuli was associated with higher ratings of autism symptom severity. These results suggest that audiovisual perception in ASD may vary for speech and object stimuli beyond what can be accounted for by stimulus complexity.


Cognitive function is associated with body composition and nutritional risk of geriatric patients.
Most patients with dementia lose body weight over the course of the disease. Yet it is not known whether this weight loss is predominantly in the form of fat-free mass (FFM) or fat mass (FM), the latter of which one would expect if the weight loss were caused simply by a chronic decrease of energy intake. To determine body composition and nutritional risk in geriatric patients and their association with cognitive function. A retrospective, cross-sectional single-center database analysis. We analyzed 4,095 consecutive geriatric hospital patients for body composition, nutritional risk, need of care and cognitive function using bioelectric impedance analysis, NRS 2002, Barthel Index and Mini Mental State Examination. Subjects with cognitive dysfunction showed significant lower body weight, body mass index (BMI), FM, fat mass index, FFM and fat-free mass index and a higher NRS score compared to cognitively intact subjects. Mean body weight decreased 10.2%, mean FM decreased 21.1%, mean FFM decreased 5.9% and mean NRS 2002 score increased from 2.1 to 3.0 points with increasing cognitive deterioration. A multivariate analysis revealed that cognitive dysfunction, age and female gender were all significant risk factors for a low body mass index and a low fat mass index. Age, male gender and need of care, but not cognitive dysfunction, were risk factors for a low fat-free mass index. Dementia patients seem to lose predominantly fat mass with weight loss. Female dementia patients are at a higher nutritional risk than male patients, presumably as a result of their different social situation in old age. That is why the nutritional state of female patients with dementia requires special attention.


[Ultrastructure of the Ranvier's nodes in myelinated nerve fibers of the shrimp Penaeus].
From a comparative point of view the axonal cytology and the ultrastructure of Ranvier nodes in non-giant myelinated fibers of the shrimp Penaeus are described.


Size Does Matter: Litter Size Strongly Determines Adult Metabolism in Rodents.
In this essay, we highlight how litter size in rodents is a strong determinant of neonatal growth and long-term metabolic health. Based on these effects, we strongly advise that scientific articles that utilize rodent models for obesity and metabolic research should include information on the litter sizes in the study to increase the data transparency of such reports.


Multiple effects of the special AT-rich binding protein 1 (SATB1) in colon carcinoma.
SATB1 (special AT-rich binding protein 1) is a global chromatin organizer regulating the expression of a large number of genes. Overexpression has been found in various solid tumors and positively correlated with prognostic and clinicopathological properties. In colorectal cancer (CRC), SATB1 overexpression and its correlation with poor differentiation, invasive depth, TNM (tumor, nodes, metastases) stage and prognosis have been demonstrated. However, more detailed studies on the SATB1 functions in CRC are warranted. In this article, we comprehensively analyze the cellular and molecular role of SATB1 in CRC cell lines with different SATB1 expression levels by using RNAi-mediated knockdown. Using siRNAs with different knockdown efficacies, we demonstrate antiproliferative, cell cycle-inhibitory and proapoptotic effects of SATB1 knockdown in a SATB1 gene dose-dependent manner. Tumor growth inhibition is confirmed in vivo in a subcutaneous tumor xenograft mouse model using stable knockdown cells. The in-depth analysis of cellular effects reveals increased activities of caspases-3, -7, -8, -9 and other mediators of apoptotic pathways. Similarly, the analysis of E- and N-cadherin, slug, twist, β-catenin and MMP7 indicates SATB1 effects on epithelial-mesenchymal transition (EMT) and matrix breakdown. Our results also establish SATB1 effects on receptor tyrosine kinases and (proto-)oncogenes such as HER receptors and Pim-1. Taken together, this suggests a more complex molecular interplay between tumor-promoting and possible inhibitory effects in CRC by affecting multiple pathways and molecules involved in proliferation, cell cycle, EMT, invasion and cell survival.


Mechanisms of wood smoke-induced increases in nasal airway resistance and reactivity in rats.
We investigated the mechanisms of wood smoke-induced increases in nasal airway resistance (RNA) and airway reactivity in anesthetized rats. Delivery of wood smoke into a functionally isolated nasal airway produced an increase in RNA, which was attenuated by CP-96,345 [a tachykinin NK(1) receptor antagonist; (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine] or atropine. Additionally, smoke pre-exposure animals displayed a greater amplitude and a longer duration of RNA responses to capsaicin or histamine provocation, as compared to air controls. This enhanced airway reactivity to capsaicin or histamine was largely alleviated by CP-96,345 or atropine. The nasal secretory responses to capsaicin or histamine in smoke pre-exposure animals were similar to those in air controls. We concluded that (1) reflex cholinergic and tachykininergic mechanisms play important roles in wood smoke-induced increases in nasal airway resistance and airway reactivity, and (2) this nasal airway hyperreactivity might not be due to an exaggerated secretory response, but is presumably due to augmented nasal swelling.


Genome sequences of three Leuconostoc citreum strains, LBAE C10, LBAE C11, and LBAE E16, isolated from wheat sourdoughs.
Leuconostoc citreum is a key microorganism in fermented foods of plant origin. Here we report the draft genome sequence for three strains of Leuconostoc citreum, LBAE C10, LBAE C11, and LBAE E16, which have been isolated from traditional French wheat sourdoughs.


Longitudinal humoral and cell-mediated immune responses in a population-based cohort in Zurich, Switzerland between March and June 2022 - evidence for protection against Omicron SARS-CoV-2 infection by neutralizing antibodies and spike-specific T-cell responses.
The correlate(s) of protection against SARS-CoV-2 remain incompletely defined. Additional information regarding the combinations of antibody and T cell-mediated immunity which can protect against (re)infection is needed. We conducted a population-based, longitudinal cohort study including 1044 individuals of varying SARS-CoV-2 vaccination and infection statuses. We assessed spike (S)- and nucleocapsid (N)-immunoglobulin(Ig)G and wildtype, Delta, and Omicron-neutralizing antibody (N-Ab) activity. In a subset of 328 individuals, we evaluated S, membrane (M), and N-specific T cells. Three months later, we reassessed Ab (n = 964) and T cell (n = 141) responses and evaluated factors associated with protection from (re)infection. At the study start, >98% of participants were S-IgG seropositive. N-IgG and M/N-T-cell responses increased over time, indicating viral (re)exposure, despite existing S-IgG. Compared to N-IgG, M/N-T cells were a more sensitive measure of viral exposure. High N-IgG titers, Omicron-N-Ab activity, and S-specific-T-cell responses were all associated with a reduced likelihood of (re)infection over time. Population-level SARS-CoV-2 immunity is S-IgG-dominated, but heterogeneous. M/N-T-cell responses can distinguish previous infection from vaccination, and monitoring a combination of N-IgG, Omicron-N-Ab, and S-T-cell responses may help estimate protection against SARS-CoV-2 (re)infection.


Positioning and atomic imaging of micron-size graphene sheets by a scanning tunneling microscope.
We present a mechanism for directly positioning the tip over a micron-size sample by tracking the trajectory of the tip and tip shadow. A bilayer graphene sheet identified by Raman spectroscopy with a lateral size of 20 μm × 50 μm was transferred on the surface of shaped gold electrodes, on which it will be rapidly captured by a homebuilt scanning tunneling microscopy (STM) with the help of an optical microscope. Using the improved line-based imaging mode, atomic-resolution images featuring a hexagonal lattice structure on the bilayer graphene sheet were obtained by our positioning-capable STM. We have also observed a unique O-ring superstructure on graphene surface that caused by the collective interference near the boundaries or defects. Furthermore, we successfully captured a graphene sheet of size as small as 1.3 nm by a rapid and large-area searching operation; this is the first time that such a small graphene sheet has been observed with atomic resolution. The STM images of a micron-size graphene sheet illustrate the significant positioning ability and imaging precision of our homebuilt STM. Our results contribute to further STM studies on samples with ultra-small size.


Effect of intestinal inhibitory peptides on vagally induced secretion from isolated perfused porcine pancreas.
Several gastrointestinal peptides inhibit pancreatic secretion in intact animals, but fail to do so in isolated pancreas preparations. Using isolated perfused porcine pancreas with intact innervation, we studied the influence of such peptides (somatostatin, peptide YY, glucagon-like peptide-1, oxyntomodulin, neuropeptide Y, galanin, and calcitonin gene-related peptide) on vagally induced secretion and on release of vasoactive intestinal polypeptide (VIP), a neuropeptide involved in fluid and bicarbonate secretion. In control experiments electrical vagus stimulation increased flow of juice from 0.9 +/- 0.1 to 37.3 +/- 5.6 ml/h and protein output from 43 +/- 5 to 1,244 +/- 336 mg/h (mean +/- SD). With somatostatin-14 at 10(-10) mol/L, the fluid response was reduced to 64 +/- 11% of controls, protein concentration to 78 +/- 3.8%, and protein output to 50 +/- 5% (p < 0.05). At 10(-8) M the response was almost abolished. VIP release, which in control experiments increased from 0.2 +/- 0.05 to 2.1 +/- 0.4 pmol/min, was similarly reduced (p < 0.01). Galanin at 10(-8) M inhibited the fluid response to 54 +/- 7% of controls, protein output to 51.7 +/- 11%, and VIP release to 54 +/- 6% (p < 0.01). None of the other inhibitory peptides affected vagus responses. It is concluded that somatostatin and galanin inhibit pancreatic secretion through interaction with intrapancreatic ganglia. The other peptides act on extrapancreatic, possibly central sites.


Plasmepsins as potential targets for new antimalarial therapy.
Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high-antiparasitic activities in P. falciparum-infected erythrocytes it is necessary to inhibit several of the haemoglobin-degrading plasmepsins. Herein we summarize the structure-activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared.


Aventis Pasteur vaccines containing inactivated hepatitis A virus: a compilation of immunogenicity data.
Inactivated hepatitis A vaccines were developed in the 1980s and were introduced during the early 1990s. The Aventis Pasteur (AvP) inactivated hepatitis A virus antigen is used in several different vaccine formulations licensed for adults and children. Presented here are the immunogenicity results compiled from 37 clinical trials performed in 20 different countries between 1991 and 2001 in which these vaccines were administered to adults (16 years of age and over), children (aged 12 months-17 years), and infants (younger than 12 months). The accumulated clinical experience with these hepatitis A virus-containing vaccines demonstrates the excellent immunogenicity of this antigen in a wide range of situations. As with other licensed inactivated hepatitis A vaccines, immunological priming is achieved in virtually all vaccinees after a single-dose primary immunization, and it may be reinforced by a booster vaccination administered 6-36 months after the primary vaccination.


Comparative viability of expanded and unexpanded axial pattern skin flaps in pigs.
A comparison of viable areas of axial pattern flaps post inset was made between expanded and non-expanded pig buttock island flaps. The deep circumflex iliac artery and vein supply approximately the proximal 14 x 10 cm area of this flap. Larger flaps were raised on expanded and control sides of eight pigs to determine if expansion increased the area of survival. In six of eight pigs whose initial tissue expansion did not create more than approximately a 50% increase in skin area, the expanded flaps had a statistically significant increase in viable skin area (proportionally) 10 days post inset than their control flaps (p less than 0.05). Two other pigs did not conform to this pattern. Their initial tissue expansion was greater than 50%, and the resulting area of flap viability was proportionally less in expanded flaps than the control flaps.


Titanium screw anchorage for protraction of mandibular second molars into first molar extraction sites.
This report describes the orthodontic treatment of a 20-year-old woman with missing mandibular first molars. Titanium screws were placed in the buccal alveolar bone between the roots of the first and second premolars to provide absolute anchorage for protraction of the second molars into the atrophic edentulous areas. More than 8 mm of protraction was done in 15 months without significant lingual tipping of the incisors. Increases in alveolar ridge width and vertical bone height were noted mesial to the second molar. Good posterior occlusion was achieved and has been maintained for 1 year after active treatment.


Vitamin D receptor knockout mice exhibit elongated intestinal microvilli and increased ezrin expression.
In addition to its principle function as a calcium regulator, vitamin D can affect cell and tissue morphology. The intestine is an important target tissue of vitamin D, as it must ensure the efficient transport of nutrients across the epithelium while excluding the passage of harmful molecules and bacteria into the organism. These functions require a highly organized morphology, which may be modified by vitamin D deficiency. To elucidate the role of vitamin D in gut morphology and barrier function, we compared the enterocyte microstructures, gut permeability, and cytoskeletal and cell junction protein expression in vitamin D receptor (VDR) knockout (KO) and wild-type (WT) mice. We found that the duodenal epithelial cells in the VDR-KO mice had longer microvilli (+19%) than those of the WT mice (P < .05). Interestingly, microvilli elongation in the VDR-KO mice was associated with higher messenger RNA and protein expression of ezrin, which is involved in the regulation of microvillus morphogenesis. Intestinal tight junction width and permeability were assessed by measuring the fluorescein isothiocyanate dextran concentrations in plasma; the concentrations were comparable between the 2 groups of mice. We further observed a decrease in the messenger RNA and protein expression of the calcium-transporting tight junction protein claudin-2 in the VDR-KO mice compared with the WT mice (P < .05). In conclusion, the mice lacking VDR had longer enterocyte microvilli, likely as a result of increased ezrin expression. However, the morphology of the tight junctions and the intestinal permeability for large molecules were not affected.


Antimicrobial functions of inflammasomes.
Inflammasomes are multi-protein complexes that assemble in response to cellular infection, cellular stress or tissue damage. Inflammasomes provide signalling platforms for the activation of caspase-1, which in turn triggers lytic cell death and the maturation and secretion of the interleukins (IL), IL-1β and IL-18, which co-ordinate host-protective inflammatory responses. Recent studies also highlight emerging roles for interleukin-independent pathways in exerting microbial control. This article reviews cytokine-dependent and cytokine-independent host defence pathways engaged by inflammasomes during infection. Such inflammatory and antimicrobial mechanisms include the recruitment and activation of immune cells, the production of lipid mediators and complement proteins, the induction of the acute-phase and fever responses, the modulation of serum metallic ion content and the release of intracellular bacteria by pyroptotic cell death.


A matter of life and death: The power of personal networks for medical crowdfunding performance.
Medical crowdfunding is an accessible alternative for individuals to meet their unaffordable health needs. This study explores the role of personal networks in medical crowdfunding performance from the perspective of tie strength and whether gender inequality persists in the returns of personal networks in this survival context, using bilateral data of both the ego and the alters collected from a large representative medical crowdfunding platform in China. It is found that kin ties play a fundamental and predominant role while pseudo-kin ties, being less strong than kin ties in terms of mutual sentiment and reciprocal obligations to help each other, play an accumulative role and are more influential in increasing crowdfunding performance, and neighbour and other role relations have the weakest effect and contribution. Importantly, women are not discriminated against when mobilizing personal networks for medical crowdfunding as they enjoy the same returns of most personal ties as men do.


Biomechanical events of swallowing are determined more by bolus consistency than by age or gender.
The biomechanics of swallowing saliva and substances of different consistencies were investigated in healthy children and adults. To this end, the duration and mean amplitude value (MAV) of surface electromyography (sEMG) of the submental muscle group (SMG) activity, the maximum anterior tongue pressure (ATP), and the rise and release slopes of ATP were measured while participants (39 female and 39 male participants, age 5-65 years) swallowed saliva, 5 mL water (reference), 5 mL thick liquid, and 5 mL solid food. Mean outcome parameters varied with the consistency of the liquid or food swallowed, with the exception of the rise slope of ATP. Moreover, outcome variables were not substantially affected by age with children of 5 years and older showing similar biomechanical events to those of adults. It is important to gain insight into the biomechanics of swallowing saliva and substances of different consistencies in order to understand the underlying mechanisms of dysphagia children and adults.


Translating gastric cancer genomics into targeted therapies.
Gastric cancer is a common disease with limited treatment options and a poor prognosis. Many gastric cancers harbour potentially actionable targets, including over-expression and mutations in tyrosine kinase pathways. Agents have been developed against these targets with varying success- in particular, the use of trastuzumab in HER2-overexpressing gastric cancers has resulted in overall survival benefits. Gastric cancers also have high levels of somatic mutations, making them candidates for immunotherapy; early work in this field has been promising. Recent advances in whole genome and multi-platform sequencing have driven the development of molecular classification systems, which may in turn guide the selection of patients for targeted treatment. Moving forward, challenges will include the development of appropriate biomarkers to predict responses to targeted therapy, and the application of new molecular classifications into trial development and clinical practice.


Estradiol benzoate can function as an unconditioned stimulus in a conditioned taste aversion paradigm.
The extent to which gonadal steroid hormones can serve as unconditioned stimuli in a conditioned taste aversion paradigm was examined in Rockland-Swiss albino mice. With saccharin serving as the conditioned stimulus, subcutaneously injected estradiol benzoate, but not progesterone or testosterone propionate, was found to be a potent unconditioned stimulus in both male and female mice. Dose-response effects were also observed; increasing dosages of estradiol benzoate led to increasingly stronger conditioned aversions in both males and females. The aversion detected in males was more resistant to extinction than that seen in females. Prepubertal gonadectomy reversed the sex-dependent effects of estradiol benzoate in learned aversions in adulthood; castration of males promoted the extinction process, whereas ovariectomy of females retarded extinction. The results may be useful for our understanding of the mechanisms involved in conditioned taste aversion learning as well as a wide array of hormone-dependent behavioral responses.


Assessing the quality of care in sick child services at health facilities in Ethiopia.
Quality of care depends on system, facility, provider, and client-level factors. We aimed at examining structural and process quality of services for sick children and its association with client satisfaction at health facilities in Ethiopia. Data from the Ethiopia Service Provision Assessment Plus (SPA+) survey 2014 were used. Measures of quality were assessed based on the Donabedian framework: structure, process, and outcome. A total of 1908 mothers or caretakers were interviewed and their child consultations were observed. Principal component analysis was used to construct quality of care indices including a structural composite score, a process composite score, and a client satisfaction score. Multilevel mixed linear regression was used to analyze the association between structural and process factors with client satisfaction. Among children diagnosed with suspected pneumonia, respiratory rate was counted in 56% and temperature was checked in 77% of the cases. A majority of children (92%) diagnosed with fever had their temperature taken. Only 3% of children with fever were either referred or admitted, and 60% received antibiotics. Among children diagnosed with malaria, 51% were assessed for all three Integrated Management of Childhood Illnesses (IMCI) main symptoms, and 4% were assessed for all three general danger signs. Providers assessed dehydration in 54% of children with diarrhea with dehydration, 17% of these children were admitted or referred to another facility, and Oral Rehydration Solution was prescribed for 67% while none received intravenous fluids. The number of basic amenities in the facility was negatively associated with the clients' satisfaction. Private facilities, when the providers had got training for care of sick children in the past 2 years, had higher client satisfaction. There was no statistical association between structure, process composite indicators and client satisfaction. The assessment of sick children was of low quality, with many missing procedures when comparing with IMCI guidelines. In spite of this, most clients were satisfied with the services they received. Structural and process composite indicators were not associated with client's satisfaction. These findings highlight the need to assess other dimensions of quality of care besides structure and process that may influence client satisfaction.


Major developments in the 2016 european guidelines for heart failure.
The European Society of Cardiology has recently published new guidelines on the diagnosis and treatment of acute and chronic heart failure (HF). This article aims to review these recommendations and their level of scientific evidence and to present the most innovative aspects. The most significant deviations from the 2012 edition are: 1) the introduction of the concept of HF with midrange LVEF (40-49%); 2) a new diagnostic algorithm for chronic HF, initially considering the clinical probability; 3) recommendations on preventing or delaying the apparition of HF; 4) indications for the use of the new sacubitril-valsartan compound, the first angiotensin receptor blocker and neprilysin inhibitor; 5) modification of indications for cardiac resynchronisation therapy; and 6) a new algorithm for a combined diagnostic and treatment strategy for acute HF based on the presence or absence of congestion and hypoperfusion.


Postoperatively parastomal infection following emergent stoma creation for colorectal obstruction: the possible risk factors.
The aim of the present study was to discuss the possible risk factors related to the parastomal infection after the patients received emergent stoma creation in colorectal obstruction that was caused by adenocarcinoma, diverticulitis, or a variety of other miscellaneous causes. A total of 360 patients with colorectal obstruction underwent emergent stoma creation, including diversion and Hartmann's procedure between January 1996 and January 2005. We analyze the patients' records to document the possible risk factors associated with parastomal infection. Patients' demographics, indication for ostomy, ostomy type/location, and risk factors were recorded. Logistic regression was used to calculate adjusted odds ratios. A p value of less than 0.05 was considered significant. Twenty patients (5.6%) with emergent stoma creation had parastomal infection. Descending colostomy had the highest incidence (6.7%) of parastomal infection, followed by transverse colostomy (6.1%) and ileostomy (3.2%). Significant predictors of parastomal infection as presented with odds ratios and 95% confidence intervals include obstruction period, obesity, operative time, serum albumin, and serum C-reactive protein (CRP). Parastomal infection is also highly associated with abdominal surgical wound infection. We concluded that risk factors for parastomal infection include obstruction period, obesity, operative time, serum albumin, and serum CRP. Furthermore, the abdominal surgical wound infection predispose to parastomal infection. Therefore, prolonged and specific antibiotics for results of culture should be used for patients with the above risk factors to prevent parastomal infection.


Inflammatory metachronous hyperostosis of the clavicle and femur in children. Report of two cases, one with long-term follow-up.
Two preteenage girls developed painful swelling of the left clavicle. This was followed by painful swelling of the femur, 7 months later in one girl and 8 years later in the other. Radiographic studies showed a predominantly sclerotic process in one patient and destruction associated with cortical thickening in the other. The patients received analgesic medications only, followed by gradual healing with cortical and medullary sclerosis. Long-term follow-up suggests that the condition is self-limited and that, with or without treatment, the bones eventually return to normal. Although the etiology of the lesions remains unknown, the radiographic features suggest an inflammatory reaction.


The effect of weight loss on hypothalamus structure and function in obese individuals: a systematic review and meta-analysis.
Obesity presents with structural and functional hypothalamic dysfunction. However, it is unclear whether weight loss can lead to hypothalamic changes. We therefore aimed to conduct a systematic review and meta-analysis to determine the effect of body mass reduction in obese individuals on hypothalamic structure and function. PubMed, Embase and Cochrane databases were searched for studies that reported the change in hypothalamic structure and function after weight loss. Qualitative and quantitative analyses were performed on magnetic resonance imaging techniques, medio-basal hypothalamus T2-relaxation time, blood oxygen level dependent (BOLD) contrast, voxel-based morphometry (VBM) and biomarkers including glucose, insulin, leptin, ghrelin and inflammatory markers of interleukins. Mean differences between pre- and post-weight loss and 95% confidence intervals (CIs) were pooled using random-effects models. Thirteen pre-post studies were included, of which six accounted for the meta-analysis. Studies showed a favorable decrease in T2-relaxation time (n = 1), favorable change in hypothalamic activity after weight loss on BOLD contrast (n = 4), with higher peak activities after surgical weight loss (n = 2). No differences were found in the gray matter density of the hypothalamus on VBM (n = 1). Pooled mean differences between pre- and post-surgical weight loss revealed a decrease of 8.53 mg/dl (95% CI: 5.17, 11.9) in glucose, 7.73 pmol/l (95% CI: 5.07, 10.4) in insulin, 15.5 ng/ml (95% CI: 9.40, 21.6) in leptin, 142.9 pg/ml (95% CI: 79.0, 206.8) in ghrelin and 9.43 pg/ml (95% CI: -6.89, 25.7) in IL-6 level. Our study showed weight reduction in obesity led to limited structural change and significant functional changes in the hypothalamus.


Sphingosine-1-phosphate acts via rho-associated kinase and nitric oxide to regulate human placental vascular tone.
Sphingosine-1-phosphate (S1P), a bioactive lipid released from activated platelets, has been demonstrated in animal models to regulate vascular tone through receptor-mediated activation of Rho-associated kinase 1 and nitric oxide synthase 3. The role of S1P in regulation of human vascular tone (particularly during pregnancy, with its unique vascular adaptations and localized platelet activation) is unknown. We hypothesized that S1P would constrict small placental arteries through activation of Rho-associated kinases with modulation by nitric oxide. Reverse transcription-polymerase chain reaction of chorionic plate artery preparations detected mRNAs encoding all five receptors for S1P, and S1P induced dose-dependent vasoconstriction of both chorionic plate and stem villous isobarically mounted arteries, which at 10 micromol/L was 32.9% +/- 3.86% (mean +/- SEM) and 34.6% +/- 7.01%, respectively. In stem villous arteries, S1P-induced vasoconstriction was enhanced significantly following inhibition of nitric oxide synthases with N(G)-nitro-L-arginine methyl ester (100 micromol/L, 52.6% +/- 6.28%, P < 0.05). The S1P-induced vasoconstriction was reversed by Y27632, an inhibitor of Rho-associated kinases (10 micromol/L) in both chorionic plate (to 14.9% +/- 4.95%) and stem villous arteries (to 2.71% +/- 6.13%). The S1P added to alpha-toxin-permeabilized, isometrically mounted chorionic plate arteries bathed in submaximal Ca(2+)-activating solution induced Ca(2+)-sensitization of constriction, which was 47.7% +/- 10.0% of that occurring to maximal Ca(2+)-activating solution. This was reduced by Y27632 to 18.4% +/- 18.4%. Interestingly, S1P-induced vasoconstriction occurred in all isobarically mounted arteries but was inconsistent in isometrically mounted chorionic plate arteries. In summary, S1P-induced vasoconstriction in human placental arteries is mediated by increased Ca(2+)-sensitization through activation of Rho-associated kinases, and this vasoconstriction also is modulated by nitric oxide. Identification of these actions of S1P in the placental vasculature is important for understanding both normal and potentially abnormal vascular adaptations with pregnancy.


Molinate induces organ defects by promoting apoptosis, inflammation, and endoplasmic reticulum stress during the developmental stage of zebrafish.
Molinate is classified as a thiocarbamate herbicide and is mainly used in paddy fields to culture rice. However, the toxic effects of molinate and the associated mechanisms in the process of development have not been completely elucidated. Therefore, in the present study, we demonstrated that molinate reduced the viability of zebrafish larvae and the probability of successful hatching using zebrafish (Danio rerio), one of the remarkable in vivo models for testing the toxicity of chemicals. In addition, molinate treatment triggered the occurrence of apoptosis, inflammation, and endoplasmic reticulum (ER) stress response in zebrafish larvae. Furthermore, we identified that an abnormal cardiovascular phenotype through wild type zebrafish, neuronal defects through transgenic olig2:dsRed zebrafish, and developmental toxicity in the liver through transgenic lfabp:dsRed zebrafish. Collectively, these results provide evidence of the hazardous effects of molinate on the developmental stage of non-target organisms by elucidating the toxic mechanisms of molinate in developing zebrafish.


Correlation of postoperative axial length growth and intraocular pressure in congenital glaucoma--a retrospective study in trabeculotomy and goniotomy.
This paper investigates the correlation of postoperative intraocular pressure (IOP) with axial length growth in children who underwent either trabeculotomy (TO) or goniotomy (GO) as primary surgery for congenital glaucoma. Thirty-seven eyes of 21 children with congenital glaucoma who underwent one or two TOs from 1992 to 1997 and 26 eyes of 16 children with congenital glaucoma who underwent one or more GOs from 1974 to 1993 were retrospectively analyzed. None of the eyes had undergone other surgery previously. Thirteen of the TOs were combined with a small trabeculectomy. IOP was measured by handheld applanation tonometry (Perkins). Axial length was measured by ultrasound. The data were analyzed for correlation of postoperative IOP reduction with postoperative axial length growth. Mean duration of follow-up was 27.3 months in the TO eyes and 37.1 months in the GO eyes. Mean pretreatment IOP before surgery was 28.4+/-6.9 mmHg in the TO eyes and 30.8+/-8.5 mmHg in the GO eyes. Mean IOP at the end of follow-up was 17.5+/-5.8 mmHg in the TO eyes and 17.4+/-10.2 mmHg in the GO eyes. Axial length growth was normalized (proportional or slowed down compared with the nomogram of axial length growth) in 31 of the 37 TO eyes and in 20 of the 26 GO eyes, and was increased in 6 of the TO eyes and 6 of the GO eyes at the end of follow-up. Regarding axial length growth, 6 of 37 TO eyes had increased axial length growth at the end of follow-up. Three of these eyes also did not fulfill the IOP success criterion; 2 of the 3 eyes with normalized IOP had only borderline increased axial length growth. Six of 26 GO eyes had increased axial length growth at the end of follow-up. Five of these eyes did not fulfill the IOP success criterion; 1 eye with normalized IOP had only borderline increased axial length growth. The data show remarkably good correlation of postoperative IOP with postoperative axial length growth. Axial length measurements can therefore help to ascertain halting or progression of congenital glaucoma and thus are considered an important parameter for congenital glaucoma follow-up.


Extending indigenous knowledge to unveil the evolutionary journey of food preferences and socio-cultural phenomena.
Food acceptance is substantially influenced by eating behavior and society norms in relation to preferences, lifestyles, and socio-cultural practices. Food innovation communities need to comprehend the impact of changing trends in eating behavior as a driving force. Meanwhile, many studies indicate that indigenous knowledge plays an important role in uncovering various social phenomena and interpreting local holistic views, cultural ecology, and behavior. However, it is not easy to employ this knowledge due to its fragmented form. This study aims to exhibit a systematic process for investigating scattered indigenous food knowledge and revealing the evolution of socio-cultural movement and food preferences. Initially, ontology-based indigenous food knowledge was structured for this study using the qualitative method, with data subsequently gathered from cookbooks and cremation festschrifts using the quantitative method to construct a knowledge-based system. A total of 2486 recipes recorded in cookbooks dating back to 1782 were retrospectively considered; the findings of which revealed the evolutionary journey of food preferences and its cultural culinary impact.


Treatment of genital herpes simplex virus infection with photodynamic inactivation.
A double-blind randomized study to evaluate the effect of proflavine in the treatment of genital herpesvirus infection was conducted. One hundred fifty-seven women were studied, of whom 75 were treated with proflavine (treated women) and 82 were treated with placebo (control group). There were 62 women with primary disease and 95 with recurrent infection. Under the conditions by which this study was conducted, there was no apparent difference in the time of healing of lesions, development of recurrences, or virus isolation following treatment in the proflavine-treated and control groups.


Control of the contamination of pig carcasses by Escherichia coli from their mouths.
Swab samples from the mouths of 40 pig carcasses all yielded Escherichia coli, at estimated log mean numbers of 2.3 per sample. Single colonies of E. coli O157:H7 were isolated from two, and single colonies of other verotoxigenic strains of E. coli from a further two of those samples. E. coli from the mouth were deposited on the surfaces of carcasses during usual, commercial carcass dressing operations for cutting open the throat and the floor of the mouth, and freeing the tongue. After those operations had been performed, E. coli were recovered from a neck site on 45 of 50 carcasses which were sampled by swabbing that site. When 50 carcasses on which those operations had been performed were pasteurized, the log mean numbers of total aerobic counts recovered from the neck site on carcasses were reduced by two as compared with the unpasteurized carcasses, and only one E. coli was recovered from those carcasses. Pasteurization bleached the small areas of cut muscle exposed during the operations on the mouth and throat, but apparently had no other effect on the appearance of the carcasses. It is suggested that pasteurization of pig carcasses after operating on and regulatory inspection of the mouth and throat may be a commercially viable approach to reducing the contamination of pork with pathogens from the mouths of carcasses.


1,25-Dihydroxyvitamin D stimulates sodium-dependent phosphate transport by renal outer cortical brush-border membrane vesicles by directly affecting membrane fluidity.
We examined the effects of several forms of vitamin D added to renal brush-border membrane suspensions on phosphate and glucose transport and on membrane fluidity. The 1,25-D stimulated and the other vitamin D decreased phosphate uptake. In contrast, glucose uptake was not affected by the treatment of vitamin D. The 1,25-D resulted in a significant shift of the lower transition temperature in Arrhenius plots for phosphate, but not for glucose uptakes, from 15 degrees C to 11.5 degrees C. These data indicate that the 1,25-D may alter membrane fluidity, limited to the phosphate transporter, thus affecting the phosphate uptake.


Structural changes of Artemia parthenogenetica (Bowen and Sterling, 1978) (Branchiopoda-Anostraca) exposed to lead acetate.
The cosmopolitan genus Artemia occurs both in saline or hypersaline waters and Artemia species are sensitive indicator organisms for environmental contamination. Scientists propose that the brine shrimp (Artemia) is a very suitable candidate for the development of identifying chemicals with adverse effects in aquatic ecosystems. In the present study, we investigated 24h the short-term toxicity of lead acetate on Artemia parthenogenetica by using electron microscopy techniques. The ultrastructural changes were studied control group and experimental group. Analysing cellular structure, structure of organelles and vacuolization were observed. The number of cells based on the toxic effects of lead acetate was increased compared with the control group.


Studies on the cytotoxicity of diamond nanoparticles against human cancer cells and lymphocytes.
Detonation nanodiamonds (DND) are a widely studied group of carbon nanomaterials. They have the ability to adsorb a variety of biomolecules and drugs onto their surfaces, and additionally their surfaces may be subjected to chemical functionalization by covalent bonds. We present a procedure for the purification and surface oxidation of diamond nanoparticles, which were then tested by spectroscopic analysis such as ATR-FTIR, Raman spectroscopy, and thermogravimetric analysis. We also examined the zeta potential of the tested material. Analysis of the cytotoxic effect of nanodiamonds against normal lymphocytes derived from human peripheral blood, the non-small cell lung cancer cell line (A549) and the human colorectal adenocarcinoma cell line (HT29) was performed using MTT colorimetric assay. Evaluation of cell viability was performed after 1-h and 24-h treatment with the tested nanoparticles applied at concentrations ranging from 1 μg/ml to 100 μg/ml. We found that the survival of the examined cells was strongly associated with the presence of serum proteins in the growth medium. The incubation of cells with nanodiamonds in the presence of serum did not exert a significant effect on cell survival, while the cell treatment in a serum-free medium resulted in a decrease in cell survival compared to the negative control. The role of purification and functionalization of nanodiamonds on their cytotoxicity was also demonstrated.


Sick Neonate Score--A Simple Clinical Score for Predicting Mortality of Sick Neonates in Resource Restricted Settings.
To evaluate an objective score to assess the condition of sick neonates at arrival and its use in predicting mortality. This descriptive study included 303 extramural neonates who were evaluated using a simple clinical score - Sick neonate score (SNS). All neonates were followed up till discharge or expiry. The score and its individual components were correlated with outcome. A receiver operating curve was plotted to determine the cutoff value for SNS in predicting mortality. The common indications for neonatal transport were sepsis (30.7 %), birth asphyxia (17.5 %) and respiratory distress (15.2 %). Sixty neonates (20 %) expired and among them 76 % were hypothermic and 10 % hypoglycemic at admission. The average SNS for all neonates was 10 while it was 6 for those who expired. A cutoff value of SNS ≤ 8 predicted mortality with a sensitivity of 58.3 % and specificity of 52.7 %. SNS is a useful scoring system to predict outcome of sick neonates in resource restricted settings.


A single oral dose of fructose induces some features of metabolic syndrome in rats: role of oxidative stress.
To determine if a single oral dose of fructose to rats reproduces some features of metabolic syndrome observed after chronic administration and if so, to investigate its mechanisms. Systolic blood pressure was measured in rats before and after oral administration of fructose, and in animals pretreated with lipoic acid, methyldopa, losartan or streptozotocin. In other rats, glucose, insulin, uric acid, and insulin sensitivity index, were determined before and after fructose or lipoic acid plus fructose. Glutathione was measured in liver before and after fructose administration. In aortic rings from other rats, incubation with mannitol, fructose, or fructose plus lipoic acid was evaluated on the relaxation by acetylcholine. Fructose produced a moderate increase in blood pressure, which was prevented by lipoic acid or streptozotocin. Methyldopa and losartan decreased the pressor response minimally. Fructose increased oxidized glutathione, plasma glucose, insulin and uric acid, and diminished the insulin sensitivity index, and the reduced glutathione. Lipoic acid prevented hyperglycemia and hyperuricemia, and improved the insulin sensitivity index. Finally, endothelial dysfunction was prevented by lipoic acid. A single dose of fructose reproduces some of the features of metabolic syndrome, most changes were caused by oxidative stress and insulin resistance.


An approach to the writing of a scientific manuscript.
Writing a scientific manuscript is one of the most important tasks facing the academician, and may also be one of the most daunting. The essentials of any paper include a description of what is known, an assessment of what is unknown, a clear statement regarding the question and hypothesis being addressed by the current study, and a discussion and summary of new information that has been learned as a result of the study. A formulaic approach is provided to guide the author through this process.


Improving communication among attending physicians, long-term care facilities, residents, and residents' families.
Effective bidirectional communication between attending physicians and long-term care facilities is of critical importance to ensure timely, appropriate, and high-quality care that is responsive to residents' needs, values, and preferences. Ongoing communication with residents and residents' families is essential to the establishment of mutual trust and respect. This earned trust and respect in turn promotes frank discussions among long-term care practitioners and the facility staff who can then better guide residents and families through difficult care decisions.


Prioritizing disease candidate genes by a gene interconnectedness-based approach.
Genome-wide disease-gene finding approaches may sometimes provide us with a long list of candidate genes. Since using pure experimental approaches to verify all candidates could be expensive, a number of network-based methods have been developed to prioritize candidates. Such tools usually have a set of parameters pre-trained using available network data. This means that re-training network-based tools may be required when existing biological networks are updated or when networks from different sources are to be tried. We developed a parameter-free method, interconnectedness (ICN), to rank candidate genes by assessing the closeness of them to known disease genes in a network. ICN was tested using 1,993 known disease-gene associations and achieved a success rate of ~44% using a protein-protein interaction network under a test scenario of simulated linkage analysis. This performance is comparable with those of other well-known methods and ICN outperforms other methods when a candidate disease gene is not directly linked to known disease genes in a network. Interestingly, we show that a combined scoring strategy could enable ICN to achieve an even better performance (~50%) than other methods used alone. ICN, a user-friendly method, can well complement other network-based methods in the context of prioritizing candidate disease genes.


Outcome of a pulmonary metastasectomy for an orthopedic malignancy.
The purpose of this study was to examine the pulmonary metastatic results in patients with orthopedic malignancies. Forty-three consecutive patients who underwent a resection of a pulmonary metastasis from an orthopedic malignancy in our hospital were retrospectively investigated. The survival following the resection of a pulmonary metastatic tumor was then analyzed using the Kaplan-Meier method. The impact of clinicopathologic variables on the prognosis including gender, patient age, primary tumor type, the number of the pulmonary metastases, the number of metastasectomies, the operation-era, and the disease-free interval was examined by the Logrank test and Cox's proportional hazards model. The 5-year overall survivals after a pulmonary metastasectomy were 20.7%. A univariate analysis revealed a significant benefit in the post-metastasectomy survival based on the patients age and the disease-free interval. A multivariate analysis demonstrated patient age to be an independent factor for the prognosis with a hazard ratio of 4.873 (p = 0.0373). When only young (less than 40 years of age) patients were investigated, the histologic type was revealed to be related to the prognosis (p = 0.0004). Pulmonary metastasis from soft tissue tumors is considered to lead to a poor prognosis for younger patients and a metastasectomy for such patients should be considered as one of the potentially effective treatments.


Prediction of the concentration of antimony in agricultural soil using data fusion, terrain attributes combined with regression kriging.
Potentially toxic elements in agricultural soils are primarily derived from anthropogenic and geogenic sources. This study aims to predict and map antimony (Sb) concentration in soil using multiple regression kriging in two distinct modeling approaches, namely Sb prediction using data fusion coupled with regression kriging (scenario 1) and Sb prediction using data fusion, terrain attributes, and regression kriging (scenario 2). Cubist regression kriging (cubist_RK), conditional inference forest regression kriging (CIF_RK), extreme gradient boosting regression kriging (EGB_RK) and random forest regression kriging (RF_RK) were the modeling techniques used in the estimation of Sb concentration in agricultural soil. The validation results suggested that in scenario 1, EGB_RK was the optimal modeling approach for Sb prediction in agricultural soil with root mean square error (RMSE) = 1.31 and mean absolute error (MAE) = 0.61, bias = 0.37, and high coefficient of determination R2 = 0.81. Similarly, the EGB_RK was also the optimal modeling approach in scenario 2, with the highest R2 = 0.76, RMSE = 0.90, bias = 0.06, and MAE = 0.48 values than the other regression kriging modeling approaches. The cumulative assessment suggested that the EGB_RK in scenario 2 yielded optimal results compared to the respective modeling approach in scenario 1. The uncertainty propagated by the modeling approaches in both scenarios indicated that the degree of uncertainty during the modeling process was distributed across the study area from a low to a moderate uncertainty level. However, cubist_RK in scenario 2 exhibited some elevated spots of uncertainty levels. As a result, the combination of data fusion, terrain attributes, and regression kriging modeling approaches produces optimal results with a high R2 value, minimal errors as well as bias. Furthermore, combining terrain attributes with data fusion is promising for reducing model error, bias and yielding high-accuracy predictions.


Effect of taurine on ulcerogenic response and impaired ulcer healing induced by monochloramine in rat stomachs.
It is well known that neutrophil-derived hypochlorous acid interacts with ammonia (NH4OH) to generate monochloramine (NH2Cl) and that NH2Cl irritates the gastric mucosa and impairs ulcer healing. To examine the effect of taurine, a hypochlorous acid scavenger, on the mucosal ulcerogenic and the impaired healing response induced by NH2Cl in rat stomachs, in comparison with those of methionine and glycine. Under anaesthesia, oral administration of NH2Cl (120 mmol/L) produced severe lesions in male Sprague-Dawley rat stomachs. Taurine (10-100 mg/kg) given p.o. 30 min prior to NH2Cl dose-dependently prevented these lesions in response to NH2Cl. This action was mimicked by methionine (3-30 mg/kg) but not by glycine (10-100 mg/kg). Under urethane anaesthesia, mucosal exposure to NH4OH (120 mmol/L) caused a marked reduction of potential difference (PD) in the ex vivo chambered stomachs after induction of ischaemia, resulting in severe lesions. These ulcerogenic and PD responses by NH4OH plus ischaemia were also mitigated by taurine and methionine, but not glycine, applied to the chamber 20 min before the onset of NH4OH plus ischaemia. Moreover, oral administration of 100% ethanol produced severe haemorrhagic lesions in rat stomachs, all of which rapidly healed within 7 days after lesion induction. Daily administration of NH2Cl (20 mmol/L) significantly delayed the healing of these lesions, but recovery of this impaired healing response was obtained by concurrent administration of taurine. Both taurine and methionine showed a potent scavenging effect against NH2Cl in vitro. (1) NH2Cl generated either exogenously or endogenously damages the gastric mucosa and impairs the healing response; (2) taurine exerts a prophylactic effect against the deleterious effects of NH2Cl, mainly due to its scavenging action against NH2Cl; and (3) this effect of taurine may be useful for treatment of gastritis associated with Helicobacter pylori infection.


Effects of oxygen tension and normalization pressure on endothelin-induced constriction of human placental chorionic plate arteries.
Fetoplacental blood vessels constrict in response to endothelin (ET-1) or reduced oxygen tension in the placental cotyledon perfused in vitro. In nonplacental resistance arteries, hypoxia and ET-1 induce constriction by promoting Ca2+ influx into smooth muscle through membrane ion channels, which include voltage-gated Ca2+ channels (VGCCs). We hypothesized that VGCCs are involved in ET-1-induced constriction of fetoplacental resistance vessels and that their contribution to constriction is enhanced at low oxygen tension. Chorionic plate small arteries from term placentas were studied using parallel wire myography. Arteries were normalized at 0.9 of L(5.1 kPa) ("low stretch" approximately 25 mm Hg; approximating physiologic vascular pressure) or 0.9 of L(13.3 kPa) ("high stretch" approximately 42 mm Hg) and experiments performed at oxygen tensions of 156, 38, and 15 mm Hg. When chorionic plate arteries were normalized at low stretch, oxygen tension did not affect constriction to ET-1. Nifedipine (10(-4) M), a blocker of L-type VGCCs, inhibited ET-1 (EC80)-induced constriction to a similar extent at each oxygen tension (52% to 64% inhibition). In contrast, when arteries were normalized at high stretch, constriction to ET-1 was greater at 38 than at 156 or 15 mm Hg oxygen and nifedipine inhibition of ET-1-induced constriction was greater at 38 and 15 mm Hg than at 156 mm Hg oxygen. VGCCs and nifedipine-insensitive processes underlie the contractile response of chorionic plate arteries to ET-1 and their relative contribution to vasoconstriction is modulated by oxygen tension when vessels are normalized at high stretch. However, contrary to our hypothesis, the response of chorionic plate arteries to ET-1 is not modulated by oxygen when vessels are normalized at physiologic pressure.


Distinctions in bone matrix nanostructure, composition, and formation between osteoblast-like cells, MG-63, and human mesenchymal stem cells, UE7T-13.
Osteoblast-like cells and human mesenchymal stem cells (hMSCs) are frequently employed as osteoprogenitor cell models for evaluating novel biomaterials in bone healing and tissue engineering. In this study, the characterization of UE7T-13 hMSCs and MG-63 human osteoblast-like cells was examined. Both cells can undergo osteogenesis and produce calcium extracellular matrix; however, calcium nodules produced by MG-63 lacked a central mass and appeared flatter than UE7T-13. The absence of growing calcium nodules in MG-63 was discovered by SEM-EDX to be associated with the formation of alternating layers of cells and calcium extracellular matrix. The nanostructure and composition analysis showed that UE7T-13 had a finer nanostructure of calcium nodules with a higher calcium/phosphate ratio than MG-63. Both cells expressed high intrinsic levels of collagen type I alpha 1 chain, while only UE7T-13 expressed high levels of alkaline phosphatase, biomineralization associated (ALPL). High ALP activity in UE7T-13 was not further enhanced by osteogenic induction, but in MG-63, low intrinsic ALP activity was greatly induced by osteogenic induction. These findings highlight the differences between the two immortal osteoprogenitor cell lines, along with some technical notes that should be considered while selecting and interpreting the pertinent in vitro model.


Developmental regulation of the base excision repair enzyme uracil DNA glycosylase in the rat.
The developmental regulation of the mammalian DNA-repair enzyme uracil DNA glycosylase was examined in the rat at specific intervals ranging from -4 days before to 106 days after birth. Enzyme activity was quantitated by in vitro biochemical assay. In the adult animal, as measured in crude cell extracts, three organs (liver, kidney and spleen) had significant levels of activity. In contrast, three organs (brain, heart and lung) had low activity. Partial purification of this enzyme identified one major species of molecular weight 32,700 Da, demonstrating the quantitation of the nuclear glycosylase. During development, with the exception of the liver, the specific activity of the glycosylase paralleled the regulation of DNA synthesis. In these organs the highest levels of the glycosylase and the rate of DNA replication were observed around the time of birth. In the liver, DNA replication was similarly regulated. However, glycosylase activity was minimal at early stages of life. Instead, maximal levels were observed at 14-21 days after birth. At that time DNA replication was severely reduced. These results demonstrate that individual organs express this DNA-repair enzyme in a distinct and specific pattern during development. Accordingly, the regulation of the uracil DNA glycosylase during development may provide a model system to examine the differential regulation of DNA-repair genes.


Post-translational modification of manganese superoxide dismutase in acutely rejecting cardiac transplants: role of inducible nitric oxide synthase.
Nitration of a critical tyrosine residue in the active site of manganese superoxide dismutase (MnSOD) can lead to enzyme inactivation. In this study, we examined the effect of inducible nitric oxide synthase (iNOS) on MnSOD expression, activity and nitration in acutely rejecting cardiac transplants. Lewis (isograft) or Wistar-Furth (allograft) donor hearts were transplanted into Lewis recipient rats. Some rats received L-N6-(1-iminoethyl) lysine (l-NIL), a specific iNOS inhibitor. Protein nitration was determined by immunohistochemical, Western blot and slot-blot analyses. MnSOD enzyme activity and gene expression were determined using Western, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoprecipitation techniques. MnSOD protein levels were decreased 50% by post-operative day 6 (POD 6), which was prevented by L-NIL. RT-PCR analysis indicated that this decrease could not be explained by any changes in MnSOD mRNA. MnSOD enzyme activity but not protein was decreased at POD 5 in untreated allografts. The loss of MnSOD activity at POD 5 was also prevented by L-NIL. Immunoreactive nitrotyrosine was apparent in untreated allografts at POD 6. Slot-blot analysis indicated that nitrotyrosine formation in allografts could be blocked by L-NIL. Nitration of MnSOD was evident upon immunoprecipitation of MnSOD followed by Western blotting for nitrotyrosine. These results suggest that the decreased MnSOD enzyme activity in acutely rejecting cardiac allografts can be attributed to a post-translational modification related to nitration arising via an iNOS-dependent pathway. This could be a potential major source of amplified oxidative stress in acute graft rejection.


Microvascular grafting to enhance perfusion in colonic long-segment oesophageal reconstruction.
Oesophagectomy with long-segment colon reconstruction is the first-line treatment when the stomach is not available. Supercharging of the newly formed conduit can improve vascular function utilizing intraoperative perfusion imaging system, following thoracoscopic oesophagectomy for distal-oesophageal and gastroesophageal junction cancer. The purpose of this study is to examine the safety and efficacy of microvascular augmentation of left colonic interposition following oesophagectomy for oesophageal cancer. A retrospective analysis of 156 consecutive oesophagectomies between January 2016 and July 2018 was performed. All oesophagectomies involving left colon interposition with microvascular augmentation were included in the study. In all cases, oesophageal mobilization was performed thoracoscopically in prone position and the left colon was used as neo-oesophagus in an isoperistaltic fashion. Conduit perfusion was assessed with the Spy system and neck supercharging was performed using microsurgical technique. A total of n = 5 (3.2%) patients were identified. Two cases had delayed and 3 had immediate reconstruction. The conduit was microsurgically augmented in 3 cases with both venous and arterial anastomoses (supercharging) and in 2 cases with venous anastomosis only (superdrainage). No anastomotic leak was identified. One case developed left recurrent laryngeal nerve palsy with associated aspiration pneumonia. Supercharged colonic interposition is a safe way of oesophageal reconstruction when long-segment interposition graft is needed. In oesophageal cancer and in the absence of a viable stomach with intact gastroepiploic arcade, it should be considered a feasible option with favourable outcomes, when the expertise and facilities are available. Use of intraoperative perfusion imaging reveals improved conduit blood supply post-supercharging.


[Clinical outcome after discontinuation of infliximab in patients with ulcerative colitis in deep remission].
Infliximab (IFX) is effective in treating ulcerative colitis (UC) and in achieving mucosal healing (MH). Little is known about the role of mucosal healing (MH) in the subsequent evolution of the disease and the consequences of discontinuing treatment. To evaluate the characteristics and evolution of patients with UC treated with IFX who discontinued treatment after disease remission. Observational, prospective study of patients with moderate to severe UC, corticosteroid-resistant/corticosteroid-dependent, naïve to anti-TNF. IFX administration regimen: 5 mg/kg at 0-2-6 weeks and every 8 weeks thereafter until week 54. In patients achieving MH, IFX was discontinued and the patients were followed-up for at least 20 months. Clinical remission (CR): mayo score <2; Clinical response: decrease in mayo score of 3 points; MH: mayo score 0-1; Deep remission: patient with CR and MH. Of the 21 patients enrolled, 19 completed the study (colectomy, n = 1; non-responder, n = 1). Mean age: 47.8 years. UC: severe (n = 13) and moderate (n = 6); most patients (n = 11) were steroid-resistant; 57.8% received combined treatment with immunosuppressants, and 31.5% intensified treatment. Week 54: 16 patients (84.2%) showed clinical response, 13 (68.4%) showed CR, and 12 (63.2%) deep remission. Of these, 6 (25%) presented a new episode of UC, and in 3 (25%) IFX was restarted within 12 weeks of discontinuation, with all patients responding. Of the total sample, 91.7% remained IFX-free at week 8, and 75% at week 12, with no remission during follow-up. None of the patients required hospitalization or surgery. Half of patients with deep remission of UC with IFX therapy presented a new episode after treatment discontinuation, and in 25% IFX therapy was restarted.


Dense-core secretory vesicle docking and exocytotic membrane fusion in Paramecium cells.
Work with Paramecium has contributed to the actual understanding of certain aspects of exocytosis regulation, including membrane fusion. The system is faster and more synchronous than any other dense-core vesicle system described and its highly regular design facilitates correlation of functional and ultrastructural (freeze-fracture) features. From early times on, several crucial aspects of exocytosis regulation have been found in Paramecium cells, e.g. genetically controlled microdomains (with distinct ultrastructure) for organelle docking and membrane fusion, involvement of calmodulin in establishing such microdomains, priming by ATP, occurrence of focal fusion with active participation of integral and peripheral proteins, decay of a population of integral proteins ("rosettes", mandatory for fusion capacity) into subunits and their lateral dispersal during fusion, etc. The size of rosette particles and their dispersal upon focal fusion would be directly compatible with proteolipid V(0) subunits of a V-ATPase, much better than the size predicted for oligomeric SNARE pins (SCAMPs are unknown from Paramecium at this time). However, there are some restrictions for a straightforward interpretation of ultrastructural results. The rather pointed, nipple-like tip of the trichocyst membrane could accommodate only one (or very few) potential V(0) counterpart(s), while the overlaying domain of the cell membrane contains numerous rosette particles. Particle size is compatible with V(0), but larger than that assumed for the SNARE complexes. When membrane fusion is induced in the presence of antibodies against cell surface components, focal fusion is seen to occur with dispersing rosette particles but without dispersal of their subunits and without pore expansion. Clearly, this is required for completing fusion and pore expansion. After cloning SNARE and V(0) components in Paramecium (with increasing details becoming rapidly available), we may soon be able to address the question more directly, whether any of these components or some new ones to be detected, serve exocytotic and/or any other membrane fusions in Paramecium.


Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period.
We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, β-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed - both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and β-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune-stimulation.


Inhibitory action of YJA20379, a new proton pump inhibitor on Helicobacter pylori growth and urease.
The activities of two types of antiulcer agents against 9 strains of Helicobacter pylori (H. pylori) were determined by the agar dilution method. The antiulcer agents were YJA20379, a newly synthesized proton pump inhibitor developed by Yung-Jin Pharmaceutical company, and omeprazole. Both compounds were found to have significant activities against this organism. The MIC values of YJA20379 and omeprazole were 11.7 and 31.25 micrograms/ml, respectively. In addition, the inhibitory potency of both compounds was investigated on H. pylori urease which is believed to be an important colonization and virulence factor in the pathogenesis of gastritis and peptic ulcers. These compounds dose-dependently inhibited urease extracted with distilled water and their IC50 values were 16.4 x 10(-5) M and 14.3 x 10(-5) M, respectively. In addition, a pH-dependent study to determine whether inhibitory potency would be activated by acid condition was performed. It was found that unlike omeprazole, YJA20379 was not affected by acid condition. To determine the inhibition pattern and optimal concentration of substrate, kinetics were evaluated at various pH levels (pH 5.0, 7.0, and 8.5). The data show that YJA20379 noncompetitively inhibited H. pylori urease and KM/Ki values were 0.96 mM/60 microM (pH 5.0), 0.56 mM/141.5 microM (pH 7.0), and 1.94 mM/34 microM (pH 8.5), respectively. Based on data obtained, it is concluded that YJA20379 is a significant inhibitor of H. pylori growth and urease and therefore, taking these results into consideration, YJA20379 might be a beneficial therapy for gastritis and peptic ulcers induced by H. pylori.


Design and characterization of core-shell mPEG-PLGA composite microparticles for development of cell-scaffold constructs.
Appropriate scaffolds capable of providing suitable biological and structural guidance are of great importance to generate cell-scaffold constructs for cell-based tissue engineering. The aim of the present study was to develop composite microparticles with a structure to provide functionality as a combined drug delivery/scaffold system. Composite microparticles were produced by incorporating either alginate/dermatan sulfate (Alg/DS) or alginate/chitosan/dermatan sulfate (Alg/CS/DS) particles in mPEG-PLGA microparticles using coaxial ultrasonic atomization. The encapsulation and distribution of Alg/DS or Alg/CS/DS particles in the mPEG-PLGA microparticles were significantly dependent on the operating conditions, including the flow rate ratio (Qout/Qin) and the viscosity of the polymer solutions (Vout, Vin) between the outer and the inner feeding channels. The core-shell composite microparticles containing the Alg/DS particles or the Alg/CS/DS particles displayed 40% and 65% DS release in 10 days, respectively, as compared to the DS directly loaded microparticles showing 90% DS release during the same time interval. The release profiles of DS correlate with the cell proliferation of fibroblasts, i.e. more sustainable cell growth was induced by the DS released from the core-shell composite microparticles comprising Alg/CS/DS particles. After seeding fibroblasts onto the composite microparticles, excellent cell adhesion was observed, and a successful assembly of the cell-scaffold constructs was induced within 7 days. Therefore, the present study demonstrates a novel strategy for fabrication of core-shell composite microparticles comprising additional particulate drug carriers in the core, which provides controlled delivery of DS and favorable cell biocompatibility; an approach to potentially achieve cell-based tissue regeneration.


Does pirenzepine distinguish between 'subtypes' of muscarinic receptors?
Pharmacological studies with pirenzepine were carried out on the isolated ileum and atrium of the guinea-pig and on the acid secretion from the isolated stomach of the mouse. Pirenzepine inhibited the bethanechol-evoked changes in all three organs in a dose-dependent manner. The slopes of the Schild-plots confirmed the competitive nature of the antagonism by pirenzepine. The estimated pA2-values were very similar. Based on these data, it might be concluded that pirenzepine is an anticholinoceptor compound without specific affinity for gastric muscarinic receptors.


Massive pulmonary calcification in two infants with congenital cardiac lesions.
Two infants with congenital heart disease and radiographically demonstrated pulmonary calcification are described. One infant also suffered from idiopathic hypercalcaemia and subcutaneous fat necrosis. Diffuse radiographic pulmonary calcification in infants has not been reported previously. The possible aetiology is discussed.


Cysts of the pineal gland. A new clinical entity to be distinguished from tumors of the pineal region.
Thirty-two cases of pineal cyst diagnosed by magnetic resonance imaging (MRI) were reviewed and are described. The pineal cyst was demonstrated to be an area with slightly less intensity than the surrounding tissue and with slightly greater intensity than the CSF on T1-weighted images. On the T2-weighted images this lesion was identified as a high-intensity area with smooth margins and was homogeneous in nature. In three cases presenting with headache, compression of the vein of Galen was identified, and compression of the quadrigeminal plate was demonstrated in five cases. No patients presented with both pineal and quadrigeminal lesions. Of the cases, 63% were not detected by CT scanning alone. There were two cases in which the cyst ruptured and collapsed spontaneously during follow-up. It is emphasized that the presence of this lesion, which was more frequent than previously expected, should be kept in mind when diagnosing pineal tumors and should not be misdiagnosed. Surgery should not be undertaken unless the lesion produces symptoms due to the compression of the quadrigeminal plate, aqueduct, or the vein of Galen.


Can smoking duration alone replace pack-years to predict the risk of smoking-related oncogenic mutations in non-small cell lung cancer? A cross-sectional study in Japan.
To investigate whether smoking duration alone can replace pack-years to predict the risk of oncogenic mutations in non-small cell lung cancer (NSCLC). A cross-sectional study using the baseline dataset from the Japan Molecular Epidemiology for Lung Cancer Study. Forty-three medical institutions nationwide in Japan. From July 2012 to December 2013, 957 patients with newly diagnosed stage I-IIIB NSCLC who underwent surgery were enrolled, and molecular analyses were performed on 876 samples (from 441 ever-smokers and 435 never-smokers). We calculated the area under the receiver operating characteristic curve (AUC) values using logistic regression to compare between the predictive values of smoking duration and pack-years for mutational frequencies in the v-Ki-ras2 Kirsten rat sarcoma (KRAS), tumour suppressor p53 (TP53), and epidermal growth factor receptor (EGFR) genes and for cytosine-to-adenine base substitution (C>A). For predicting KRAS mutations, the AUC values for smoking duration and pack-years were 0.746 (95% CI 0.682 to 0.800) and 0.759 (95% CI 0.700 to 0.810), respectively (p=0.058). For predicting KRAS mutations in smokers, the AUC values for smoking duration and pack-years were 0.772 (95% CI 0.697 to 0.833) and 0.787 (95% CI 0.714 to 0.845), respectively (p=0.036). There were no significant differences between the AUC values for smoking duration and pack-years in terms of predicting TP53 and EGFR mutations and C>A. Pack-years was a significantly better predictor of KRAS mutations than smoking duration. Smoking duration was not significantly different from pack-years in predicting the likelihood of smoking-related gene mutations. Given the recall bias in obtaining smoking information, smoking duration alone should be considered for further investigation as a simpler alternative to pack-years.


Photocatalytic transformation fate and toxicity of ciprofloxacin related to dissociation species: Experimental and theoretical evidences.
Chemical speciation of ionizable antibiotics greatly affects its photochemical kinetics and mechanisms; however, the mechanistic impact of chemical speciation is not well understood. For the first time, the impact of different dissociation species (cationic, zwitterionic and anionic forms) of ciprofloxacin (CIP) on its photocatalytic transformation fate was systematically studied in a UVA/LED/TiO2 system. The dissociation forms of CIP at different pH affected the photocatalytic degradation kinetics, transformation products (TPs) formation as well as degradation pathways. Zwitterionic form of CIP exhibited the highest degradation rate constant (0.2217 ± 0.0179 min-1), removal efficiency of total organic carbon (TOC) and release of fluoride ion (F-). Time-dependent evolution profiles on TPs revealed that the cationic and anionic forms of CIP mainly underwent piperazine ring dealkylation, while zwitterionic CIP primarily proceeded through defluorination and piperazine ring oxidation. Moreover, density functional theory (DFT) calculation based on Fukui index well interpreted the active sites of different CIP species. Potential energy surface (PES) analysis further elucidated the reaction transition state (TS) evolution and energy barrier (ΔEb) for CIP with different dissociation species after radical attack. This study provides deep insights into degradation mechanisms of emerging organic contaminants in advanced oxidation processes associated to their chemical speciation.


Low molecular weight heparin inhibits melanoma cell adhesion and migration through a PKCa/JNK signaling pathway inducing actin cytoskeleton changes.
Low molecular weight heparin (LMWH) has significant antimetastatic capabilities and affects cancer progression in humans through, not fully defined mechanisms. Here we evaluated its activity at the intracellular level and how it is correlated with melanoma cell adhesion and migration. LMWH inhibited M5 and A375 melanoma cell adhesion and migration in a dose-dependent manner (p⩽0.01). Treatment of M5 melanoma cells with LMWH caused a marked down regulation of constitutive as well as the FN-induced phosphorylation (p⩽0.01) of protein kinase C alpha (PKCa). This was associated with a profound decrease in the cytoplasmic pPKCa (p⩽0.05) and a simultaneous enhancement of nuclear pPKCa localization (p⩽0.01). A significant decrease in the levels of pJNK (p⩽0.01), which is a downstream effector of PKCa, was also demonstrated in the LMWH-treated cells. Furthermore, LMWH-treated cells had disorganized actin stress fibers correlated to a strong decrease in cell-substratum interface area (p⩽0.05) and altered morphology. The decrease in the activation of PKCa, which is an important regulator of cell motility, was directly correlated to the reduced ability of the LMWH-treated melanoma cells to adhere onto and migrate towards the fibronectin (FN) substrate (p⩽0.01). The lineage activation of PKCa-JNK/p38 and their correlation to M5 cell adhesion was confirmed with the utilization of specific inhibitors. In conclusion, LMWH through the downregulation of pPKCa and redistribution to nuclear region attenuates JNK activation, which in turn induces cytoskeleton changes correlated to M5 cell decreased adhesion/migration. This may provide clues for the pharmacological targeting of melanoma.


Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance.
Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite's own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation. When damaged proteins enter the proteasome, their attached PIs inhibit protease function, potentiating the parasiticidal action of ART and overcoming ART resistance. Binding of the PI moiety to the proteasome active site is enhanced by distal interactions of the extended attached peptides, providing a mechanism to overcome PI resistance. ATZs have an extra mode of action beyond that of each component, thereby overcoming resistance to both components, while avoiding transient monotherapy seen when individual agents have disparate pharmacokinetic profiles.


What has vaccination against COVID-19 in CKD patients taught us?
Effective vaccination strategies are of crucial importance to protecting patients who are vulnerable to infections, such as patients with chronic kidney disease. This is because the decreased efficiency of the immune system in chronic kidney disease impairs vaccine-induced immunisation. COVID-19 has prompted investigation of the immune response to SARS-CoV-2 vaccines in chronic kidney disease and in kidney transplant recipients in an effort to improve efficacy. The seroconversion rate after two vaccine doses is reduced, especially in kidney transplant recipients. Furthermore, although the seroconversion rate in chronic kidney disease patients is as high as in healthy subjects, anti-spike antibody titres are lower than in healthy vaccinated individuals, and these titres decrease rapidly. Although the vaccine-induced anti-spike antibody titre correlates with neutralising antibody levels and with protection against COVID-19, the protective prognostic significance of their titre is decreased due to the emergence of SARS-CoV-2 variants other than the Wuhan index virus against which the original vaccines were produced. Cellular immunity is also relevant, and because of cross-reactivity to the spike protein, epitopes of different viral variants confer protection against newly emerging variants of SARS-CoV-2. A multi-dose vaccination strategy is the most effective way to obtain a sufficient serological response. In kidney transplant recipients, a 5-week discontinuation period from antimetabolite drugs in concomitance with vaccine administration may also increase the vaccine's efficacy. The newly acquired knowledge obtained from COVID-19 vaccination is of general interest for the success of other vaccinations in chronic kidney disease patients.


Disaccharidase activities in Belgian children: reference intervals and comparison with non-Belgian Caucasian children.
To establish reference values for disaccharidase activities in Belgian children and to compare enzyme activities with those of non-Belgian Caucasian children. Data from Belgian children who had undergone endoscopic jejunal biopsies (1994-2000) for suspected malabsorption were reviewed. The patients were divided into three groups based on histology: (A) normal (n = 201), (B) moderate changes (n = 58) and (C) (sub)total atrophy (n = 14). The 95% reference limits for disaccharidase activities (U/g protein) were calculated for group A after exclusion of patients with a positive hydrogen breath test, a history of lactose intolerance or coeliac disease (final population: n = 151, 0.1-12 y). Values were compared with those of 34 non-Belgian Caucasian children with normal histology (28 of Mediterranean origin). The reference limits (90% confidence interval) were 86 (65-111)-423 (366-494) for maltase, 9 (6-12)-91 (78-122) for lactase and 24 (18-30)-155 (120-184) for sucrase. No gender-related differences in enzyme activities were found. Lactase levels showed a slight decrease with increasing age. Disaccharidase activities of children with histologically confirmed mucosal injury were significantly lower than those of children with normal histology: median values for groups A, B and C were 208, 181 and 96, respectively, for maltase, 40, 28 and 7, respectively, for lactase and 69, 54 and 25, respectively, for sucrase. Median disaccharidase activities in biopsies with normal histology were lower in non-Belgian children, the difference being only statistically significant for lactase, 33 versus 40. The reference values for Belgian children are well in line with other reported values from Caucasian children. Although enzyme activities are lower in children with histologically confirmed mucosal damage, they do not allow differentiation between histology groups. Lower lactase values were found in non-Belgian children.


[Forecast about number of patients with pulmonary tuberculosis 2001 - 2010].
To forecast the number of patients with pulmonary tuberculosis in 2010. A mathematical model was established based on the nationwide epidemiological survey on tuberculosis conducted in 2000 so as to forecast the numbers of patients with pulmonary tuberculosis in 2000s. (1) The number of patients with pulmonary tuberculosis would be a little more than that in 2000, with the pulmonary tuberculosis case detection rate rho of 0.26 being adopted. (2) The number of patients with pulmonary tuberculosis would be smaller than that in 2000, with the pulmonary tuberculosis case detection rate rho of 0.30 being adopted. (3) If the current intervention strategy manages to keep the pulmonary tuberculosis case detection rate at the level of 0.35, the decline in number of patients with pulmonary tuberculosis will approach the goal set by the national program that the number of patients with pulmonary tuberculosis be decreased by 50%. The goal set by the national program can be achieved only when the pulmonary tuberculosis case detection rate reaches 0.35.


Integrated bulk and single-cell RNA-sequencing reveals SPOCK2 as a novel biomarker gene in the development of congenital pulmonary airway malformation.
Congenital pulmonary airway malformation (CPAM) is the most frequent pulmonary developmental malformation and the pathophysiology remains poorly understood. This study aimed to identify the characteristic gene expression patterns and the marker genes essential to CPAM. Tissues from the cystic area displaying CPAM and the area of normal appearance were obtained during surgery. Bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) were performed for integrating analysis. Iterative weighted gene correlation network analysis (iWGCNA) was used to identify specifically expressed genes to CPAM. In total, 2074 genes were significantly differentially expressed between the CPAM and control areas. Of these differentially expressed genes (DEGs), 1675 genes were up-regulated and 399 genes were down-regulated. Gene ontology analysis revealed these DEGs were specifically enriched in ciliated epithelium and involved in immune response. We also identified several CPAM-related modules by iWGCNA, among them, P15_I4_M3 module was the most influential module for distinguishing CPAMs from controls. By combining the analysis of the expression dataset from RNA-seq and scRNA-seq, SPOCK2, STX11, and ZNF331 were highlighted in CPAM. Through our analysis of expression datasets from both scRNA-seq and bulk RNA-seq of tissues obtained from patients with CPAM, we identified the characteristic gene expression patterns associated with the condition. Our findings suggest that SPOCK2 could be a potential biomarker gene for the diagnosis and therapeutic target in the development of CPAM, whereas STX11 and ZNF331 might serve as prognostic markers for this condition. Further investigations with larger samples and function studies are necessary to confirm the involvement of these genes in CPAM.


Trichotillomania and personality traits from the five-factor model.
To examine whether personality traits have predictive validity for trichotillomania (TTM) diagnosis, pulling severity and control, and hair pulling style. In study 1, logistic regression was used with TTM cases (n=54) and controls (n=25) to determine if NEO Five-Factor Inventory (NEO-FFI) personality domains predicted TTM case vs. control classification. In study 2, hierarchical multiple regression was used with TTM cases (n=164) to determine whether NEO-FFI personality domains predicted hair pulling severity and control as well as focused and automatic pulling styles. TTM case vs. control status was predicted by NEO-FFI neuroticism. Every 1-point increase in neuroticism scores resulted in a 10% greater chance of TTM diagnosis. Higher neuroticism, higher openness, and lower agreeableness were associated with greater pulling severity. Higher neuroticism was also associated with less control over hair pulling. Higher neuroticism and lower openness were associated with greater focused pulling. None of the personality domains predicted automatic hair pulling. Personality traits, especially neuroticism, can predict TTM diagnosis, hair pulling severity and control, and the focused style of pulling. None of the personality traits predicted automatic pulling. Longitudinal studies are needed to determine whether personality variables predispose to TTM onset, impact disorder course, and/or result from hair pulling behavior.


Behavioral and biochemical stereoselectivity of sigma opiate/PCP receptors.
The relative potencies of the stereoisomers of ketamine, N-allylnormetazocine and cyclazocine were determined at mu opiate and sigma opiate/phencyclidine (PCP) receptors in vitro in rat brain homogenates, as well as in a discriminative stimulus behavioral paradigm in rats trained to discriminate PCP from saline. In all cases the in vivo and in vitro data were in agreement. The (+)-isomers of N-allylnormetazocine and cyclazocine are highly specific sigma opiate/PCP ligands.


Multiplane transesophageal echocardiographic assessment of left atrial appendage anatomy and function.
Anatomic indexes of the LAA are dependent on the plane in which the appendage is viewed. Greater LAA neck width and cross-sectional area are observed at 135 degrees than at 45 degrees or 90 degrees, consistent with the characteristic 3-dimensional ungular shape of this structure. Appendage ejection and inflow velocity measurements are independent of the imaging plane.