[Etiology of nocturia and clinical efficacy of naftopidil on nocturia in patients with benign prostatic hyperplasia--analysis of frequency volume charts].
The etiology of nocturia in 70 patients with benign prostatic hyperplasia (BPH) who had nocturia of two or more times were examined based on frequency volume charts (FVC). Nocturia was classified into four groups: nocturnal polyuria, low capacity, combined nocturia, and no evidence of abnormality. Nearly half of the cases had nocturnal polyuria only. A little under 70% of patients had associated nocturnal polyuria (nocturnal polyuria+combined nocturia). Naftopidil was administered for three months to the patients with BPH who had nocturia with a urinary frequency of two or more times. Clinical efficacy was evaluated in 32 patients based on FVC and naftopidil was shown to improve nocturia. The improvement in nocturia was determined by the increment in voided volume.


Multiplatform, Non-Breath-Hold Fast Scanning Protocols: Should We Stop Giving Breath-Hold Instructions for Routine Chest CT? [Formula: see text].
We assessed if non-breath-hold (NBH) fast scanning protocol can provide respiratory motion-free images for interpretation of chest computed tomography (CT). In our 2-phase project, we first collected baseline data on frequency of respiratory motion artifacts on breath-hold chest CT in 826 adult patients. The second phase included 62 patients (mean age 66 ± 15 years; 21 females, 41 males) who underwent an NBH chest CT on either single-source (n = 32) or dual-source (n = 30) multidetector-row CT scanners. Clinical indications for chest CT, reason for using NBH CT, scanner type, scan duration, and radiation dose (CT dose index volume, dose length product) were recorded. Two thoracic radiologists (R1 and R2) independently graded respiratory motion artifacts (1 = no respiratory motion artifacts with unrestricted evaluation; 2 = minor motion artifacts limited to one lung lobe or less with good diagnostic quality; 3 = moderate motion artifacts limited to 2 to 3 lung lobes but adequate for clinical diagnosis; 4 = poor evaluability or unevaluable from severe motion artifacts; and 5 = limited quality due to other causes like high noise, beam hardening, or metallic artifacts), and recorded pulmonary and mediastinal findings. Descriptive analyses, Cohen κ test for interobserver agreement, and Student t test were performed for statistical analysis. No NBH chest CT were deemed uninterpretable by either radiologist; most NBH CT (R1-59 of 62, 95%; R2-62 of 62, 100%) had no or minimal motion artifacts. Only 3 of 62 (R1) NBH chest CT had motion artifacts limiting diagnostic evaluation for lungs but not in the mediastinum. Non-breath-hold fast protocol enables acquisition of diagnostic quality chest CT free of respiratory motion artifacts in patients who cannot hold their breath.


Pharmacologic agents for acute hemodynamic instability: recent advances in the management of perioperative shock- a systematic review.
Despite the growing body of evidence evaluating the efficacy of vasoactive agents in the management of hemodynamic instability and circulatory shock, it appears no agent is superior. This is becoming increasingly accepted as current guidelines are moving away from detailed algorithms for the management of shock, and instead succinctly state that vasoactive agents should be individualized and guided by invasive hemodynamic monitoring. This extends to the perioperative period, where vasoactive agent selection and use may still be left to the discretion of the treating physician with a goal-directed approach, consisting of close hemodynamic monitoring and administration of the lowest effective dose to achieve the hemodynamic goals. Successful therapy depends on the ability to rapidly diagnose the etiology of circulatory shock and thoroughly understand its pathophysiology as well as the pharmacology of vasoactive agents. This review focuses on the physiology and resuscitation goals in perioperative shock, as well as the pharmacology and recent advances in vasoactive agent use in its management.


The effect of incorporating Fréchet dendrons into rotaxanes and molecular shuttles containing the 1,2-bis(pyridinium)ethane⊂[24]crown-8 templating motif.
Fréchet-type dendrons (G0-G3) were added as both axle stoppering units and cyclic wheel appendages in a series of [2]rotaxanes, [3]rotaxanes, and molecular shuttles that employ 1,2-bis(pyridinium)ethane axles and 24-membered crown ethers wheels. The addition of dendrimer wedges as stoppering units dramatically increased the solubility of simple [2]rotaxanes in nonpolar solvents. The X-ray structure of a G1-stoppered [2]rotaxane shows how the dendritic units affect the structure of the interlocked components. Increased solubility allows observation of how the interaction of dendritic units on separate components in interlocked molecules influences switching properties and molecular size. In a series of [2]rotaxane molecular shuttles incorporating two recognition sites, it was demonstrated that an increase in generation on either the stoppering unit or cyclic wheel could influence both the rate of shuttling and the site preference of the wheel on the axle.


Assessment of psychological distress pattern & its correlates among people receiving COVID-19 vaccination during the COVID-19 pandemic: A cross-sectional study.
There is a possibility that vaccinated people may experience lesser psychological distress due to the sense of safety felt by them against getting the COVID-19 infection as compared to those who are not vaccinated. However, there is a paucity of research examining the mental health status of this important sub-group of population. Thus, the present study was aimed to examine the pattern of psychological distress and its correlates among people receiving COVID-19 vaccine. This cross-sectional study assessed individuals receiving COVID-19 vaccine at a tertiary care hospital. Psychological distress and COVID-19-related anxiety were assessed using the Depression Anxiety Stress Scale (DASS-21) and the COVID-19 Anxiety Scale-7, respectively. The study comprised 728 individuals with a mean age of 44.8 yr. Moderate levels of depression, anxiety and stress were reported by about 50, six and 15 per cent of the participants, respectively, as assessed on DASS-21. Generalized linear model and quantile regression analyses revealed COVID-19-related anxiety, and being a healthcare worker or front-line worker as significant correlates of psychological distress. About half of the study participants receiving COVID-19 vaccine reported moderate to severe symptoms of depression. Strategies focusing on alleviation of COVID-19-related fear and anxiety might be effective in improving the symptoms of psychological distress.


Evidence for a lack of an effect of dietary fluoride level on reproduction in mice.
The possible essentiality of fluoride for reproduction was studied in female mice fed a low-fluoride ( less than 0.5 ppm F) basal diet for three generations. Reproduction of mice fed this basal diet was the same as when mice were fed the basal diet supplemented with 2 or 100 ppm F. A previous study [Messer et. al. (1973) J. Nutr. 103, 1319-1326], utilizing the same diet did result in an impairment of reproduction and the development of an anemic condition. The results of the present study suggest that the apparent essentiality of fluoride previously observed was due to a pharmacological effect of fluoride in improving iron utilization in a diet marginally sufficient in iron. The data do not support the previous claims of an essential role of fluoride in reproduction.


Recent Advances in Glyoxalase-I Inhibition.
Glyoxalase system is a ubiquitous system in human cells which has been examined thoroughly for its role in different disease conditions. It is composed of Glyoxalase-I (Glo-I) and Glyoxalase- II which perform an essential metabolic process inside the cell by detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic D-lactic acid. Tumor cells are well-known for their high metabolic rate which results in elevated levels of toxic metabolites. The over-expression of Glo-I in tumor cells makes this enzyme a pivotal target for anticancer drug development. Glo-I is metalloenzyme with two polypeptide chains and encompasses two active sites with an integral zinc atoms at their center. This review aims to highlight the important role of Glo-I in different pathogenic conditions, and more importantly, it provides a thorough discussion of all known human Glo-I inhibitors since its discovery, a hundred years ago, up to date. It embraces the different classes they belong to, their design and chemical structures. We believe this review will help guide the design of novel and potent human Glo-I inhibitors by providing a handy reference for interested researchers in this target.


Early Passage Mesenchymal Stem Cells Display Decreased Radiosensitivity and Increased DNA Repair Activity.
Cell therapies using human mesenchymal stem cells (MSCs) have received much attention in the past decade. In pursuit of the therapeutic potential of MSCs, cell expansion is required to generate a great number of cells with desired phenotype and functionality. Long-term expansion in vitro, however, can lead to altered functions. To explore the changes in DNA damage responses (DDR) in MSCs expanded, DDR pathways following irradiation were characterized in early- and late-passage bone marrow MSCs. Seventy-two hours after irradiation, the percentage of sub-G1 cells in early-passage MSCs did not change significantly. Reduced TUNEL staining was observed in early-passage MSCs compared to late-passage MSCs 4 h after irradiation. Comet assay also revealed that early-passage MSCs were more resistant to irradiation or DNA damages induced by genotoxic agents than late-passage MSCs. ATM phosphorylation and γ-H2AX and phospho-p53 increased in early-passage MSCs while decreased in late-passage MSCs. Through inhibition by KU55933, DDR pathway in early-passage MSCs was shown to be ATM-dependent. Higher levels of poly (ADP-ribose) polymerase-1 (PARP-1) and PAR synthesis were observed in early-passage MSCs than in late-passage MSCs. Knockdown of PARP-1 in early-passage MSCs resulted in sensitization to irradiation-induced apoptosis. Overexpression of PARP-1 in late passage MSCs could render irradiation resistance. Lower activity of DDR in late-passage MSCs was associated with rapid proteasomal degradation of PARP-1. In conclusion, early-passage MSCs are more irradiation-resistant and have increased DDR activity involving PARP-1, ATM and their downstream signals. Stem Cells Translational Medicine 2017;6:1504-1514.


A Novel Approach to Transforming Smoking Cessation Practice for Pregnant Aboriginal Women and Girls Living in the Pilbara.
Tobacco smoking during pregnancy contributes to a range of adverse perinatal outcomes; but is a potentially modifiable behavior. In Australia Aboriginal and Torres Strait Islander women face a range of barriers that hinder; rather than support smoking cessation. Few smoking cessation programs consider the broader social determinants of women's lives; the gendered nature of these or the complexities which impinge on behavior change in the presence of social and economic disadvantage and substantial individual and intergenerational trauma. Drawing on the salient gender and trauma-informed literature this paper describes the rationale underpinning formative research which will inform the design of a localized, culturally meaningful smoking cessation program for Aboriginal women living in the Hedland and Western Desert communities of the remote Pilbara region of Western Australia. We contend that a women-centered, trauma-informed approach to smoking cessation has much to offer those seeking to address this critical public health issue.


[RADICAL RECONSTRUCTIVE TORACOPLASTY - A NEW METHOD OF TREATMENT OF PATIENTS WITH CHOANOID DEFORMATION OF BREAST].
Objective - development of a new method of surgery correction of choanoid deformation of breast, leading to significant improvement of the treatment results of the patients with this pathotology. The new method is being developed based on the analysis of the own long experience of treatment of the patients with choanoid deformation of breast. In total, over than 70 patients have been surged, with the age ranging from 5 to 35. The surgeries have been implemented in Leningrad Pediatric Medical Institute clinic as well as clinics in Georgia. In the course of formation of conception of the new surgery, all methods of surgery treatment of the patients having the indicated disease, applied up to now, have been critically analyzed. As a result, a new method of the surgery correction of the choanoid deformation of breast has been developed and tested which enables restoration of the natural architectonics of the deformed part of the patient's thoracic wall. Meanwhile, the strut consisting of the sterno-costal-cartilage fragments according to "stone arch" type stably and strongly fixes breast bone in the correct position, not requiring application of any artificial constructions for fixation of the breast bones. The basic and general principles of treatment of the patients with the bones trauma (repositions and immobilization of the bone fragments) have been observed within the developed method, possibility of occurrence of diastalsis or tangling the bones-cartilage fragments is excluded thus guaranteeing their fastest consolidation. Our results confirmed the correctness of new conceptual approach and technical realization of the developed method. Only 5% of the patients during the surgery have been observed to have insignificant damages of the parietal and visceral pleura. All patients have been released frpm the hospital on 3-5 day after the surgery. We have observed the patients during from 1 to 13 years after the surgery. No late post-surgery complications observed. The patients have been rehabilitated in psychological and emotional point of view, the quality of life has been significantly improved, and the ability to work has been completely recovered. Therefore, the method of surgery correction of the coanoid deformation of the breast, provided that the surgery technique is completely learnt and the surgeon is of proper qualification, enables reaching the guaranteed positive result of treatment even in those patients suffering from heavier form of the diseases as well as excluded the possibility of recidivism.


The effect of rubber closures on the haze state of ceftriaxone sodium for injection.
The migration of volatile components into the headspace of glass vials from rubber closures is a potential source of haze formation in reconstituted solutions of powders for parenteral administration. In this paper, a headspace method was used to extract volatile substances from different types of rubber closures used in ceftriaxone sodium for injection whose clarity were poor. The extracts obtained were analyzed by gas chromatography (GC)-mass spectrometry (MS). An antioxidant in rubber closures, butylated hydroxytoluene (BHT), was found to affect the haze state of ceftriaxone sodium for injection.


Synthesis and pharmacological activities of hydrazones, Schiff and Mannich bases of isatin derivatives.
Schiff bases and phenyl hydrazone of isatins were prepared by reacting isatin and the appropriate aromatic primary amine/hydrazines. A new series of the corresponding N-mannich bases were synthesized by reacting them with formaldehyde and diphenylamine. The chemical structures were confirmed by means of their 1H-NMR, IR spectral data and elemental analysis. The compounds were screened for analgesic, antiinflammatory and antipyretic activity. 1-Diphenylaminomethyl-3-(1-naphthylimino)-1,3-dihydroindol-3-one (4), 3-(1-naphthylimino)-5-bromo-1,3-dihydroindol-2-one (2) and 1-diphenylaminomethyl-3-(4-methylphenylimino)-1,3-dihydroindol-3-one (7) were found to exhibit the highest analgesic, anti-inflammatory and antipyretic activity respectively. 1-Diphenylaminomethyl-3-(4-methylphenylimino)-1,3-dihydroindol-3-one (7) was found to be the most active compound of the series.


[Pancreatic pseudocyst. A review of 10 years].
In the hope of finding those patients whose pancreas pseudocyst resolution were spontaneous, we undertook a retrospective review of such cases admitted at the Hospital Central de San Cristobal y Hospital Patrocinio Peñuela Ruiz (from IVSS), with the diagnosis of acute pancreatitis. From 619 patients with pancreatitis, 40 developed a pseudocyst (5.78%). The most frequent ethiology was biliary disease (47.5%) and abdominal pain in 87.5%, the most common symptom. Abdominal ultrasonography was the best diagnostic aid. Spontaneous resolution occur in 24 cases (60%) in juntion with the normalization of seric and urinary amylases values, the size of the cyst in these patients was less than 5 cms. Sixteen patients needed surgery, in 8 of them the seric amylase value remained high and in 3 cases this value was normal but with a cyst size more than five cms. Internal drainage in 11, external in 4 and surgical resection in one. There was no deaths in this review.


Prevalence of Mupirocin Resistance Among Staphylococci, its Clinical Significance and Relationship to Clinical Use.
Mupirocin competitively inhibits bacterial isoleucyl transfer-RNA synthetase and inhibit bacterial protein synthesis. Widespread usage and over the counter availability of the drug has resulted in resistance among Staphylococcus species. This study aimed to determine the overall prevalence of mupirocin resistance among staphylococci. Correlate clinical significance of mupirocin resistance and its relationship to clinical use. Consecutive, nonrepetitive, clinical isolates of Staphylococcus aureus (n = 98), and coagulase-negative staphylococci (CoNS) (n = 45) from skin and soft-tissue infections between January 2014 and June 2014 were studied. Antibiotic susceptibility testing was done according to Clinical and Laboratory Standards Institute guidelines. Low- and high-level mupirocin resistance was screened by using 5 µg and 200 µg discs respectively and confirmed by agar dilution. Annual consumption of mupirocin was studied and correlated with resistance. High-level mupirocin resistance was found in 8.2% S. aureus and 15.6% of CoNS, while low-level mupirocin resistance was found in 17% S. aureus and 8.9% CoNS. High-level mupirocin resistance was more common in methicillin-sensitive S. aureus isolates when compared with methicillin-resistant S. aureus isolates (P < 0.05). Mupirocin resistant S. epidermidis were associated with methicillin resistance and constitutive clindamycin resistance. High prevalence of mupirocin resistance was found in the present study. Increased prevalence of mupirocin resistance among community-acquired staphylococci demands the judicious use of the drug in the community.


Dysplasia in Gastric Mucosa and its Reporting Problems.
The recognition, terminology used and histopathologic evaluation of two essential elements in gastric carcinogenesis, atrophy and dysplasia, are characterized by controversy. One hundred fifteen cases, with slides and their histopathologic reports from the archive of the Laboratory of Pathology were studied for the diagnostic value, reporting of dysplasia, interobserver variability, the relation of dysplastic lesions with inflammation, atrophy and metaplasia. After retrospectively studying the histopathologic reports from the archive we distributed the cases according to endoscopic and histopathologic diagnosis, together with the reexamination of the slides. The comparison of the median values of the numeric variables was made with the Mann-Whitney test (non-parametric equivalent of the Student's "t" test). The endoscopic clinical diagnosis were: malignancy/suspicious for malignancy 88 cases (76%) and non-neoplastic diagnosis (like ulcer or gastritis) 27 cases (24%). From the reexamination of the cases it resulted that there is no difference in reporting the malignancy, but there is a difference in the cases reported as dysplasia (p = 0.001) and negative for neoplasia (p = 0.063, borderline). Clinicians and pathologists can feel directly the discrepancy called "interobserver variability" and should be assured that the use of guidelines will cause a lowering of this variability.


Adenosine receptors and brain diseases: neuroprotection and neurodegeneration.
Adenosine acts in parallel as a neuromodulator and as a homeostatic modulator in the central nervous system. Its neuromodulatory role relies on a balanced activation of inhibitory A(1) receptors (A1R) and facilitatory A(2A) receptors (A2AR), mostly controlling excitatory glutamatergic synapses: A1R impose a tonic brake on excitatory transmission, whereas A2AR are selectively engaged to promote synaptic plasticity phenomena. This neuromodulatory role of adenosine is strikingly similar to the role of adenosine in the control of brain disorders; thus, A1R mostly act as a hurdle that needs to be overcame to begin neurodegeneration and, accordingly, A1R only effectively control neurodegeneration if activated in the temporal vicinity of brain insults; in contrast, the blockade of A2AR alleviates the long-term burden of brain disorders in different neurodegenerative conditions such as ischemia, epilepsy, Parkinson's or Alzheimer's disease and also seem to afford benefits in some psychiatric conditions. In spite of this qualitative agreement between neuromodulation and neuroprotection by A1R and A2AR, it is still unclear if the role of A1R and A2AR in the control of neuroprotection is mostly due to the control of glutamatergic transmission, or if it is instead due to the different homeostatic roles of these receptors related with the control of metabolism, of neuron-glia communication, of neuroinflammation, of neurogenesis or of the control of action of growth factors. In spite of this current mechanistic uncertainty, it seems evident that targeting adenosine receptors might indeed constitute a novel strategy to control the demise of different neurological and psychiatric disorders.


Dependence of acetylcholine and ADP dilation of pial arterioles on heme oxygenase after transfusion of cell-free polymeric hemoglobin.
Polymers of cell-free hemoglobin have been designed for clinical use as oxygen carriers, but limited information is available regarding their effects on vascular regulation. We tested the hypothesis that the contribution of heme oxygenase (HO) to acetylcholine-evoked dilation of pial arterioles is upregulated 2 days after polymeric hemoglobin transfusion. Dilator responses to acetylcholine measured by intravital microscopy in anesthetized cats were blocked by superfusion of the HO inhibitor tin protoporphyrin-IX (SnPPIX) in a group that had undergone exchange transfusion with hemoglobin 2 days earlier but not in surgical sham and albumin-transfused groups. However, immunoblots from cortical brain homogenates did not reveal changes in expression of the inducible isoform HO1 or the constitutive isoform HO2 in the hemoglobin-transfused group. To test whether the inhibitory effect of SnPPIX was present acutely after hemoglobin transfusion, responses were measured within an hour of completion of the exchange transfusion. In control and albumin-transfused groups, acetylcholine responses were unaffected by SnPPIX but were blocked by addition of the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine (l-NNA) to the superfusate. In hemoglobin-transfused groups, the acetylcholine response was blocked by either SnPPIX or l-NNA alone. The effect of another HO inhibitor, chromium mesoporphyrin (CrMP), was tested on ADP, another endothelial-dependent dilator, in anesthetized rats. Pial arteriolar dilation to ADP was unaffected by CrMP in controls but was attenuated 62% by CrMP in rats transfused with hemoglobin. It is concluded that 1) polymeric hemoglobin transfusion acutely upregulates the contribution of HO to acetylcholine-induced dilation of pial arterioles in cats, 2) this upregulation persists 2 days after transfusion when 95% of the hemoglobin is cleared from the circulation, and 3) this acute upregulation of HO signaling is ubiquitous in that similar effects were observed with a different endothelial-dependent agonist (i.e., ADP) in a another species (rat).


Alveolar macrophages from atopic asthmatics, but not atopic nonasthmatics, enhance interleukin-5 production by CD4+ T cells.
Recent studies have demonstrated that different antigen-presenting cell (APC)-related factors in the microenvironment of a T cell may determine its profile and quantity of cytokine expression and production. We have therefore examined the effects of alveolar macrophages and peripheral blood monocytes on interleukin (IL)-5 production by peripheral blood CD4+ T cells from atopic people with asthma (AA), atopic people without asthma (AN), and nonatopic normal subjects (N). In response to allergen stimulation, IL-5 production was significantly enhanced by the addition of monocytes to CD4+ cell cultures in AA and AN patients (p < 0.05 and 0.01, respectively), but not in N subjects. In mitogen-stimulated CD4+ cell plus monocyte cocultures, there was a small increase in IL-5 production in all three groups (p < 0.05 for AN). In contrast, the addition of alveolar macrophages to parallel cultures significantly amplified IL-5 production only in AA patients (p < 0.05 or 0.01). Furthermore, IL-5 production by CD4+ cells in alveolar macrophage cocultures, stimulated by allergen or mitogen, was higher than that in monocyte cocultures in AA patients (p < 0.05). Conversely, in AN and N subjects, the IL-5 values for alveolar macrophage cocultures were lower than those for peripheral blood monocytes. In blocking studies, antibodies against IL-1alpha, IL-1beta, IL-6, or tumor necrosis factor-alpha differentially suppressed macrophage-enhanced IL-5 production (p < 0.05 for IL-1beta and IL-6) and expression of the activation marker CD25 (p < 0.05 for IL-1alpha and IL-6) by allergen-stimulated CD4+ cells in AA patients. These observations suggest that alveolar macrophages influence the quantity of IL-5 production by T cells in the airways and, as a consequence, the development of asthma in atopic individuals.


The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma.
Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated. AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC). Although AEG-1 was suggested to be potentially modified by protein palmitoylation, the regulatory roles of AEG-1 palmitoylation in tumor progression of HCC has not been explored. Methods: Techniques as Acyl-RAC assay and point mutation were used to confirm that AEG-1 is indeed palmitoylated. Moreover, biochemical experiments and immunofluorescent microscopy were applied to examine the cellular functions of AEG-1 palmitoylation in several cell lines. Remarkably, genetically modified knock-in (AEG-1-C75A) and knockout (Zdhhc6-KO) mice were established and subjected to the treatment of DEN to induce the HCC mice model, through which the roles of AEG-1 palmitoylation in HCC is directly addressed. Last, HCQ, a chemical compound, was introduced to prove in principal that elevating the level of AEG-1 palmitoylation might benefit the treatment of HCC in xenograft mouse model. Results: We showed that AEG-1 undergoes palmitoylation on a conserved cysteine residue, Cys-75. Blocking AEG-1 palmitoylation exacerbates the progression of DEN-induced HCC in vivo. Moreover, it was demonstrated that AEG-1 palmitoylation is dynamically regulated by zDHHC6 and PPT1/2. Accordingly, suppressing the level of AEG-1 palmitoylation by the deletion of Zdhhc6 reproduces the enhanced tumor-progression phenotype in DEN-induced HCC mouse model. Mechanistically, we showed that AEG-1 palmitoylation adversely regulates its protein stability and weakens AEG-1 and staphylococcal nuclease and tudor domain containing 1 (SND1) interaction, which might contribute to the alterations of the RISC activity and the expression of tumor suppressors. For intervention, HCQ, an inhibitor of PPT1, was applied to augment the level of AEG-1 palmitoylation, which retards the tumor growth of HCC in xenograft model. Conclusion: Our study suggests an unknown mechanism that AEG-1 palmitoylation dynamically manipulates HCC progression and pinpoints that raising AEG-1 palmitoylation might confer beneficial effect on the treatment of HCC.


Inducible microRNA expression by an all-in-one episomal vector system.
Here we describe an episomal, one-vector system which allows the generation of cell populations displaying homogenous, inducible gene inactivation by RNA interference in a one step procedure. A dual tet-repressor/activator system tightly controls a bi-directional promoter, which simultaneously drives expression of microRNAs and a fluorescent marker protein. We demonstrate the effectiveness of this vector by knockdown of p53 expression in a human cell line which resulted in the expected loss of G1-arrest after DNA damage. The generation of a cell pool homogenously expressing the ectopic microRNAs was achieved in 1 week without the need for viral infections. Induction of microRNA expression did not elicit an interferon response. Furthermore, the vector was adapted for convenient ligation-free transfer of microRNA cassettes from public libraries. This conditional knockdown-system should prove useful for many research and gene therapeutic applications.


Multiple pathways to allograft rejection.
Allograft rejection results from a complex process involving both the innate and acquired immune systems. The innate immune system predominates in the early phase of the allogeneic response, during which chemokines and cell adhesion play essential roles, not only for leukocyte migration into the graft but also for facilitating dendritic and T-cell trafficking between lymph nodes and the transplant. This results in a specific and acquired alloimmune response mediated by T cells. Subsequently, T cells and cells from innate immune system function synergistically to reject the allograft through nonexclusive pathways, including contact-dependent T cell cytotoxicity, granulocyte activation by either Th1 or Th2 derived cytokines, NK cell activation, alloantibody production, and complement activation. Blockade of individual pathways generally does not prevent allograft rejection, and long-term allograft survival is achieved only after simultaneous blockade of several of them. In this review, we explore each of these pathways and discuss the experimental evidence highlighting their roles in allograft rejection.


Self-protective responses to norvaline-induced stress in a leucyl-tRNA synthetase editing-deficient yeast strain.
The editing function of aminoacyl-tRNA synthetases (aaRSs) is indispensible for formation of the correct aminoacyl-tRNAs. Editing deficiency may lead to growth inhibition and the pathogenesis of various diseases. Herein, we confirmed that norvaline (Nva) but not isoleucine or valine is the major threat to the editing function of Saccharomyces cerevisiae leucyl-tRNA synthetase (ScLeuRS), both in vitro and in vivo. Nva could be misincorporated into the proteome of the LeuRS editing-deficient yeast strain (D419A/ScΔleuS), potentially resulting in dysfunctional protein folding and growth delay. Furthermore, the exploration of the Nva-induced intracellular stress response mechanism in D419A/ScΔleuS revealed that Hsp70 chaperones were markedly upregulated in response to the potential protein misfolding. Additionally, proline (Pro), glutamate (Glu) and glutamine (Gln), which may accumulate due to the conversion of Nva, collectively contributed to the reduction of reactive oxygen species (ROS) levels in Nva-treated D419A/ScΔleuS cells. In conclusion, our study highlights the significance of the editing function of LeuRS and provides clues for understanding the intracellular stress protective mechanisms that are triggered in aaRS editing-deficient organisms.


The 'Chalky Culprit' of acute locked knee.
Acute locked knee is commonly caused by tears of the menisci in the knee, osteochondral injuries and also by the stump of a ruptured anterior cruciate ligament. We present two cases of acute locked knee atypically caused by gouty tophaceous lesions in the knee.


Reduced-Order Model for Surfactant-Laden Electrified Sessile Droplets.
A comprehensive understanding of the physics of electrowetting of a surfactant-laden droplet is important for applications in rapid healthcare diagnostics. A majority of biological samples examined during point-of-care (POC) diagnostics are biofluids with dissolved surfactants, such as the respiratory droplets containing protein (mucin) and surfactant molecules like dipalmitoylphosphatidylcholine. The presence of these surfactant molecules is anticipated to have a significant impact on the performance of electrowetting-based POC diagnostic devices. A reduced-order model is developed using the weighted residual integral boundary layer theory for the electrowetting of a surfactant-laden sessile droplet in a parallel plate electrode configuration. Thin film evolution equations are obtained for the fluid-fluid interface, the surfactant concentration, the depth-integrated flow rate, and the interfacial charge density. We show that the presence of surfactants opposes and decreases the strength of the electrohydrodynamic flow due to Marangoni stress-driven convection. The droplet then responds to an AC field with a suppressed amplitude of oscillation and the same mean deformation as that under DC forcing. Thus, low-frequency AC forcing with a suitable surfactant can plausibly be employed as a viable alternative to more energy-intensive high-frequency AC forcing.


Herd-level and territorial-level factors influencing average herd somatic cell count in France in 2005 and 2006.
Mastitis is a multifactorial disease and the most costly dairy production issue. In spite of extensive literature on udder-health risk factors, effects of metabolic diseases, farmers' competencies and livestock farming system on somatic cells count (SCC) are sparsely described. Herd-level or territorial-level factors affecting monthly composite milk weighted mean cow SCC (CMSCC) were analysed with a linear mixed effect model. The average CMSCC was 266,000 cells/ml. Half of the herds had CMSCC >300,000 cells/ml for 2-6 months a year, and 15% of herds for more than 7 months a year. CMSCC was positively associated with the number of cows, having a beef or fattening herd in addition to the dairy herd, the monthly average days in milk, the yearly age at first calving, the yearly proportion of purchased cows and the yearly culling rate. Moreover, a positive association is reported between CMSCC and the monthly proportion of cows probably with subacute ruminal acidosis (fat percentage minus protein percentage ≤0·30%, for Holstein) and negative energy balance (protein to fat ratio ≤0·66, for Holstein), the yearly average calving interval, having at least one dead cow and the mean monthly temperature. The association was negative for a predominant breed other than Holstein, the monthly milk production, the yearly dry-off period length, the monthly first calving cow proportion, having an autumn calving peak, being a Good Breeding Practices member, the monthly number of days with rain, the altitude and the territorial cattle density. CMSCC varied widely among the 11 dairy production areas. In conclusion, this study showed the average CMSCC for the French dairy cows, compared with international results. Moreover, it quantified the contribution of several factors to CMSCC, in particular metabolic diseases and the farm environment.


Preventive Effect of Alkaloids from Lotus plumule on Acute Liver Injury in Mice.
Lotus plumule is a traditional Chinese food that can be used as a beverage. In this study, three kinds of Lotus plumules from different regions of China were selected to observe the preventive effects of extracted alkaloids on CCl₄-induced liver injuries. Animal experiments revealed that alkaloids extracted from Lotus plumules decreased the serum AST (aspartate aminotransferase), ALT (alanine aminotransferase), and TBIL (total bilirubin) levels, enhanced SOD (superoxide dismutase) activity, and reduced MDA (malondialdehyde) level in the liver tissues of mice with liver injury. H&E observation confirmed that alkaloids from Lotus plumules could alleviate CCl₄-induced injuries of liver tissues and inhibit the inflammatory effect on hepatocytes. Further qPCR experiments also demonstrated that alkaloids from Lotus plumules upregulated the expression of IκB-α (inhibitor of NF-κB alpha), Cu/Zn-SOD (copper/zinc superoxide dismutase), Mn-SOD (manganese superoxide dismutase), and CAT (catalase) mRNA and downregulated TNF-α (tumor necrosis factor alpha) and NF-κB (nuclear factor kappa B) expression in the liver tissues of mice with liver injury. All three kinds of alkaloids from Lotus plumules could prevent CCl₄-induced liver injuries by regulating the levels of oxidative stress and inflammation in mice, and the therapeutic effect was comparable to that of silymarin, the medicine commonly used in the treatment of liver diseases. In summary, alkaloids from Lotus plumules contain bioactive substances with hepatic protective efficacy and possess potential application value in the field of functional food.


Role of interferon alpha-inducible protein 6 in modulating the proliferation, apoptosis and senescence of oesophageal squamous cell carcinoma cells.
Oesophageal cancer is one of the most malignant tumors worldwide. Dysfunction of interferon alpha-inducible protein 6 (IFI6) has been implicated in numerous human diseases, including cancer. We performed the study to investigate the function and potential molecular pathways of IFI6 in oesophageal squamous cell carcinoma (ESCC) cells. IFI6 expression was analysed using databases-derived data and paraffin-embedded tissue samples. CCK-8-based analyses and EdU staining, colony formation, β-galactosidase staining and Annexin V/PI double-staining assays were used to determine the influence of IFI6 on cell growth, senescence and apoptosis. Tumor growth in vivo was investigated in mouse xenograft models. RNA sequencing (RNA-seq) was performed to identify the transcripts and pathways affected by IFI6. The results showed that IFI6 expression was elevated in ESCC and correlated with poor clinical prognosis (P<0.05). IFI6 was overexpressed and silenced in TE-1 and TE-10 cells using lentiviruses. Upregulation of IFI6 promoted cell growth both in vitro and in vivo, whereas downregulation induced opposite effects. IFI6 overexpression inhibited cell senescence and apoptosis but did not influence cell cycle progression, while IFI6 downregulation increased cell senescence and apoptosis. RNA-seq revealed that 3 mRNAs (EPHA5, CLIP1 and GTF2F2) were consistently associated with both IFI6 overexpression and silencing. IFI6 appeared to modulate TE-1 cells via complex mechanisms. In conclusion, IFI6 plays a positive role in the proliferation of ESCC cells both in vitro and in vivo, which could be a novel therapeutic target for treating ESCC.


C59T mutation in exon 2 of monocytic leukemia-associated antigen-34 gene indicates a high risk of recurrence of acute myeloid leukemia.
Monocytic leukemia-associated antigen-34 (MLAA-34) is a novel monocytic leukemia-associated antigen and a candidate oncogene. The aim of the present study was to investigate the involvement of the MLAA-34 gene in acute myeloid leukemia (AML). MLAA-34 expression level, chromosome location, gene copy number and single nucleotide polymorphisms (SNPs) of 40 patients with AML and 5 healthy volunteers were analyzed by reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and DNA sequencing. The effects of MLAA-34 mutation on overall survival (OS) and progression-free survival (PFS) of patients with AML were also analyzed. MLAA-34 was significantly upregulated in patients with AML when compared with volunteer controls, and this upregulation was associated with a C59T SNP site located in the second exon of MLAA-34. MLAA-34 was mapped to 13q14.2 and no translocation was observed in patients with AML. In addition, this SNP site is affinitive to the well-known molecular markers of AML, including Fms-like tyrosine kinase 3 and DNA methyltransferase 3A, as well as extramedullary lesions, periphery leukocyte numbers, remission and cytogenetic abnormalities of patients with AML. Patients with AML with MLAA-34 C59T mutations had significantly shorter OS and PFS times compared with that of patients without C59T mutations. The present findings indicated that the MLAA-34 C59T mutation was a high-risk factor for recurrence of AML, and may be a candidate target for AML therapy.


Quantitative benefit-risk assessment of methylprednisolone in multiple sclerosis relapses.
High-dose short-term methylprednisolone is the recommended treatment in the management of multiple sclerosis relapses, although it has been suggested that lower doses may be equally effective. Also, glucocorticoids are associated with multiple and often dose-dependent adverse effects. This quantitative benefit-risk assessment compares high- and low-dose methylprednisolone (at least 2000 mg and less than 1000 mg, respectively, during at most 31 days) and a no treatment alternative, with the aim of determining which regimen, if any, is preferable in multiple sclerosis relapses. An overall framework of probabilistic decision analysis was applied, combining data from different sources. Effectiveness as well as risk of non-serious adverse effects were estimated from published clinical trials. However, as these trials recorded very few serious adverse effects, risk intervals for the latter were derived from individual case reports together with a range of plausible distributions. Probabilistic modelling driven by logically implied or clinically well motivated qualitative relations was used to derive utility distributions. Low-dose methylprednisolone was not a supported option in this assessment; there was, however, only limited data available for this treatment alternative. High-dose methylprednisolone and the no treatment alternative interchanged as most preferred, contingent on the risk distributions applied for serious adverse effects, the assumed level of risk aversiveness in the patient population, and the relapse severity. The data presently available do not support a change of current treatment recommendations. There are strong incentives for further clinical research to reduce the uncertainty surrounding the effectiveness and the risks associated with methylprednisolone in multiple sclerosis relapses; this would enable better informed and more precise treatment recommendations in the future.


Cementless Fixation Is Associated With Increased Risk of Early and All-Time Revision After Hemiarthroplasty But Not After THA for Femoral Neck Fracture: Results From the American Joint Replacement Registry.
Despite ample evidence supporting cemented femoral fixation for both hemiarthroplasty and THA for surgical treatment of displaced femoral neck fractures, cementless fixation is the preferred fixation method in the United States. To our knowledge, no nationally representative registry from the United States has compared revision rates by fixation for this surgical treatment. After controlling for relevant confounding variables, is femoral fixation method (cemented or cementless) in hemiarthroplasty or THA for femoral neck fracture associated with a greater risk of (1) all-cause revision or (2) revision for periprosthetic fracture? Patients with Medicare insurance who had femoral neck fractures treated with hemiarthroplasty or THA reported in the American Joint Replacement Registry database from 2012 to 2017 and Centers for Medicare and Medicaid Services claims data from 2012 to 2017 were analyzed in this retrospective, large-database study. Of the 37,201 hemiarthroplasties, 42% (15,748) used cemented fixation and 58% (21,453) used cementless fixation. Of the 7732 THAs, 20% (1511) used cemented stem fixation and 80% (6221) used cementless stem fixation. For both the hemiarthroplasty and THA cohorts, most patients were women and had cementless femoral fixation. Early revision was defined as a procedure that occurred less than 90 days from the index procedure. All patients submitted to the registry were included in the analysis. Patient follow-up was limited to the study period. No patients were lost to follow-up. Due to inherent limitations with the registry, we did not compare medical complications, including deaths attributed directly to cemented fixation. A logistic regression model including the index arthroplasty, age, gender, stem fixation method, hospital size, hospital teaching affiliation, and Charlson comorbidity index score was used to determine associations between the index procedure and revision rates. For the hemiarthroplasty cohort, risk factors for any revision were cementless stem fixation (odds ratio 1.42 [95% confidence interval 1.20 to 1.68]; p < 0.001), younger age (OR 0.96 [95% CI 0.95 to 0.97]; p < 0.001), and higher Charlson comorbidity index (OR 1.06 [95% CI 1.02 to 1.11]; p = 0.004). Risk factors for early revision were cementless stem fixation (OR 1.77 [95% CI 1.43 to 2.20]; p < 0.001), younger age (OR 0.98 [95% CI 0.97 to 0.99]; p < 0.001), and higher Charlson comorbidity index (OR 1.09 [95% CI 1.04 to 1.15]; p < 0.001). Risk factors for revision due to periprosthetic fracture were cementless fixation (OR 6.19 [95% CI 3.08 to 12.42]; p < 0.001) and higher Charlson comorbidity index (OR 1.16 [95% CI 1.06 to 1.28]; p = 0.002). Risk factors for early revision due to periprosthetic fracture were cementless fixation (OR 7.38 [95% CI 3.17 to 17.17]; p < 0.001), major teaching hospital (OR 2.10 [95% CI 1.08 to 4.10]; p = 0.03), and higher Charlson comorbidity index (OR 1.20 [95% CI 1.09 to 1.33]; p < 0.001). For the THA cohort, there were no associations. These data suggest that cemented fixation should be the preferred technique for most patients with displaced femoral neck fractures treated with hemiarthroplasty. The fact that stem fixation method did not affect revision rates for those patients with displaced femoral neck fractures treated with THA may be due to current practice patterns in the United States. Level III, therapeutic study.


Environmental Distribution of Personal Care Products and Their Effects on Human Health.
Personal care products (PCPs) are generally used for personal hygiene, cleaning, grooming, and beautification. These include hair and skin care products, baby care products, UV blocking creams, facial cleansers, insect repellents, perfumes, fragrances, soap, detergents, shampoos, conditioners, toothpaste, etc., thus exposing humans easily. Personal preferences related to PCPs usage frequency are highly variable and depend on socioeconomic status and lifestyle factors. The increasing availability and diversity of PCPs from the retailer outlets consequently result in higher loading of PCPs into wastewater systems and, therefore, the environment. These compounds persistently and continuously release biologically active and inactive ingredients in the atmosphere, biosphere, geosphere, and demonstrating adverse effects on human, wild, and marine life. Advanced techniques such as granular activated carbon filtration and algae-based system may help biotransformation and remove PCP contaminants from water with improved efficiency. Additionally, harmony among PCPs related regulations of different countries may encourage standard checks to control their manufacturing, sale, and distribution across the borders to ensure consumers' safety. Furthermore, all intended ingredients, their concentrations, and instructions for frequency of use as per age groups may be clearly labeled on packages of PCPs. In conclusion, the emerging environmental contaminants of PCPs and their association with the growing risks of negative effects on human health and globally on the environment emphasize the chemical-free simple lifestyle.


Assessment of exposure to depleted uranium.
In most circumstances, measurement of uranium excreted in urine at known times after exposure is potentially the most sensitive method for determining the amount of depleted uranium (DU) incorporated. The problems associated with this approach are that natural uranium is always present in urine because of the ingestion of natural uranium in food and drink, and that the uncertainties in the intakes as assessed from excretion measurements can be quite large, because many assumptions concerning the exposure characteristics (time pattern of exposure, route of intake, chemical form, solubility, biokinetics within the body) must be made. Applying currently available methods and instruments for the measurement of uranium in urine samples, DU incorporations of levels relevant with respect to potential health hazards can be detected reliably, even a long time after exposure.


Quality of life and insulin resistance in patients with coronary heart disease.
Diabetes mellitus and impaired glucose tolerance have not only been associated with increased morbidity and mortality, but also with poor quality of life. The purpose of this study was to determine whether there is a relationship between poor quality of life and insulin resistance in patients with myocardial infarction without known diabetes mellitus. One hundred and nineteen patients, men and women aged between 31 and 80 years with a hospital-diagnosed myocardial infarction occurring 3 months before inclusion, were studied. Minor symptoms evaluation profile was used to estimate the quality of life at entry. Low quality of life (contentment and vitality) was significantly negatively (P<0.05) associated with insulin resistance. In patients with coronary heart disease and without known diabetes mellitus an estimated measure of quality of life was significantly and independently associated with poor insulin resistance.


A miniature electronic nose system based on an MWNT-polymer microsensor array and a low-power signal-processing chip.
This article introduces a power-efficient, miniature electronic nose (e-nose) system. The e-nose system primarily comprises two self-developed chips, a multiple-walled carbon nanotube (MWNT)-polymer based microsensor array, and a low-power signal-processing chip. The microsensor array was fabricated on a silicon wafer by using standard photolithography technology. The microsensor array comprised eight interdigitated electrodes surrounded by SU-8 "walls," which restrained the material-solvent liquid in a defined area of 650 × 760 μm(2). To achieve a reliable sensor-manufacturing process, we used a two-layer deposition method, coating the MWNTs and polymer film as the first and second layers, respectively. The low-power signal-processing chip included array data acquisition circuits and a signal-processing core. The MWNT-polymer microsensor array can directly connect with array data acquisition circuits, which comprise sensor interface circuitry and an analog-to-digital converter; the signal-processing core consists of memory and a microprocessor. The core executes the program, classifying the odor data received from the array data acquisition circuits. The low-power signal-processing chip was designed and fabricated using the Taiwan Semiconductor Manufacturing Company 0.18-μm 1P6M standard complementary metal oxide semiconductor process. The chip consumes only 1.05 mW of power at supply voltages of 1 and 1.8 V for the array data acquisition circuits and the signal-processing core, respectively. The miniature e-nose system, which used a microsensor array, a low-power signal-processing chip, and an embedded k-nearest-neighbor-based pattern recognition algorithm, was developed as a prototype that successfully recognized the complex odors of tincture, sorghum wine, sake, whisky, and vodka.


Urban wastewater treatment by a nutrient film technique system with a valuable commercial plant species (Chrysanthemum cinerariaefolium Trev.).
Urban wastewater causes rapid eutrophication of natural waters and requires treatment before discharge. This is expensive and produces huge quantities of sludge. In the European Community, it will no longer be lawful to dispose of this sludge as landfill after 2005 (European Directive 91/271/CEE of May 21, 1991). Wastewater treatment by the Chrysanthemum cinerariaefolium plants in horizontal flow was investigated using the nutrient film technique (NFT), a widely used hydroponic system in the commercial greenhouse industry. After a 48 h plant treatment, the purification efficiency was 95%, 91%, and 99% with respect to suspended solids (SS), biochemical oxygen demand (BOD5), and chemical oxygen demand (COD), and the elimination of nutrients (total nitrogen and total phosphorus) varied between 40% and 80%. SS and thus indirectly BOD5 and COD were removed by filtration and adsorption; the solids trapped in the root systems were then decomposed and mineralized. The system with 25 plants purified 30 L of wastewater in 48 h. One-hundred people communities wastewater could be treated with a 6 m2 area of production. Pyrethrin contents and chlorophyll a fluorescence of plants grown on raw urban waters were not significantly different from those grown on a standard nutrient solution.


[The arterial blood supply of the human mandible].
The arteries of 22 mandibles injected with Kallocryl M were examined. The first group consisted of mandibles with the full complement of teeth. At the inner side, there were numerous anastomoses between the submental artery, the sublingual artery, the ascending palatine artery and the mylohyoid ramus. Furthermore, the dental rami branched into the periost. At the outside, the mental artery as well as the submental and inferior labial arteries contributed to the arterial supply. In the second group of mandibles (with intact incisors), these war a marked reduction of the anastomoses of the inferior alveolar artery in the middle region. The third group of mandibles (which were edentulous) showed anastomoses of the submental and sublingual arteries in the region of the incisors. The outside was supplied by the submental and inferior labial arteries. The mental artery exislar artery was demonstrated in 4 cases. The reduction of anastomoses concerned the inferior alveolar artery.


Monofluoromethyl-Substituted Sulfonium Ylides: Electrophilic Monofluoromethylating Reagents with Broad Substrate Scopes.
Two electrophilic monofluoromethylating reagents, monofluoromethyl(phenyl)sulfonium bis(carbomethoxy)methylide (3 a) and monofluoromethyl(4-nitrophenyl)sulfonium bis(carbomethoxy)methylide (3 b), and their reactions under mild conditions with a variety of nucleophiles, such as alcohols and malonate derivatives, sulfonic and carboxylic acids, phenols, amides, and N heteroarenes, are described. Mechanistic studies with deuterated reagents [D2 ]3 a/[D2 ]3 b suggest that these monofluoromethylation reactions proceed through an electrophilic substitution pathway.


The threat of multidrug-resistant/extensively drug-resistant Gram-negative respiratory infections: another pandemic.
Antibiotic resistance is recognised as a global threat to human health by national healthcare agencies, governments and medical societies, as well as the World Health Organization. Increasing resistance to available antimicrobial agents is of concern for bacterial, fungal, viral and parasitic pathogens. One of the greatest concerns is the continuing escalation of antimicrobial resistance among Gram-negative bacteria resulting in the endemic presence of multidrug-resistant (MDR) and extremely drug-resistant (XDR) pathogens. This concern is heightened by the identification of such MDR/XDR Gram-negative bacteria in water and food sources, as colonisers of the intestine and other locations in both hospitalised patients and individuals in the community, and as agents of all types of infections. Pneumonia and other types of respiratory infections are among the most common infections caused by MDR/XDR Gram-negative bacteria and are associated with high rates of mortality. Future concerns are already heightened due to emergence of resistance to all existing antimicrobial agents developed in the past decade to treat MDR/XDR Gram-negative bacteria and a scarcity of novel agents in the developmental pipeline. This clinical scenario increases the likelihood of a future pandemic caused by MDR/XDR Gram-negative bacteria.


Pien Tze Huang Overcomes Multidrug Resistance and Epithelial-Mesenchymal Transition in Human Colorectal Carcinoma Cells via Suppression of TGF-β Pathway.
The traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used as a folk remedy for cancer. To elucidate the mode of action of PZH against cancer, in the present study we used a 5-FU resistant human colorectal carcinoma cell line (HCT-8/5-FU) to evaluate the effects of PZH on multidrug resistance (MDR) and epithelial-mesenchymal transition (EMT) as well as the activation of TGF-β pathway. We found that PZH dose-dependently inhibited the viability of HCT-8/5-FU cells which were insensitive to treatment of 5-FU and ADM, demonstrating the ability of PZH to overcome chemoresistance. Furthermore, PZH increased the intercellular accumulation of Rhodamine-123 and downregulated the expression of ABCG2 in HCT-8/5-FU cells. In addition, drug resistance induced the process of EMT in HCT-8 cells as evidenced by EMT-related morphological changes and alteration in the expression of EMT-regulatory factors, which however was neutralized by PZH treatment. Moreover, PZH inhibited MDR/EMT-enhanced migration and invasion capabilities of HCT-8 cells in a dose-dependent manner and suppressed MDR-induced activation of TGF-β signaling in HCT-8/5-FU cells. Taken together, our study suggests that PZH can effectively overcome MDR and inhibit EMT in human colorectal carcinoma cells via suppression of the TGF-β pathway.


Aspartic acid at position 57 of the HLA-DQ beta chain in insulin-dependent diabetes mellitus: an association with one DRw9-DQw9 subtype in the Chinese population.
Eighteen unrelated Chinese patients with insulin-dependent diabetes mellitus (IDDM) were analyzed for HLA Class II genes using a variety of molecular biological techniques including restriction fragment length polymorphism (RFLP), polymerase chain reaction with allele-specific oligonucleotides (PCR-ASO) and direct DNA sequencing. The high frequency of DR3/DR4 heterozygotes found in the Chinese with IDDM strengthens the importance of this combination of haplotypes in IDDM susceptibility since it is present in two genetically distant populations--Chinese and Caucasians. The frequency of DRw9, a rare allele in the Caucasian population, is much higher in the Chinese. Moreover, the DQ beta chain linkage of DRw9 was different in IDDM patients compared with control subjects. In contrast with previous results, codon 57 of the DQ beta chain was aspartic acid in DRw9 Chinese IDDM patients. Furthermore, one particular DRw9-DQw9 haplotype may be associated with IDDM susceptibility in the Chinese population.


Prevalence and factors associated with the use of antibiotics in non-bloody diarrhoea in children under 5 years of age in sub-Saharan Africa.
To estimate the prevalence and determine the factors associated with the use of antibiotics in the management of non-bloody diarrhoea in children under 5 years of age in sub-Saharan Africa (SSA). We conducted a meta-analysis of demographic and health survey data sets from 30 countries in SSA. Pooled prevalence estimates were calculated using random effects model. Χ2 tests were employed to determine the factors associated with the antibiotic use. The pooled prevalence of antibiotic use among cases of non-bloody diarrhoea in children under 5 years of age was 23.1% (95% CI 19.5 to 26.7). The use of antibiotics in children with non-bloody diarrhoea in SSA was associated with (p<0.05) the source of care, place of residence, wealth index, maternal education and breastfeeding status. We found an unacceptably high use of antibiotics to treat episodes of non-bloody diarrhoea in children under the age of 5 in SSA.


Item analysis of Halstead's Speech-Sounds Perception Test: quantitative and qualitative analysis of errors.
The pattern and type of errors on the Speech-Sounds Perception Test was examined in a sample of 513 patients referred for neuropsychological evaluation. There was considerable variability in the rate of correct response. Groups of patients with independently documented lesions were compared in regard to number and type of errors. It was found that patients with left-hemisphere lesions made a higher percentage of ending errors and a lower percentage of beginning errors than patients with right-hemisphere or bilateral lesions. These differences were maintained when the total error score was included as a covariate. It was also found that a cutoff score based on the percentage of ending errors correctly classified the unilateral-lesion patients at a statistically significant level. The potential clinical utility of these results were discussed.


Technology-Mediated Communication in Familial Relationships: Moderated-Mediation Models of Isolation and Loneliness.
We examined whether technology-mediated communication has functional or emotional equivalence to face-to-face (FtF) contact in familial relationships, by scrutinizing the effects of phone, text/e-mail, and video contact on isolation and loneliness. We tested whether FtF contact with a relative would mediate the pathway between proximity to family and (i) isolation and (ii) loneliness. We then tested hypotheses that telephone, text/e-mails, and video contact would moderate this mediated pathway. We compared models for younger (<75) and older (≥75) cohorts, expecting to observe moderation effects for text/e-mail and video contact in the younger cohort only. Data were drawn from Wave 2 of CFAS Wales (United Kingdom) study (N = 2,099). Proximity to a relative had a significant indirect effect on isolation and loneliness through the mediating variable FtF contact. Phone and text/e-mail contact moderated the effect of FtF contact on isolation for all samples. None of the technologies moderated the impact of FtF contact on loneliness for the full sample. Telephone contact had a moderating influence on loneliness for the younger cohort only. Video calls had no significant moderation effect. Telephone and text/e-mail contact have functional equivalence to FtF contact in familial relationships. None of the forms of technological communication have emotional equivalence to the "gold standard" of embodied presence. The study demonstrates the importance of theorizing about the pathways to isolation and loneliness to better understand the likelihood of implementing successful interventions using technology-mediated communication within families.


Phase-only hologram generated by a convolutional neural network trained using low-frequency mixed noise.
A phase-only hologram generated through the convolution neutral network (CNN) which is trained by the low-frequency mixed noise (LFMN) is proposed. Compared with CNN based computer-generated holograms, the proposed training dataset named LFMN includes different kinds of noise images after low-frequency processing. This dataset was used to replace the real images used in the conventional hologram to train CNN in a simple and flexible approach. The results revealed that the proposed method could generate a hologram of 2160 × 3840 pixels at a speed of 0.094 s/frame on the DIV2K valid dataset, and the average peak signal-to-noise ratio of the reconstruction was approximately 29.2 dB. The results of optical experiments validated the theoretical prediction. The reconstructed images obtained using the proposed method exhibited higher quality than those obtained using the conventional methods. Furthermore, the proposed method considerably mitigated artifacts of the reconstructed images.


Effects of osmotic dehydration treatment on volatile compound (Myristicin) content and antioxidants property of nutmeg (Myristica fragrans) pericarp.
The effects of osmotic dehydration (OD) treatment on volatile compound (myristicin) content and the antioxidant capacity of nutmeg (Myristica fragrans) were studied. Fresh nutmeg pericarps were treated with varying sugar concentrations (60, 70, 80%) with different soaking periods at ambient temperature. The OD-treated nutmeg extracts were analyzed for myristicin content via Gas Chromatography Flame Ionization Detector. The phenolic content and antioxidant capacity were analyzed using Follin-Ciocalteu and a free radical scavenging activity assay. The myristicin content was highest (1.69 mg/100 mg) at 80% sugar concentration after 3 h of soaking. Total phenolic content and free radical scavenging activity were highest at 3 h of 80% sugar solution treatment with values of 76.90% and 1.75 mg GAE/g, respectively. OD treatment at varying sugar concentration levels and durations affects the production of myristicin and antioxidant composition. Treatment of nutmeg with OD at 80% sugar concentration for 3 h is preferable, resulting in an acceptable level of myristicin and high antioxidants.


Manual vacuum aspirator: a safe and effective tool for decentralization of post miscarriage care.
To compare the efficacy and safety of Manual Vacuum Aspiration (MVA) performed as outpatient versus inpatient procedure in terms of success rate, blood loss, hospital stay and procedure related complications. A quasi-experimental study. Maternal and Child Health Centre (MCHC), Unit-I, Pakistan Institute of Medical Sciences (PIMS), Islamabad, from December 2009 to December 2010. Cases with early pregnancy failure (incomplete, missed and an embryonic) at gestational age less than 12 weeks were allocated to MVA as outpatient or elective procedure performed in the operation theatre. Studied variables were noted as above. A total of 177 women were eligible for study, out of whom 78 underwent MVA as outpatient procedure and 99 as indoor procedure. The baseline characteristics were comparable in both groups except significantly high multipara in the indoor group. Complete evacuation was achieved in 96.1% in outpatient vs. 79.7% in indoor cases (p=0.001). Outpatient group had a shorter hospital stay (median 3 hours, IQR-1 vs. 10 hours, IQR-4; p < 0.001), though the median hospital cost was less but statistically insignificant (Rs. 800, IQR-25 vs. 735, IQR-1265; p=0.728). Blood loss was comparable in both groups (median 60 ml, IQR-20 vs. 60 ml-IQR-30; p=0.350). There were two uterine perforations noted in the inpatient group (2.02%) vs. none in outpatient setting. Outpatient based manual vacuum aspiration is a safe and effective tool for management of early pregnancy loss. A decentralized approach proved useful in reducing hospital stay.


Tenebrio molitor PGRP-LE Plays a Critical Role in Gut Antimicrobial Peptide Production in Response to Escherichia coli.
Invading pathogens are recognized by peptidoglycan recognition proteins (PGRPs) that induce translocation of NF-κB transcription proteins and expression of robust antimicrobial peptides (AMPs). Tenebrio molitor PGRP-LE (TmPGRP-LE) has been previously identified as a key sensor of Listeria monocytogenes infection. Here, we present that TmPGRP-LE is highly expressed in the gut of T. molitor larvae and 5-day-old adults in the absence of microbial infection. In response to Escherichia coli and Candida albicans infections, TmPGRP-LE mRNA levels are significantly upregulated in both the fat body and gut. Silencing of TmPGRP-LE by RNAi rendered T. molitor significantly more susceptible to challenge by E. coli infection and, to a lesser extent, Staphylococcus aureus and C. albicans infections. Reduction of TmPGRP-LE levels in the larval gut resulted in downregulation of eight AMP genes following exposure to E. coli, S. aureus, and C. albicans. However, the transcriptional levels of AMPs more rapidly reached a higher level in the dsEGFP-treated larval gut after challenge with E. coli, which may suggest that AMPs induction were more sensitive to E. coli than S. aureus and C. albicans. In addition, TmPGRP-LE RNAi following E. coli and C. albicans challenges had notable effects on TmRelish, TmDorsal X1 isoform (TmDorX1), and TmDorX2 expression level in the fat body and gut. Taken together, TmPGRP-LE acts as an important gut microbial sensor that induces AMPs via Imd activation in response to E. coli, whereas involvement of TmPGRP-LE in AMPs synthesize is barely perceptible in the hemocytes and fat body.


Enzymatic Self-Assembly Confers Exceptionally Strong Synergism with NF-κB Targeting for Selective Necroptosis of Cancer Cells.
As a promising molecular process for selectively inhibiting cancer cells without inducing acquired drug resistance, enzyme-instructed self-assembly (EISA) usually requires relatively high dosages. Despite its discovery 30 years ago, the translation of the knowledge about NF-κB signaling into clinic remains complicated due to the broad roles of NF-κB in cellular regulation. Here we show that integrating EISA and NF-κB targeting boosts the efficacy of EISA over an order of magnitude without compromising selectivity against cancer cells. That is, in situ enzymatic self-assembly of a tetrapeptide results in nanofibers, which hardly affect cell viability, but lead to inductive expression of tumor necrosis factor receptor 2 (TNFR2) and decreased expression of three key proteins at the upstream of NF-κB pathway in the cancer cells. Adding the inhibitors targeting NF-κB further decreases the expressions of those upstream proteins, which turns the otherwise innocuous nanofibers to being lethal to the cancer cells, likely causing necroptosis. As the first case of using supramolecular processes to enable synthetic lethality, this work illustrates a versatile approach to translate key regulatory circuits into promising therapeutic targets.


Problems in the construction of a small diameter graft.
Hyperplasia at the graft host artery anastomosis is probably the commonest cause of intermediate and late failure and is seen most frequently and most severely in small diameter grafts. An arterial substitute with an internal diameter of less than 4 mm which can maintain patency in a flow rate not in excess of 50 cc per minute is the sought after graft. Contributing to the formation of this hyperplastic lesion are activated platelets, activated monocytes, dedifferentiated endothelial cells, and probably other elements which under these circumstances of activation produce smooth muscle cell and other mitogens. A multidisciplinary approach utilizing the information from polymer chemistry, fluid engineering, cell biology, and the essentials of thrombosis is required.


Immunohistochemical staining of pancreatic cancer with CA19-9, KM01, unabsorbed CEA, and absorbed CEA. A comparison with normal pancreas and chronic pancreatitis.
In order to test the effectiveness of CA19-9, KM01, unabsorbed CEA (carcinoembryonic antigen) and absorbed CEA by immunoperoxidase staining, we evaluated the staining distribution, intensity, and cellular localization in pancreatic cancer. The results were then compared with those of normal pancreas and chronic pancreatitis. The positive staining rate of the pancreatic cancer with any of the four tumor markers was higher than that of the normal pancreas. However, all markers except absorbed CEA showed a higher positive staining rate for chronic pancreatitis than for pancreatic cancer. There was no stromal type in normal pancreatic or chronic pancreatitis tissues with any of the four tumor markers. Our findings, therefore, indicate that absorbed CEA is useful in differentiating pancreatic cancer from normal pancreatic tissues. It is not useful in distinguishing chronic pancreatitis, however, unless a specific staining pattern is observed.


Multiple splenic infarctions in a dog with immune-mediated hemolytic anemia: therapeutic implications.
Splenic infarction (SI) is a rare clinical entity seldom encountered in veterinary medicine. Its most frequent causes include thromboembolic status, splenomegaly, and cardiac disease. Although thrombotic elements from the circulation provide the most common context for thromboembolic SIs, immune-mediated hemolytic anemia (IMHA) has not been reported as an underlying disease in canine SI. A 2-year-old, female spayed Dachshund, was referred with vomiting, hematochezia, and brown colored urine over the preceding 4 days. Physical examination revealed abnormalities including generalized weakness, jaundice, and splenomegaly; blood work showed pancytopenia and hyperbilirubinemia. Erythrocyte agglutination, polychromasia, and spherocytes on a peripheral blood smear were observed and IMHA concurrent with thrombocytopenia was diagnosed. Although erythrocyte agglutination and leukopenia disappeared after treatment, anemia and thrombocytopenia were unresponsive to oral immunosuppressive drugs and repeated transfusions. Further abdominal ultrasound identified an occlusive splenic vein thrombus. Splenic histopathology found marked multifocal to coalescing necrosis, and hemorrhage consistent with multiple SI. Symptoms resolved following splenectomy combined with 1 month of immunosuppressive medication, and the dog was healthy on follow-up evaluation after 2 years. Immune-mediated hemolytic anemia is an incompletely characterized cause of SI. This report establishes a potential and novel causal role for IMHA in canine SI. We believe it to be the first case report of SI in a dog with refractory IMHA and thrombocytopenia, successfully managed by splenectomy combined with short-term immunosuppressive therapy.


Research progress in the application of time in range: more than a percentage.
Glucose monitoring is an important part of medical care in diabetes mellitus, which not only helps assess glycemic control and treatment safety, but also assists with treatment adjustment. With the development of continuous glucose monitoring (CGM), the use of CGM has increased rapidly. With the wealth of glucose data produced by CGM, new metrics are greatly needed to optimally evaluate glucose status and guide the treatment. One of the parameters that CGM provides, time in range (TIR), has been recognized as a key metric by the international consensus. Before the adoption of TIR in clinical practice, several issues including the minimum length of CGM use, the setting of the target range, and individualized TIR goals are summarized. Additionally, we discussed the mounting evidence supporting the association between TIR and diabetes-related outcomes. As a novel glucose metric, it is of interest to compare TIR with other conventional glucose markers such as glycated hemoglobin A1c. It is anticipated that the use of TIR may provide further information on the quality of glucose control and lead to improved diabetes management.


Blood pressure lowering, fibrinolysis enhancing and antioxidant activities of cardamom (Elettaria cardamomum).
Elettaria cardamomum (L.) Maton. (Small cardamom) fruit powder was evaluated for its antihypertensive potential and its effect on some of the cardiovascular risk factors in individuals with stage 1 hypertension. Twenty, newly diagnosed individuals with primary hypertension of stage 1 were administered 3 g of cardamom powder in two divided doses for 12 weeks. Blood pressure was recorded initially and at 4 weeks interval for 3 months. Blood samples were also collected initially and at 4 weeks interval for estimation of lipid profile, fibrinogen and fibrinolysis. Total antioxidant status, however, was assessed initially and at the end of the study. Administration of 3 g cardamom powder significantly (p<0.001) decreased systolic, diastolic and mean blood pressure and significantly (p<0.05) increased fibrinolytic activity at the end of 12th week. Total antioxidant status was also significantly (p<0.05) increased by 90% at the end of 3 months. However, fibrinogen and lipid levels were not significantly altered. All study subjects experienced a feeling of well being without any side-effects. Thus, the present study demonstrates that small cardamom effectively reduces blood pressure, enhances fibrinolysis and improves antioxidant status, without significantly altering blood lipids and fibrinogen levels in stage 1 hypertensive individuals.


Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction?
Thrombolytic therapy significantly improves the natural history of acute myocardial infarction, but recent data suggest that current reperfusion strategies have yet to realize the maximum potential for reduction of mortality and salvage of ventricular function. Coronary patency rates as high as 85% assessed by angiography 90 minutes after initiation of treatment greatly overestimate the efficacy of thrombolytic regimens, as this conventional angiographic "snapshot" view does not satisfactorily reflect the dynamic processes of coronary artery recanalization and reocclusion or the adequacy of myocardial perfusion. In fact, only the unusual patient appears to achieve optimal reperfusion for acute myocardial infarction, with a substantial deterioration of benefit in many patients due to insufficiently early or rapid recanalization, incomplete patency with TIMI grade 2 flow or critical residual coronary stenoses, absence of myocardial tissue reflow despite epicardial artery patency, intermittent coronary patency, subsequent reocclusion, or reperfusion injury. Recently developed techniques to critically assess the quality of reperfusion, coupled with the introduction of novel pharmacological agents and an improved understanding of the roles and mechanisms of existing thrombolytic and adjunctive drugs, have provided the opportunity to overcome many of the present limitations of reperfusion therapy. Emerging strategies to achieve optimal reperfusion are directed at enhancement of the velocity and quality of thrombolysis, amelioration of the adverse effects of reperfusion, and use of alternative pathways to myocardial salvage.


Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse.
Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the COOH-terminal amidation of peptide hormones. We previously had found high expression of PAM in several regions of the developing rodent. To determine the function of PAM during mouse embryogenesis, we produced a null mutant of the PAM gene. Homozygous mutants die in utero between e14.5 and e15.5 with severe edema that is likely due to cardiovascular deficits. These defects include thinning of the aorta and carotid arteries and are very similar to those of the recently characterized adrenomedullin (AM) gene KO despite the presence of elevated immunoreactive AM in PAM KO embryos. No peptide amidation activity was detected in PAM mutant embryos, and there was no moderation of the AM-like phenotype that could be expected if any alternative peptide amidation mechanism exists in the mouse. Despite the proposed contribution of amidated peptides to neuronal cell proliferation, no alteration in neuroblast proliferation was observed in homozygous mutant embryos prior to lethality. Mice heterozygous for the mutant PAM allele develop normally and express wildtype levels of several amidated peptides despite having one half the wildtype levels of PAM activity and PAM protein. Nonetheless, both an increase in adiposity and a mild glucose intolerance developed in aged (>10 months) heterozygous mice compared to littermate controls. Ablation of PAM thus demonstrates an essential function for this gene during mouse development, while alterations in PAM activity in the adult may underlie more subtle physiologic effects.


Rapid optical μ-printing of polymer top-lensed microlens array.
Microlenses have wide applications for light beam focusing or shaping in micro-optical systems. However, it remains challenging for conventional microfabrication methods to rapidly fabricate arrays of microlenses with complex profiles like lens-on-lens structures. In this paper, we present the rapid fabrication of polymer microlenses with lens-on-lens structures by using a digital optical μ-printing technology. An improved dynamic optical exposure method is developed to directly and precisely fabricate polymer top-lensed microlenses (TLMLs). Arrays of TLMLs with either elongated focal depth or two separate foci have been numerically investigated and experimentally demonstrated.


E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study.
E7777, a recombinant cytotoxic fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2, shares an amino acid sequence with denileukin diftitox but has improved purity and an increased percentage of active protein monomer species. A phase I study was carried out to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma. E7777 (6, 12, and expanded 9 μg/kg/day) was given to 13 patients by i.v. infusion on five consecutive days per 21-day cycle. Dose-limiting toxicities, including increased alanine aminotransferase, hyponatremia (n = 2), hypokalemia, lymphopenia, fatigue, hypoalbuminemia, rash, and increased lipase (n = 1), were observed in all three patients in the 12 μg/kg/day cohort, whereas two of six patients in the 9 μg/kg/day cohort showed decreased appetite or fatigue. The maximum tolerated and recommended dose of E7777 was 9 μg/kg/day for five consecutive days per 21-day cycle. The objective response rate was 38% (5/13) and did not appear to depend on tumor expression of CD25. E7777 was well tolerated, assuming careful management of adverse events during treatment, and preliminary but clinically meaningful antitumor activity was observed. Subsequent studies of E7777 for T-cell lymphomas are warranted. This study was registered with www.ClinicalTrials.gov (NCT1401530).


[Alterations of expression level of RASSFIA gene in primary epithelial tumors of various locations].
Tumor-suppressor activity was established for RASSF1A gene by in vitro and in vivo including studies of knock-out mutated mice cells. Data on methylation of promoter region and expression decrease revealed mainly in cancer cell lines were reported. Here, analysis of RASSF1A mRNA quantity was performed for the first time in primary epithelial malignant tumors of five various locations from 130 patients by semi-quantitative RT-PCR. Representative sets of kidney, lung and breast carcinomas samples were studied. Preliminary data for RASSF1A expression in ovarian and colorectal carcinomas are also reported. Our system studies showed unexpected expression profiles, namely mRNA level increase more frequently (2-7 times) than decrease in renal, breast, ovarian, and colorectal carcinomas. Increasing RASSF1A mRNA level was revealed significantly more frequently in renal cell carcinoma (24/38, 63% vs. 8/38, 21%, P = 0.0004, by Fisher exact test) and ovarian carcinomas (8/13, 62% vs. 2/13, 15%, P = 0.0114). Only in non-small cell lung cancer decreasing and increasing of RASSF1A expression were observed with equal frequency (16/38, 42%). Noteworthy, for early clinical stages prevalence of increasing expression both in squamous cell lung cancer and in adenocarcinoma was revealed, and for advanced clinical stages evident prevalence of decreasing RASSF1A expression was established. Cases with increasing expression both in early and advanced stages of clear cell renal cell carcinoma were in prevalence, in advanced stages it was proved significantly (P = 0.0094). These data suggested that RASSF1A expression alterations were tumor specific. Mentioned above regularity could point onto ambivalent RASSF1A functions in tumors--a tumor-suppressor gene and a proto-oncogene as well.


3D characterization of pores in the cortical bone of human femur in the elderly at different locations as determined by synchrotron micro-computed tomography images.
Diaphysis, inferior, and lateral superior regions of the femoral neck are subjected to diverse mechanical loads. Using micro-CT based on synchrotron radiation, three-dimensional morphology and connectivity of the pore network are location dependent, underlying different remodeling mechanisms. The three-dimensional (3D) morphology and connectivity of the pore network at various locations in human femurs subjected to diverse mechanical loads were assessed using micro-CT based on synchrotron radiation. The cortex from 20 human femurs (mean age, 78.3 ± 12.4 years) was taken from the diaphysis (D), the inferior (IN), and the lateral superior (LS) regions of the femoral neck. The voxel size of the 3D reconstructed image was 7.5 μm. Cortical thickness and pore volume/tissue volume (Po.V/TV), pore diameter (Po.Dm) and spacing (Po.Sp) were determined. The pore surface/pore volume ratio (Po.S/Po.V), the number of pores (Po.N), the degrees of anisotropy (DA), and the connectivity density (ConnD), the degree of mineralization (DMB) were also determined. The characteristics of the pore network in femoral cortical bone were found to be location dependent. There was greater porosity, Po.Dm, and Po.N, and more large (180-270 μm), extra-large (270-360 μm) and giant pores (>360 μm) in the LS compared to the IN and D. The difference in porosity in between the periosteal and endosteal layers was mostly due to an increase of Po.Dm rather than Po.N. There was a lower DMB of bone in the LS, which is consistent with a higher remodeling rate. The results provide evidence for large variations in the structure of the internal pore network in cortical bone. These variations could involve different underlying remodeling mechanisms.


Group I introns are inherited through common ancestry in the nuclear-encoded rRNA of Zygnematales (Charophyceae).
Group I introns are found in organellar genomes, in the genomes of eubacteria and phages, and in nuclear-encoded rRNAs. The origin and distribution of nuclear-encoded rRNA group I introns are not understood. To elucidate their evolutionary relationships, we analyzed diverse nuclear-encoded small-subunit rRNA group I introns including nine sequences from the green-algal order Zygnematales (Charophyceae). Phylogenetic analyses of group I introns and rRNA coding regions suggest that lateral transfers have occurred in the evolutionary history of group I introns and that, after transfer, some of these elements may form stable components of the host-cell nuclear genomes. The Zygnematales introns, which share a common insertion site (position 1506 relative to the Escherichia coli small-subunit rRNA), form one subfamily of group I introns that has, after its origin, been inherited through common ancestry. Since the first Zygnematales appear in the middle Devonian within the fossil record, the "1506" group I intron presumably has been a stable component of the Zygnematales small-subunit rRNA coding region for 350-400 million years.


The origin of muscle fasciculations and cramps.
The anatomic site of origin of muscle fasciculations and cramps has been debated for many years. Many authors have argued for a central origin of the abnormal discharges in the anterior horn cells. However, most of the evidence favors a very distal origin in the intramuscular motor nerve terminals. The factors giving rise to these discharges are not well understood. Fasciculations may be related to chemical excitation of motor nerve terminals, whereas cramps may result from mechanical excitation of motor nerve terminals during muscle shortening.


25 Hydroxyvitamin D Levels are Negatively and Independently Associated with Fat Mass in a Cohort of Healthy Overweight and Obese Subjects.
Obesity is associated with lower serum vitamin D (25(OH)D) levels through several mechanisms. The aim of the study was to examine the possibility of a negative association between fat mass and 25(OH)D levels in a cohort of otherwise healthy overweight and obese subjects, independently of age, sex, blood pressure levels and anthropometric and metabolic parameters. 147 overweight and obese subjects (106 women and 41 men), aged between 18 and 69 years, were enrolled into the study. All of them did not show any clinically evident metabolic or chronic diseases (i.e. hypertension, diabetes mellitus, renal failure, etc.) and did not use any kind of drug. Serum fasting levels of 25(OH)D, insulin, glucose, uric acid and lipids (triglycerides, total, HDL and LDL cholesterol) were measured. The season in which the blood samples were collected was autumn. Insulin resistance was assessed by using the Homeostasis Model Assessment (HOMA-IR). Body composition parameters (Fat Mass [FM], Fat Free Mass [FFM], body cell mass [BCM], Total Body Water [TBW]) were measured by electrical Bioimpedance Analysis (BIA). Lastly, demographic, anthropometric and clinical parameters (age, Body Mass Index [BMI], Waist Circumference [WC], Systolic (SBP) and Diastolic (DBP) blood pressure) were also assessed. 25(OH)D levels were significantly and negatively correlated with BMI (P <0.001), WC (P <0.01), DBP (P <0.05), insulin (P <0.001), HOMA-IR (P <0.01), triglycerides (P <0.01), and fat mass (P <0.001). A multivariate regression analysis was performed by considering 25(OH)D levels as the dependent variable and sex, waist circumference, fat mass, DBP, triglycerides, and insulin (or HOMAIR) as the independent ones, and 25(OH)D levels maintained a significant and independent relationship only with fat mass (negative) (P <0.01). This study clearly shows that 25(OH)D circulating levels are progressively lower with the increase of fat mass, independently of sex, body fat distribution, blood pressure and insulin and metabolic parameters. These data strongly show that adipose tissue accumulation per se is absolutely the main factor responsible factor for lower 25(OH)D levels in obese subjects, possibly through sequestration of fat soluble 25(OH)D in fat mass.


[Radiation therapy of cervix cancer with special reference to radiation effects upon the intestine (author's transl)].
The evaluation of the therapeutical preference of succession in the treatment of the uterine cervix, the radiation therapy today presents a special importance. This is established upon two facts; that is, the age-distribution and the incidence of the inoperability of the cases (one patient in every three cases of the cervical cancer is over 60 years of age; nearly 60% of the cases are in an inoperable stage). Although in our department only partially or completely inoperable cases went through a radiation therapy, 757 ( = 47,7% out of 1586 cases) achieved to survive for more than five years. At a discussion concerning the intestinal complications which occur due to irradiation, it has been proved, that 18,6% show reversible reactions. The permanent reactions like recto-vaginal-fistula etc. were only seen in 2,4%. It is interesting to note, that the patients subjected to intestinal complications were seen by advanced cases (stage III: 65,1%) and 69% of them were over 60 years of age. Irradiation consequences are by younger patients and by cases with a possible local operability rather rare. At the end, physiopathology and the treatment of the intestinal post-irradiation effects are discussed.


Forms of selenium in vitamin-mineral mixes differentially affect serum prolactin concentration and hepatic glutamine synthetase activity of steers grazing endophyte-infected tall fescue.
The goal of this study was to test the hypothesis that sodium selenite (ISe), SEL-PLEX (OSe), vs. an 1:1 blend (MIX) of ISe and OSe in a basal vitamin-mineral (VM) mix would differentially affect metabolic parameters and performance of growing steers grazing toxic endophyte-infected tall fescue mixed forage (E+) pasture. Predominately-Angus steers (BW = 183 ± 34 kg) were randomly selected from herds of fall-calving cows grazing E+ pasture and consuming VM mixes that contained 35 ppm Se as ISe, OSe, and MIX forms. Steers were weaned, depleted of Se for 98 d, and subjected to summer-long common grazing of an E+ pasture (0.51 ppm total ergovaline per ergovalinine; 10.1 ha). Steers were assigned (n = 8 per treatment) to the same Se-form treatments upon which they were raised. Selenium treatments were administered by daily top-dressing 85 g of VM mix onto 0.23 kg soyhulls, using in-pasture Calan gates. The PROC MIXED procedure of SAS was used to assess effect of Se-form treatments on whole blood Se (ng/mL) and serum prolactin (ng/mL) at day 0, 22, 43, 64, and 86, and caudal arterial area (mm2) at day -7, 43, and 86. The effect of Se treatment on ADG (day 86), and liver glutamine synthetase (GS) mRNA, protein, and activity (nmol/mg wet tissue/min) were assessed using the PROC GLM procedure of SAS. Fisher's protected LSD procedure was used to separate treatment means. Whole blood Se increased (P < 0.01) for all treatments from day 0 to 22 and then did not change (P ≥ 0.17), and was greater (P ≤ 0.04) for MIX and OSe steers. Serum prolactin decreased (P < 0.01) over time and was greater (P < 0.05) for MIX and OSe steers. Liver GS mRNA content was 66% and 59% greater (P < 0.05) in MIX and OSe steers, respectively, than ISe steers. Liver GS protein content in MIX steers was 94% more (P < 0.01) than ISe steers. Moreover, MIX and OSe steers had 99% and 55% more (P ≤ 0.01) liver GS activity, respectively, than ISe steers. ADG was not affected (P = 0.36) by Se treatments. We conclude that consumption of 3 mg Se/d as OSe or MIX forms of Se in VM mixes increased 1) whole blood Se content, an indicator of greater whole-body Se assimilation; 2) serum prolactin, the reduction of which is a hallmark of fescue toxicosis; and 3) hepatic GS activity, indicating greater hepatic assimilation of acinar ammonia. However, 4) these positive effects on metabolic parameters were not accompanied by increased growth performance.


A dual role of the Wnt signaling pathway during aging in Caenorhabditis elegans.
Wnt signaling is a major and highly conserved developmental pathway that guides many important events during embryonic and larval development. In adulthood, misregulation of Wnt signaling has been implicated in tumorigenesis and various age-related diseases. These effects occur through highly complicated cell-to-cell interactions mediated by multiple Wnt-secreted proteins. While they share a high degree of sequence similarity, their function is highly diversified. Although the role of Wnt ligands during development is well studied, very little is known about the possible actions of Wnt signaling in natural aging. In this study, Caenorhabditis elegans serves, for the first time, as a model system to determine the role of Wnt ligands in aging. Caenorhabditis elegans has five Wnt proteins, mom-2, egl-20, lin-44, cwn-1, and cwn-2. We show that all five Wnt ligands are expressed and active past the development stages. The ligand mom-2/Wnt plays a major detrimental role in longevity, whereas the function of lin-44/Wnt is beneficial for long life. Interestingly, no evidence was found for Wnt signaling being involved in cellular or oxidative stress responses during aging. Our results suggest that Wnt signaling regulates aging-intrinsic genetic pathways, opening a new research direction on the role of Wnt signaling in aging and age-related diseases.


Genetic features of antidepressant induced mania and hypo-mania in bipolar disorder.
The present study investigated possible genetic association between some polymorphisms possibly involved in antidepressant response and the occurrence of manic or hypo-manic switches during antidepressant treatment. We retrospectively examined 169 individuals with a diagnosis of bipolar disorder (BP) type I ( n=103) and II ( n=66), who presented at least one sudden manic or hypo-manic episode (according to DSM IV criteria) during antidepressant therapy, that occurred within a period of 3 weeks from the beginning of the treatment and without any interposed period of well being ("manic switch"). They were compared with a sex, age, and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects, who never showed switches. We then randomly selected from the whole sample ("switched" and "not switched") a sub-sample of patients not under mood stabiliser treatment at the time of the index episode (65 "switched" and 117 "not switched") and compared them with a sex, age and ethnicity matched group of 133 subjects, randomly selected from our pool of major depressed patients, who did not present manic switches. The functional polymorphism in the upstream regulatory region of the serotonin transporter (SERTPR), tryptophan hydroxylase (TPH), G-protein beta 3 subunit (Gbeta3), monoamine oxidase A (MAO-A), catechol- O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2) and dopamine receptor D4 (DRD4) gene variants were analysed using PCR-based techniques. The distribution of the genetic polymorphisms was not significantly different between switched and not-switched patients ( P>0.006-Bonferroni corrected). Moreover, no significant difference was found between switched and not switched sub-samples and the sample of major depressed subjects. Further studies are required to investigate other possible related genetic variants influencing the timing of manic-depressive cycle.


In-vacuum projection of nanoparticles for on-chip tunneling spectroscopy.
Starting with a discussion of the percolation problem applied to the trapping of conducting nanoparticles between nanometer-spaced electrodes, we show that a good strategy to trap a single nanoparticle between the electrodes is to prepare chips with low coverage of nanoparticles to avoid percolating current paths. To increase the probability of trapping a single nanoparticle, we developed a new method where nanoparticles are projected in-vacuum on the chip, followed by a measure of the tunnel current, in a cycle that is repeated up to a few thousand times until a preset threshold value is reached. A plot of the tunneling current as a function of time allows discriminating between the two possible current paths, i.e., a single nanoparticle trapped between the electrodes or a percolating path across many nanoparticles. We applied the method to prepare chip circuits with single gold nanoparticles, as demonstrated by the observation of Coulomb blockade. Furthermore, we applied the method to trap single magnetite nanoparticles for the study of electric-field-induced switching from insulator to metal in single nanoparticles.