Pharmacokinetics and safety of single intravenous and oral doses of dolasetron mesylate in healthy women.
Twenty-four healthy women received 2.4 mg kg-1 dolasetron mesylate (1.8 mg kg-1 dolasetron base) by a 10 min intravenous administration and by oral administration. Pharmacokinetics of dolasetron and of its active reduced metabolite MDL 74156 were monitored for 48 h in plasma. Urine was collected from 0 to 48 h, blood pressure and heart rate were measured at 0, 0.08, 1, 2, 12, 24, and 36 h, and ECGs were measured at 0, 0.08 (intravenous only), 1, 2, and 36 h after dosing. Dolasetron was widely distributed and rapidly reduced (mean t1/2 = 0.23 h) to MDL 74156 (mean t1/2 = 8.05 and 9.12 h after intravenous and oral administration respectively). MDL 74156 was extensively distributed; between 27 (oral route) and 33% (intravenous route) was eliminated unchanged in urine. Safety assessment showed mild to moderate headache, dizziness, and hot flushes after the intravenous administration and headache, abdominal cramps or pain, and constipation after oral administration. Small and clinically non-significant changes in PR, QRS, and QTc intervals were observed. We conclude that there is no obvious difference in dolasetron pharmacokinetics between healthy women and men and that dolasetron can be used as safely in women as in men.


Midostaurin-induced Sweet syndrome in a patient with FLT3-ITD-positive AML.
Sweet syndrome (SS), also referred as acute febrile neutrophilic dermatosis, is an inflammatory process characterised by the abrupt appearance of erythematous papules or nodules with predominant neutrophilic infiltration in the dermis. Fever and neutrophilia are common presenting features. However, extracellular manifestations, including ocular and musculoskeletal, may occur. SS is divided into three subtypes: classical (or idiopathic), malignancy associated and drug induced. Medication-induced subtype accounts for up to 26% of cases. In recent years, emerging evidence has showed that SS may also occur in neutropenic patients who underwent induction for acute myeloid leukemia (AML). The identification of FMS-like tyrosine kinase 3 (FLT3) gene mutation in approximately 30% of patients with AML has promoted the targeted therapy with FLT3-internal tandem duplication (ITD) inhibitors. Midostaurin, a recently Food and Drug Administration-approved medication for FLT3-ITD-positive AML, was reported once as cause for SS. We report a midostaurin-induced SS with neutropenia in a patient following induction chemotherapy of AML.


[Diagnostic progress in spinal muscular atrophy].
Progress of diagnostic methods in recognition of spinal muscular atrophy (SMA), the most common degenerative disease of the nervous system in children has been observed in the last years. It has been proved, that all types of SMA, phenotypically variable Werdnig-Hoffman and Kugelberg-Welander diseases are results of homozygous absence of the telomeric copy of SMN gene located on the long arm of chromosome 5; this discovery was very important for mechanisms investigation. Based on the evolution of SMA diagnostic, the results of diagnostic in 18 children hospitalized in the Department of Pediatric Neurology Collegium Medicum of Jagiellonian University are presented. In the years 1995-1997 the basic procedure for confirming the diagnosis of SMA has been muscle biopsy. Molecular studies introduced in 1998 were a chance for confirmation not only classical, but other than three main clinical SMA phenotypes. The molecular analysis performed in children allowed to confirm diagnosis in 7 patients, showing in 5 cases absence of exon 7 of the SMN gene and in 2 children detecting deletions involving SMN and NAIP genes. In the less typical cases the results of molecular analysis were less definite.


Kinetic control of Ca(II) signaling: tuning the ion dissociation rates of EF-hand Ca(II) binding sites.
EF-hand Ca(II) binding sites share a conserved architecture and are prevalent in Ca(II) signaling pathways. The ion binding kinetics of these sites are carefully tuned to provide the physiologically appropriate activation and inactivation time scales. Here we examine kinetic tuning by the side chain at the ninth position of the EF-loop. A model is proposed in which both the size and charge of the side chain contribute to kinetic tuning. To test this model, the ninth loop position of the EF-hand-like site in the Escherichia coli D-galactose binding protein has been engineered and the Tb(III) dissociation kinetics of the resulting sites have been analyzed. Substitutions at this position are observed to generate up to 10(4)-fold changes in Tb(III) dissociation rates, with little effect on Tb(III) affinity. Furthermore, the observed pattern of rate changes confirm the model's predictions; long side chains at the ninth loop position yield slow dissociation kinetics as predicted for a steric block, whereas acidic side chains yield slow dissociation kinetics as expected for an electrostatic barrier.


One-year surgical outcomes of the PreserFlo MicroShunt in glaucoma: a multicentre analysis.
To evaluate the efficacy and safety of the PreserFlo MicroShunt glaucoma device in a multicentre cohort study. All consecutive patients who received the microshunt with mitomycin-C (MMC) 0.4 mg/mL from May 2019 to September 2020 in three UK tertiary centres. Primary outcome at 1 year was a complete success, with failure defined as intraocular pressure (IOP) >21 mmHg or <20% reduction, IOP≤5 mmHg with any decreased vision on two consecutive visits, reoperation or loss of light perception vision. Secondary outcomes were IOP, best-corrected visual acuity, medications, complications, interventions and reoperations. We also performed subgroup analyses for severe glaucoma and assessed risk factors for failure. 104 eyes had 1-year follow-up. Complete and qualified success at 1 year were achieved in 51.9% (N=54) and 16.4% (N=17), respectively, and failure occurred in 31.7% (N=33). There was a significant reduction in IOP (mmHg) from preoperatively (23.4±0.8, N=104) to 12 months (14.7±0.6, N=104) (p<0.0001). Antiglaucoma medications also decreased from preoperatively (3.4±0.1, N=104) to 12 months (0.7±0.1, N=104) (p<0.0001). Multivariate analyses showed an association between higher mean deviation and failure (HR 1.055, 95% CI 1.0075 to 1.11, p=0.0227). Complications were hypotony (19.2%; N=20), choroidal detachments (10.6%; N=11), hyphaema (5.8%; N=6) and bleb leak (5.8%; N=6). Needling and 5-fluorouracil injections were performed in 12.5% (N=13) and 33.7% (N=35), respectively, and 11.5% (N=12) required revision surgery. The PreserFlo MicroShunt with MMC 0.4 mg/mL showed an overall success rate of 68.3% at 1 year, and led to significant IOP and medication reduction with a low rate of adverse effects.


[Which hormone determinations are necessary in the initial assessment of erectile dysfunction?].
The assessment of an erectile dysfunction (ED) includes the history, a clinical examination and blood tests. There is some confusion about which basic hormonal tests are needed at the beginning of clinical evaluation. We feel that with the results from our patients we could help to answer this question. From 1 January 1990 until the December 31 1993 we evaluated 1134 patients for ED. Those who favoured a surgical correction of their ED were fully evaluated by nocturnal penile tumescence testing, penile arteriography, intracavernosal injection of vasoactive agents and dynamic pharmaco-cavernosometry. The results from these tests were correlated with luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and prolactin. 183 (16.1%) of our patients with a mean age of 45 +/- 14 were fully evaluated. From these patients 76 were excluded because their ED was posttraumatic, undoubtedly psychogenic or could not be proven by the tests mentioned above. From the 107 patients finally included in this study, 90 had normal endocrine parameters. 17 patients had low testosterone. 14 of these patients had otherwise completely normal hormonal tests without evidence of secondary hypogonadism. Three patients had their low testosterone levels confirmed by repeated measurements. In addition, prolactin was significantly increased, and FSH and LH were near or below the lower reference value. When evaluating patients for the first time because of an erectile dysfunction, the measurement of testosterone as a single endocrine test is adequate. If testosterone is low, repeated measurements, combined with LH, FSH and prolactin, will identify patients with an ED due to an endocrine disease.


Influence of water quality and associated contaminants on survival and growth of the endangered Cape Fear shiner (Notropis mekistocholas).
The Cape Fear shiner (Notropis mekistocholas) is a recently described cyprinid species endemic to the Cape Fear River Basin of North Carolina, USA. Only five populations of the fish remain; thus, it is listed as endangered by the U.S. Government. Determining habitat requirements of the Cape Fear shiner, including water quality and physical habitat, is critical to the survival and future restoration of the species. To assess water quality in the best remaining and in the historical habitats, we conducted a 28-d in situ bioassay with captively propagated Cape Fear shiners. Fish were deployed at 10 sites in three rivers, with three cages per site and 20 fish per cage. Water and sediment samples were collected and analyzed for selected metals and organic contaminants. Passive sampling devices also were deployed at each site and analyzed for organic contaminants at test termination. Fish survival, growth (as measured by an increase in total length), and contaminant accumulation were measured on completion of the bioassay. Survival of caged fish averaged 76% (range, 53-100%) and varied significantly among sites and rivers. Caged fish accumulated quantities of cadmium, mercury, polychlorinated biphenyls, and other persistent contaminants over the test duration and grew significantly at only four sites. No apparent relations were observed between exposure to or accumulation of a specific contaminant and reduced growth or survival of fish among all the sites. However, a generalized hazard assessment showed that certain sites exhibited trends in cumulative contaminant presence with reduced fish survival and growth, thereby enabling the identification of the existing riverine habitat most suitable for reintroduction or population augmentation of this endangered fish.


Factitious food allergy and failure to thrive.
To examine the relationship between parental beliefs about factitious food allergies and failure to thrive in their children. Retrospective case review. Tertiary care referral center in Denver, Colo. A consecutive sample of more than 700 patients referred for evaluation of food allergies was screened for age; negative results to double-blind, placebo-controlled food challenges; and failure to thrive. After identifying two probands, we identified nine additional children with failure to thrive in the context of parents' beliefs in allergic reactions to multiple foods. The results of puncture skin tests conducted for foods suspected of causing allergic reactions were negative for seven (64%) of the 11 children. There were no allergic reactions to open challenges (ie, children, staff, and parents knew which food was being tested). Only two patients reacted during double-blind, placebo-controlled food challenges. One reacted to milk (one of 14 suspected foods) and the other reacted to eggs and milk (two of 15 suspected foods). Parental beliefs about food allergies can lead to dietary restrictions severe enough to cause failure to thrive in their children. Because of the wide-spread belief by parents that children are allergic to food, pediatricians are frequently faced with the question of whether to subject children to food restrictions. Their collaboration with unsubstantiated parental beliefs can have long-term, deleterious consequences.


Dynamic Calibration Enables High-Accuracy Charge Measurements on Individual Ions for Charge Detection Mass Spectrometry.
Charge detection mass spectrometry (CDMS) depends on the measurement of the charge induced on a cylinder by individual ions by means of a charge-sensitive amplifier. For high-accuracy charge measurements, the detection cylinder is embedded in an electrostatic linear ion trap (ELIT), and the ions oscillate back and forth through the cylinder so that multiple measurements are made. To assign the charge state with a low error rate, the charge of each ion must be determined with an uncertainty (root-mean-square deviation) of around 0.2 elementary charges. We show here that high-accuracy charge measurements can be achieved for large ions by dynamic calibration of the charge measurement using an internal standard. The internal standard is generated by irradiating the detection cylinder, by means of a small antenna, with a radiofrequency signal. Using this approach, we have obtained a relative charge uncertainty of around 5 × 10-4, allowing charge-state resolution to be achieved for single ions with up to 500 charges. In another application of this approach, the detection cylinder is irradiated with a signal that counteracts the transients generated when the potentials on the ELIT end-caps are switched to trapping mode. Using this approach, the dead time after switching (during which the signal cannot be analyzed) has been reduced by more than an order of magnitude. With charge-state resolution for ions with up to 500 charges, we were able to calibrate the charges precisely. The results show that the response of the charge-sensitive amplifier with dynamic calibration is linear to within a small fraction of an elementary charge.


Early clinical experience with water-jet dissection (hydro-jet) during nerve-sparing radical retropubic prostatectomy.
Successful preservation of the neuro-vascular bundle (NVB) during anatomical nerve-sparing radical retropubic prostatectomy (NS-RRP) for patients with clinically localized prostate cancer is a great operative challenge. We employed a new dissection method using water-jet technology for the preservation of the NVB. We evaluated intraoperative parameters, complications and early functional results regarding continence and potency. The results were compared to a conventional operative technique. Bilateral NS-RRP was performed by the same urologist in 36 consecutive cases between January and December 2000. Eighteen patients underwent NS-RRP using water-jet dissection (ERBE Helix Hydro-Jet). Eighteen patients underwent a standard NS-RRP. Water-jet dissection was used exclusively for nerve-sparing. We assessed blood loss, operation time, complications and incidence of blood transfusions. Early continence and potency rates were evaluated. Nerve-sparing using the Hydro-Jet technique appeared to be easier, more subtle and faster compared with the standard surgical technique. The exact dissection of the layers allowed a selective dissection and better control of crossing vessels to the prostate. Blood loss was reduced by 36% (p=0.02), no blood transfusion was necessary and the operation time was reduced by 20% (p=0.02). There were no major complications. Continence rates 3 months after RRP were 77.7% in the water jet group and 66.6% in the standard group, and overall potency rates (any grade of erection) were 77.7% and 55.5% respectively. Water-jet dissection is a feasible, safe and efficient technique to facilitate NS-RRP. There is a minimal learning curve with comparable functional results to the conventional procedure. Further improvements in the water-jet application and a longer follow-up might lead to further improvements in continence and potency rates in patients undergoing NS-RRP.


Distinct sequence determinants direct intracellular sorting and modification of a yeast vacuolar protease.
We have mapped a sequence determinant in the vacuolar glycoprotein carboxypeptidase Y (CPY) that directs intracellular sorting of this enzyme. Through the study of hybrid proteins, consisting of amino-terminal segments of CPY fused to the secretory enzyme invertase, we have found that the N-terminal 50 amino acids of CPY are sufficient to direct delivery of a CPY-Inv hybrid protein to the yeast vacuole. Our data suggest that this 50 amino acid segment of CPY contains two distinct functional domains; an N-terminal signal peptide followed by a segment of 30 amino acids that contains the vacuolar sorting signal. Deletion of this putative vacuole sorting signal from an otherwise wild-type CPY protein leads to missorting of CPY. Furthermore, examination of the Asn-linked oligosaccharides present on CPY and CPY-Inv hybrid proteins suggests that an additional determinant in CPY specifies the extent to which these proteins are glycosylated in the Golgi complex.


Noncanonical retinoic acid signaling.
All-trans retinoic acid (atRA) is the principle active metabolite of Vitamin A. atRA is well known to act through nuclear RA receptors (RARs) to regulate gene expression involved in a wide spectrum of biological processes such as growth, differentiation, and function. Recently, novel activities of atRA, independent of the action of RARs, have been increasingly reported and referred to as noncanonical activities. We have determined cellular retinoic acid binding protein 1 (CRABP1) as the primary mediator of the noncanonical activities of atRA. At the molecular level, atRA binds CRABP1, which then immediately acts as an adaptor in the formation of specific signaling scaffolds to rapidly modulate downstream signaling pathways in a cell context-dependent manner. The first established CRABP1-atRA activity is to rapidly dampen the activation of the mitogen-activated protein kinase (MAPK) cascade in response to growth factor stimulation, thereby suppressing cell cycle progression of stem cells. The second established activity is to rapidly reduce Ca2+/calmodulin dependent kinase II (CaMKII) activity in differentiated cells such as cardiomyocyte in response to β-adrenergic stimulation. This chapter describes in vivo and in vitro experimental systems and methodologies appropriate for determining the noncanonical activities of atRA that are mediated by CRABP1 and cell context dependent.


Differences between pulsatile or continuous exposure to melatonin on MCF-7 human breast cancer cell proliferation.
We studied the different in vitro antiproliferative actions of melatonin on MCF-7 cells, depending on whether the cells are exposed to hormone concentrations which remain constant in culture media (Group I, 10(-9) M; Group II, 10(-11) M melatonin) or varying at 12 h intervals, thus simulating a diurnal rhythm: Group III, 12 h in 10(-9) M melatonin/12 h without melatonin (10(-9) M/0 12/12 h); Group IV, 10(-11) M/0 12/12 h; Group V, 10(-9) M/10(-11) M 12/12 h. After 5 days of culture, cell proliferation appeared significantly inhibited in Groups I and III, but not in Groups II and IV. However, the highest antiproliferative effect was obtained by sequential exposure to 10(-9) M/10(-11) M melatonin (Group V), which mimics the physiological rhythm of serum melatonin concentration.


Uptake of pharmaceuticals, hormones and parabens into vegetables grown in soil fertilized with municipal biosolids.
Several recent greenhouse studies have established the potential for uptake of human pharmaceuticals from soil fertilized with municipal biosolids into a variety of crops. In the present study, a field experiment was undertaken to evaluate the uptake of organic micropollutants from soil fertilized with municipal biosolids at a regulated application rate into tomatoes, carrots, potatoes and sweet corn produced under normal farming conditions. The vegetables were grown according to farming practices mandated by the province of Ontario Canada, the key feature being a one-year offset between biosolid application and the harvest of crops for human consumption. Biosolids at application, and crop samples following harvest were analyzed for 118 pharmaceuticals and transformation products, 17 hormones or hormone transformation products, and 6 parabens. Analyte concentrations in the biosolids were consistent with those detected in other surveys. Eight of the 141 analytes were detected in one or two crop replicates at concentrations ranging from 0.33 to 6.25 ng/g dry weight, but no analytes were consistently detected above the detection limit in all triplicate treated plots. Overall, this study suggests that the potential for micropollutant uptake into crops under normal farming conditions is low.


Controversies and certitudes on the upper digestive hemorrhage through rupture of esophageal varices. II. The therapy of portal hypertension and of variceal bleeding.
The present-day therapy of portal hypertension and of variceal bleeding includes new drugs (propranolol, glypressin, somatostatin, a.o.) and methods of hemostasis (variceal sclerotherapy). This second part of a paper concerned with the upper digestive hemorrhage through rupture of the esophageal varices presents the main drug therapies and other various methods used to decrease the portal pressure, to achieve a direct hemostasis in case of active variceal bleeding and to prevent the rebleedings.


Case Report: Cord blood-derived natural killer cells as new potential immunotherapy drug for solid tumor: a case study for endometrial cancer.
Adoptive transfer of natural killer (NK) cells represents a viable treatment method for patients with advanced malignancies. Our team previously developed a simple, safe, and cost-effective method for obtaining high yields of pure and functional NK cells from cord blood (CB) without the need for cell sorting, feeder cells, or multiple cytokines. We present the case of a 52-year-old female patient diagnosed with poorly differentiated stage IVB (T3N2M1) endometrial cancer, who exhibited leukemoid reaction and pretreatment thrombocytosis as paraneoplastic syndromes. The patient received two courses of CB-derived NK (CB-NK) cell immunotherapy between March and September 2022, due to her extremely low NK cell activity. Two available CB units matched at 8/10 HLA with KIR-mismatch were chosen, and we were able to produce NK cells with high yield (>1.0×1010 NK cells), purity (>90%), and function (>80%) from CB without cell sorting, feeder cells, or multiple cytokines. These cells were then adoptively transferred to the patient. No adverse effects or graft-versus-host disease were observed after infusion of CB-NK cells. Our clinical experience supports the efficacy of CB-NK cell treatment in increasing NK cell activity, depleting tumor activity, improving quality of life, and reducing the size of abdominal and pelvic masses with the disappearance of multiple lymph node metastases through the regulation of systemic antitumor immunity. Remarkably, the white blood cell and platelet counts decreased to normal levels after CB-NK cell immunotherapy. This clinical work suggests that CB-NK cell immunotherapy holds promise as a therapeutic approach for endometrial cancer.


Detection of outliers in reference distributions: performance of Horn's algorithm.
Medical laboratory reference data may be contaminated with outliers that should be eliminated before estimation of the reference interval. A statistical test for outliers has been proposed by Paul S. Horn and coworkers (Clin Chem 2001;47:2137-45). The algorithm operates in 2 steps: (a) mathematically transform the original data to approximate a gaussian distribution; and (b) establish detection limits (Tukey fences) based on the central part of the transformed distribution. We studied the specificity of Horn's test algorithm (probability of false detection of outliers), using Monte Carlo computer simulations performed on 13 types of probability distributions covering a wide range of positive and negative skewness. Distributions with 3% of the original observations replaced by random outliers were used to also examine the sensitivity of the test (probability of detection of true outliers). Three data transformations were used: the Box and Cox function (used in the original Horn's test), the Manly exponential function, and the John and Draper modulus function. For many of the probability distributions, the specificity of Horn's algorithm was rather poor compared with the theoretical expectation. The cause for such poor performance was at least partially related to remaining nongaussian kurtosis (peakedness). The sensitivity showed great variation, dependent on both the type of underlying distribution and the location of the outliers (upper and/or lower tail). Although Horn's algorithm undoubtedly is an improvement compared with older methods for outlier detection, reliable statistical identification of outliers in reference data remains a challenge.


[Long-term treatment of venous thromboembolism in patients with cancer].
The treatment with low-molecular-weight heparin (LMWH) is recommended for patients with cancer associated thrombosis (CAT) during the first 6 months; the initial therapeutic dose can be reduced to 60-75 % after one month. The therapy should be reevaluated after 6 month and subsequent therapy using LMWH or warfarin is recommended indefinitely, unless the cancer is resolved or any major contraindications arise. To analyze the usage of various treatment modalities in CAT patients after the initial 6 month period according to the course of cancer. 87 patients with CAT were followed prospectively during the treatment period. The proportion of patients, in whom LMWH was replaced by warfarin during the first 6 months and during the entire follow up, was analyzed in relation to the course of the cancer. The χ2 test and χ2 test with Yates correction were used for the statistical evaluation. The median follow-up was 445 days, mean duration of follow up was 743 days. 6 months after the diagnosis of thrombosis 9/30 (31.0 %) patients with complete remission (CR) of the cancer were treated with warfarin, while only 3/12 (25 %), 0/9 (0 %) and 1/13 (7.7 %) of the patients with partial remission (PR), stable disease (SD) and progression, respectively, were treated with warfarin. Patients with CR and PR were more frequently treated with warfarin than patients with SD or progression (P = 0.02). 13 patients died during the first 6 months, and 8 patients were followed less than 6 months. During the entire follow up, 25/30 (83.3 %) patients with CR switched to warfarin, while only 5/12 (41.7 %), 1/9 (11.1 %) and 1/13 (7.7 %) patients with PR, SD, and progression, respectively, were treated with warfarin. The proportion of patients with CR which switched to warfarin was higher, than the proportion of patients with PR (P = 0.007), with SD (P = 0.0003), and with progression (P < 0.0001). Median time from thrombosis onset to the switch from LMWH to warfarin was 219 days in patients in complete remission after 6 months and was not reached in patients in PR,SD, and progression. The course of malignant disease is important for the choice of appropriate therapy of CAT after the initial period of LMWH therapy. The patients achieving complete remission are more prone to switch from LMWH to warfarin. cancer - low-molecular-weight-heparin - venous thromboembolism - warfarin.


1H NMR-based urinary metabolic profiling reveals changes in nicotinamide pathway intermediates due to postnatal stress model in rat.
The maternal separation protocol in rodents is a widely recognized model of early life stress allowing acute and chronic physiological consequences to be studied. An (1)H NMR-based metabolomic approach was applied to urines to evaluate the systemic metabolic consequences of maternal separation stress in female rats after the beginning of weaning and 4 weeks later when the rats were reaching adulthood. Furthermore, because maternal separation is considered as a model mimicking the inflammatory bowel syndrome, the lactulose/mannitol test was used to evaluate the influence of postnatal maternal separation on gut permeability and mucosal barrier function by (1)H NMR spectroscopy analysis of urine. The results showed no statistical differences in gut permeability due to maternal separation. The application of ANOVA simultaneous component analysis allowed the contributions of physiological adaptations to the animal's development to be separated from the metabolic consequences due to postnatal stress. Systemic metabolic differences in the maternally separated pups were mainly due to the tryptophan/NAD pathway intermediate levels and to the methyladenosine level. Urinary NMR-based metabolic profiling allowed us to disentangle the metabolic adaptive response of the rats to postnatal stress during the animal's growth, highlighting the metabolic changes induced by weaning, gut closure, and maturity.


[The placebo effects of good communication].
- Good communication is important for patients and can elicit placebo effects: true psychobiological effects not attributable to the medical-technical intervention.- It is, however, often unclear which communication behaviours influence specific patient outcomes.- In this article we present insights into the potential effect of specific communication, via specific mechanisms, on specific patient outcomes, including patients' perception of pain.- A recent systematic review and additional literature demonstrate that (a) manipulating patients' expectations, (b) demonstrating empathy, and (c) providing procedural information, might influence patient outcomes.- These placebo effects probably occur via (a) neurobiological responses comparable to the effects of pain medication, (b) reduction of anxiety and stress, and


Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial.
In the phase 3 CheckMate 025 study, previously treated patients with advanced renal cell carcinoma who were randomly assigned to nivolumab had an overall survival benefit compared with those assigned to everolimus. We aimed to compare health-related quality of life (HRQoL) between treatment groups in this trial. CheckMate 025 was an open-label study done at 146 oncology centres in 24 countries. Patients were randomly assigned to treatment between Oct 22, 2012, and March 11, 2014. Patients with advanced renal cell carcinoma were randomly assigned (1:1, block size of four) to receive nivolumab every 2 weeks or everolimus once per day. The study was stopped early at the planned interim analysis in July, 2015, because the study met its primary endpoint. A protocol amendment permitted patients in the everolimus group to cross over to nivolumab treatment. All patients not on active study therapy are being followed up for survival. At the interim analysis, HRQoL was assessed with the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaires. Prespecified endpoints were to assess, in each treatment group, disease-related symptom progression rate based on the FKSI-DRS and changes in reported global health outcomes based on the EQ-5D. Other endpoints were post hoc. We calculated the proportion of FKSI-DRS questionnaires completed using the number of patients with non-missing data at baseline and at least one post-baseline visit. We defined FKSI-DRS completion as completion of five or more of the nine items in the questionnaire; otherwise data were treated as missing. FKSI-DRS symptom index score was prorated for missing items. We made no adjustments for missing EQ-5D data. We used descriptive statistics and multivariate analyses, including mixed-effects model repeated-measures, for between group comparisons. Analyses were powered according to the original study protocol, and we analysed FKSI-DRS and EQ-5D data for all patients who underwent randomisation and had a baseline assessment and at least one post-baseline assessment. CheckMate 025 is registered with ClinicalTrials.gov, number NCT01668784. HRQoL data were collected at baseline for 362 (88%) of 410 patients in the nivolumab group and 344 (84%) of 411 patients in the everolimus group. The mean difference in FKSI-DRS scores between the nivolumab and everolimus groups was 1·6 (95% CI 1·4-1·9; p<0·0001) with descriptive statistics and 1·7 (1·2-2·1; p<0·0001) with mixed-effects model repeated-measures analysis. In terms of FKSI-DRS score, more patients had a clinically meaningful (ie, an increase of at least 2 points from baseline) HRQoL improvement with nivolumab (200 [55%] of 361 patients) versus everolimus (126 [37%] of 343 patients; p<0·0001). Median time to HRQoL improvement was shorter in patients given nivolumab (4·7 months, 95% CI 3·7-7·5) than in patients given everolimus (median not reached, NE-NE). Nivolumab was associated with HRQoL improvement compared with everolimus in previously treated patients with advanced renal cell carcinoma. Bristol-Myers Squibb.


Alkaline stability of quaternary ammonium cations for alkaline fuel cell membranes and ionic liquids.
The alkaline stability of 26 different quaternary ammonium groups (QA) is investigated for temperatures up to 160 °C and NaOH concentrations up to 10 mol L(-1) with the aim to provide a basis for the selection of functional groups for hydroxide exchange membranes in alkaline fuel cells and of ionic-liquid cations stable in basic conditions. Most QAs exhibit unexpectedly high alkaline stability with the exception of aromatic cations. β-Protons are found to be far less susceptible to nucleophilic attack than previously suggested, whereas the presence of benzyl groups, nearby hetero-atoms, or other electron-withdrawing species promote degradation reactions significantly. Cyclic QAs proved to be exceptionally stable, with the piperidine-based 6-azonia-spiro[5.5]undecane featuring the highest half-life at the chosen conditions. Absolute and relative stabilities presented herein stand in contrast to literature data, the differences being ascribed to solvent effects on degradation.


Contrasting diversity values: statistical inferences based on overlapping confidence intervals.
Ecologists often contrast diversity (species richness and abundances) using tests for comparing means or indices. However, many popular software applications do not support performing standard inferential statistics for estimates of species richness and/or density. In this study we simulated the behavior of asymmetric log-normal confidence intervals and determined an interval level that mimics statistical tests with P(α) = 0.05 when confidence intervals from two distributions do not overlap. Our results show that 84% confidence intervals robustly mimic 0.05 statistical tests for asymmetric confidence intervals, as has been demonstrated for symmetric ones in the past. Finally, we provide detailed user-guides for calculating 84% confidence intervals in two of the most robust and highly-used freeware related to diversity measurements for wildlife (i.e., EstimateS, Distance).


Obstructive sleep apnoea syndrome and genes.
Obstructive sleep apnoea (OSA) is a complex disease entity strongly influenced by genetic factors, especially those that affect obesity and fat distribution, upper airway muscle tone, craniofacial morphology, ventilatory control and sleep, giving rise to the OSA phenotype. OSA can also be considered a metabolic syndrome which adversely affects multiple organ systems, especially the cardiovascular system and the brain. The most widely used clinical marker for the diagnosis of OSA is the apnoea-hypopnoea index, calculated by polysomnography. A percentage of 35 to 40% of its variance can be attributed to genetic factors. Therefore, the identification and elucidation of the genes implicated in the pathogenesis of OSA becomes a matter of extensive research and could lead to the development of therapeutic agents that can have a beneficial effect on the natural course of OSA.


Photodynamic therapy in the palliation of late stage obstructing non-small cell lung cancer.
Photodynamic therapy selectively destroys malignant tumors by laser activation of injected hematoporphyrin derivative. Between July 1985 and January 1989, ten patients underwent 13 courses of PDT for relief of endobronchial tumor obstruction due to endstage primary non-small lung cancer. Initial biopsy specimens demonstrated squamous carcinoma in eight patients and adenocarcinoma in two. At the time of treatment, all patients were considered surgically unresectable: T4N2M1(one), T4N2M0(one), T3N3M1(two), T3N2M0(five), and T2N1M0(one). This latter patient had exclusionary medical conditions. The average Karnofsky status was 75 (worst was 60, best was 90). Obstruction was mainstem for six, bronchus intermedius in one, and left upper lobe in three. The average obstruction was 86 +/- 2 percent. Following treatment, the average obstruction was 57 +/- 3 percent. Responses were greater than 50 percent reduction in four and less than 50 percent in six. Half of the patients still had more than 70 percent obstruction following PDT. However, all patients had a decrease in symptoms, especially coughing. Six of ten patients subsequently received external beam radiation. Three of these patients developed significant problems during and following radiation. Side effects of HPD were minimal and included burns in two and mild anasarca in one patient. PDT appears to offer palliation of obstructive symptoms in patients with late stage lung cancer. Since life span is so short in these individuals, physicians must weigh carefully the potential side effects of combination therapy.


Diagnosis of Helicobacter pylori infection in adults with intellectual disability.
Helicobacter pylori infection is common among adults with intellectual disability. The acceptabilities and accuracies of different diagnostic tests in this population are unknown. We aimed to determine (i) patient acceptability and (ii) performance characteristics of serology, fecal-antigen, and urea breath tests among adults with intellectual disability. One hundred sixty-eight such adults underwent H. pylori testing with serology and fecal-antigen tests, and a portion underwent treatment. One year later, the participants were retested with fecal-antigen, serology, and urea breath tests. The numbers of specimens obtained and difficulties in collection reported by caregivers were noted. Test performance characteristics were assessed among participants and 65 of their caregivers, using serology as the reference. All participants provided at least one specimen, despite reported collection difficulties for 23% of fecal and 27% of blood specimens. Only 25% of the participants provided breath specimens; failure to perform this test was associated with lower intellectual ability and higher maladaptive behavior. The sensitivity, specificity, and positive and negative predictive values of the fecal test (baseline and 12 months versus caregivers) were 70 and 63 versus 81, 93 and 95 versus 98, 96 and 92 versus 93, and 53 and 74 versus 93%, respectively; those of the urea breath test (12 months versus caregivers) were 86 versus 100, 88 versus 95, 75 versus 89, and 94 versus 100%, respectively. With assistance, fecal or blood specimens for H. pylori assessment can be provided by most patients with intellectual disability regardless of their level of function or behavior. Only those with greater ability can perform the urea breath test. Using serology as the reference test, the limitations of performance characteristics of the fecal-antigen and urea breath tests are similar to those among a control group of caregivers.


[Study on characteristics of fluorescence spectra of dissolved organic matter with different water quality].
The fluorescence spectra of dissolved organic matter (DOM) in several types of water samples in combination with laser-induced fluorescence (LIF) measurements were measured in the laboratory, and the spectral characteristics of DOM were analysed. The curve of normalized fluorescence intensity against corresponding concentration of humic acid is showed. The results demonstrate the possibilities of water quality monitoring based upon fluorescence spectral characteristics of DOM by means of LIF method.


Location of Disc Hemorrhage and Direction of Progression in Glaucomatous Retinal Nerve Fiber Layer Defects.
To investigate the relationship between glaucomatous disc hemorrhage (DH) location with respect to the nasal or temporal margin of the retinal nerve fiber layer defect (RNFLD) and the direction of RNFLD widening. This is a retrospective, cross-sectional study. Patients with any documented episode of glaucomatous DH throughout the follow-up period, and definite RNFLD widening on retinal nerve fiber layer photographs were analyzed. The location of DH was recorded as either nasal or temporal, and the direction of RNFLD widening was investigated. The laterality of DH location on the RNFLD border and the direction of RNFLD widening were correlated with each other. We also compared clinical parameters between eyes with nasal versus temporal margin DHs. We analyzed 123 eyes from 116 patients with definite widening of the RNFLD and glaucomatous DH at the border between the healthy and damaged retinal nerve fiber layer. The most common diagnosis was normal-tension glaucoma (109, 87.9%). The most frequent location of DH was the temporal margin of an inferotemporal RNFLD (75, 61.0%), and the most frequent pattern of change in RNFLD was temporal widening (89, 72.4%). The absolute congruency was 82.9% and the total congruency was 99.2%. No significant differences were identified between eyes with nasal versus temporal margin DHs. The lateral location of DH on the RNFLD border was highly congruent with the direction of RNFLD widening. This correspondence of laterality between DH development and progression of RNFLD may suggest an intimate structural relationship during the pathogenesis of DH, at the enlarging RNFLD border.


Thrombolysis versus surgery as the initial management for native artery occlusion: efficacy, safety, and cost.
A controversy has evolved as to which therapy, thrombolysis or thromboembolectomy, represents the optimal initial treatment for acute native artery occlusion. Forty-eight cases of acute class I or II limb ischemia caused by native artery occlusion were retrospectively analyzed between 1988 and 1993. Nineteen of the patients were initially treated with thrombolysis (group 1), and 29 underwent thromboembolectomy (group 2). Initial clinical improvement was seen in 11 (57.9%) of 19 extremities in group 1, with complete clot resolution in 21%, partial lysis in 47.4%, and no angiographic improvement in 31.6%. Significantly superior results were achieved in group 2; 28 (97%) of 29 limbs showed clinical improvement after initial surgical therapy (p = 0.001). Limb salvage was 88.2% in group 1 and 96.6% in group 2 (p = 0.5). Adjunctive procedures for limb salvage were necessary in 10 (52.6%) of 19 limbs in group 1 compared with only five (17.2%) of 29 limbs in group 2 (p = 0.013). Perioperative mortality was 10.5% and 10.3% (p = 1.0), whereas major postoperative complications occurred in 63.2% and 37% of patients in groups 1 and 2, respectively (p = 0.14). Hospital and professional patient charges were analyzed for the 12 most recent patients from each group. Total mean charges per patient were higher in group 1 ($45,171) than in group 2 ($24,898) (p = 0.046). Patients initially treated surgically achieved better immediate clinical results with significant cost savings and without significant differences in morbidity, mortality, or limb salvage compared with patients treated initially by thrombolysis.


The role of the perioperative vascular nurse specialist.
The role of the vascular surgical service specialist is both challenging and rewarding. It encompasses the nursing process as well as aspects of budgeting, research, inventory management, education, and leadership. Developing and maintaining the skills necessary to perform in the role requires constant focus and a sincere interest in the specialty.


Increased class I and class II MHC products and mRNA in kidneys of MRL-lpr/lpr mice during autoimmune nephritis and inhibition by cyclosporine.
The expression of MHC products in the kidneys of MRL-1pr/1pr mice was investigated. As previously described, these mice develop lupus-like nephritis with intraglomerular and peritubular Ig deposition, vasculitis, and interstitial mononuclear cell infiltration at about 12 wk of age. As the nephritis appeared, the expression of MHC class I and II products rose, as demonstrated by absorption and by specific binding of radiolabeled antibodies. Hybridization of kidney RNA with specific probes revealed an increase in specific mRNA for MHC class I and II genes and for beta2 microglobulin. Using rat monoclonals against mouse class I and II MHC products, and goat anti-rat Ig as second antibody, we showed that the increase in renal class I and II expression was localized to the basolateral membranes of tubular cells, and, in the case of class I, in arteries and glomeruli. The sites of tubular MHC expression corresponded closely to the sites of extensive peritubular Ig deposition. High doses of cyclosporine given for 6 to 8 wk reduced the peritubular Ig deposits, renal Ia and H-2K expression, and specific mRNA for beta 2-microglobulin and MHC genes, but did not reduce anti-DNA antibody levels in serum. Thus the peritubular Ig deposits and tubular MHC induction coincided in timing and location, and in their resolution with cyclosporine. The results raise the possibility that the increase in renal MHC expression not only accompanies the renal lesions, but may play a role in their pathogenesis.


Subpicometer length measurement using heterodyne laser interferometry and all-digital rf phase meters.
We present an all-digital phase meter for precision length measurements using heterodyne laser interferometry. Our phase meter has a phase sensitivity of 3 μrad/√Hz at signal frequencies of 1 Hz and above. We test the performance of our phase meter in an optical heterodyne interferometric configuration, using an active Sagnac interferometer test bed that is flexible and low noise. We demonstrate more than 70 dB of laser frequency noise suppression to achieve an optical phase sensitivity of 5 μrad/√Hz and a corresponding displacement sensitivity of 0.5 pm/√Hz at signal frequencies above 10 Hz. In addition, we demonstrate the ability of our phase meter to follow full fringe signals accurately at 100 Hz and to track large signal excursions in excess of 10(5) fringes without cycle slipping. Finally, we demonstrate a cyclic error of ≤1 pm/√Hz, above 10 Hz.


Brief psychotic disorder in COVID-19 patient with no history of mental illness.
COVID-19 pandemic affects mental health globally. Reports showed the increase of mental illness as a response to the COVID-19 pandemic. However, the correlation between the COVID-19 and mental illness is not fully understood yet. We reported a brief psychotic disorder in a COVID-19 patient with no history of mental illness who was hospitalized in Persahabatan Hospital, Jakarta, Indonesia. Psychotic symptoms appeared five days after COVID-19 onset and laboratory tests showed elevated levels of d-dimer and fibrinogen. Elevated levels of d-dimer and fibrinogen suggest an ongoing COVID-19-associated coagulopathy that might cause a microdamage in the central nervous system. It might contribute to the manifestation of psychotic symptoms. The correlation between brief psychotic disorder and COVID-19 requires further investigation.


Bacillus cereus strains fall into two clusters (one closely and one more distantly related) to Bacillus anthracis according to amino acid substitutions in small acid-soluble proteins as determined by tandem mass spectrometry.
Small acid-soluble proteins (SASPs) are located in the core region of Bacillus spores and have been previously demonstrated as reliable biomarkers for differentiating Bacillus anthracis and Bacillus cereus. Using MS and MS-MS analysis of SASPs further phylogenetic correlations among B. anthracis and B. cereus strains are described here. ESI was demonstrated to be a more comprehensive method, allowing for the analysis of intact proteins in both MS and MS-MS mode, thus providing molecular weight (MW) and sequence information in a single analysis, and requiring almost no sample preparation. MALDI MS was used for determination of MW of intact proteins; however, MS-MS analysis can only be achieved after enzymatic digestion of these proteins. It was demonstrated that the combination of the two different approaches provides confirmatory and complementary information, allowing for unambiguous protein characterization and sequencing. This study established that B. cereus strains fall into two clusters (one closely and one more distantly related) to B. anthracis as exhibited by amino acid substitutions. The closely related cluster was characterized by a beta-SASP with a single amino acid substitution, localized either close to the C terminus (phenylalanine-->tyrosine, 16 masses change) or close to the N terminus (serine-->alanine serine, also 16 masses change). The more distantly related cluster displayed both amino acid substitutions (32 masses change). One strain of B. cereus isolated from a patient with severe pneumonia (an anthrax-like disease) fell into the more distantly related cluster implying that pathogenicity and phylogenicity are not necessarily correlated features. Unlike PCR and DNA sequencing, protein sequence variation assessed by ESI MS-MS, essentially occurs in real-time, and involves simply extracting the protein and injecting into the instrument for analysis.


Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine.
Despite different embryological origins, islet beta-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human beta-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by beta-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous L-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in beta-cells.


Sjögren's Syndrome and Silicosis - a Case Report.
Sjögren's syndrome is an autoimmune disease of unknown etiology where immune response to self-antigens is believed to result from interactions between genetic and environmental factors. We describe the case of a patient who has been diagnosed with Sjögren's syndrome based on typical clinical and immunological parameters. The clinical picture was dominated by the respiratory symptoms, and radiographic and multislice computed tomography examination of the chest showed certain changes characteristic of pneumoconiosis. Given that the patient has worked in a foundry where he has been exposed to the silica dust, he was subject to examination by occupational health specialists under the suspicion of lung silicosis, who confirmed the silicosis. This case report points to the possible connection between a professional exposure to silica and Sjögren's syndrome. Occupational exposure to silica is a possible risk factor for the development of autoimmune diseases, and in the evaluation of patients with connective tissue diseases it is important to consider work-related history.


Day to day reproducibility of Doppler sonographic measurements in patients with valvular aortic stenosis.
High reproducibility of Doppler gradient measurements is necessary for both the reliable noninvasive assessment of the severity of aortic stenosis and for repeated follow-up examinations in individual patients. We therefore studied day to day reproducibility of Doppler sonographically measured peak pressure drops in 46 patients with valvular aortic stenosis. Clinically stable patients were examined twice within 29 +/- 18.2 days by the same examiner. Peak pressure drop (PPD) and peak flow velocity differed between the two examinations by 8.6 +/- 7.0 (range 0-29) mmHg and by 0.25 +/- 0.18 (range 0-0.7) m/s, respectively. Reproducibility was comparable in patients with excellent, good, and moderate quality examinations, but was lower in the 6 patients with poor quality examination. Variability of PPD, but not of peak flow velocity was higher (p less than 0.05) in patients with severe (PPD greater than 60 mmHg) stenosis. Reproducibility was comparable in patients with or without concomitant aortic incompetence and in patients with normal or reduced left ventricular function. Similar reproducibility was obtained in patients with heart rate changes below or above 10 beats/min between the two examinations. It is concluded that good reproducibility of Doppler measurements in patients with aortic stenosis allows reliable noninvasive assessment of the severity of the stenosis. In follow-up studies of patients with mild to moderate aortic stenosis increases in peak flow velocity in excess of 15% (mean day to day variability +2 SD) are highly indicative of the true progress of the stenosis.


Moving from the 'why' to the 'how': reflections on humanitarian response in urban settings.
Given the rising numbers of crises in urban settings, Médecins Sans Frontières (MSF) is currently shifting its focus from 'why' it should intervene to 'how' it should intervene effectively in these contexts. Beyond communities affected by natural disasters and epidemics, MSF has chosen to target populations in urban settings that are affected by violence or by marginalisation and neglect: these groups appear to suffer the greatest number of severe threats to their health and well-being. Recent reflection within MSF has identified a number of key operational challenges to confront in order to respond efficiently to the needs of these populations. These include: appropriate assessments; measurable indicators of vulnerability and impact; pertinent operational approaches and medical strategies; adapted security management; and responsible closure of activities. This paper summarises the main lessons learned from working in urban settings with the principal aim of mutual sharing and understanding.


Biarticular muscles are most responsive to upper-body pitch perturbations in human standing.
Balancing the upper body is pivotal for upright and efficient gait. While models have identified potentially useful characteristics of biarticular thigh muscles for postural control of the upper body, experimental evidence for their specific role is lacking. Based on theoretical findings, we hypothesised that biarticular muscle activity would increase strongly in response to upper-body perturbations. To test this hypothesis, we used a novel Angular Momentum Perturbator (AMP) that, in contrast to existing methods, perturbs the upper-body posture with only minimal effect on Centre of Mass (CoM) excursions. The impulse-like AMP torques applied to the trunk of subjects resulted in upper-body pitch deflections of up to 17° with only small CoM excursions below 2 cm. Biarticular thigh muscles (biceps femoris long head and rectus femoris) showed the strongest increase in muscular activity (mid- and long-latency reflexes, starting 100 ms after perturbation onset) of all eight measured leg muscles which highlights the importance of biarticular muscles for restoring upper-body balance. These insights could be used for improving technological aids like rehabilitation or assistive devices, and the effectiveness of physical training for fall prevention e.g. for elderly people.


Effect of buyang huanwu decoction on platelet activating factor content in arterial blood pre- and post-arterial thrombosis in rats.
To explore the effect of Buyang Huanwu Decoction (BHD) on platelet activating factor (PAF) content in arterial blood pre- and post-arterial thrombosis in rats, male Wistar rats were randomly divided into 3 groups, the medicine group treated with BHD, the control group with dexamethasone liquid, and the blank group with distilled water. Oral administration was given for 14 consecutive days, once daily. Model of arterial thrombosis was established in the animals 2 hours after final medication, the blood content of PAF, dry weight (DW) and occlusion time (OT) of thrombus, and dry weight of thrombus/body weight (TW/BW) ratio were observed. Results indicated that BHD could markedly lower the arterial blood content of PAF after thrombosis, increase the OT of thrombus, reduce the dry weight of thrombus and the TW/BW ratio (P < 0.05). It is suggested that BHD can inhibit the pathologic PAF metabolism and formation and development of arterial thrombus.


Recurrence and prognosis in intrahepatic cholangiocarcinoma patients with different etiology after radical resection: a multi-institutional study.
We aimed to evaluate the prognosis and adjuvant chemotherapy (ACT) in intrahepatic cholangiocarcinoma (ICC) patients with different etiology after radical resection. A total of 448 patients with ICC who underwent radical resection between 2010 and 2018 at ten Chinese tertiary hospitals were analyzed in the study. These patients were divided into conventional ICC (Con-ICC, n = 261, 58.2%), hepatitis B virus ICC (HBV-ICC, n = 102, 22.8%) and hepatolithiasis (Stone-ICC, n = 85,19.0%) subtypes according to different etiology. Propensity score matching (PSM) was conducted to mitigate the baseline differences between Con-ICC and HBV-ICC, Con-ICC and Stone-ICC, HBV-ICC and Stone-ICC subtypes. Univariate and multivariate analysis showed that different etiology was a prognostic factor for overall survival and relapse-free survival, and different etiology was an independent risk factor for overall survival in ICC patients, respectively (P < 0.05). In addition, there was a statistical difference for overall survival in early recurrence patients among the three etiological subtypes (P < 0.05). After PSM, the overall survival of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes (P < 0.05), while the relapse-free survival of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC (P > 0.05). In Stone-ICC patients, the median overall survival was 16.0 months and 29.7 months, and the median relapse-free survival was 9.0 months and 20.0 months for non-ACT and ACT patients, respectively (P < 0.05). The prognosis of Stone-ICC patients was significantly worse than those of Con-ICC and HBV-ICC patients. Interestingly, postoperative adjuvant chemotherapy can improve the prognosis of Stone-ICC patients effectively.


Interventions to increase vaccine uptake among people who live and work in prisons: A global multistage scoping review.
The objective of this study is to examine interventions implemented to increase vaccine uptake among people who live and work in prisons around the world. Peer-reviewed and gray literature databases were searched systematically to identify relevant information published from 2012 to 2022. Publications were evaluated by two researchers independently and underwent quality assessment through established tools. Of the 11,281 publications identified through peer-reviewed (2607) and gray literature (8674) search, 17 met the inclusion criteria. In light of limited data, the identified interventions were categorized into two categories of educational and organizational interventions, and are discussed in the text. The lack of availability of vaccination services and interventions to increase vaccine uptake among people who live and work in prisons, worldwide, is a serious public health concern. These interventions reported in this review can be adapted and adopted to mitigate the burden of infectious diseases among people who live and work in prisons.


Comparison of temporal changes in trunk flexion angle and gluteal pressure during continuous sitting.
[Purpose] This study investigated temporal changes in trunk flexion angle and gluteal pressure during computer work with continuous sitting. [Subjects and Methods] This study involved 10 males subjects aged 21-29 years. During 30 min of data collection with a Tekscan system and a video camera, peak gluteal pressure and changes in trunk flexion angle were analyzed with the COMFOM at research 6.20 and Pro-Trainer 10.1 programs, respectively, at 10, 20, and 30 min. [Results] The result showed no significant change in gluteal pressure after 10, 20, or 30 min. However, changes in trunk flexion angle increased significantly after 10 min <20 min <30 min. [Conclusion] Trunk flexion is necessary for repositioning, unless one can maintain a posture for a long time without movement. Future research should analyze repositioning methods according to individual characteristics.


[Localization of hepatitis C virus core protein in the nucleus of peripheral blood mononuclear cells of hepatitis C patients].
To study the significance of the expression of HCV core protein in PBMC of patients with chronic hepatitis C and to evaluate the relationship between HCV core protein expression and clinical states. Identification of HCV protein antigen (Ag) in PBMC of 66 hepatitis C patients by immunohistochemical method and clinical status of the patients with HCV protein positive expression were investigated. In 27 out off 66 patients the HCV RNA and HCV Ag in PBMC were detected with RT-PCR and immunohistochemical method. The HCV Ag (core+NS3) was identified in PBMC in 51 out of 66 patients (77.27%). It was also demonstrated that HCV core protein in nucleus showed strong expression and NS3 protein in cytoplasm showed weak expression. The expression of core protein in nucleus of PBMC were 35.29% in advanced chronic hepatitis patients, which was significantly higher than that from moderate cases (5.88%). This study suggested that the expression of PMBC-HCV core protein may be related to the clinical state of the patients. The nuclear expression of HCV core protein in PBMC of patients with hepatitis C may be related to the persistence and activity of the chronic hepatitis C virus and play an important role in the pathogenesis of cirrhrosis and hepatocellular carcinoma.


The concept and treatment of psychological trauma.
Despite a large and rapidly expanding literature on psychological trauma, many fundamental questions remain about its basic nature: Is it a psychological problem or a biological one?; Is it a past event somehow stuck in the present or is it something new which has been triggered and shaped by that event?; Does it reside only within the patient or does it live between the patient and other people (including within the therapeutic relationship)? This presentation will review the history of the concept of psychological trauma and explore the theoretical bases for current evidence-based psychotherapies for PTSD, each of which will be shown to describe psychological trauma as a problem in bringing the past and the present together in memory and cognition. These theories primarily differ on the question of whether a traumatic memory becomes pathogenic, because it cannot be biologically processed or because it must be psychologically avoided. Psychoanalytic concepts of transference and countertransference will be shown to be of practical importance regardless of the type of treatment chosen. If researchers and clinicians can build on what they hold in common rather than become divided by their differences, we can improve our ability to understand and alleviate the effects of psychological trauma.


Cervical magnetic stimulation as a method to discriminate between diaphragm and rib cage muscle fatigue.
Inspiratory muscle fatigue can probably determine hypercapnic respiratory failure. Diaphragm fatigue is detected by electrical phrenic stimulation (ELS), but there is no simple tool to assess rib cage muscle (RCM) fatigue. Cervical magnetic stimulation (CMS) costimulates the phrenic nerves and RCM. We reasoned that changes in transdiaphragmatic pressure twitch (Pdi,tw) with CMS and ELS should be different after selective diaphragm vs. RCM fatigue. Five volunteers performed inspiratory resistive tasks while voluntarily uncoupling diaphragm and RCM. Baseline Pdi,twELS and Pdi,twCMS were 28.57 +/- 1.68 and 32.83 +/- 2.92 cmH2O. After selective diaphragm loading, Pdi,twELS and Pdi,twCMS were reduced by 39 and 26%, with comparable decreases in gastric pressure twitch (Pga,tw). Esophageal pressure twitch (Pes,tw) was better preserved with CMS. Therefore Pes,tw/Pga,tw was lower with ELS than CMS (-1.24 +/- 0.16 vs. -1.73 +/- 0.11, P = 0.05). After selective RCM loading, there was no diaphragm fatigue, but Pes,twCMS was significantly reduced (-30%). These findings support the role of rib cage stiffening by CMS-related RCM contraction in the ELS-CMS differences and suggest that CMS can be used to assess RCM fatigue.


Effects of terlipressin on systolic pulmonary artery pressure of patients with liver cirrhosis: an echocardiographic assessment.
Portopulmonary hypertension is a serious complication of chronic liver disease. Our aim was to search into the effect of terlipressin on systolic pulmonary artery pressure among cirrhotic patients. Twelve patients (6 males and 6 females) with liver cirrhosis were recruited in the study. Arterial blood gas samples were obtained in sitting position at rest. Contrast enhanced echocardiography and measurements of systolic pulmonary artery pressure were performed before and after the intravenous injection of 2 mg terlipressin. Of 12 patients studied, the contrast enhanced echocardiography was positive in 5, and the positive findings in contrast enhanced echocardiography were reversed to normal in two after terlipressin injection. The mean systolic pulmonary artery pressure was 25.5+/-3.6 mmHg before terlipressin injection, and was 22.5+/-2.5 mmHg after terlipressin (P=0.003). The systolic pulmonary artery pressure was above 25 mmHg in seven of these 12 patients. After the terlipressin injection, systolic pulmonary artery pressure was <25 mmHg in four of these cases (58.3% vs 25%, P=0.04). Terlipressin can decrease the systolic pulmonary artery pressure in patients with liver cirrhosis.


Treatment compliance and noncompliance in psychoses.
Compliance or noncompliance with treatment significantly influences course and outcome of psychiatric disorders. While noncompliance has been extensively researched, compliance has received less attention. The current study was conducted to elicit reasons for compliance and noncompliance in patients having psychoses attending psychiatric clinics. A total of 196 compliant and 150 noncompliant patients were interviewed using self-designed tools to elicit sociodemographic data, details of illness, and treatment. Factors contributing to compliance and noncompliance were grouped under illness-related, clinician-related, medication-related, family-related, and economic-related domains and compared. Compliance was significantly more in females and middle- and high-socioeconomic status patients. They had less substance use, high physical comorbidity, high attendance in the outpatient department, and better remission. Clinician-related, family-related, and medication-related domains were contributing more to compliance whereas illness-related and economic-related domains seemed to have more bearing on noncompliance. Compliance and noncompliance are determined multidimensionally. Domains related to clinician, family, and medications have to be reinforced to enhance compliance. Illness-related and economic domains have to be resolved to reduce noncompliance.


Pain management issues for cancer survivors.
The authors review issues that cancer survivors face daily related to pain management, the etiologies of pain in survivors, and ways to achieve successful pain management for cancer survivors. The review includes a discussion of pain issues in the 6-month period after diagnosis and pain issues that may arise throughout survivorship. The authors describe a successful pain management program as including thorough and ongoing assessment, communication among the healthcare team members, interdisciplinary interventions, and reassessment of the whole management process. Various barriers to effective pain management are described. It is hoped that this review may give members of the multidisciplinary cancer care team new insights into the issues encountered by survivors regarding pain and potential therapeutic techniques.


Multiple controls by adenosine receptors on the adenylate cyclase in the rat hepatic membrane.
The effects of an adenosine analog, N6-phenyl-isopropyl-adenosine (PIA), on the glucagon-stimulated adenylate cyclase activity in rat hepatic membranes were studied. Adenosine at high concentrations (greater than 10 microM) has been reported exclusively to inhibit the adenylate cyclase via intracellular P-sites of the hepatic membrane. The stimulation by glucagon of the enzyme was attenuated by nanomolar concentrations of PIA in the presence of low concentrations (less than 1.0 microM) of GTP, indicating the effect of the guanine nucleotide inhibitory system (Ni). This inhibition by PIA required the presence of sodium chloride and was antagonized with isobutyl methylxanthine, an antagonist for the extracellular R-site receptors. The inhibitory effects of PIA disappeared and reversed into a stimulatory phase with increasing concentrations of GTP, suggesting the presence of a stimulatory (Ns) and an inhibitory (Ni) guanine nucleotide system of the enzyme in the action of the adenosine. PIA concentrations over a micromolar were observed to stimulate the enzyme activity in a GTP-dependent manner, indicating the presence of the stimulatory receptor (A2 or Ra) coupled to the Ns. These results suggest that receptors for adenosine of the inhibitory type (A1 or Ri) and the stimulatory type (A2 or Ra) are present on the rat hepatic membrane, showing multiple controls of the adenylate cyclase system, depending on the cellular concentrations of GTP and/or sodium chloride.


Interactions of T7 RNA polymerase with T7 late promoters measured by footprinting with methidiumpropyl-EDTA-iron(II).
The interactions of T7 RNA polymerase with T7 late promoters were studied by using quantitative footprinting with methidiumpropyl-EDTA X Fe(II) [MPE-Fe(II)] as the DNA cleaving agent. Class II and class III T7 promoters have a highly conserved 23 base pair sequence from -17 to +6. Among class III promoters the -22 to -18 region is also highly conserved. For a class II promoter, T7 RNA polymerase protects the -17 to -4 region from MPE-Fe(II) cleavage; when GTP is present, protection extends from -17 to +5 (noncoding strand). For a class III promoter, protection extends from -20 to -4 and in the presence of GTP from -20 to +5 (noncoding strand). The protected regions for the coding strands of both promoters were nearly identical with that seen for the noncoding strands. The binding constant for the class III promoter is (4 +/- 1.5) X 10(7) M-1 and in the presence of GTP increases to (10 +/- 1.7) X 10(7) M-1. These binding constants are about 1000 and 200 times greater, respectively, than values reported previously [Ikeda, R. A., & Richardson, C. C. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 3614-3618]. The differences in binding constants are probably due to tRNA and high salt used in those earlier experiments. Both tRNA and high salt (greater than 50 mM NaCl and greater than 10 mM MgCl2) inhibit the binding of the polymerase to the promoter. Optimal binding conditions occur at 2-5 mM MgCl2 and 0-10 mM NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)


Outcome of definitive and postoperative radiotherapy in patients with sinonasal squamous cell carcinomas.
To evaluate outcomes in patients with sinonasal squamous cell carcinoma (SCC) treated with definitive radiotherapy (DRT) and postoperative radiotherapy (PORT). Between 1990 and 2013, 73 patients with sinonasal SCC were treated with radiotherapy. Fifty-two patients (71.2%) were treated with DRT and 21 (28.8%) were treated with PORT. The primary tumor sites were the maxillary sinus in 47 patients (64.4%), the nasal cavity in 18 (24.7%), the ethmoid sinus in 7 (9.6%), and the frontal sinus in 1 (1.4%). Four (5.4%), 11 (15.1%), 24 (32.9%), 17 (23.3%), and 17 (23.3%) patients had T1, T2, T3, T4a, and T4b tumors, respectively. N stage was N0, N1, N2a, N2b, N2c, and N3 in 60 (82.2%), 6 (8.2%), 2 (2.7%), 2 (2.7%), and 3 (4.1%) patients, respectively. The median follow-up period was 23 months (range 3-196). The 5-year local progression-free survival (LPFS), regional progression-free survival (RPFS), distant metastasis-free survival (DMFS), and overall survival (OS) in the DRT and PORT groups were 50.6%, 82.1%, 91.1%, and 84.4% and 85.7%, 72.1%, 76.1%, and 83.5%, respectively, without any statistically significant differences. The LPFS, RPFS, DMFS, and OS were not significantly different between the DRT and PORT groups. Given the possibility of functional disability and cosmetic disfigurement with facial surgery, DRT might be considered as a surrogate to surgery followed by PORT for patients with locally advanced sinonasal SCC.


Assessment of Preschool's Inclusive Participation in Social Responsibility Program Under Institutional Pressure: Evidence From China.
China set the goal of expanding early childhood education (ECE) in 2018, by encouraging the development of public interest kindergartens (PIK) to provide high-quality, low-cost preschool services to the general public. This is in response to the challenges of accessibility, affordability, and accountability besetting China's current ECE system. However, the transition toward PIK has been slow due to various complex problems, including the lackluster willingness of ECE providers to become PIK. To better understand the challenges leading to low participation, this study explores the external pressures affecting ECE providers and evaluates the external factors that influence their level of social responsibility. A stratified-random sampling questionnaire survey solicited responses from 832 ECE personnel representing 261 kindergartens from across China. Our findings suggest that institutional pressure has a positive effect on social responsibility and inclusive participation. We also found that institution visibility positively regulates the relationship between institutional pressure and social responsibility. At the same time, the level of environmental perception positively governs the relationship between social responsibility and participation willingness. Kindergartens should have certain social values, including assuming certain behaviors and participating in social activities in the spirit of social service and ensure multiple subjects' synergetic governance.


Philosophy and nursing.
It is claimed that philosophy has a distinctive contribution to make to the education of nurses and their teachers, as well as to the development of nursing theory and research. After a brief characterization of philosophy and philosophy of education, stressing its relationship with thinking processes, and the development of personal values, the above claim is supported in the body of the article by discussion of four central concerns in nursing. First the concept of caring where cognitive, moral and attitudinal aspects are examined and secondly, the importance of gaining a moral and political consciousness of assumptions underlying a nurse's work. Thirdly, a discussion of some ethical and other implications in adopting a systems approach to the nursing process. Finally an anlysis of nursing theory and research which draws attention to the value of non-empirical work, and reiterates criticisms of the objectives approach as a research tool.


Osteolysis of the Greater Trochanter Caused by a Foreign Body Granuloma Associated with the Ethibond® Suture after Total Hip Arthroplasty.
The present case shows a case of progression of osteolysis of the greater trochanter caused by a foreign body granuloma associated with the number 5 Ethibond suture in cementless THA with the direct lateral approach that was completely healed by removal of the Ethibond suture. A 55-year-old Japanese woman with secondary osteoarthritis caused by acetabular dysplasia underwent left cementless THA with the direct lateral approach. After setting of the total hip prosthesis, the gluteus medius muscle and vastus lateralis muscle were reattached to the greater trochanter through two bone tunnels using number 5 Ethibond EXCEL sutures. The left hip pain disappeared after surgery, but the bone tunnels enlarged gradually and developed osteolysis at 10 weeks. The removal of the Ethibond sutures and debridement improved the osteolysis. Histological examination showed the granuloma reaction to a foreign body with giant cell formation. The Ethibond suture has the lowest inflammatory tissue reaction and relatively high tension strength among nonabsorbable suture materials. However, number 5 Ethibond has the potential to cause osteolysis due to a foreign body granuloma, as in the present case.


No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia.
Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P < 0.001), no effect of 'Group' (P = 0.64) and no 'Time*Group' interaction (P = 0.77). For REY, SF-36, PSP and PANSS, only significant 'Time' effects were found. The non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment.


Roseola infantum caused by human herpesvirus-6: report of 7 cases with emphasis on complications.
Roseola infantum is not an uncommon disease in children. The etiology was not known until 1988 when Yamanishi et al in Japan first demonstrated that human herpesvirus-6 (HHV-6) was the causative agent. In the fall of 1989, we began to study the role of HHV-6 in roseola infantum in Taiwan. A total of 7 cases of suspected roseola infantum were studied and all were proven to have primary HHV-6 infections. Six were classic cases of roseola infantum, while one had only fever without the rash. Two cases developed complications; one had leukopenia and thrombocytopenia and the other had aseptic meningitis and mononucleosis. This is the first report to substantiate that HHV-6 is an important cause of roseola infantum in Taiwan, and that the virus could cause meningitis and thrombocytopenia.


Fibrocalculous pancreatic diabetes.
The aim of this paper is to review the relevant literature related to the epidemiology, pathophysiology, natural history, clinical features and treatment of fibrocalculous pancreatic diabetes (FCPD). We review the English-language literature on this topic published between 1956 and 2014. FCPD is a form of diabetes usually associated with chronic calcific pancreatitis. It has been predominantly, though not exclusively, described in lean, young adults living in tropical developing countries. Historically linked to malnutrition, the etiology of this phenotype has not been clearly elucidated, nor has there been a clear consensus on specific diagnostic criteria or clinical features. Affected individuals usually present with a long-standing history of abdominal pain, which may begin as early as childhood. Progressive pancreatic endocrine and exocrine dysfunction, consistent with chronic pancreatitis is expected. Common causes of chronic pancreatitis, such as alcohol abuse, are usually absent. Typical radiographic and pathological features include coarse pancreatic calcifications, main pancreatic duct dilation, pancreatic fibrosis and atrophy. Progressive microvascular complications are common, but diabetic ketoacidosis is remarkably unusual. Pancreatic carcinoma is an infrequently described long term complication. FCPD is an uncommon diabetes phenotype characterized by early onset non-alcoholic chronic pancreatitis with hyperglycemia, insulin deficiency and a striking resistance to ketosis.


A survey of patient contact shielding in dental teaching hospitals in the UK.
A high volume of dental imaging is carried out each year. In the UK, guidance on the use of patient contact shielding for these investigations is published by the British Institute of Radiology (BIR) and in a document jointly produced by the Faculty of General Dental Practice and Public Health England (FGDP/PHE). Both these sources of guidance have been updated recently and patient contact shielding is no longer recommended for most imaging settings in dental radiology. It is unclear whether radiology departments at dental teaching hospitals in the UK are aware of these sources of guidance, and how this relates to clinical practice within these departments. A survey was carried out exploring the awareness of current guidelines and clinical practice at dental teaching hospitals in the UK. The survey was sent to a representative at 17 different dental teaching hospital radiology departments. Responses were received from 11 departments. The range of intra-oral and extra-oral imaging carried out at these departments was comparable. Ten departments were aware of the existence of national guidelines for patient contact shielding, however only four were specifically aware of the recent BIR guidelines and only four were specifically aware of the FGDP/PHE guidelines. No department was aware of both sets of guidelines. No departments used thyroid protection for bitewing, periapical, lower 45 degree occlusal, panoramic or lateral cephalometric radiographs. Six departments sometimes or always used thyroid protection for upper standard occlusal imaging. Two departments used thyroid protection for cone beam CT imaging. No departments routinely used lead aprons on patients for dental imaging. In conclusion, radiology departments at dental teaching hospitals in the UK do not use patient contact shielding for most imaging situations in dental radiology. There is mixed awareness of current national guidelines, but the reported clinical practice aligns well with the current guidelines.


Combined eight-long noncoding RNA signature: a new risk score predicting prognosis in elderly non-small cell lung cancer patients.
The elderly are the majority of patients with non-small cell lung cancer (NSCLC). Compared to the overall population's predictive guidance, an effective predictive guidance for elderly patients can better guide patients' postoperative treatment and improve overall survival (OS) and disease-free survival (DFS). Recently, the long non-coding RNAs (lncRNAs) have been found to play an important role in predicting tumor prognosis. To identify potential lncRNAs to predict survival in elderly patients with NSCLC, in the present study, we chose 456 elderly patients with NSCLC and analyzed differentially expressed lncRNAs from four Gene Expression Omnibus (GEO) datasets (GSE30219, GSE31546, GSE37745 and GSE50081). We then constructed an eight-lncRNA formula to predict elderly patients' prognosis in NSCLC. Furthermore, we validated the prognostic values of the new risk model in two independent datasets, TCGA (n=670) and GSE31210 (n=130). Our data suggested a significant association between risk model and patients' prognosis. Finally, stratification analysis further revealed the eight-lncRNA signature was an independent factor to predict OS and DFS in stage I elderly patients from both the discovery and validation groups. Functional prediction revealed that 8 lncRNAs have potential effects on tumor immune processes such as lymphocyte activation and TNF production in NSCLC. In summary, our data provides evidence that the eight-lncRNA signature could serve as an independent biomarker to predict prognosis in elderly patients with NSCLC especially in elderly stage I patients.


Active Surveillance Cultures and Targeted Decolonization Are Associated with Reduced Methicillin-Susceptible Staphylococcus aureus Infections in VLBW Infants.
Methicillin-susceptible Staphylococcus aureus (MSSA) is a major contributor to infectious episodes of very low birth weight infants (VLBWI), resulting in significant morbidity and mortality. To examine the efficacy and safety of surveillance cultures and the decolonization of MSSA-colonized VLBWI. VLBWI admitted to our neonatal wards in 2011-2016 were retrospectively analyzed. Rates of MSSA-attributable infections were compared before and after the implementation of active surveillance cultures and the decolonization of MSSA-colonized patients. The mupirocin susceptibility of isolated MSSA strains was routinely tested. A total of 1,056 VLBWI were included in the study, 552 in the pre-intervention period and 504 in the post-intervention period. The implementation of surveillance cultures and decolonization of colonized patients resulted in a 50% reduction of incidence rates per 1,000 patient-days of MSSA-attributable infections (1.63 [95% CI 1.12-2.31] vs. 0.83 [95% CI 0.47-1.35], p = 0.024). No adverse effects were observed from application of the decolonization protocol with mupirocin and octenidin. No mupirocin-resistant MSSA strains were detected during the study period. Implementation of an active surveillance and decolonization protocol resulted in a reduction of MSSA-attributable infections in VLBWI.


New Antibiotic Candidates against Helicobacter pylori.
Helicobacter pylori is a Gram-negative bacterium that colonizes the gut of over 50% of the world's population. It is responsible for most peptic ulcers and is an important risk factor for gastric cancer. Antibiotic treatment for H. pylori infections is challenging as drug resistance has developed to antibiotics with traditional mechanisms of action. H. pylori uses an unusual pathway for menaquinone biosynthesis with 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzing an essential step. We validated MTAN as a target with a transition-state analogue of the enzyme [Wang, S.; Haapalainen, A. M.; Yan, F.; et al. Biochemistry 2012, 51, 6892-6894]. MTAN inhibitors will only be useful drug candidates if they can both include tight binding to the MTAN target and have the ability to penetrate the complex cell membrane found in Gram-negative H. pylori. Here we explore structural scaffolds for MTAN inhibition and for growth inhibition of cultured H. pylori. Sixteen analogues reported here are transition-state analogues of H. pylori MTAN with dissociation constants of 50 pM or below. Ten of these prevent growth of the H. pylori with IC90 values below 0.01 μg/mL. These remarkable compounds meet the criteria for potent inhibition and cell penetration. As a consequence, 10 new H. pylori antibiotic candidates are identified, all of which prevent H. pylori growth at concentrations 16-2000-fold lower than the five antibiotics, amoxicillin, metronidazole, levofloxacin, tetracyclin, and clarithromycin, commonly used to treat H. pylori infections. X-ray crystal structures of MTAN cocrystallized with several inhibitors show them to bind in the active site making interactions consistent with transition-state analogues.


Selection and expansion of T cell from untreated patients with CLL: source of cells for immune reconstitution?
Lymphocyte-derived malignancies can be treated with combinations of drugs that efficiently eradicate normal and malignant lymphocytes. Lack of T lymphocytes after treatment of B lymphocyte CLL (B-CLL) makes the patients susceptible to serious infections and may limit the benefit of the therapy. The aim of the study was to purify and culture-expand normal T lymphocytes from B-CLL patients prior to therapy. These cells could be frozen and given to the patients in the lymphopenic period post-chemotherapy. T lymphocytes were isolated from the mononuclear cell apheresis products from five patients with previously untreated B-CLL. The apheresis products were red-cell depleted by density gradient centrifugation. B-lymphocyte purging was performed by incubating with MAbs to four different B-cell epitopes, followed by magnetic-bead depletion. One round of negative selection removed >90% of the B lymphocytes. The T-lymphocyte enriched cell suspension was cultured for 10/11 days in the presence of IL-2 and the anti-T cell receptor Ab OKT3. In addition, in some cultures anti-CD22 ricin immunotoxin was added. T cells from CLL patients expanded 4.7-21-fold over a 10/11 days culture interval. After culture, CLL cells could no longer be identified by flow cytometric evaluation. The cultured T lymphocytes were predominantly CD8(+), and were capable of lysing autologous CLL cells through a fas-dependent mechanism. Selection and expansion of T lymphocytes by this method may represent a strategy for enhancing immunity in the lymphopenic period following CLL treatment.


The relationship of serum asprosin level with diabetic and non-diabetic retinopathy.
This study was aimed at investigating the role of serum asprosin level in diabetic retinopathy pathogenesis and differential diagnosis diabetic and non-diabetic retinopathy. The cross-sectional study was conducted between May 2021 and August 2021. A total of 21 subjects with diabetic retinopathy, 21 subjects with non-diabetic retinopathy, 21 subjects with type 2 diabetes mellitus (T2DM) without retinopathy and 21 healthy controls were included in the study. Biochemical parameters, serum asprosin, serum IL-6 and TNF-α levels were measured in all participants. Fasting blood glucose (FBG), HbA1c, HOMA-IR and LDL levels were higher in diabetic patients than non-diabetic. The blood asprosin levels were higher in the diabetic retinopathy group compared to the healthy control group (p=0.001), T2DM without diabetic retinopathy (p=0.010), and non-diabetic retinopathy group (p=0.043). There is a significant positive relationship between asprosin level and high FBG, HbA1c and HOMA-IR scores. Serum asprosin level is significantly increased in DRP group than others. A high asprosin level might be a risk factor for the development of diabetic complications, such as diabetic retinopathy. These findings suggest that the measurement of serum asprosin level may support clinicians in determining the risk of DRP development.


Recurrent diabetic myonecrosis -an under-diagnosed cause of acute painful swollen limb in long standing diabetics.
Diabetic myonecrosis (DMN) is an under-diagnosed complication of long-standing poorly controlled diabetes mellitus. It presents as abrupt pain and swelling of the extremity, mostly lower limbs. Diagnosis is often delayed as it mimics a number of clinical entities such as deep vein thrombosis (DVT), cellulitis, necrotizing fasciitis and malignancy. Failure to properly identify this condition can result in increased morbidity through exposure to unnecessary tests and biopsy. A 56-year-old male with a history of complicated type 2 diabetes mellitus, hypertension presented to emergency with gradually worsening left calf pain for last 2 weeks. A lower-extremity venous Doppler was negative for DVT. Magnetic resonance imaging (MRI) was suggestive of muscle edema likely of inflammatory etiology. Muscle biopsy revealed myonecrosis with ischemic myopathy and was negative for vasculitis or inflammatory myopathy. He was managed conservatively and his symptoms resolved in 4 weeks. After 6 months he had recurrence in right thigh which was managed conservatively too. Given these findings, a diagnosis of recurrent diabetic myonecrosis was made. Myonecrosis is a less known microvascular complications of diabetes and should always be keep in mind when evaluating a diabetic patient with muscle pain. Diagnosis can be made on MRI in appropriate clinical settings. The clinical course is usually self-limiting and patients respond well to supportive medical therapy that involves bed rest, strict glycemic control along with analgesic.


Cost effectiveness of molecular profiling for adjuvant decision making in patients with node-negative breast cancer.
To conduct an economic evaluation of the 70-gene signature used to guide adjuvant chemotherapy decision making both in patients with node-negative breast cancer (NNBC) and in the subgroup of estrogen receptor (ER) -positive patients. We used a mixed approach combining patient-level data from a multicenter validation study of the 70-gene signature (untreated patients) and secondary sources for chemotherapy efficacy, unit costs, and utility values. Three strategies on which to base the decision to administer adjuvant chemotherapy were compared: the 70-gene signature, Adjuvant! Online, and chemotherapy in all patients. In the base-case analysis, costs from the French National Insurance Scheme, life-years (LYs), and quality-adjusted life-years (QALYs) were computed for the three strategies over a 10-year period. Cost-effectiveness acceptability curves using the net monetary benefit were computed, combining bootstrap and probabilistic sensitivity analyses. The mean differences in LYs and QALYs were similar between the three strategies. The 70-gene signature strategy was associated with a higher cost, with a mean difference of €2,037 (range, €1,472 to €2,515) compared with Adjuvant! Online and of €657 (95% CI, -€642 to €3,130) compared with systematic chemotherapy. For a €50,000 per QALY willingness-to-pay threshold, the probability of being the most cost-effective strategy was 92% (76% in ER-positive patients) for the Adjuvant! Online strategy, 6% (4% in ER-positive patients) for the systematic chemotherapy strategy, and 2% (20% in ER-positive patients) for the 70-gene strategy. Optimizing adjuvant chemotherapy decision making based on the 70-gene signature is unlikely to be cost effective in patients with NNBC.


Standardized ileal digestible amino acid contents of canola meal from Canadian crushing plants for growing pigs.
Studies have shown that there are variations in the chemical and nutritive composition of canola meal (CM) produced in Canada, some of which may result from differences among the canola seed crushing plants. Therefore, it is necessary to determine the variability in the nutritive value of CM as its end users desire increased meal consistency and more information on any potential variability in AA digestibility. Thus, 18 ileal cannulated barrows (average initial BW = 23.3 kg) were used to determine the apparent (AID) and standardized (SID) ileal digestibility of N and AA and standardized ileal digestible N and AA contents in CM from 6 processing plants in Canada. Two processing plants provided CM in both mash and pellet forms, whereas the other 4 provided it only in mash form, giving a total of 8 CM samples. The barrows were fed 9 cornstarch-based diets. The first 8 diets were formulated to contain the CM samples as the only source of AA. The ninth diet was a casein-cornstarch diet to determine ileal endogenous AA losses. All diets contained 0.3% titanium dioxide as an indigestible marker. Pigs were housed individually in pens and were fed the 9 diets in a completely randomized design for 3 periods to give 6 pigs per diet. Each experimental period lasted for 7 d, consisting of 5 d of adaptation and 2 d of ileal digesta collection at 2-h intervals from 0800 to 2000 h on d 6 and 7. There was an effect ( < 0.05) of CM source on 1) the AID of N, Met, Cys, Thr, Val, Gly, and Ser; 2) the SID of N, Met, and Cys; and 3) the standardized ileal digestible content of all AA. Pelleting reduced ( < 0.05) the standardized ileal digestible content of Arg, Ile, Glu, and Gly in 1 of the CM samples tested and of all AA except His in the other CM sample. The SID values for Arg, Lys, Met, and Thr averaged 87.2%, 78.2%, 84.5%, and 74.1%, respectively. The standardized ileal digestible contents of Arg, Lys, Met, and Thr averaged 2.10%, 1.71%, 0.50%, and 1.01%, respectively. In conclusion, there were variations in the AID, SID, and standardized ileal digestible AA contents of CM among crushing plants in Canada.