Gastric emptying in children with gastroesophageal reflux. II. The relationship to retching symptoms following antireflux surgery.
Following antireflux surgery, children with persistent retching symptoms are presumably more likely to have delayed gastric emptying. We report 66 children between 2 weeks and 16 years of age who had an operation to control gastroesophageal reflux (GER). All patients had GER confirmed by 18- to 24-hour esophageal pH monitoring. Preoperative gastric emptying studies were performed in each patient with 99m-Tc sulfur colloid in apple juice. In addition to the percent gastric emptying (%GE), an effective gastric emptying was estimated by correcting the %GE for postcibal reflux (corrected %GE). Repeat 18- to 24-hour esophageal pH monitoring was performed postoperatively in all patients, and a repeat gastric emptying study was performed in 32 patients. After an average postoperative follow up of 6 months (range of 1 to 18 months), persistent retching was present in 12 (18%) patients. The retching was associated with dumping symptoms in six patients. Retching was seen in patients with a preoperative increase in effective gastric emptying (10/34, 29%, P less than .05) or a decrease in effective gastric emptying (2/15, 13%, NS), and not in patients with an effective gastric emptying within the control range (0/17, 0%). Postoperatively, retching with dumping symptoms was associated with an increased effective gastric emptying, and retching without dumping symptoms with a decreased effective gastric emptying. In conclusion, persistent retching followed anti-reflux surgery in children is related to extremes in effective gastric emptying. The preoperative measurement of corrected %GE identifies children at increased risk for this postoperative problem.


Standardized fluoroscopy-guided implantation technique enables optimal electrode placement in sacral neuromodulation: a cadaver study.
Sacral neuromodulation (SNM) is an established treatment option for patients with faecal incontinence. The location of the stimulating electrode is considered to be essential for treatment success. The purpose of this study was to evaluate the position of SNM electrodes after using a standardized fluoroscopy-guided implantation technique. For this cadaver study, SNM electrodes were implanted bilaterally in 5 lower body specimens. The lower edge of the sacroiliac joint and the medial edge of the sacral foramina were marked using fluoroscopy to draw an 'H' with the crossing points identifying S3. After electrode placement the pelvis was dissected to describe the exact position of the SNM electrodes. The electrodes were inserted at an angle with a median degree measure of 60° (range 50-65°) to the skin, with a median distance of 9 mm (range 0-13 mm) from the S3 marking. All electrodes entered the third sacral foramen. The median distance of the electrodes to the sacral nerve was 0 mm (range 0-3 mm) for the most proximal, 0.5 mm (range 0-5 mm) for the second, 2.25 mm (range 0-11 mm) for the third and 1.75 mm (range 0-16 mm) for the most distant electrode. There was neither a significant difference in the proximity of the electrodes to the nerve between the right and left side (proximal to distal electrode: p = 0.18, p = 0.16, p = 0.07, p = 0.07) nor between male and female cadavers (p = 0.25, p = 0.21, p = 0.66, p = 0.66). A standardized fluoroscopy-guided implantation technique enables a close contact between electrode and nerve. This can potentially result in an improved clinical outcome.


Initial radiologic appearance rather than management strategy predicts the outcomes of sleeve gastrectomy leaks.
Initial radiologic appearance rather than management strategy predicts the outcomes of sleeve gastrectomy leaks. Multiple modalities have been advocated for the treatment of sleeve gastrectomy leak, and there remains no consensus on the best treatment paradigm. For more than 10 years, we have variably attempted luminal occlusive therapies and repeated endoscopic debridement as treatment options. By evaluating the outcomes from these approaches, we aimed to determine whether the first management strategy is superior to the second in terms of outcomes. Patients were analyzed by group (luminal occlusive therapy versus repeated endoscopic debridement). Leaks were then stratified by radiologic appearance on computed tomography, defined as phlegmon, collection, contrast medium leak, or fistula. The primary outcome was length of stay (LOS). Secondary outcomes were comprehensive complication index and the need for resection. There were 54 patients, with 22 in the luminal occlusion group and 32 in the repeated debridement group. There was no difference in LOS (59.8 ± 41.6 versus 46.5 ± 51.2 days, P = .179) and no difference in the requirement for resection (4 versus 3 resections, p = .425). Subset analysis suggested that patients who underwent operative versus conservative management (P = .006) had a longer LOS. Excluding management strategy, radiologic appearance on admission significantly predicted LOS (P = .0053). Patients presenting with fistula (84 ± 25.4 days) and contrast medium leak (64.1 ± 40 days) had a significantly longer LOS than those diagnosed with phlegmon (13.5 ± 5.5 days). Radiologic appearance was predictive of complication severity (P < .0001) and salvage resection (P = .008). There was no significant difference in outcomes between patients treated with intraluminal occlusion or repeated debridement. Initial radiologic appearance was predictive of LOS and complication severity. This highlights the need for routine use of a validated classification system in studies reporting outcomes and treatment of sleeve leaks.


Quaternary 2D monolayer Cu2Cl2Se2Hg2: anisotropic carrier mobility and tunable bandgap for transistor and photocatalytic applications.
Despite the advantages of quaternary two-dimensional (2D) materials, fewer studies have been done on them than binary 2D materials. Calculations of quaternary 2D monolayer Cu2Cl2Se2Hg2based on density functional theory and Green's function surface analysis provide insights into its structural, dynamic, and thermal stability. This material has a direct band gap of 0.91/2.0 eV (Perdew-Burke-Ernzerhof/Heyd-Scuseria-Ernzerhof) and demonstrates anisotropic carrier mobility. The electron mobility in theadirection is 1.2 × 103cm2V-1s-1, which is significantly higher than the hole mobility of 0.48 × 103cm2V-1s-1. In thebdirection, the electron mobility is 1.01 × 103cm2V-1s-1and is 8.9 times larger than the hole mobility of 0.11 × 103cm2V-1s-1. The light absorption coefficients of Cu2Cl2Se2Hg2are 1.0 × 105cm-1and 2.5 × 105cm-1in the visible and ultraviolet ranges, respectively. Uniaxial strain leads to an anisotropic alteration in the band gap and band edge position. By manipulating the strain direction and level in Cu2Cl2Se2Hg2, it is possible to increase the current ON/OFF ratio for field-effect transistors (FETs) and to facilitate photocatalytic water splitting through a redox reaction. The research reveals that Cu2Cl2Se2Hg2, a 2D monolayer in the quaternary form, has promising capabilities as an alternative for creating crystal-oriented FETs and photocatalytic water splitting systems.


Pulmonary DNA vaccination: concepts, possibilities and perspectives.
Mucosal immunity establishes the first line of defence against pathogens entering the body via mucosal surfaces. Besides eliciting both local and systemic immunity, mucosal vaccination strategies that are non-invasive in nature may increase patient compliance and reduce the need for vaccine application by trained personnel. A relatively new concept is mucosal immunization using DNA vaccines. The advantages of DNA vaccines, such as the opportunity to combine the genetic information of various antigen epitopes and stimulatory cytokines, the enhanced stability and ease of production make this class of vaccines attractive and suitable for mucosal application. In contrast to the area of intranasal vaccination, only a few recent studies have focused on pulmonary immunization and the involvement of the pulmonary immune system in eliciting protective immune responses against inhaled pathogens. This review focuses on DNA vaccine delivery to the lung as a promising approach to prevent pulmonary-associated diseases caused by inhaled pathogens. Attractive immunological features of the lung as a site for immunization, the mechanisms of action of DNA vaccines and the pulmonary application of such vaccines using novel delivery systems will be discussed. We also examine pulmonary diseases prone to prevention or therapeutical intervention by application of DNA vaccines.


Apocynin protects against neurological damage induced by quinolinic acid by an increase in glutathione synthesis and Nrf2 levels.
Apocynin (APO) is a well-known NADPH oxidase (NOX) inhibitor. However, several studies have reported its ability to increase glutathione (GSH) levels. Due to GSH is a major non-enzymatic antioxidant in brain, the aim of this study was to evaluate, in the striatum of control and quinolinic acid (QUIN) injected rats, the effect of APO administration on: (1) GSH levels, (2) activity of some enzymes involved in the GSH metabolism, and (3) nuclear factor erythroid-2-related factor 2 (Nrf2) mRNA levels. Animals received QUIN 240nmol in right striatum and APO (5mg/kg, i.p.), 30min before and 60min after intrastriatal injection. APO treatment prevented the QUIN-induced histological damage to the striatum. In control rats, APO treatment increased GSH and Nrf2 mRNA levels and the activities of gamma-glutamylcysteine ligase (γ-GCL), glutathione-S-transferase (GST) and glutathione peroxidase (GPx). On the other hand, APO treatment prevented the QUIN-induced decrease in GSH and Nrf2 levels, and in γ-GCL and GPx activities. These data indicate that APO is able to increase GSH levels and the activity of proteins involved in its metabolism, which could be associated with its ability to increase the Nrf2 mRNA levels.


Adolescent circadian patterns link with psychiatric problems: A multimodal approach.
Circadian rhythms orchestrate brain function and mental wellbeing. We compared circadian patterns derived from continuous measurements of body temperature, sleep actigraphy and self-reported circadian preference in relation to different psychiatric disorders. 342 adolescents (70% females) aged 17.4y underwent M.I.N.I. psychiatric interviews, wore Ibutton 1922L skin temperature loggers (n = 281; 3 days), completed one-week GeneActiv Original actigraphy measurements (n = 306) and responded to Morningness-Eveningness Questionnaire (MEQ; n = 330). We derived circadian period length and amplitude from the temperature loggers. Actigraphy measures included sleep duration, midpoint, efficiency, and irregularity as well as Delayed Sleep Phase (DSP) characteristics (bedtime after 1 a.m. 3 times/week). M.I.N.I. psychiatric interviews suggested that 36% of participants had one or more psychiatric problem, with 21% suffering from comorbidity. Severe depression was associated with longer circadian period (p = 0.002). Suicidality was associated with later midpoint (p = 0.007) and more irregular sleep (p = 0.007). Those with agoraphobia slept longer (p = 0.013). Manic episodes and psychotic disorders were associated with irregular sleep (p-values <0.02). DSP was related to suicidality (p = 0.026), panic disorder (p = 0.022), and greater comorbidity (p = 0.026). Preference for eveningness was similarly related to higher prevalence of Generalized Anxiety Disorder (p = 0.014), social anxiety (p = 0.03), agoraphobia (p = 0.026), panic disorder (p = 0.004), suicidality (p = 0.018), severe depression (p < 0.001), and comorbidity (p < 0.001). Deviations in circadian rhythms were widely associated with psychiatric problems, whereas sleep duration was not. Especially suicidality linked with several markers of circadian disruption: later sleep midpoint, irregular sleep, and DSP characteristics. Longer circadian period length was associated with severe depression.


Knowledge and practices of dairy farmers relating to brucellosis in urban, peri-urban and rural areas of Assam and Bihar, India.
Brucellosis is one of the most common zoonotic diseases in the world. This study aimed at assessing farmers' knowledge about brucellosis as well as practices relevant to transmission of brucellosis and their associated determinants. Few farmers knew about brucellosis (3.4%, n = 18) and its zoonotic importance (0.8%, n = 4). Knowledge about brucellosis was higher for farmers with a larger herd size (p < 0.001) and fully using a stall-fed system (p < 0.001). Training on dairy cattle management (p < 0.001), training on animal disease (p < 0.01), consultation with veterinarians (p < 0.001) and farms being in urban areas (p < 0.01) were also significantly positively associated with knowledge about brucellosis. No significant association was observed between farmers' knowledge about brucellosis and state, family size, education, age or gender of the farmers. Farmers knowledge about brucellosis was significantly associated with certain practices that include use of disinfectant while cleaning farms (p < 0.05), animal movement (p < 0.01), introduction of new animals (p < 0.05) and raw milk consumption (p < 0.05). The study did not find any association between knowledge about brucellosis and method of disposal of aborted materials, personal hygiene and quarantine practices. More interaction with veterinarians and training on animal management may be an important tool for generating awareness among the farming community for reducing transmission of the disease.


Management of posterior lenticonus complicated by unilateral cataract.
We studied 21 patients with 23 eyes with posterior lenticonus. Twenty-one of the eyes developed progressive cataractous changes that required lens aspiration in 19 eyes when vision reduction was 6/30 (20/100) or less. The inherent weakness of the diaphanous portion of the posterior lens capsule contributed to disruption of the normal lamellar arrangement of the lens fibers resulting in cataractous changes. Amblyopia was the most significant visual problem associated with posterior lenticonus. Fifteen of the 19 operated eyes in this study were amblyopic and nine of the 15 were improved to 6/15 (20/50) or better vision with occlusion therapy, after surgical aspiration of the cataractous lens and contact lens therapy.


The mycoflora and toxicity of feedstuffs from a production plant in córdoba, Argentina.
Feedstuffs used for poultry nutrition in Argentina were analyzed for fungal flora and natural incidence of mycotoxins. Survey of 120 samples of poultry feeds, taken from May 1998 to April 1999, showed the presence of 15 genera of filamentous fungi. The predominant genera wereFusarium spp. andPenicillium ssp., isolated in 67.5 % of the samples, followed byAspergillus spp. (57.5 %). Yeast, were significantly isolated from most of the samples. Species identification was carried down for the toxigenic genera. Fungal total counts of poultry feeds ranged from 2.0 × 10(3) to 3.0 × 10(5) CFU g(-1) The fungal total counts during two months of sampling, were slightly over the limit value of 1 × 105 CFU g(-1), which ensure the hygienic quality of the feed. Potentially toxicogenic species presented moderate mean colony counts. Many of the fungi isolated from poultry feeds are mycotoxin producers. Fumonisins had the highest incidence, and were found in 97 % of the analyzed samples followed by aflatoxin B1 (46 %), zearalenone (18 %) and deoxynivalenol (6 %). On the co-occurrence of both carcinogenic mycotoxins, all of the FBs contaminated feed samples were co-contaminated with AFB1. The results show the relevance of the samples screening for viable fungi propagules and the surveillance of their associated mycotoxins in poultry feeds.


Spinal subdural hematoma. A review.
Fifty-eight cases of spinal subdural hematoma were obtained from a review of the literature. Of these, 50 that were reported in detail are analyzed. The data corroborate the opinion that early diagnosis and treatment result in a better prognosis.


[Multicystic kidney disease in a segment of horseshoe kidney: an uncommon combination of malformations].
Multicystic dysplasia is the most common type of renal cystic disease, and it is one of the most common causes of an abdominal mass in infants. The contralateral system is also frequently abnormal. The most commonly associated anomalies are contralateral ureteropelvic junction obstruction and contralateral vesicoureteral reflux. In a few cases, multicystic dysplasia involves a horseshoe kidney or one pole of a duplex kidney. We present a female patient diagnosed with this condition at 9 years old, when she was being studied due to recurrent abdominal pain. The renal function was normal.


Draft Genome Sequence of Bacillus velezensis 3A-25B, a Strain with Biocontrol Activity against Fungal and Oomycete Root Plant Phytopathogens, Isolated from Grassland Soil.
Here, we present the draft genome of Bacillus velezensis 3A-25B, which totaled 4.01 Mb with 36 contigs, 3,948 genes, and a GC content of 46.34%. This strain, which demonstrates biocontrol activity against root rot causal phytopathogens in horticultural crops and friendly interactions in roots of pepper plantlets, was obtained from grassland soil in Zacatecas Province, Mexico.


Toward the robust resolution of taxonomic ambiguity within Lepocinclis (Euglenida) based on DNA sequencing and morphology.
DNA sequences were analyzed for three groups of species from the Lepocinclis genus (L. acus-like, L. oxyuris-like, and L. tripteris-like) along with cellular morphology. Phylogenetic analyses were based on nuclear SSU rDNA, LSU rDNA, and plastid-encoded LSU rDNA. DNA sequences were obtained from species available in culture collections (L. acus SAG 1224-1a and UTEX 1316) and those isolated directly from the environment in Poland (48 isolates), resulting in 79 new sequences. The obtained phylogenetic tree of Lepocinclis included 27 taxa, five of which are presented for the first time (L. convoluta, L. gracillimoides, L. longissima, L. pseudospiroides, and L. torta) and nine taxonomically verified and described. Based on morphology, literature data, and phylogenetic analyses, the following species were distinguished: in the L. acus-like group, L. longissima and L. acus; in the L. tripteris-like group, L. pseudospiroides, L. torta, and L. tripteris; in the L. oxyuris-like group, L. gracillimoides, L. oxyuris var. oxyuris, and L. oxyuris var. helicoidea. For all verified species, diagnostic descriptions were emended, nomenclatural adjustments were made, and epitypes were designated.


Immune signaling in sex-specific neural and behavioral development: Adolescent opportunity.
Sex differences in neural and behavioral development are integral to understanding neurodevelopmental, mental health, and neurodegenerative disorders. Much of the literature has focused on late prenatal and early postnatal life as a critical juncture for establishing sex-specific developmental trajectories, and data are now clear that immune signaling plays a central role in establishing sex differences early in life. Adolescence is another developmental period during which sex differences arise. However, we know far less about how immune signaling plays a role in establishing sex differences during adolescence. Herein, we review well-defined examples of sex differences during adolescence and then survey the literature to speculate how immune signaling might be playing a role in defining sex-specific adolescent outcomes. We discuss open questions in the literature and propose experimental design tenets that may assist in better understanding adolescent neurodevelopment.


Preliminary assessment of patient and physician satisfaction with the use of teleconsultation in urology during the COVID-19 pandemic.
Lockdown during the COVID-19 pandemic compelled urologists to change access to healthcare, especially for oncology patients. Teleconsultation is a safe way to receive medical advice without a risk of infection, and was implemented urgently in our academic centres. Our purpose was to evaluate patient and physician satisfaction with teleconsultation set up during the COVID-19 pandemic. From March 16th 2020, all face-to-face consultations were cancelled in France, except for emergencies. Teleconsultation was started immediately by five senior urologists in two academic hospitals. All patients received an email survey including the validated Teleconsultation Satisfaction Questionnaire (TSQ) and demographic questions. Data were collected prospectively. Physicians also responded to the TSQ. Patient satisfaction was measured objectively with the validated 14-item TSQ. Each item was scored on a 5-point Likert scale. Factors associated with positive satisfaction with teleconsultation were assessed by multivariable logistic regression. Overall, 105 patients replied to the survey (91.3%). Median age was 66 years (IQR: 55‒71) and 95 were men (90.5%). Median overall TSQ score was 67 (IQR: 60‒69); teleconsultation was judged to be a good experience by 88 patients (83.8%) and four physicians (80%). Patients who met their surgeon for the first time were more likely to have a good experience (OR = 1.2 [95% CI 1.1‒1.5], p = 0.03). Introduced rapidly during the COVID-19 lockdown, urology teleconsultation attained a high level of satisfaction among both patients and physicians. A major change in telemedicine use is foreseen in the post COVID-19 era.


Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling.
Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling.


Order of inoculation affects the success of co-invading entomopathogenic fungi.
The effect of order of inoculation of Pandora blunckii and Zoophthora radicans co-infecting Plutella xylostella (L.) (Lepidoptera: Plutellidae) was investigated. After co-inoculation, the proportion of larvae infected by either species was greatly reduced compared to when they were inoculated singly. The order of inoculation influenced the final outcome; the isolate inoculated last always killed more larvae than the isolate inoculated first.


A mild form of mucolipidosis type III in four Baluch siblings.
Four Baluch siblings with mucolipidosis type III (pseudo-Hurler polydystrophy) are described. The patients had features commonly found in mucolipidosis III, including claw hands, joint stiffness, aortic valve involvement and radiological dysostosis multiplex. However, intelligence was normal, there were no eye abnormalities on slit-lamp examination and skin elasticity was normal. Many lysosomal enzymes were elevated in serum and diminished in cultured fibroblasts, although the findings for beta-galactosidase were atypical. Assays for the two enzymes involved in formation of the phosphomannose recognition marker revealed normal activity of the phosphotransferase with alpha-methylmannoside as an acceptor, and normal activity of the phosphodiester glycosidase. Metabolic labelling of fibroblasts with 32P followed by immunoprecipitation of cathepsin D, electrophoresis and fluorography showed that this enzyme was not labelled in the patients' cells, although some label was detected in the secreted precursor polypeptide. The data are consistent with the assumption that activity of the phosphotransferase is low towards lysosomal enzymes as substrates, and that the patients belong to complementation group C.


Correction to: Effect of periodic abstinence from dairy products for approximately half of the year on bone health in adults following the Christian Orthodox Church fasting rules for decades.
The original version of this article, published on 27 June 2019, unfortunately contained a mistake.


Patterns of depressive symptoms over 16 Years with incident dementia: The Health and Retirement Study.
The associations of patterns of depressive symptoms, including trajectories of depressive symptoms and significant depressive symptoms among older adults over a long period of time with incident dementia are not frequently studied. We aimed to examine the associations of patterns of depressive symptoms among older adults with incident dementia. Participants of the Health and Retirement Study from 1994 to 2018 with information of incident dementia and complete measurements of depressive symptoms were included. Depressive symptoms assessed on 8 waves between 1994 and 2010 using the 8-item Center for Epidemiologic Studies Depression (CES-D) Scale. Significant depressive symptoms were defined as ≥4 points in the CES-D. Trajectories of depressive symptoms and significant depressive symptoms were identified. Cox proportional hazards models were used to examine the associations of patterns of depressive symptoms with incident dementia. A total of 6317 participants were included in the analysis. Over the follow-up period of 8 years, trajectories of "increase from mild" (hazards ratio (HR): 1.84, 95% confidence interval (CI): 1.29, 2.63) and "persistently high" (HR: 1.76, 95% CI: 1.17, 2.65) depressive symptoms were associated with higher risk of incident dementia, after adjustment for covariates. Future studies are needed to examine the interaction of depression in different stages of life on incident dementia. Studies are also expected to estimate the effect of preventing dementia through reducing depressive symptoms.


Effects of radiofrequency catheter ablation on patients with permanent pacemakers.
The objective of this study was to assess the effects of radiofrequency energy application on implanted pacemaker functions. Radiofrequency (RF) catheter ablation may cause pacemaker dysfunction due to electromagnetic interferences. The effects of RF on pacemaker behavior were studied in a series of 38 pacemakers, implanted 18 +/- 26 months prior to a RF procedure using either a right ventricular approach (AV node ablation, n = 35) or a left ventricular approach (left concealed accessory pathway ablation, n = 1; VT ablation, n = 2). The 38 patients (mean age 65 +/- 9 years) included 20 men and 18 women. Before energy applications, the 23 different pacemaker models were programmed to the VVI mode at the lowest available rate. The continuous surface ECG was recorded throughout the procedure. Thorough testing of the devices was performed before and after each RF delivery. Unusual pacemaker responses occurred in 20 of the 38 cases studied (53%). The impact of RF delivery was unpredictable, and variable dysfunctions were observed at different times for a given patient or could vary for a given model. Unusual pacemaker responses included pacemaker inhibition (n = 8), untoggled backup mode (n = 3), electromagnetic interference noise mode (n = 3), temporary RF-induced pacemaker tachycardia (n = 2), erratic behavior (n = 1), oversensing of RF onset and offset (n = 8), and transient loss of ventricular capture, (n = 1). Postablation, most devices automatically toggled back to full functionality. The three devices in the untoggled backup mode had to be reprogrammed to obtain normal operations. At the end of the procedure, pacing thresholds remained unchanged in all but one patient, in whom the increase in ventricular threshold was due to a nicked lead. In conclusion, implanted pacemakers frequently exhibit transient, unpredictable responses to RF energy application. Although all pacemaker functions were restored postablation, some devices had to be reset manually. The anomalies observed during the RF application argue for the simultaneous use of an external pacemaker in pacing-dependent patients.


Neuromedin U alters bioenergetics and expands the cancer stem cell phenotype in HER2-positive breast cancer.
Neuromedin U (NmU) is a neuropeptide belonging to the neuromedin family. Recently, we reported a significant association between NmU and breast cancer, particularly correlating with increased aggressiveness, resistance to HER2-targeted therapies and overall significantly poorer outcome for patients, although the mechanism through which it exerts this effect remained unexplained. Investigating this, here we found that ectopic over-expression of NmU in HER2-positive breast cancer cells induced aberrant metabolism, with increased glycolysis, likely due to enhanced pyruvate dehydrogenase kinase activity. Similar results were observed in HER2-targeted drug-resistant cell variants, which we had previously shown to display increased levels of NmU. Overexpression of NmU also resulted in upregulation of epithelial-mesenchymal transition markers and increased IL-6 secretion which, together with aberrant metabolism, have all been associated with the cancer stem cell (CSC) phenotype. Flow cytometry experiments confirmed that NmU-overexpressing and HER2-targeted drug-resistant cells showed an increased proportion of cells with CSC phenotype (CD44+ /CD24- ). Taken together, our results report a new mechanism of action for NmU in HER2-overexpressing breast cancer that enhances resistance to HER2-targeted drugs through conferring CSC characteristics and expansion of the CSC phenotype.


Glucose-lowering drug use in migrants and native Danes with type 2 diabetes: Disparities in combination therapy and drug types.
To examine disparities in glucose-lowering drug (GLD) usage between migrants and native Danes with type 2 diabetes (T2D). In a nationwide, register-based cross-sectional study of 253 364 individuals with prevalent T2D on December 31, 2018, we examined user prevalence during 2019 of (i) GLD combination therapies and (ii) individual GLD types. Migrants were grouped by origin (Middle East, Europe, Turkey, Former Yugoslavia, Pakistan, Sri Lanka, Somalia, Vietnam), and relative risk (RR) versus native Danes was computed using robust Poisson regression to adjust for clinical and socioeconomic characteristics. In 2019, 34.7% of native Danes received combination therapy, and prevalence was lower in most migrant groups (RR from 0.78, 95% confidence interval CI 0.71-0.85 [Somalia group] to 1.00, 95% CI 0.97-1.04 [former Yugoslavia group]). Among native Danes, the most widely used oral GLD was metformin (used by 62.1%), followed by dipeptidyl peptidase-4 inhibitors (13.3%), sodium-glucose cotransporter-2 inhibitors (11.9%) and sulphonylureas (5.2%), and user prevalence was higher in most migrant groups (RR for use of any oral GLD: 0.99, 95% CI 0.97-1.01 [Europe group] to 1.09, 95% CI 1.06-1.11 [Sri Lanka group]). Furthermore, 18.7% of native Danes used insulins and 13.3% used glucagon-like peptide-1 receptor agonists (GLP-1RAs), but use was less prevalent in migrants (RR for insulins: 0.66, 95% CI 0.62-0.71 [Sri Lanka group] to 0.94, 95% CI 0.89-0.99 [Europe group]; RR for GLP-1RAs: 0.29, 95% CI 0.22-0.39 [Somalia group] to 0.95, 95% CI 0.89-1.01 [Europe group]). Disparities in GLD types and combination therapy were evident between migrants and native Danes. Migrants were more likely to use oral GLDs and less likely to use injection-based GLDs, particularly GLP-1RAs, which may contribute to complication risk and mortality among this group.


An out of the box treatment for an infected pseudoaneurysm: Deep to superficial femoral artery transposition.
An infected pseudoaneurysm is a condition that has become more common in recent years, with the proliferation of endovascular intervention and the use of intravenous drugs. If left untreated, an infected pseudoaneurysm can progress to rupture, which can lead to life-threatening hemorrhage. No clear consensus has been reached among vascular surgeons regarding the management of infected pseudoaneurysms, and the literature describes a wide range of treatment techniques. In the present report, we describe an "out of the box" approach to infected pseudoaneurysms: a superficial femoral artery to deep femoral artery transposition, as an alternative to ligation with or without bypass reconstruction. We also describe our experience with six patients who underwent this procedure with 100% technical success and limb salvage rates. Although we implemented this technique for cases of infected pseudoaneurysms, we believe it can also be applied to other cases of femoral pseudoaneurysms when angioplasty or graft reconstruction is not feasible. However, further research with larger cohorts is warranted.


Inhibitor of cyclooxygenase-2 induces cell-cycle arrest in the epithelial cancer cell line via up-regulation of cyclin dependent kinase inhibitor p21.
Cyclooxygenase-2 is the rate-limiting enzyme in synthesis of prostaglandins and other eicosanoids. Prior reports have shown that inhibition of cyclooxygenase-2 activity, either by selective inhibitors or by antisense oligonucleotide, results in suppression of growth of squamous cell carcinoma cell lines which express high cyclooxygenase-2 levels, such as NA, a cell line established from a squamous cell carcinoma of the tongue. To investigate the mechanisms by which cyclooxygenase-2 inhibitors suppressed growth of these cells, the effects of NS-398, the selective cyclooxygenase-2 inhibitor, on cell-cycle distribution were examined. NS-398 induced G0/G1 cell-cycle arrest in NA cells which expressed cyclooxygenase-2. G0/G1 arrest induced by NS-398 was accompanied by up-regulation of cyclin-dependent kinase inhibitor p21, but not by up-regulation of the other cyclin-dependent kinase inhibitors. Transfection with p21 antisense oligonucleotide inhibited cell-cycle arrest induced by NS-398. Accumulation in G0/G1 was also observed in NA cells transfected with cyclooxygenase-2 antisense oligonucleotide. On the other hand, NS-398-treated NA cells showed a loss of plasma membrane asymmetry, a marker of early events in apoptosis. However, NS-398 did not induce other morphological and biochemical changes related to apoptotic cell death. These results suggest that cyclooxygenase-2 inhibitor induces G0/G1 cell-cycle arrest in NA cells by up-regulation of p21. Our results also suggest that NS-398 is not sufficient to complete the whole process of apoptosis in NA cells, although it induces an early event in apoptosis.


Surgical site infection after laparoscopic resection of colorectal cancer is associated with compromised long-term oncological outcome.
We evaluated the influence of infectious complications, particularly surgical site infection (SSI), on long-term oncological results after elective laparoscopic resection of colorectal cancer. A total of 199 patients who underwent laparoscopic elective resection with negative resection margins for stage I-III colorectal cancer were retrospectively examined. The postoperative course was recorded based on hospital records, and cancer relapse was diagnosed based on radiological or pathological findings under a standardized follow-up program. The severity of complications was graded using Clavien-Dindo (CD) classification. SSI was found in 25 patients (12.6%), with 12 (6.0%) showing anastomotic leak. The postoperative relapse-free survival (RFS) rate was significantly lower in patients with SSI (49.2%) than in patients without SSI (87.2%, P<0.001). Differences in RFS were found after both colectomy and rectal resection (P<0.001 and P<0.001, respectively). RFS did not differ between patients who had major SSI CD (grade III) and those who had minor SSI CD (grades I or II). Multivariate Cox regression analysis identified the occurrence of SSI and pathological stage as independent co-factors for RFS (P<0.001 and P=0.003). These results suggest that postoperative SSI compromises long-term oncological results after laparoscopic colorectal resection. Further improvements in surgical technique and refinements in perioperative care may improve long-term oncological results.


Distinct expression of NK2 homeobox 1 (NKX2-1) and goblet cell hyperplasia in nasal polyps with different endotypes.
Decreased expression of airway epithelial-specific transcription factor NK2 homeobox 1 (NKX2-1) was associated with allergic inflammation in asthma patients. However, the expression and role of NKX2-1 in nasal polyps (NPs) with different endotypes were undefined yet. We examined the expression of key cytokines (interleukin [IL]-4 IL-5, IL-13, and IL-17A, etc.) and NKX2-1 in NPs with different endotypes and control tissues by immunohistochemistry staining, qualitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. We found 23% of chronic rhinosinusitis (CRS) with NP (CRSwNP) patients had IL-5+ eosinophilic NPs, 40.7% of NPs were key cytokines negative NPs (KCN NPs) with less eosinophil accumulation. The expression of NKX2-1 in IL-5+ NPs was significantly lower than KCN NPs and normal controls (p < 0.05). The expression of mucin 5AC (MUC5AC) and MUC5B, as well as goblet cells hyperplasia, were significantly elevated in IL-5+ NPs, which correlated with the decreased expression of NKX2-1 (p < 0.05). Moreover, "SAM pointed domain containing ETS transcription factor" (SPDEF) was significantly elevated, while expression of Forkhead Box A2 (FoxA2) was significantly decreased in IL-5+ NPs (p < 0.05). The expression of chemokine (C-C motif) ligand 17 (CCL17) and IL-4 was significantly increased in IL-5+ NPs, which was associated with eosinophil accumulation(p < 0.05). The downregulation of NKX2-1 in IL-5+ NPs may be associated with tissue eosinophilia and goblet cells hyperplasia.


Congenital bilateral diaphragmatic eventration with membranous chest wall hamartoma.
The case of a 2-month-old girl with congenital bilateral eventration of the diaphragm is reported. After normal delivery from cephalic position, the patient developed respiratory distress. Mechanical ventilation started immediately but extubation was difficult. A membranous lesion was found on computed tomography of the chest. Resection of the membrane between the right middle and lower lobes and bilateral diaphragmatic plication was performed. Histologically the membrane was a chest wall hamartoma. The patient was extubated on 6 day postoperatively and is alive and well 4 months after surgery.


Anatomical basis of the coordination between smooth and striated urethral and anal sphincters: loops of regulation between inferior hypogastric plexus and pudendal nerve. Immuno-histological study with 3D reconstruction.
(1) Describe both nervous pathways to the sphincters, and highlight the anatomical support of their coordination. (2) Obtain a 3D representation of this complex innervation system. A computer-assisted anatomical dissection technique was used. Serial histological sections were cut in the pelvis of four female human foetuses (aged 19-32 weeks of gestation). The sections were treated with conventional staining, and with seven different immunostainings. The sections were digitalized and, finally, a 3D representation was built from the corresponding images. Myelinated and sensory fibres were detected at the inferior hypogastric plexus (IHP) level. Our analysis showed that most of the afferent sensory fibres come from the urinary and anal sphincters through the anterior and posterior branches of the IHP respectively. A highly positive nitrergic (anti-NOS1) and sensitive (anti-CGRP) labelling was found in the external layer of the urethral sphincter. The 3D representation allowed describing the two components of the innervation system. A sensory-motor regulation loop was found for both sphincters. A 3D description of the components of both nervous pathways to the sphincters has been established. Our findings on the innervation of the sphincters tend to question the classical infra/supra levatorian muscle description. The coordinated work of the internal and external layers of the anal and urethral sphincter is probably mediated by multiple roles regulation.


Traditional Chinese Medicine: Salvia miltiorrhiza Enhances Survival Rate of Autologous Adipose Tissue Transplantation in Rabbit Model.
This study aimed to explore the influence of traditional Chinese medicines: Salvia miltiorrhiza on the survival of auto-transplantation of adipose tissue in a rabbit model. Minced adipose tissue harvested from the scapular region was transplanted into the dorsum of the ears of New Zealand rabbits. The experimental groups were intra-peritoneally injected with S. miltiorrhiza for a total 4 weeks. The rabbits in control group were intra-peritoneally injected with normal saline. Plasma VEGF levels were assayed at week 1, 2, 4, 6, and 8 after fat tissue auto-transplantation in the dorsum of rabbit ears. Graft samples were collected and measured at week 2, 4, and 12. Survival rates were calculated, and histologic morphology was evaluated. The expression of CD31 was detected by means of immune-histochemical staining to observe neo-vascularization of the auto-transplanted fat tissue. Perilipin was detected by means of immune-histochemical staining to observe the survival of fat cells. At 12 weeks, the survival rates in the experimental group were statistically greater than that in the control group, respectively (p < 0.05). Plasma levels of VEGF in the experimental group at different time points were significantly higher than that in the control group (p < 0.05). Histologically, grafts in the experimental group showed better survival of adipocytes and neo-vascularization. By perilipin immuno-histochemical staining, the experimental group demonstrated better adipocyte survival. In the rabbit model, S. miltiorrhiza can promote the neo-vascularization of adipose tissue grafts and significantly improves the survival rate of auto-transplanted adipose tissue. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.


Bioprocess development for the production of novel oleogels from soybean and microbial oils.
This study presents the production of novel oleogels via circular valorisation of food industry side streams. Sugarcane molasses and soybean processing side streams (i.e. soybean cake) were employed as fermentation feedstocks for the production of microbial oil. Fed-batch bioreactor fermentations carried out by the oleaginous yeast Rhodosporidium toruloides led to the production of 36.9 g/L total dry weight with an intracellular oil content of 49.8% (w/w) and 89.4 μg/g carotenoids. The carotenoid-rich microbial oil and soybean oil were evaluated as base oils for the production of wax-based oleogels. The wax esters, used as oleogelators, were produced via enzymatic catalysis, using microbial oil or soybean fatty acid distillate as raw materials. All oleogels presented a gel-like behaviour (G' > G″). However, the highest G' was determined for the oleogel produced from soybean oil and microbial oil-wax esters, which indicated a stronger network. Thermal analysis showed that this oleogel had a melting temperature profile up to 35 °C, which is favorable for applications in the confectionery industry. Also, texture analysis demonstrated that soybean oil-microbial oil wax oleogel was stable (1.9-2.2 N) within 30-days storage period. This study showed the potential of novel oleogels production through the development of bioprocesses based on the valorisation of various renewable resources.


Technical and biological aspects of pseudomosaicism and mosaicism.
In 471 amniotic fluid cell cultures, single abnormal cells were found to be randomly distributed. The expected number of pseudomosaicisms for aneuploidy due to randomly distributed cells was 3.9, and the observed number was 4. Expected number of mosaicism for aneuploidy was 0.6, and none was observed. The findings indicated that pseudomosaicisms as well as mosaicisms may be diagnosed from randomly distributed single abnormal cells. The probability of erroneously confirming mosaicism increased with the number of cells analysed in the second culture.


Somatic DNA demethylation generates tissue-specific methylation states and impacts flowering time.
Cytosine methylation is a reversible epigenetic modification of DNA. In plants, removal of cytosine methylation is accomplished by the four members of the DEMETER (DME) family of 5-methylcytosine DNA glycosylases, named DME, DEMETER-LIKE2 (DML2), DML3, and REPRESSOR OF SILENCING1 (ROS1) in Arabidopsis thaliana. Demethylation by DME is critical for seed development, preventing experiments to determine the function of the entire gene family in somatic tissues by mutant analysis. Here, we bypassed the reproductive defects of dme mutants to create somatic quadruple homozygous mutants of the entire DME family. dme; ros1; dml2; and dml3 (drdd) leaves exhibit hypermethylated regions compared with wild-type leaves and rdd triple mutants, indicating functional redundancy among all four demethylases. Targets of demethylation include regions co-targeted by RNA-directed DNA methylation and, surprisingly, CG gene body methylation, indicating dynamic methylation at these less-understood sites. Additionally, many tissue-specific methylation differences are absent in drdd, suggesting a role for active demethylation in generating divergent epigenetic states across wild-type tissues. Furthermore, drdd plants display an early flowering phenotype, which involves 5'-hypermethylation and transcriptional down-regulation of FLOWERING LOCUS C. Active DNA demethylation is therefore required for proper methylation across somatic tissues and defines the epigenetic landscape of intergenic and coding regions.


Cell-cycle phospho-regulation of the kinetochore.
The kinetochore is a mega-dalton protein assembly that forms within centromeric regions of chromosomes and directs their segregation during cell division. Here we review cell cycle-mediated phosphorylation events at the kinetochore, with a focus on the budding yeast Saccharomyces cerevisiae and the insight gained from forced associations of kinases and phosphatases. The point centromeres found in the budding yeast S. cerevisiae are one of the simplest such structures found in eukaryotes. The S. cerevisiae kinetochore comprises a single nucleosome, containing a centromere-specific H3 variant Cse4CENP-A, bound to a set of kinetochore proteins that connect to a single microtubule. Despite the simplicity of the budding yeast kinetochore, the proteins are mostly homologous with their mammalian counterparts. In some cases, human proteins can complement their yeast orthologs. Like its mammalian equivalent, the regulation of the budding yeast kinetochore is complex: integrating signals from the cell cycle, checkpoints, error correction, and stress pathways. The regulatory signals from these diverse pathways are integrated at the kinetochore by post-translational modifications, notably phosphorylation and dephosphorylation, to control chromosome segregation. Here we highlight the complex interplay between the activity of the different cell-cycle kinases and phosphatases at the kinetochore, emphasizing how much more we have to understand this essential structure.


Biochar carrier application for nitrogen removal of domestic WWTPs in winter: challenges and opportunities.
Biofilm processes have a better nitrogen removal ability than traditional activated sludge at low temperatures (< 15 °C). Many biofilm processes, as well as integrated biofilm and activated sludge processes, are potential and realizable nitrogen removal upgrading methods for domestic wastewater treatment plants (WWTPs). Therefore, biofilm packing material is attractive for domestic WWTP upgrading and reconstruction in winter. For a half decade, researchers have successfully applied activated carbon to biochar as biofilm carrier in the wastewater treatment field. Biochar, as a biostable soil amendment with pores and crevices on its surface, has been applied in the soil-plant system, which promoted the adsorption of NH4+ and NO3-, decreased N2O emission, transcriptional level of narG, nxrA, and nirS, and changed the microbial community composition for better nitrogen removal. However, in the field of wastewater treatment, the study of biochar-packed process is merely in the laboratory stage of simulated wastewater, which deserves further research in the future. In this mini review, we will discuss the performances of different processes at low temperatures, the related mechanism of the biochar-packed process for nitrogen removal, and other potential applications of biochar carriers.


Metabolic rates associated with distress and begging calls in birds.
Rates of oxygen consumption during begging behaviour in nestlings of seven species and distress call behaviour in adults of eight species of Australian birds were measured. A transparent mask coupled to an open-flow respirometry system was used, and calling was elicited by the presentation of food or by the perceived threat of a predator. Distress calling significantly increased oxygen consumption above the measured resting levels in six of the species of birds tested. The factorial increase in oxygen consumption during distress calling was independent of body mass. In most cases, begging behaviour in juvenile birds caused a significant increase in metabolic rate, with some individuals showing factorial increases over fourfold. There was a significant negative correlation between body mass and the factorial cost of begging behaviour.


Zygomatico-maxillary fractures. Late results after traction-hook reduction.
A simple, closed method for zygomatico-maxillary fracture treatment is described i.e. replacement by the use of a traction bone-hook. After X-ray and clinical examination had excluded undisplaced fractures, blow out fractures and comminuted fractures, the postreduction stability was assessed peroperatively and again one week after. Sophisticated preoperative fracture-classifications predicting postoperative stability appeared redundant. In the present study, this procedure could be performed in 55.4% of the total fractures which needed to be reduced. At re-evaluation, two to eight years later, the results remained satisfactory. The method appeared, in addition to its simplicity, to require less complicated postoperative care and, therefore, a short hospitalization.


The human intracellular Mx-homologous protein is specifically induced by type I interferons.
The murine Mx-1 protein is one of the best biochemically and functionally characterized interferon (IFN)-induced proteins that is necessary, and sufficient, for providing resistance to murine cells against viral influenza infection. Recently an intracellular human protein homologous to the murine Mx-1 protein has been identified by means of a specific monoclonal antibody. The restricted induction of this intracellular protein in human mononuclear cells (MNC) by various cytokines was investigated. MNC from 26 of 28 healthy people and 35 of 36 cancer patients before IFN-alpha therapy had no detectable Mx-homologous protein. Incubation of human MNC with IFN-alpha and IFN-beta for 24 h at different concentrations led to a dose-dependent induction of the Mx-homologous protein. All IFN-alpha or IFN-beta preparations tested were equally effective in eliciting this intracellular protein. IFN-gamma induced only 1% of the Mx amount elicited by type-1 IFN compared on a weight basis. Neither interleukin (IL) 1 nor IL3, IL4, IL5, IL6, tumor necrosis factor-alpha/beta, granulocyte colony-stimulating factor (CSF) or granulocyte macrophage-CSF at any of the concentrations tested were capable of eliciting any detectable amount of the Mx homolog, while IL2 was a poor Mx-homologous protein inducer. In the presence of high-titered IFN-alpha antisera both IL2 and IFN-gamma were unable to stimulate this protein, proving that IFN-gamma and IL2 indirectly induce the Mx homolog via IFN-alpha. Therefore, the human Mx-homologous protein is a strictly by type I IFN-regulated protein in human peripheral blood lymphocytes.


A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes.
Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase the expression of inhibitory immune checkpoint molecules. We conducted the first randomized phase 2 study of azacitidine plus the immune checkpoint inhibitor durvalumab vs azacitidine monotherapy as first-line treatment for higher-risk myelodysplastic syndromes (HR-MDS). In all, 84 patients received 75 mg/m2 subcutaneous azacitidine (days 1-7 every 4 weeks) combined with 1500 mg intravenous durvalumab on day 1 every 4 weeks (Arm A) for at least 6 cycles or 75 mg/m² subcutaneous azacitidine alone (days 1-7 every 4 weeks) for at least 6 cycles (Arm B). After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arm A received a median of 7.9 treatment cycles and those in Arm B received a median of 7.0 treatment cycles with 73.7% and 65.9%, respectively, completing ≥4 cycles. The overall response rate (primary end point) was 61.9% in Arm A (26 of 42) and 47.6% in Arm B (20 of 42; P = .18), and median overall survival was 11.6 months (95% confidence interval, 9.5 months to not evaluable) vs 16.7 months (95% confidence interval, 9.8-23.5 months; P = .74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (Arm A) and 81% (Arm B). Grade 3 or 4 hematologic AEs were reported in 89.5% (Arm A) vs 68.3% (Arm B) of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased programmed cell death ligand 1 (PD-L1 [CD274]) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining azacitidine with durvalumab in patients with HR-MDS was feasible but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. This trial was registered at www.clinicaltrials.gov as #NCT02775903.


Autophagy and bacterial infectious diseases.
Autophagy is a housekeeping process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic constituents. Over the past several years, accumulating evidence has suggested that autophagy can function as an intracellular innate defense pathway in response to infection with a variety of bacteria and viruses. Autophagy plays a role as a specialized immunologic effector and regulates innate immunity to exert antimicrobial defense mechanisms. Numerous bacterial pathogens have developed the ability to invade host cells or to subvert host autophagy to establish a persistent infection. In this review, we have summarized the recent advances in our understanding of the interaction between antibacterial autophagy (xenophagy) and different bacterial pathogens.


Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of pKa Values.
The new empirical rules for protein pKa predictions implemented in the PROPKA3.0 software package (Olsson et al. J. Chem. Theory Comput.2010, 7, 525-537) have been extended to the prediction of pKa shifts of active site residues and ionizable ligand groups in protein-ligand complexes. We present new algorithms that allow pKa shifts due to inductive (i.e., covalently coupled) intraligand interactions, as well as noncovalently coupled interligand interactions in multiligand complexes, to be included in the prediction. The number of different ligand chemical groups that are automatically recognized has been increased to 18, and the general implementation has been changed so that new functional groups can be added easily by the user, aided by a new and more general protonation scheme. Except for a few cases, the new algorithms in PROPKA3.1 are found to yield results similar to or better than those obtained with PROPKA2.0 (Bas et al. Proteins: Struct., Funct., Bioinf.2008, 73, 765-783). Finally, we present a novel algorithm that identifies noncovalently coupled ionizable groups, where pKa prediction may be especially difficult. This is a general improvement to PROPKA and is applied to proteins with and without ligands.


The use of the electromagnetic field in microbial process bioengineering.
An electromagnetic field (EMF) has been shown to have various stimulatory or inhibitory effects on microorganisms. Over the years, growing interest in this topic led to numerous discoveries suggesting the potential applicability of EMF in biotechnological processes. Among these observations are stimulative effects of this physical influence resulting in intensified biomass production, modification of metabolic activity, or pigments secretion. In this review, we present the current state of the art and underline the main findings of the application of EMF in bioprocessing and their practical meaning in process engineering using examples selected from studies on bacteria, archaea, microscopic fungi and yeasts, viruses, and microalgae. All biological data are presented concerning the classification of EMF. Furthermore, we aimed to highlight missing parts of contemporary knowledge and indicate weak spots in the approaches found in the literature.


Distribution of T- and B-cells and of immunoglobulin-producing cells in tumor tissue of patients with nasopharyngeal carcinoma.
Various subtypes of 17 European nasopharyngeal carcinomas are examined by immunocytological and immunohistological methods. The T- and B-Cells in the inflammatory infiltrate are determined quantitatively and correlated with the amount and type of intracellular immunoglobulin. This data is compared with peripheral T-Cell values and the serum anti Epstein-Barr virus (EBV) titers, and finally with the tumor type and stage. Three of the 17 patients had marked local immunoglobulin producing cells, 8 only moderate, and 6 had nearly none. The intracellular immunoglobulin was primarily IgG/kappa, and no significant increase of IgA producing cells was observed as suggested by others. No clearcut correlation was found between local T- and B-Cell infiltrates and the tumor type, stage of disease, or anti EBV titers in the patients' serum. The possible implication of this data is discussed.


Epigenetic silencing of the MUPCDH gene as a possible prognostic biomarker for cyst growth in ADPKD.
Although autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease, and is characterized by the formation of multiple fluid-filled cysts, which results in renal failure, early diagnosis and treatment of ADPKD have yet to be defined. Herein, we observed that the promoter region of the gene encoding mucin-like protocadherin (MUPCDH) was hypermethylated in the renal tissue of patients with ADPKD compared to non-ADPKD controls. Inversely, MUPCDH was significantly repressed in ADPKD, especially in cyst-lining cells. Our results indicate that aberrant methylation of MUPCDH promoter CpG islands may be negatively correlated with reduced expression level of MUPCDH and that this contributes to abnormal cell proliferation in ADPKD. It suggests that methylation status of MUPCDH promoter can be used as a novel epigenetic biomarker and a therapeutic target in ADPKD.


PfCG2, a Plasmodium falciparum protein peripherally associated with the parasitophorous vacuolar membrane, is expressed in the period of maximum hemoglobin uptake and digestion by trophozoites.
A Plasmodium falciparum gene closely linked to the chloroquine resistance locus encodes PfCG2, a predicted 320-330kDa protein. In the parasitized erythrocyte, PfCG2 expression rises sharply in the trophozoite stage and is detected in electron-dense patches along the parasitophorous vacuolar membrane (PVM), in the cytoplasm and in the digestive vacuole (DV). Results of extraction and partitioning experiments show that PfCG2 is a peripheral membrane protein. Exposure of trophozoite-infected erythrocytes to trypsin-containing buffer after streptolysin O permeabilization indicates that PfCG2 is exposed to the erythrocyte cytosol at the outer face of the PVM. PfCG2 is highly susceptible to hydrolysis by aspartic and cysteine proteases and shows dose-dependent accumulation in the presence of protease inhibitors. These results suggest that PfCG2 is delivered from the outside face of the PVM to the DV, where it is broken down by parasite proteases. PfCG2 interacts with erythrocyte cytoplasm and may be associated with processes of hemoglobin uptake and digestion by erythrocytic-stage parasites.


Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial.
We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow-up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow-up, 55·5 months); median progression-free survival (PFS) was 35·3 months and median overall survival (OS) was not reached. In patients with high-risk versus standard-risk cytogenetics, median PFS was 19·9 vs. 43·6 months (P < 0·0001), and median OS was 54·7 months versus not reached (P = 0·0022). VCD is an effective and tolerable induction regimen; results suggest that VCD induces high response rates independently of cytogenetic risk status, but after long-term follow-up, cytogenetic high risk is associated with markedly reduced PFS and OS post-ASCT.


Mce1C and Mce1D facilitate N. farcinica invasion of host cells and suppress immune responses by inhibiting innate signaling pathways.
The mammalian cell entry (Mce) family of proteins consists of invasin-like membrane-associated proteins. The roles of Mce1C and Mce1D proteins in host-pathogen interactions have not been investigated. In this study, we demonstrate that Mce1C and Mce1D protein is localized in the cell wall fraction of N. farcinica. Both N. farcinica Mce1C and Mce1D proteins are expressed at the level of protein and mRNA and elicit antibody responses during infection. Mce1C and Mce1D facilitate the internalization of Escherichia coli expressing Mce1C protein or latex beads coated with Mce1D protein by HeLa cells, respectively. We further demonstrate that Mce1C and Mce1D can suppress the secretion of the proinflammatory factors TNF-α and IL-6 in macrophages infected with Mycobacterium smegmatis expressing Mce1C or Mce1D and promote the survival of M. smegmatis expressing Mce1C or Mce1D in macrophages. In addition, Mce1C and Mce1D supress the activation of the NF-κB and MAPK signaling pathways by blocking the phosphorylation of AKT, P65, ERK1/2, JNK, or P38 in macrophages. These findings suggest that Mce1C and Mce1D proteins facilitate N. farcinica invasion of HeLa cells and suppress host innate immune responses by manipulating NF-κB and MAPK signaling pathways, which may provide a target for N. farcinica treatment.


Microstructure and chemical data of the thermoelectric ZnSb material after joining to metallic electrodes and heat treatment.
The data presented in this article are related to the research article entitled: "Solder free joining as a highly effective method for making contact between thermoelectric materials and metallic electrodes" (Malik et al., 2017) [1]. This article presents microstructure obtained by scanning electron microscopy (SEM) and chemical analysis by energy dispersive X-ray spectroscopy (EDX) point measurements of the thermoelectric ZnSb legs after joining to metallic electrodes using solder (Zn-2Al) and free-soldering methods.


Impact of a single-session education program on parental knowledge of and approach to childhood fever.
We evaluated knowledge of and approach to childhood fever in parents before and after attending a single reinforced educational session on the subject given by the pediatrician during a visit with their sick child. The study group consisted of 155 consecutive parents of children who visited the pediatrician for treatment of low-grade fever (<38.5 degrees C) once during the period of July 1999-2000, and again, within 6 months later. The parents received the standard short explanation for fever at the first visit and a reinforced educational session which included discussion supported by written and pictorial material at the second. At the follow-up examination, performed 3-7 days after each visit, the parents completed a questionnaire on their approach to the management of childhood fever, and the responses to the two questionnaires were compared. High-grade fever was correctly defined by 75% of the parents after the reinforced education session compared to 46% before, and over 95% of the parents correctly treated fever after the reinforced session compared to only 50% before. Knowledge of the correct utilization of health services was also improved after the intervention. All these differences were statistically significant. This study suggests that parental knowledge of fever management in children can be significantly improved by a reinforced educational session.


Topography of primitive reflexes in dementia: an F-18 fluorodeoxyglucose positron emission tomography study.
Although primitive reflexes (PRs) are inhibited during the first years of childhood, they may reappear with brain injury. PRs have been linked to frontal lobe dysfunction, but their precise topography has not yet been defined. The purpose of this study was to map which regions of the brain display a reduced glucose metabolism in patients with cognitive impairment and PRs. A prospective study was conducted to evaluate PRs in a group of patients assessed due to suspected cognitive decline. Neurological and neuropsychological examinations and (18) F-fluorodeoxyglucose positron emission tomography fused with computerized tomography were performed. Voxel-based brain mapping analysis by means of statistical parametric mapping was used to compare patients with and without PRs. The study included 99 patients (33 diagnosed with Alzheimer's disease, 33 on the frontotemporal dementia spectrum and 33 with other diagnoses). Mean age was 71 ± 9.7 years; time since symptom onset was 3.6 ± 2.9 years. At least one PR was observed in 43 cases (43.4% of the whole sample; 48.5% in the Alzheimer disease group, 63.6% in frontotemporal dementia and 18.2% in the group with other diagnoses). The group of patients with PRs exhibited a decreased cerebral metabolism in the bilateral superior frontal gyri (Brodmann area 6), bilateral putamina and thalami. The presence of PRs was associated with hypometabolism at the superior frontal gyrus and putamen. This suggests that dysfunction in the corticostriatal motor circuit (supplementary motor area-putamen-thalamus) may constitute the anatomical basis of the recurrence of PRs.


New quantification procedure for the analysis of chlorinated paraffins using electron capture negative ionization mass spectrometry.
An improved quantification procedure for the analysis of chlorinated paraffins (CPs) is presented based on electron capture negative ionization mass spectrometry. It compensates differences in response factors between reference CP mixtures and the CP pattern present in environmental samples. The use of a CP standard with a matching degree of chlorination is no longer necessary. It could be shown that the response factors of C10-, C11-, C12- and C13-CP mixtures of both 50 and 60% chlorine content were only slightly influenced by the carbon chain length. A linear correlation (R2 = 0.965) between the total response factor of a CP mixture and its chlorine content was obtained for seven short chain chlorinated paraffin mixtures (SCCP, C10-C13) with different composition and chlorine content (51-69%). Maximum single deviations were <7% for this reference set. It allowed to determine the correct total response factor of the CP composition present in a sample. The deviations were not more than 7-33% for five independent SCCP control samples compared to up to 373% for the conventional procedure. The procedure was tested by quantifying the SCCP and MCCP levels in 10 fish liver samples. The proposed method allowed to compensate the influence of the degree of chlorination of the applied reference standard on the total response factor.


Rise and fall of the delta globin gene.
This paper examines the molecular basis for the origin and subsequent silencing of the delta globin gene during the evolution of higher primates. We cloned and sequenced the delta gene from representatives of the two most distantly related types of Old World monkeys in which the gene is silent. The silent delta genes of these two monkeys (rhesus and colobus) are highly homologous to each other (97.5%) and to the functional human delta gene (94%). The presumed mutation that silenced the delta gene is therefore unlikely to be obscured by later mutations at the same site. This silencing mutation could have affected transcription since we find no delta transcript in rhesus bone marrow. Furthermore, the delta globin genes from colobus and rhesus monkeys are many times less efficient than the human delta gene in a cell-free transcription assay. The two Old World monkeys share only three nucleotide substitutions in the first 100 base-pairs of the DNA sequence 5' to the site for initiation of transcription when compared to human delta. It is likely that the in vitro silencing of the delta gene was brought about by one (or a combination) of these three substitutions. Three analysis shows how the delta sequences are related to those for other beta-like genes, including the colobus beta gene whose sequence we report. One part of the delta gene appears to be derived from a (pseudo?) beta gene that diverged from beta before the divergence of mice and men. The other part is closely related to the beta gene of higher primates. The mosaic nature of the delta gene is apparently due to a partial conversion which took place between the pseudo beta and the functional beta gene before the divergence of the lineages leading to Old World monkeys and hominoids.


Equilibrium and kinetic aspects of sodium cromoglycate adsorption on chitosan: mass uptake and surface charging considerations.
Chitosan has more and more been suggested as a material for use as adsorbent in the treatment of effluents as well as in the synthesis of drug-loaded nanoparticles for controlled release. In both cases, a good understanding of the process of adsorption, both kinetically and in terms of equilibrium, has an importance of its own. In this manuscript we study the interaction between sodium cromoglycate, a drug used in asthma treatment, and chitosan. Equilibrium experiments showed that Sips (or Freundlich-Langmuir) isotherm described well the resultant data and adsorption possibly occurred as in multilayers. A model based on ordinary reaction-rate theory, compounded of two processes, each one with a correlated velocity constant, described the kinetics of sorption. Kinetic and equilibrium data suggested the possibility of surface rearrangement, favored by the increase of temperature.


Computed tomography and magnetic resonance imaging of the acute abdomen.
CT is a noninvasive investigation that in many instances is more sensitive in elucidating intra-abdominal and retroperitoneal disease than is conventional radiography. With modern scanners, the procedure is rapid and efficient and suitable for the most severely ill and infirm. The scans are easily interpretable, and the anatomic and morphologic depiction of disease is readily understood by those with surgical training. Information regarding the state of the bowel wall, mesentery, and intraperitoneal and retroperitoneal structures is displayed in greater detail than by any other diagnostic imaging modality. The use of intravenous contrast medium is rarely essential. The concentration of iodinated contrast needed for opacification of the bowel is no greater than 2 per cent to 5 per cent and will not complicate bowel surgery, as would standard upper gastrointestinal or barium enema studies. Abscess, free air, calcium, and intraperitoneal fluid are very sensitively detected. CT is extremely useful in aiding surgical decision making in the acute abdomen and is complementary to or has replaced conventional studies.


Histopathologic and dietary prognostic factors for canine mammary carcinoma.
Histologic and dietary prognostic factors for survival following naturally occurring breast cancer were studied for 145 pet dogs. Information was collected from the dog's owner and veterinarian regarding medical and reproductive history, nutritional status, treatment, tumor recurrence, and length of survival. The usual intake of all dog and table foods consumed 1 year prior to diagnosis was obtained using a validated quantitative food frequency questionnaire. A histologic malignancy score was derived based on 7 histopathologic criteria. The mean age of the dogs was 10.4 +/- 2.5 years; 37% had been ovariohysterectomized prior to diagnosis. Product-limit estimates of survival indicated that 6 factors, namely body conformation 1 year prior to diagnosis (p = 0.03), histologic tumor type (p = 0.004), histologic malignancy score (p = 0.02), histologic invasion (p = 0.002), tumor recurrence (p less than 0.0001), and completeness of surgery (p = 0.01) were of prognostic significance. In addition, when dogs were characterized by the percent of total calories they derived from fat and protein, the median survival time for dogs in the low fat group (less than 39%) with protein greater than 27%, 23-27%, and less than 23% was 3 years, 1.2 years, and 6 months, respectively (p = 0.008). For dogs in the high fat group (greater than or equal to 39%), there was no difference in survival for the different intake levels of dietary protein (p = 0.84). When these data were fitted to a proportional hazards model, recurrence, histologic score, tumor type, percent of calories derived from protein, fat group, and a protein-fat group interaction term were statistically significant. Predicted 1 year survival for dogs on a low fat diet with 15%, 25%, and 35% of total calories derived from protein was 17%, 69%, and 93%, respectively.


The effectiveness of tobramycin and Ocuflox in a prophylaxis model of Staphylococcus keratitis.
To determine the effectiveness of prophylactic antibiotic treatment prior to intra-corneal infection with Staphylococcus aureus. One topical drop of Tobrex (0.3% tobramycin), tobramycin (0.3%) in the Tobrex vehicle with 0.05% dodecyl maltoside (DDM)/4.0% hydroxypropylmethycellulose (HPMC), Ocuflox (0.3% ofloxacin) or DDM/HPMC vehicle were applied to rabbit eyes at one or five hours prior to injection of bacteria. Approximately 500 colony-forming units (CFU) of S. aureus strain 8325-4 were injected into the corneal stroma. Rabbits were sacrificed five hours after infection and corneal homogenates were cultured to determine the number of colony forming units (CFU) per cornea. Rabbits treated at five hours prior to infection with tobramycin-DDM/HPMC reduced the bacterial load by approximately 2.4 log CFU/cornea as compared to the untreated control (3.47 +/- 0.98 vs. 5.71 +/- 0.14 log CFU/cornea, respectively; P = 0.0010); however, Ocuflox, Tobrex, or DDM/HPMC vehicle did not significantly reduce the log CFU (P >or= 0.4837). Rabbits treated at 1 hour prior to infection with Ocuflox or tobramycin-DDM/HPMC had significantly reduced CFU/cornea (1.31 +/- 0.86 and 0.48 +/- 0.31 log CFU/cornea, respectively) as compared to the untreated group (5.71 +/- 0.14 log CFU/cornea; P <or= 0.0001). Neither Tobrex nor the DDM/HPMC vehicle significantly reduced the CFU/cornea compared to the untreated group (P >or= 0.2312). This pre-treatment model of Staphylococcus keratitis quantitatively measured the prophylactic effectiveness of topical antibiotic formulations. An important finding was that a tobramycin-DDM/HPMC formulation was highly effective as a prophylactic medication.


The association between antibodies to neurotropic pathogens and bipolar disorder : A study in the Dutch Bipolar (DB) Cohort and meta-analysis.
Exposure to neurotropic pathogens has been hypothesized to be a risk factor for the development of bipolar disorder (BD). However, evidence so far is inconsistent. We, therefore, analyzed the seroprevalence and titer levels of IgG antibodies against several herpesviruses and Toxoplasma gondii (T. gondii) in plasma of 760 patients with a bipolar disorder, 144 first-degree matched relatives and 132 controls of the Dutch Bipolar (DB) Cohort using ELISA. In addition, we performed a literature-based meta-analysis on the seroprevalence of IgG antibodies against these pathogens (n = 14). Our results in the DB Cohort and subsequent meta-analysis (n = 2364 BD patients, n = 5101 controls) show no association between exposure to herpesviruses and bipolar disorder (HSV-1 [adjusted OR 0.842, 95% CI 0.567-1.230], HSV-2 [adjusted OR 0.877, 95% CI 0.437-1.761], CMV [adjusted OR 0.884 95% CI 0.603-1.295], EBV [adjusted OR 0.968 95% CI 0.658-1.423]). In the DB Cohort, we did not find an association between bipolar disorder and T. gondii titer or seroprevalence either [adjusted OR 1.018, 95% CI 0.672-1.542]. The overall OR was not significant for T. gondii [OR: 1.4, 95% CI 0.95-1.90, p = 0.09), but subgroup analyses in age groups below 40 years showed a significantly increased seroprevalence of T. gondii IgGs in BD [OR: 1.8 (95% CI 1.10-2.89, p = 0.021]. Our meta-analysis indicates that T. gondii exposure may be a risk factor for BD in certain subpopulations.


Does the natural maxillary dentition influence the survival rate of mandibular metal-resin implant-supported fixed complete dentures? A systematic review and meta-analysis.
Consensus is lacking regarding the influence of the maxillary dentition on the survival rate of a mandibular metal-resin implant-supported fixed complete denture (MRISFCD) with distal cantilevers. The purpose of this systematic review was to identify whether an opposing natural dentition influences the survival rate of mandibular MRISFCDs. A literature search was performed up to February 2018 from MEDLINE/PubMed, Scopus, Web of Science, Cochrane Library, BBO/LILACS databases and also in the non-peer-reviewed literature through Open Grey. Clinical studies regarding natural (ND), removable prostheses (RP), and complete fixed maxillary implant dentitions (ID) with at least a year of follow-up were included. The quality of the included studies was analyzed, and the risk of bias was reported. A meta-analysis comparing the survival rate of ND with RP and ND with ID was performed with a confidence interval (CI) of 95%, and heterogeneity was tested by an I2 index. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence. From a total of 112 ND, 69 ID, and 204 RP in the maxillary dentition, the overall prevalence of failures was 5.4% (6/112; 95% CI [2.3 to 10.76]) for ND, 13.99% (20/69; 95% CI [0.77 to 39.41]) for ID, and 4.9% (10/204; 95% CI [0.69 to 12.18]) for RP. No statistical differences were detected in the success rates between ND and RP (risk difference = 0.00 [-0.06, 0.06]; P=.93; I2=27%) or between ND and ID (risk difference=0.00 [-0.06, 0.07]; P=.97; I2=0%), both with moderate evidence. With a moderate certainty of evidence, it is suggested that natural maxillary dentitions do not affect the survival rate of mandibular MRISFCDs differently from other prosthetic designs.


Pharmacists' liability into the year 2000.
To educate the pharmacy community regarding areas of potential liability arising from the pharmacist's role in the changing health care delivery system. Published cases (LEXIS and Westlaw), literature (NEXIS and Westlaw), and abstracts available through July 1998. CASE SELECTION AND DATA ABSTRACTION: Selected on the basis of the authors' objectives and the usefulness of the information for practicing pharmacists. As the pharmacist's role in the health care delivery system continues to change, so too does the pharmacist's exposure to liability. Although historically a pharmacist had no common law "duty to warn," new laws requiring a pharmacist to counsel patients, along with increased scrutiny by the media, have increased the pharmacist's potential for liability. An evaluation of recent case law indicates that state courts are increasingly willing to extend a pharmacist's duty to warn where the pharmacist has special knowledge of the patient or the patient's condition, contraindicated drug usage, where a prescription substantially exceeds the maximum safe dosage, or where a pharmacist fills or refills a prescription without physician authorization. A recent issue that may add to the list of potential liability concerns is the substitution of generically equivalent narrow therapeutic index drug products. The pharmacist's role in the ever changing health care delivery system, along with the public's increased scrutiny of pharmacists' dispensing practices, may inevitably extend a pharmacist's duty to warn a patient of potential problems related to prescription drug products. This trend is expected to continue into the new millennium.


Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy.
The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.


Effect of acute on chronic liver failure over post-transplant survival.
Acute-on-chronic liver failure (ACLF) is associated with reduced short-term survival, and liver transplantation is frequently the only therapeutic option. Nonetheless, the post-transplantation prognosis seems to be worse in ACLF patients. The databases of two university centers were retrospectively evaluated, and adult patients with cirrhosis who underwent transplantation between 2013 and 2020 were included. One-year survival of patients with ACLF was compared to that of patients without ACLF. Variables associated with mortality were identified. A total of 428 patients were evaluated, and 303 met the inclusion criteria; 57.1% were male, the mean age was 57.1 ± 10.2 years, 75 patients had ACLF, and 228 did not. The main etiologies of ACLF were NASH (36.6%), alcoholic liver disease (13.9%), primary biliary cholangitis (8.6%) and autoimmune hepatitis (7.9%). Mechanical ventilation, renal replacement therapy, the use of vasopressors and the requirement of blood product transfusion during liver transplantation were significantly more frequent in ACLF patients. Among those recipients without and with ACLF, survival at 1, 3 and 5 years was 91.2% vs. 74.7%, 89.1% vs. 72.6% and 88.3% vs. 72.6%, respectively (p=0.001). Among pre-transplantation variables, only the presence of ACLF was independently associated with survival (HR 3.2, 95% CI: 1.46-7.11). Post-transplantation variables independently associated with survival were renal replacement therapy (HR 2.8, 95% CI: 1.1-6.8) and fungal infections (HR 3.26, 95% CI: 1.07-9.9). ACLF is an independent predictor of one-year post-transplantation survival. Importantly, transplant recipients with ACLF require the use of more resources than patients without ACLF.


Expression of the carbohydrate tumour marker Sialyl Lewis A, Sialyl Lewis X, Lewis Y and Thomsen-Friedenreich antigen in normal squamous epithelium of the uterine cervix, cervical dysplasia and cervical cancer.
The carbohydrate molecules Sialyl Lewis X (SLeX), Sialyl Lewis A (SLeA), Lewis Y (LeY) and Thomsen-Friedenreich antigen (TF) are known to mediate the adhesion between tumor cells and endothelium. They are used as serum markers in diagnosis and treatment in a broad spectrum of human carcinomas, but their expression profile and role in the development of cervical cancer remains unclear. The aim of this study was to investigate the expression of SLeX, SLeA, LeY and TF in normal cervical squamous epithelium, cervical dysplasia and cervical cancer. Slides of paraffin-embedded tissue were fixed and incubated with monoclonal antibodies against SLeX, SLeA, LeY and TF. Immunohistochemical staining was evaluated by using a semi-quantitative score (IRS Score). We found a significant difference of SLeA expression in invasive cervical cancer compared to normal epithelium (p=0.006) and all grades of dysplasia (p=0.002). The expression of SLeX in normal epithelium was less intense than in carcinoma in situ (p=0.036). Staining for LeY showed the weakest results of the investigated markers. Significant differences were found when normal epithelium was compared to CIN I (p=0.011), to CIN II (p=0.013) and to invasive cervical cancer (p=0.005). For TF, significant differences were found in normal epithelium compared to CIN I (p=0.011), CIN II (p=0.013) and compared to invasive cervical cancer (p=0.005). This is the first study on the expression of SLeA, SLeX, LeY and TF in normal cervical endothelium, cervical dysplasia, carcinoma in situ and invasive cervical cancer. Further studies and higher numbers are desirable.


Rapid wound-induced resistance in white birch (Betula pubescens) foliage to the geometrid Epirrita autumnata: a comparison of trees and moths within and outside the outbreak range of the moth.
Two strains of a geometrid defoliator, Epirrita autumnata, were used in bioassays to test existence and relative efficacy of rapid, wound-induced foliage resistance in two provenances of the white birch. One birch and one moth strain originated in the outbreak range of the moth and another outside it. Both birch provenances responded to manual leaf damage by changes in foliage quality which significantly retarded growth of the insects, reducing their pupal weights and protracting larval periods. Leaves which were previously damaged were lower quality as Epirrita food than adjacent intact leaves. Both of them were lower quality than intact leaves without damaged leaves nearby. Because of variance between years in the efficacy of the response, and because of different transfer distances of the provenances to the common garden where the experiments were performed, we could not ascertain whether there is any overall difference in the efficacy of rapid inducible responses between the provenances. Both moth strains were affected by wound-induced deterioration in foliage quality. There were no differences in how the moth strains experienced inducible resistance in the two birch provenances. Moths achieved relatively higher pupal weights on the birch provenance matching their origin. Moths from the outbreak range completed their larval period in a shorter time and pupated in a smaller size and, due to dependence of fecundity on size, had a lower potential rate of increase than insects outside the outbreak range.


Reconstruction of the vermilion after "lip-shave".
During the year 1986, 12 "lip-shave" defects were reconstructed using orbicularis oris myomucosal flaps, in the Northern Ireland Plastic and Maxillo-Facial Service. Three of these were extended lip-shaves. The planning of a V-Y plasty for myomucusal advancement is described and some representative results are shown. We feel that the myomucosal advancement flap is a valuable technique to overcome some of the problems in reconstruction of the vermilion after lip-shave.


Prognostic value of the changes in the mode of ventricular tachycardia induction during therapy with amiodarone or amiodarone and a class 1A antiarrhythmic agent.
The prognostic value of 3 previously reported programmed stimulation efficacy criteria was studied in 70 patients taking amiodarone for sustained ventricular tachycardia (VT). At baseline all patients had VT inducible by programmed stimulation. After amiodarone loading (935 +/- 271 mg/day for 16 +/- 7 days), efficacy of amiodarone was determined by 3 programmed stimulation criteria (criterion I = VT not inducible or 15 beats or less; criterion II = VT not inducible or harder to induce; criterion III = VT not easier to induce). Amiodarone was effective in 12, 25 and 49 of 70 patients by criteria I, II and III, respectively. There were 16 recurrences or cardiac arrest during the follow-up period (19 +/- 19 months). Actuarial arrhythmia-free survival rates at 1 and 2 years were: 90% and 90% in patients with efficacy by criterion I and 78% and 78% in patients with inefficacy, respectively; 84% and 84% in patients with efficacy by criterion II and 78% and 78% in patients with inefficacy, respectively; and 80% and 80% in patients with efficacy by criterion III and 79% and 79% in patients with inefficacy, respectively (difference not significant for all). From the results of follow-up at 2 years, sensitivities of criteria I, II and III were 92%, 75% and 33%, respectively. Specificities were 17%, 26% and 70%, respectively, and predictive accuracies were 43%, 43% and 67%, respectively. Thus, patients with efficacy by criterion I appear to have a better prognosis when compared with patients with inefficacy. However, many patients with inefficacy by criterion I had a good outcome (nonspecificity).(ABSTRACT TRUNCATED AT 250 WORDS)


Extrarenal sites of calcitriol synthesis: the particular role of the skin.
Calcitriol (1alpha,25(OH)2D3), the hormonally active form of vitamin D3 (D3) is produced by a cascade of reactions, including photochemical D3 synthesis in the skin and subsequent hydroxylation at the C-25 atom in the liver and finally at C-1alpha position in the kidney. However, there is substantial evidence for additional extrarenal sites of calcitriol synthesis. In vitro, many nonrenal cells, including bone, placenta, prostata, keratinocytes, macrophages, T-lymphocytes and several cancer cells (e.g., from lung, prostata and skin) can enzymatically convert calcidiol (25OHD3) to 1alpha,25(OH)2D3. We have demonstrated that keratinocytes of the skin have unique properties in the D3 pathway; they are not only capable of producing D3 from 7-dehydrocholesterol (7-DHC), but also generate 1alpha,25(OH)2D3 from the substrates 25OHD3, lalpha-hydroxyvitamin D3 (1alpha-OHD3) and even D3. It is evident that keratinocytes possess at least 1alpha-OH-, 25OH- and 24OHase activity, which is necessary for enzymatic conversion of D3 to 1alpha,25(OH)2D3, and the 24OHase activity for initiation of catabolism of 1alpha,25(OH)2D3 to more polar metabolites. Thus, the skin is apparently the only extrarenal tissue where the complete UVB-induced pathway from 7-DHC to 1alpha,25(OH)2D3 takes place under physiological circumstances.


Rheumatoid meningitis occurring during adalimumab and methotrexate treatment.
Rheumatoid arthritis is well known for multiple extra-articular manifestations. Here, we present a case of chronic rheumatoid meningitis occurring during treatment with methotrexate and the tumour necrosis factor (TNF) alpha antibody adalimumab. Nine and seven months, respectively, into the course of these two treatments, a 59-year-old Caucasian lady with mild, early, seropositive rheumatoid arthritis developed headaches and psychomotor retardation followed by seizures. The diagnosis was confirmed by a brain biopsy showing a necrotizing granulomatous meningitis. Withdrawal of both drugs and high dose corticosteroids led to marked improvement. The addition of the anti-CD20 antibody rituximab allowed discontinuation of the corticosteroids. This is the fifth published case describing the occurrence of rheumatoid meningitis during treatment with TNF blockers. TNF blockers and methotrexate thus do not appear to prevent this complication, and may even contribute to its development.


A novel protection liner to improve graft-tunnel interaction following anterior cruciate ligament reconstruction: a finite element analysis.
Deteriorated bone-graft interaction at the tunnel entrance following ACL reconstruction (ACLR) is considered one of the primary causes of long-term tunnel enlargement and graft wear. Methods have been introduced to improve the long-term outcome, such as novel graft materials or alternative fixation methods, but have been met with varying degrees of success. This study aims to design a protection liner to improve the bone-graft interaction at the tunnel entrances. A finite element model of a human cadaveric knee was used to simulate traditional ACLR and ACLR using the protection liner. Stress distribution around the tunnel entrances and on the ACL graft were calculated under a combined loading of 103 N anterior tibial load, 7.5 Nm internal tibial moment, and 6.9 Nm valgus tibial moment at a joint flexion angle of 20°. Results were compared between the traditional ACLR and ACLR using a double liner (femoral and tibial) setup, as well as between the ACLR using a double liner setup and a single liner (femoral side) setup. Different materials (PEEK, Ti-6Al-4V, CoCrMo) for the liner were also evaluated. The traditional ACLR resulted in concentrated stress on the graft where it contacted the tunnel entrance. Correspondingly, there were stress concentrations at the distal posterior zone of the femoral tunnel entrance and medial posterior zone of the tibial tunnel entrance, while the other zones suffered from a stress reduction. Use of the protection liner reduced the stress concentration around the tunnel entrances by up to 89% and increased the stress at the unloaded zones by up to 106%. Also, stress concentration on the graft was slightly decreased (15.4 vs 15.1 MPa) after using the liner. The single liner setup increased the stress concentration around the tibial tunnel entrance. Stiffer materials improved the stress distribution around tunnel entrances but had little effect on the stress on the graft. The novel protection liner can improve the stress distribution on the graft and at the tunnel entrances, which may be beneficial for improving the clinical outcome of ACLR.


On the role of structural class of a protein with two-state folding kinetics in determining correlations between its size, topology, and folding rate.
The time it takes for proteins to fold into their native states varies over several orders of magnitude depending on their native-state topology, size, and amino acid composition. In a number of previous studies, it was found that there is strong correlation between logarithmic folding rates and contact order for proteins that fold with two-state kinetics, while such correlation is absent for three-state proteins. Conversely, strong correlations between folding rates and chain length occur within three-state proteins, but not in two-state proteins. Here, we demonstrate that chain lengths and folding rates of two-state proteins are not correlated with each other only when all-alpha, all-beta, and mixed-class proteins are considered together, which is typically the case. However, when considering all-alpha and all-beta two-state proteins separately, there is significant linear correlation between folding rate and size. Moreover, the sets of data points for the all-alpha and all-beta classes define asymptotes of lower and upper limits on folding rates of mixed-class proteins. By analyzing correlation of other topological parameters with folding rates of two-state proteins, we find that only the long-range order exhibits correlation with folding rates that is uniform over all three classes. It is also the only descriptor to provide statistically significant correlations for each of the three structural classes. We give an interpretation of this observation in terms of Makarov and Plaxco's diffusion-based topomer-search model.