Copper(I)-catalyzed electrophilic thiocyanation/dearomatization/spirocyclization of benzofurans to synthesize benzannulated spiroketals.
A Lewis acid-catalyzed electrophilic dearomatizative thiocyanation and cyclization of benzofurans with N-thiocyanatosuccinimide has been accomplished by Lewis acid catalysis with CuOTf under mild conditions. It was suggested that the electrophilic thiocyanating reagent was activated by CuOTf, and difunctionalization was achieved through a thiocyanation/spirocyclization pathway. Thus, a series of thiocyanato-containing spiroketals were obtained in moderate to high yields. It provides an alternative approach for the synthesis of functionalized [6,5]/[5,5]-spiroketals.


Cardiac epigenetics: Driving signals to the cardiac epigenome in development and disease.
Conrad Waddington's famous illustration of a ball poised at the top of an undulating epigenetic landscape is often evoked when one thinks of epigenetics. Although the original figure was a metaphor for gene regulation during cell fate determination, we now know that epigenetic regulation is important for the homeostasis of every tissue and organ in the body. This is evident in the cardiovascular system, one of the first organs to develop and one whose function is vital to human life. Epigenetic mechanisms are central in regulating transcription and signaling programs that drive cardiovascular disease and development. The epigenome not only instructs cell and context specific gene expression signatures, but also retains "memory" of past events and can pass it down to subsequent generations. Understanding the various input and output signals from the cardiac epigenome is crucial for unraveling the molecular underpinnings of cardiovascular disease and development. This knowledge is useful for patient risk stratification, understanding disease pathophysiology, and identifying novel approaches for cardiac regeneration and therapy. In this special issue, a series of high-quality reviews and original research articles examining the field of cardiac epigenetics will broaden our insights into this fundamental aspect of molecular and cellular cardiology. Topics include DNA methylation, histone modifications, chromatin architecture, transcription factors, and long non-coding RNA biology in the diverse cell types that comprise the cardiovascular system. We hope that our readers will expand their horizons and be challenged to envision innovative strategies to further probe the epigenome and develop diagnostic and therapeutic solutions for cardiovascular pathologies.


Inverted Papilloma of the Middle Ear: Two New Cases and Systematic Review.
Inverted papillomas of the middle ear are extremely rare tumors that carry an increased risk of recurrence and malignant transformation. There are currently 59 cases of middle ear inverted papillomas reported in the literature. The objective in this study was to systematically evaluate outcomes regarding middle ear inverted papillomas with respect to demographics, anatomical tumor sites, malignant transformation status, recurrence rate and HPV status. Retrospective case series and systematic review. A systematic review was completed on June 25, 2020 with a search strategy including PubMed, Embase, Scopus and Google Scholar. This revealed 181 articles. Full-text review was completed, and 66 articles were included. 115 articles were eliminated due to duplication of articles from databases, article titles not applicable to the aims of the systematic review and articles describing inverted papilloma of body sites other than middle ear. Thirty-one cases of primary inverted papillomas of the middle ear were found in the literature with an additional 26 cases of secondary tumors. Four case reports did not specify primary versus secondary. The malignant transformation rate was 34.4% with a 53.6% recurrence rate. Treatment of middle ear inverted papillomas is primarily surgical with adjuvant radiation therapy considered for patients with recurrence or malignant transformation. Frequent clinical follow up of these patients is critical due to the increased rate of recurrence and malignant transformation. Inverted papillomas of the middle ear are rare tumors that carry a high risk of recurrence and malignant transformation necessitating complete resection and frequent clinical follow up.


Opposite effects of interleukin-4 and interleukin-10 on nitric oxide production in murine macrophages.
Interleukin-4 (IL-4) and interleukin-10 (IL-10) were evaluated for their ability to inhibit the production of nitric oxide (NO) by interferon-gamma (IFN-gamma)- or lipopolysaccharide (LPS)-activated murine macrophages (RAW 264.7 and J774.2). Macrophages pre-treated with IL-4 and then stimulated with IFN-gamma or LPS showed significant inhibition in their ability to produce NO as measured by nitrite production. Simultaneous treatment of IL-4 pre-incubated cells with IFN-gamma and LPS together augmented nitrite accumulation. On the other hand, similar exposures of the macrophages to IL-10 followed by IFN-gamma or LPS treatments resulted in significantly increased NO production. Thus IL-10 failed to suppress IFN-gamma or LPS-induced NO production and showed opposite effects in these experiments to IL-4. We conclude that the two lymphokines have differing roles in the control of production of NO and might act to control the secretion of nitric oxide in vivo.


Effects of interaction of an early experience of reward through maternal contact or its denial with social stress during adolescence on the serotonergic system and the stress responsiveness of adult female rats.
Experiences during critical periods, such as the neonatal and adolescence, play a critical role in determining adult stress-coping behavior. Based on the aforementioned we developed an experimental protocol, which included a neonatal experience and a social stress during adolescence. The serotonergic system is known as an important modulator of coping ability and, in general, emotional balance in both normal and pathological states, such as depression and anxiety, for which females are more vulnerable. Thus in the present work we used female rats and determined 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and 5-hydroxytryptamine receptor type 1A (5-HT(1A)) receptor levels in the prefrontal cortex (PFC) and the amygdala (AMY). During postnatal days 10-13 (PND 10-13) rat pups were exposed to a T-maze, one arm of which lead to the mother. One group of animals was allowed contact with the mother (rewarded-receiving expected reward (RER)), whereas the other was denied the expected reward (DER). High performance liquid chromatography (HPLC) analysis revealed that in both the PFC and in AMY, adult RER animals had higher basal 5-HT levels. Furthermore, in the AMY of this group of animals, higher levels of 5-HT(1A) receptors were detected by Western blot analysis. In adulthood rats were exposed to the Forced Swimming Test/Stress (FST/S). RER animals not exposed to the adolescent stress exhibited longer immobility time during both the first and second day of FST. Corticosterone levels following the FST fell faster in the DER animals. Adolescent stress affected the responses to the adult FSS only in the DER animals, which had decreased 5-HT in the AMY and increased immobility time on both days of the FST, compared with the DER, not stressed in adolescence. The phenotype of the DER animals is in line with the "match-mismatch" hypothesis, which states that if two events during critical periods of life "match" in being mildly stressful, their interaction can be adaptive.


Carcinoembryonic antigen in urine in patients with urothelial carcinoma. An expression for the extent of inflammatory reaction of the urinary tract.
The concentration of carcinoembryonic antigen (CEA) in urine and serum was determined repeatedly during one year in 213 patients followed because of previously treated urothelial carcinoma of the bladder. The findings were correlated to grade and stage of previously treated tumour, given therapy, recurrence and the cytological evaluation of a midstream urine specimen. During the period of follow up 43 recurrences were clinically observed. With the exception for the content of inflammatory cells no correlation was found between the CEA levels in urine or blood and the parameters studied. Thus CEA in urine and/or serum cannot substitute for cystourethroscopy, urography and exfoliative cytology in the follow-up of patients previously treated for urothelial carcinoma.


Fluvoxamine for somatoform disorders: an open trial.
Although the pharmacologic treatment of somatoform disorders has scarcely been investigated, there is reason to believe that antidepressants might be useful. We examined the response of 29 patients with somatoform disorders from a general medicine clinic to a selective serotonin reuptake inhibitor, fluvoxamine. The drug was administered in doses of up to 300 mg daily for 8 weeks. Sixty-one percent of the patients who took medication for at least 2 weeks were at least moderately improved. In addition to antidepressant effects, fluvoxamine had other beneficial effects and was well-tolerated. The benefits of drug therapy were modest but appear to warrant a placebo-controlled trial.


E,E-2-Benzylidene-6-(nitrobenzylidene)cyclohexanones: syntheses, cytotoxicity and an examination of some of their electronic, steric, and hydrophobic properties.
Three series of structurally isomeric 2-benzylidene-6-(nitrobenzylidene) cyclohexanones 1-3 were prepared and evaluated against human Molt/C8 and CEM T-lymphocytes as well as murine L1210 cells. The IC(50) values of the majority of compounds are less than 10microM and in some assays, the figures for 1d and 1e are submicromolar. Correlations were discerned between cytotoxic potencies and the atomic charges on one of the olefinic carbon atoms, the torsion angles between an aryl ring, and the adjacent unsaturated group as well as logP values. Three representative compounds were examined for their effect on respiration in rat liver mitochondria.


3-Hy-droxy-4-phenyl-1-(prop-2-en-1-yl)-2,3,4,5-tetra-hydro-1H-1,5-benzodiazepin-2-one.
The asymmetric unit of the title compound, C(18)H(18)N(2)O(2), contains three independent mol-ecules. In each, the seven-membered diazepine ring adopts a boat conformation with the hy-droxy-substituted C atom at the prow and fused-ring C atoms at the stern. In the crystal, the mol-ecules are linked by O-H⋯O and N-H⋯O hydrogen bonds. The allyl group of one mol-ecule is equally disordered over two positions.


Radionuclide angiocardiography: use in the detection of myocardial rhabdomyoma.
A neonate with a large rhabdomyoma of the heart was evaluated with radionuclide angiocardiography. The images revealed a "cold" area on the inferior surface of the heart which displaced the left ventricle. The findings were correlated with radiographic angiocardiography and were verified at surgery and autopsy. The value of this noninvasive technique in the evaluation of a seriously ill neonate is stressed.


Effects of glucose and D-3-hydroxybutyrate on human pancreatic islet cell function.
Beta-Cell function in human islets derived from a number of kidney donors was investigated by using various types of islet preparations. With fresh islets, both insulin release and biosynthesis were increased by raising glucose concentrations, although the response was a variable one. In fresh islets, the effects of 5 mmol of glucose/l on release were potentiated by 10 mmol of D-3-hydroxybutyrate/l. Insulin release at 20 mmol of glucose/l was inhibited by adrenaline (0.1 mmol/l), and potentiated by theophylline (10 mmol/l) in the presence of 5 mmol of glucose/l, in islets cultured for 4 days. After culture for 8 days, islets still showed an increase in insulin release and biosynthesis in response to glucose. Pancreas slices derived from fresh human tissue also responded to increasing concentrations of glucose with a sigmoidal curve for insulin release.


Circulating tumor cell detection: A prospective comparison between CellSearch® and RareCyte® platforms in patients with progressive metastatic breast cancer.
Circulating tumor cells (CTCs) are prognostic in patients with breast cancer. Several technical platforms exist for their enumeration and characterization. Comparative studies between these platforms are scarce. The RareCyte CTC detection is theoretically more sensitive than the established CellSearch platform, which identifies only CTCs that express EpCAM and cytokeratin. This study prospectively compares CTC enumeration in patients with breast cancer in a paired analysis using these two platforms. It investigates survival outcomes in groups defined by a CTC count threshold. CTC enumeration was performed on 100 samples obtained from 86 patients with progressive metastatic breast cancer (MBC) in two independent laboratories each blinded to the clinical data and the results from the other platform. One hundred paired samples were collected and CTC counts were determined using the CellSearch and RareCyte CTC platforms. In total, 65% and 75% of samples had at least one detectable CTC in 7.5 mL blood with the CellSearch and the RareCyte systems, respectively. CTC counts with the CellSearch system ranged from 0 to 2289 with a median of 3 CTCs, the RareCyte CTC counts ranged from 0 to 1676 with a median of 3 CTCs. The number of samples with 5 or more CTCs in 7.5 mL of blood (the poor prognosis cut-off validated with the CellSearch system) blood was 45% with the CellSearch test and 48% with the RareCyte test. CTC counts quantified with the CellSearch and the RareCyte systems were strongly correlated (Spearman's r = 0.8235 (0.7450-0.8795) p < 0.001). 86 patients were included for Kaplan-Meier survival analysis. An increased mortality risk in patients with CellSearch of 5 CTCs or more per 7.5 mL blood, with a log-rank hazard ratio of 5.164 (2.579-10.34) (p < 0.001) was confirmed. The survival analysis with RareCyte CTC counts with the identical cut-off showed a significantly impaired survival with a hazard ratio of 4.213 (2.153-8.244) (p < 0.001). Our data demonstrate the analytical and prognostic equivalence of CellSearch and RareCyte CTC enumeration platforms in patients with MBC using the CellSearch cut-off. This is the first demonstration of prognostic significance using the RareCyte platform.


[Publication of pediatric medical dissertations in France].
A medical dissertation is mandatory during medical studies in France. Often these dissertations are only considered an old-fashioned tradition but nonetheless require scientific research. According to recent publications, only 10% are secondarily published; however, there are no specific studies on pediatric medical dissertations. For all medical dissertations from students assigned to pediatrics in 2003, a subsequent publication was searched for on Pubmed and Google Scholar. When such a publication was found, data on the student's rank, the impact factor (IF), the language of publication, and the number of citations were retrieved. For students assigned to pediatrics in 2003, 27.9% of the 172 medical theses were published, with a mean delay of 2.21 years. French was the language in 29%, and the mean IF was 2.3. There was no statistical association between student sex, age, university, size of the medical dissertation and publication. More than 25% of the pediatric medical dissertations are published. According to available data, this is a good rate but nonetheless still low. We found no clear factor associated with publication. Only a small fraction of pediatric medical dissertations are published.


Femoropopliteal occlusions and the adductor canal hiatus, Duplex study.
The majority of lower limb arterial occlusions are located in the distal third of the thigh. However, the exact location of occlusions in relation to the surrounding anatomy has never been examined. Duplex ultrasound was used to determine the location of femoropopliteal occlusions in 50 patients by comparing the level of occlusions to the level of the adductor canal hiatus. We found that although the level of the adductor canal hiatus may vary, 72% of occlusions are related to the site of the adductor canal hiatus. Short occlusions were located in the hiatus region, longer occlusions extended mainly in the proximal direction.


Emergency Severity Index (ESI) algorithm in trauma patients: The impact of age during the pandemic.
The ESI algorithm is widely used to triage patients in the emergency room. However, few studies have assessed the reliability of ESI to accurately triage trauma patients. The aim of this study was to compare vital signs, resource utilization, and patient outcomes among trauma patients during the pandemic in 2020 vs. the previous year prior to the pandemic. This retrospective study was conducted over a 24-month period at an urban adult level one trauma center. Demographic and clinical characteristics, resource utilization, and patient outcomes were extracted from the electronic medical records and trauma registry. Trauma patients assigned ESI level 2 were stratified by age (<65 years and ≥ 65 years) and year (2019 vs. 2020) for data analysis. A total of 3,788 trauma patients were included in the study. Males represented 68.4% (2,591) of patients and the median age was 50 years (IQR: 31, 69). The majority of patients were assigned ESI level 2 (2,162, 57.1%) and had a blunt mechanism of injury (3,122, 82.4%). In 2020, patients <65 years of age utilized less resources compared to 2019 (p < 0.001). Likewise, patients >65 years of age required less lab tests [OR: 0.1, 95% CI: (0.05 - 0.4)], IV fluids [OR: 0.2, 95% CI: (0.2 -0.3)], IV medications [OR: 0.6, 95% CI: (0.4 - 0.7)], and specialty consultations [OR: 0.4, 95% CI: (0.3 -0.5)] compared to 2019 (p < 0.0001). Within 2020, vital signs and resources utilized between younger and elderly patients varied significantly (p < 0.01). Correspondingly, the clinical outcomes between younger and elderly patients within 2020, differed significantly (p < 0.01). The COVID-19 pandemic affected the triage of trauma patients. During 2020, patients utilized less resources compared to the previous year. Additionally, younger and elderly patients had different vital signs, resource utilization, and clinical outcomes although both being assigned ESI level 2. Younger trauma patients may have been over-triaged in 2020 due to the COVID-19 pandemic.


Immunoglobulins in urine from patients with ileal and colonic conduits and reservoirs.
Gel chromatography of proteins in urine from continent cecal urinary reservoirs revealed an abundance of high molecular weight proteins, especially secretory immunoglobulin A. Quantitation of immunoglobulins in urine from ileal and colonic conduits and ileal and cecal reservoirs showed secretory immunoglobulins A, G and M in amounts considerably greater than in urine from normal urinary tracts, whether or not bacteriuria was present. More secretory immunoglobulin A was found in reservoir than in conduit urine, but there was no such difference for immunoglobulin G and immunoglobulin M. In hemagglutination-inhibition tests, immunoglobulin A antibodies from cecal reservoir urine in 1 patient inhibited adherence (mannose-resistant) to human and animal erythrocytes of Escherichia coli obtained from reservoir urine from that same patient. High levels of secretory immunoglobulin A may constitute a host defense mechanism against urinary tract infection in patients with reservoirs and conduits.


From the chemical imbalance to the power imbalance: A psychiatry trainee's perspectives on service-user supervision.
This paper describes perspectives and insights of a trainee's experience of service-user supervision. This includes the background to this novel approach, outlining its process and content, key themes arising, applications in practice, limitations of the approach, and future considerations. Service-user supervision promotes education and experiences at this important stage of professional development and can promote clinical, cultural, and systemic changes required to support the paradigm shift towards recovery-oriented and human rights-based practice.


LC-ESI-MS/MS quantification of carnosine, anserine, and balenine in meat samples.
The histidine-containing imidazole dipeptide carnosine and its methylated analogs anserine and balenine are present at high concentrations in vertebrate tissues. Although the physiological functions of the imidazole dipeptides have not been elucidated yet, it has been suggested that they play significant biological roles in animals. Despite increasing interest, few studies have challenged the quantifications of carnosine, anserine, and balenine by a single HPLC run because they have similar retention times. In this study, we developed a method to quantify these imidazole dipeptides in meat samples using an LC-ESI-MS/MS triple-quadrupole mass spectrometer. We improved the liquid chromatographic separation of the imidazole dipeptides by applying a mix-mode column, which provides both normal phase and ion exchange separations, and developed multiple reaction-monitoring of the transitions for quantification of m/z 227 → 110 for carnosine, m/z 241 → 126 for anserine, m/z 241 → 124 for balenine, and m/z 269 → 110 for L-histidyl-L-leucine (internal standard). The established method met all pre-defined validation criteria. Intra- and inter-day accuracy and precision were ±10.0% and ≤14.8%, respectively. The ranges of quantifications were 14.7 ng/mL to 1.5 mg/mL for carnosine, 15.6 ng/mL to 1.6 mg/mL for anserine, and 15.6 ng/mL to 1.6 mg/mL for balenine. In conclusion, the validated method was successfully applied to the quantification of imidazole dipeptides in biological samples without derivatization.


Efficient degradation of 2,4-dichlorophenol in water by sequential electrocatalytic reduction and oxidation with a Pd-MWCNTs/Ni-foam electrode.
Our previous study indicated excellent dechlorination efficiency and phenol conversion rate in the electrocatalytic reduction of 2,4-dichlorophenol (2,4-DCP) with a Pd-MWCNTs/Ni-foam electrode; it is deserved to investigate whether this electrode can efficiently degrade phenol in electro-Fenton oxidation (EFO) process and realize the effective mineralization of 2,4-DCP in aqueous solution. In this work, the sequential electrocatalytic reduction and oxidation of 2,4-DCP were studied after examining phenol degradation in the EFO process. The results showed that the removal efficiency of 0.31 mM phenol could reach 96.76% after 90-min degradation with the rate constant of 0.0367 min-1, and hydroxy radicals (·OH) were the main active species in the EFO process. In the sequential electrocatalytic reduction and oxidation processes, the removal efficiencies of 2,4-DCP, phenol, and total organic carbon (TOC) reached 99.72%, 97.07%, and 61.45%, respectively. The possible degradation mechanism of 2,4-DCP was proposed through monitoring the reaction products, and the stability and reusability of the electrode were also examined. This study suggested that 2,4-DCP in wastewater can be effectively mineralized to realize its efficient degradation through the sequential electrocatalytic reduction and oxidation.


Influence of observer experience and training on proficiency in coronary CT angiography interpretation.
To assess the influence of experience and training on the proficiency in coronary CT angiography (CCTA) interpretation of practitioners with different levels of experience. Nine radiologist and cardiologist observers with varying prior CCTA experience ranging from novice to expert independently analyzed two case series of 50 catheter-correlated CCTA studies for coronary artery stenosis (0%, ≤49%, 50-74%, 75-99%, or 100%). Results of the first case series were unblinded and presented along with catheter angiography results to each reader before proceeding to the second series. Diagnostic accuracy on a per-segment basis was compared for all readers and both case series, respectively. Correlation coefficients between CCTA and catheter angiography initially ranged between good (r=0.87) and poor (r=0.26), depending on reader experience, and significantly (p<0.05) improved in the second case series (range: r=0.42 to r=0.91). Diagnostic accuracy was significantly (p<0.05) higher for more experienced readers (range: 96.5-97.8%) as compared to less experienced observers (range: 90.7-93.6%). After completion of the second case series for less experienced readers sensitivity and PPV significantly (p<0.05) improved (range: 62.7-67.8%/51.4-84.1%), but still remained significantly (p<0.05) lower as compared to more experienced observers (range: 89.8-93.3%/80.6-93.3%). The level of experience appears to be a strong determinant of proficiency in CCTA interpretation. Limited one-time training improves proficiency in novice readers, but not to clinically satisfactory levels.


Guided implant surgery with modification of the technique involving the raising of a semicircular miniflap: a preliminary study.
An evaluation is made of pain, swelling and peri-implant attached mucosal width after implant-based rehabilitation involving guided surgery and a modification of the technique with the raising of a semicircular miniflap, in single and partial replacements. A case-control study was carried out. The study group consisted of 12 patients with the placement of 19 implants using a guided surgery and miniflap technique. The control group consisted of 12 patients with the placement of 22 implants using the conventional technique. Each patient scored postoperative swelling and pain by means of a visual analog scale (VAS). Attached vestibular mucosa width was evaluated 12 weeks after implant placement. Twelve operations were carried out in each group. Immediate aesthetics were established for all implants of the study group. One implant failed in each group. Maximum pain was recorded after 6 hours in both groups (mean VAS score 4 and 4.9 in the study and control group, respectively). Maximum swelling was recorded after 24 hours (mean VAS score 2.5) in the study group and on the second day (mean VAS score 3.4) in the control group. The mean attached vestibular mucosa width was 2.9 mm in the study group and 3.2 mm in the control group. In this preliminary study, guided implant surgery with a semicircular miniflap in single and partial replacements resulted in slightly less postoperative pain and swelling than with the conventional implant technique. The attached vestibular mucosa width was greater in the control group, though the differences were very small.


eMPRess: a systematic cophylogeny reconciliation tool.
We describe eMPRess, a software program for phylogenetic tree reconciliation under the duplication-transfer-loss model that systematically addresses the problems of choosing event costs and selecting representative solutions, enabling users to make more robust inferences. eMPRess is freely available at http://www.cs.hmc.edu/empress. Supplementary data are available at Bioinformatics online.


Prevalence of incidental colorectal cancer and polyps in autopsies of different populations: a systematic review with meta-regression analysis.
The colorectal cancer (CRC) and polyps incidentally found in autopsies represent the lesions that have not actually caused problems throughout the lifetime and thus may not need to be removed during screening. This study aimed to investigate the prevalence of incidental CRC (iCRC) and polyps in autopsies of different populations. A systematic search was performed on 19 August 2022 to identify autopsy studies that provided data on prevalence of iCRC, adenomatous polyps, hyperplastic polyps, and/or all polyps combined. The prevalence was pooled with the random-effects model. Subgroup and multivariable meta-regression analyses were conducted to investigate the heterogeneity. Forty-three eligible studies including 59,656 autopsies were identified, with 94% conducted before 1990 when CRC screening was uncommon or not available. The pooled prevalence was 0.7% (95% confidence interval [CI], 0.3-1.2%) for iCRC, 18.4% (95% CI, 13.3-24.1%) for adenomatous polyps, 16.4% (95% CI, 8.7-25.9%) for hyperplastic polyps, 26.3% (95% CI, 15.4-38.8%) for all polyps combined, and 29.9% (95% CI, 14.8-47.6%) for iCRC plus polyps. The prevalence of iCRC was higher (1.2%) in white-predominant populations but lower (0.4%) after excluding low-quality studies. Multivariable analyses showed that the prevalence of polyps was higher in white-predominant populations and higher-quality studies, increased with age, and showed a downward trend from "before 1975" through "after 1985". In conclusion, the prevalence of iCRC in autopsies was not low, considering the average lifetime risk of CRC, while incidental polyps were common. Both varied greatly in different populations. These findings may have implications when weighing the benefits and harms of screening.


Effects of Dapagliflozin in Asian Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.
Patients with heart failure with reduced ejection fraction (HFrEF) in Asia exhibit many differences from those in other parts of the world. This study sought to investigate the efficacy and safety of dapagliflozin, compared with placebo, in HFrEF patients in Asia, compared with those elsewhere, enrolled in the DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for the DAPA-HF trial. The primary outcome in the DAPA-HF trial was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4,744 patients in the DAPA-HF trial, 1,096 (23.1%) were enrolled in Asia; 721 (15.2% overall, 65.8% of patients in Asia) were enrolled in East Asia (237 in China, 343 in Japan, and 141 in Taiwan), 138 (2.9% overall, 12.6% in Asia) in South-East Asia (Vietnam), and 237 (5.0% overall, 21.6% in Asia) in South Asia (India). Patients from Asia had similar rates of worsening HF events and mortality compared with patients elsewhere. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients from Asia (HR: 0.65; 95% CI: 0.49 to 0.87) as elsewhere (HR: 0.77; 95% CI: 0.66 to 0.89) (P for interaction = 0.32). Consistent benefits were observed for the other prespecified outcomes and among the regions of Asia. Study drug discontinuation and prespecified adverse events did not differ between regions. Dapagliflozin, compared with placebo, reduced the risk of worsening HF events and cardiovascular death to the same extent in Asian patients as elsewhere. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).


Analysis of Falls within Paediatric Hospital and Community Healthcare Settings.
To identify characteristics of paediatric falls within a healthcare setting. A retrospective analysis of falls occurring within inpatient, outpatient, emergency and community healthcare settings of children aged 0-<18 years was conducted using data from the Children's Health Queensland Hospital and Health Service (CHQ-HHS) Clinical Incident Database and Electronic Medical Record between January 1st 2015 and December 31st 2017. One-sample and two-sample Chi-squared tests with post-hoc tests were performed to assess relationships between categorical variables. The final dataset contained 385 fall events. Children 0-2 years fell most frequently (46.75%) and falls were higher in males (55.58%). Falls from bed were the most common mechanism (30.65%). The incidence rate of inpatient falls was 0.53 falls per 1000 bed days in the tertiary hospital setting and 1.2% of presentations to inpatient community health facilities. Falls from bed were most common in the tertiary hospital inpatient setting (39.84%, p < .001) and the emergency department (72.13%, p < .001). Falls from furniture/equipment constituted 26.04% of outpatient falls. Most falls occurred in the presence of parents/caregivers (79.48%) and 4.66% of fallers sustained multiple falls. This study provides a comprehensive review of the characteristics of fall events in CHQ-HHS over a three-year period and summarises the existing literature in paediatric fall prevention. Risk assessment and management plans should focus on education, particularly surrounding bed safety. Our findings have informed the development of an integrated evidence-based paediatric-specific fall risk assessment tool and management plan to prevent falls in hospital and community healthcare settings.


Steroids Regulate CXCL4 in the Human Endometrium During Menstruation to Enable Efficient Endometrial Repair.
Repair of the endometrial surface at menstruation must be efficient to minimize blood loss and optimize reproductive function. The mechanism and regulation of endometrial repair remain undefined. To determine the presence/regulation of CXCL4 in the human endometrium as a putative repair factor at menses. Endometrial tissue was collected throughout the menstrual cycle from healthy women attending the gynecology department. Menstrual blood loss was objectively measured in a subset, and heavy menstrual bleeding (HMB) was defined as >80 mL per cycle. Monocytes were isolated from peripheral blood. CXCL4 messenger RNA (mRNA) and protein were identified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The function/regulation of endometrial CXCL4 was explored by in vitro cell culture. CXCL4 mRNA concentrations were significantly increased during menstruation. Intense staining for CXCL4 was detected in late secretory and menstrual tissue, localized to stromal, epithelial and endothelial cells. Colocalization identified positive staining in CD68+ macrophages. Treatment of human endometrial stromal and endothelial cells (hESCs and HEECs, respectively) with steroids revealed differential regulation of CXCL4. Progesterone withdrawal resulted in significant increases in CXCL4 mRNA and protein in hESCs, whereas cortisol significantly increased CXCL4 in HEECs. In women with HMB, CXCL4 was reduced in endothelial cells during the menstrual phase compared with women with normal menstrual bleeding. Cortisol-exposed macrophages displayed increased chemotaxis toward CXCL4 compared with macrophages incubated with estrogen or progesterone. These data implicate CXCL4 in endometrial repair after menses. Reduced cortisol at the time of menses may contribute to delayed endometrial repair and HMB, in part by mechanisms involving aberrant expression of CXCL4.


Staining of glycosaminoglycans in intervertebral disc cells.
Disc material from horse, ox, sheep, pig, dog and cat was stained by the Alcian-blue-critical electrolyte concentration technique and with the standard and two-step periodic acid Schiff methods. The effects of pretreatment with hyaluronidase and with chondroitinase was also evaluated. There appears to be a small increase in total cellular glycosaminoglycan content with age in all species: cellular material of high molecular weight however only increases in aged animals. The degree of sulphation of cellular glycosaminoglycans does not vary with age or with position in the disc.


Pathophysiology of restless legs syndrome: evidence for iron involvement.
Neuroimaging, analysis of cerebrospinal fluid, and studies on postmortem tissue are generating data that support the concept that iron availability to the brain is a contributory process to, if not a cause of, restless legs syndrome. These data are reviewed and related to the dopaminergic system because of the use of dopamine agents in treating restless legs syndrome.


Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence.
Cloning and sequence analysis of cDNA for the Electrophorus electricus electroplax sodium channel indicate that this protein, consisting of 1,820 amino acid residues, exhibits four repeated homology units, which are presumably oriented in a pseudosymmetric fashion across the membrane. Each homology unit contains a unique segment with clustered positively charged residues, which may be involved in the gating structure, possibly in conjunction with negatively charged residues clustered elsewhere.


[Primary obstructive megaureters: long-term follow-up].
The objective of this study was to evaluate the clinical outcome of primary megaureters and to evaluate predictive factor for surgery need based on ultrasound values. A total of 43 primary obstructive megaureters detected in 41 patients have been evaluated between January 2000 and may 2010. Mostly boys (73%) were concerned by megaureters, mainly on the left side (66%). Twenty patients were prenatally diagnosed. Surgical indications were: pyonephrosis (3), recurrent pyelonephritis (14), scintigraphic damage (3), ureteric diameter aggravation (7), disease occurring on unique kidney (2). Regarding the 30 patients who benefit surgery, the retrovesical ureter measured, before surgery 19.15 mm (± 7.17) on average and 3.18 mm, 44 months later. Over the 10 patients treated medically, the initial diameter was 9.91 mm and at the end of the study, five patients had megaureter completely regressed, three patients had a diameter greater than 10mm at the end of the study and two faced a worsening evolution with sudden and complete renal damage on scintigraphic nephrogram, after recurrent pyelonephritis despite antibioprophylaxis. We recommend a careful watch-fulling of primary megaureters; mainly for those with recurrent infections and whenever the retrovesical ureter diameter exceeds 14 mm at first ultrasound.


Treatment of bilateral renal pelvic and ureteral tumors. A review of 45 cases.
A particular type of kidney disease, the so-called Balkan nephropathy, is to be observed in some areas in Yugoslavia. This type of disease is very often associated with ureteral and pelvic tumors. 495 cases were observed (308 of pelvic and 187 of ureteral origin). Taking into consideration the frequency of bilaterality (9%) as well as of renal insufficiency (50%), we have been forced to preserve the kidney in tumoral cases instead of performing radical nephrectomy. The results on 45 bilateral pelvic and ureteral tumors are presented in this paper.


Mastering the descriptive statistics used in otorhinolaryngology.
As a key player in modern scientific methodology, statistics, the science of collecting, processing and analyzing data from observation of random phenomena (i.e., in which chance is a factor), is an essential part of the process of formulating a research hypothesis, choosing the study variables and research method, analyzing the results and drawing conclusions. In this technical note, the authors touch on the main notions to be mastered for optimal use of descriptive statistics in this process, facilitating publication of articles submitted to the European Annals of Otorhinolaryngology, Head and Neck Diseases.


Effect of Salvia officinalis L. extract on chemical, microbial, sensory and shelf life of rainbow trout fillet.
The present study aimed at extending shelf life of rainbow trout fillet. Fish and seafoods are the most valuable nutrients, however, high levels of moisture, free amino acids, unsaturated fatty acids, and the content of nutrients make them to be categorized as spoilable and unstable foods. The objective of this research was to study of the shelf life of rainbow trout fillets using Salvia officinalis L. extract. Chemical and microbial analyses were performed on treatments. The usage of hydro-ethanol extract of S. officinalis L. significantly decreased microbial growth in fish fillet and there were significant differences among concentrations of the extract (p ≤ 0.05). The presence of extract of S. officinalis L. resulted in an inhibitory effect on the formation of TVB-N and FFA in comparison with the control group at all analytical times. In conclusion, the shelf life of fish fillets was increased noticeably using extract at 4 ± 1 °C.


Somatostatin receptor 1, a novel EBV-associated CpG hypermethylated gene, contributes to the pathogenesis of EBV-associated gastric cancer.
Somatostatin receptor 1 (SSTR1) was preferentially methylated in Epstein-Barr virus (EBV)-positive gastric cancer using promoter methylation array. We aimed to analyse the epigenetic alteration and biological function of SSTR1 in EBV-associated gastric cancer (EBVaGC). Promoter methylation was examined by combined bisulphite restriction analysis (COBRA) and pyrosequencing. The biological functions of SSTR1 were evaluated by loss- and gain-of-function assays. Promoter hypermethylation of SSTR1 was detected in EBV-positive gastric cancer cell lines (AGS-EBV) with SSTR1 transcriptional silence, but not in EBV-negative gastric cancer cell lines with SSTR1 expression. Expression level of SSTR1 was restored in AGS-EBV by exposure to demethylating agent. Moreover, methylation level of SSTR1 was significantly higher in EBV-positive primary gastric cancers compared with EBV-negative gastric cancers (P=0.004). Knock-down of SSTR1 in gastric cancer cell lines (AGS and BGC823) increased cell proliferation and colony formation ability, and promoted G1 to S-phase transition, enhanced cell migration and invasive ability. In contrast, ectopic expression of SSTR1 in gastric cancer cell lines (MKN28 and MGC803) significantly suppressed cell growth in culture conditions and reduced tumour size in nude mice. The tumour suppressive effect of SSTR1 was associated with upregulation of cyclin-dependent kinase inhibitors (p16, p15, p27 and p21); downregulation of oncogenes (MYC and MDM2), key cell proliferation and pro-survival regulators (PI3KR1, AKT, BCL-XL and MET); and inhibition of the migration/invasion-related genes (integrins, MMP1 (matrix metallopeptidase 1), PLAUR (plasminogen activator urokinase receptor) and IL8 (interleukin 8)). Somatostatin receptor 1 is a novel methylated gene driven by EBV infection in gastric cancer cells and acts as a potential tumour suppressor.


Negative feedback control of serotonin release in vivo: comparison of 5-hydroxyindolacetic acid levels measured by voltammetry in conscious rats and by biochemical techniques.
All evidence that serotonin release from central neurones is controlled by a negative feedback mechanism comes from in vitro studies. To study this problem in vivo we performed differential pulse voltammetry in conscious rats, in which carbon fibre electrodes had been implanted 2-15 weeks previously. The effects of monoamine oxidase inhibition (which decreases the amount of 5-hydroxyindoleacetic acid), as well as that of probenecid (which increases 5-hydroxyindoleacetic acid), suggests that 5-hydroxyindoleacetic acid rather than serotonin is measured. Blockade of the presynaptic serotoninergic autoreceptors by methiothepin, metergoline or quipazine led to an increase in differential current of the peak attributed to 5-hydroxyindoleacetic acid in hippocampus, hypothalamus and striatum. Stimulation of these receptors by m-chlorophenylpiperazine, MK-212 or LSD decreased the signal attributed to 5-hydroxyindoleacetic acid. A decrease in the signal was also seen with cinanserin. Stimulation of presynaptic alpha 2-adrenoreceptors by clonidine decreased the signal. Metergoline, quipazine and cinanserin showed biphasic effects, and no effect was observed with methysergide. In general, a reasonable agreement with the results of Baumann & Waldmeier obtained in vitro with electrically stimulated [3H]serotonin prelabelled cortex slices was achieved with differential pulse voltammetry. Only partial agreement with the results of voltammetry was obtained if 5-hydroxyindoleacetic acid was determined biochemically under comparable conditions. Qualitatively, the effects observed with methiothepin, m-chlorophenylpiperazine, clonidine and LSD were in good agreement with those measured with voltammetry as well as with the in vitro effects obtained in electrically stimulated cortex slices. No, or only partial correlation with the results obtained with voltammetry was found with MK 212, cinanserin, metergoline and quipazine. It is concluded that voltammetry preferentially measures extraneuronal 5-hydroxyindoleacetic acid rather than overall changes of this metabolite.


A case report of Nocardia asiatica constrictive pericarditis in a patient with Human Immunodeficiency Virus.
Nocardiosis commonly affects the respiratory system and is a rare cause of purulent pericarditis. Invasive nocardial infections occur more frequently in patients with immunosuppression. A misdiagnosis as tuberculosis infection is not uncommon, especially in the context of immunosuppression in high burden tuberculosis settings. The risk factors and clinical features of the two disease entities overlap substantially. Misdiagnosis may lead to a delay in appropriate treatment and may result in poor outcomes. It is important to note that these conditions may also co-exist in the same patient. We describe, to the best of our knowledge, the first case of Nocardia asiatica pericarditis in a 32-year-old man with Human Immunodeficiency Virus infection. The patient was initially diagnosed in September 2020 with a lower respiratory tract infection and pulmonary tuberculosis was suspected. A chest radiograph, performed at admission, revealed a pericardial effusion and N. asiatica was cultured from a pericardial fluid specimen that was collected 5 days following admission. Despite a good initial clinical response to a combination of trimethoprim/sulfamethoxazole and imipenem/cilastatin, the patient demised after 16 weeks of treatment. Previous reports of laboratory confirmed nocardial pericarditis are also reviewed and summarized.


Synthesis and X-ray structure of the MnIICl2 and MnIIIF2 complexes of N,N'-dimethyl-2,11-diaza[3,3](2,6)pyridinophane. High-field electron paramagnetic resonance and density functional theory studies of the MnIII complex. Evidence for a low-lying spin triplet state.
Two manganese complexes, (py2(NMe)2)MnIICl2 (1) and [(py2(NMe)2)MnIIIF2]+ (2), are here described with the macrocyclic ligand py2(NMe)2 (py2(NMe)2 = N,N'-dimethyl-2,11-diaza[3,3](2,6)pyridinophane). For both, the crystal structure is reported. The UV-visible spectrum of 2 exhibits a very broad near-infrared (NIR) band corresponding to the transition between the two e(g)-type orbitals split by the Jahn-Teller effect. A negative D value of ca. -4 cm(-1) was estimated by high-field and high-frequency electron paramagnetic resonance (HF-EPR) spectroscopy, which was consistent with symmetry considerations. Density functional theory (DFT) calculations on 2 support the 5B1 electronic ground state predicted from the X-ray structure. Moreover, to explain the large value of the D parameter, a spin triplet first excited spin state was postulated to occur at low energy. This was confirmed by the DFT calculations.


Association of serum phosphate concentration with the incidence of intervention for peripheral artery disease in patients undergoing hemodialysis: 10-year outcomes of the Q-Cohort Study.
Peripheral artery disease (PAD) is mainly caused by atherosclerosis and is a critical cardiovascular complication in patients undergoing hemodialysis. Although hyperphosphatemia is a risk factor for cardiovascular events, whether serum phosphate concentration is associated with PAD remains unclear. This study was performed to clarify the relationship between serum phosphate concentration and the risk of intervention for PAD in patients undergoing hemodialysis. In total, 3505 patients undergoing hemodialysis registered in the Q-Cohort Study were followed up for 10 years. The primary outcome was the incidence of major adverse limb events (MALE) as a surrogate endpoint of intervention for PAD. The patients were divided into quartiles according to the baseline serum phosphate concentration: Q1 (n = 886), <4.2 mg/dL; Q2 (n = 837), 4.2-4.8 mg/dL; Q3 (n = 909), 4.9-5.6 mg/dL; and Q4 (n = 873), ≥5.7 mg/dL. A multivariable-adjusted Cox proportional hazards risk model was employed to examine the association between the serum phosphate concentration and the risk of MALE. During a median follow-up period of 8.2 years, 257 patients required intervention with MALE. The Cox proportional hazards risk model showed that the risk of MALE in Q4 was significantly higher than that in Q1 (hazard ratio, 1.81; 95% confidence interval, 1.25-2.63). Every 1-mg/dL increase in serum phosphate concentration was also significantly associated with the increased incidence of MALE (hazard ratio, 1.24; 95% confidence interval, 1.10-1.39). An elevated serum phosphate concentration was associated with an increased risk of MALE in patients undergoing hemodialysis.


Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial.
Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft (CABG) surgery. We investigated the safety and efficacy of this procedure. Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre, Essen, Germany, between April, 2008, and October, 2012. Patients were prospectively randomised to receive remote ischaemic preconditioning (three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia) or no ischaemic preconditioning (control). The primary endpoint was myocardial injury, as reflected by the geometric mean area under the curve (AUC) for perioperative concentrations of cardiac troponin I (cTnI) in serum in the first 72 h after CABG. Mortality was the main safety endpoint. Analysis was done in intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT01406678. 329 patients were enrolled. Baseline characteristics and perioperative data did not differ between groups. cTnI AUC was 266 ng/mL over 72 h (95% CI 237-298) in the remote ischaemic preconditioning group and 321 ng/mL (287-360) in the control group. In the intention-to-treat population, the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 (95% CI 0·70-0·97, p=0·022). cTnI release remained lower in the per-protocol analysis (0·79, 0·66-0·94, p=0·001). All-cause mortality was assessed over 1·54 (SD 1·22) years and was lower with remote ischaemic preconditioning than without (ratio 0·27, 95% CI 0·08-0·98, p=0·046). Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery. German Research Foundation.


Role of lipoprotein lipases in postprandial lipid metabolism.
The pivotal role of heparin-releasable lipases in the clearing of postprandial lipids is known for a long time. The hydrolysis of triglycerides under influence of lipoprotein lipase is among the first recognised and well defined processes in postprandial lipid metabolism. More recently, also hepatic lipase has been implicated in the clearing of postprandial lipoproteins. Lipoprotein lipase as well as hepatic lipase are also involved in the metabolism of several other lipoproteins. However, their capacity is limited. This may lead to interaction of different metabolic processes and competition for the available lipase by different lipoproteins. Indeed, it is generally accepted that the exaggerated postprandial response in subjects with hypertriglyceridemia is at least partially due to competition between endogenous (VLDL) and exogenous (chylomicrons) lipoproteins. Similar mechanisms may also take place in the liver where hepatic lipase plays a role in the metabolism of several lipoproteins. In this short review, the roles of lipoprotein lipase and hepatic lipase in postprandial lipoprotein metabolism are discussed in relation(s) to their suggested function in the metabolism of different lipoproteins.


Atypical glomerulopathy associated with the cblE inborn error of vitamin B₁₂ metabolism.
The cblE disorder is an inherited disorder of vitamin B12 metabolism that results in elevated levels of homocysteine and decreased methionine in body fluids. Renal complications have been reported in patients with cblC disease, but not in those with cblE disease. The renal complications of cblC disease include thrombotic microangiopathy (TMA), neonatal hemolytic uremic syndrome, chronic renal failure, tubulointerstitial nephritis and proximal renal tubular acidosis. Previously, we reported a patient with cblC disease who had an atypical glomerulopathy that manifested with proteinuria and progressive renal insufficiency. Studies were done on cultured fibroblasts. Renal biopsy tissue was examined by light and electron microscopy. There was decreased incorporation of labeled methyltetrahydrofolate and decreased synthesis of methylcobalamin. Complementation analysis placed the patient into the cblE complementation group. The findings from the histological and ultrastructural studies of renal biopsy were similar, but not identical, to those of idiopathic membranoproliferative glomerulonephritis (MPGN) and overlapped with those of TMA. We describe a patient with cblE disease who had an atypical glomerulopathy similar to MPGN. Additional findings included migraine headaches, hypothyroidism and livedo reticularis.


Randomised controlled trial of the short-term effects of osmotic-release oral system methylphenidate on symptoms and behavioural outcomes in young male prisoners with attention deficit hyperactivity disorder: CIAO-II study.
Research has shown that 20-30% of prisoners meet the diagnostic criteria for attention-deficit hyperactivity disorder (ADHD). Methylphenidate reduces ADHD symptoms, but effects in prisoners are uncertain because of comorbid mental health and substance use disorders. To estimate the efficacy of an osmotic-release oral system methylphenidate (OROS-methylphenidate) in reducing ADHD symptoms in young adult prisoners with ADHD. We conducted an 8-week parallel-arm, double-blind, randomised placebo-controlled trial of OROS-methylphenidate versus placebo in male prisoners (aged 16-25 years) meeting the DSM-5 criteria for ADHD. Primary outcome was ADHD symptoms at 8 weeks, using the investigator-rated Connors Adult ADHD Rating Scale (CAARS-O). Thirteen secondary outcomes were measured, including emotional dysregulation, mind wandering, violent attitudes, mental health symptoms, and prison officer and educational staff ratings of behaviour and aggression. In the OROS-methylphenidate arm, mean CAARS-O score at 8 weeks was estimated to be reduced by 0.57 points relative to the placebo arm (95% CI -2.41 to 3.56), and non-significant. The responder rate, defined as a 20% reduction in CAARS-O score, was 48.3% for the OROS-methylphenidate arm and 47.9% for the placebo arm. No statistically significant trial arm differences were detected for any of the secondary outcomes. Mean final titrated dose was 53.8 mg in the OROS-methylphenidate arm. ADHD symptoms did not respond to OROS-methylphenidate in young adult prisoners. The findings do not support routine treatment with OROS-methylphenidate in this population. Further research is needed to evaluate effects of higher average dosing and adherence to treatment, multi-modal treatments and preventative interventions in the community.


Cell-penetrating hollow spheres based on milk protein.
Hollow protein nanospheres are prepared in aqueous solution by molecular self-assembly, and they show extraordinary capability to penetrate cell barriers in an energy-independent fashion.


Effects of maternal hyperphenylalaninemia on fetal brain development: a biochemical study.
We examined the effects of maternal hyperphenylalaninemia on body and brain growth, and the biochemical maturation of the fetal and neonatal rat brain. Elevated concentrations of plasma phenylalanine were induced in pregnant rats under two experimental conditions from the 14th through the 21st days of gestation. In the first treatment, pregnant rats were injected subcutaneously with alpha-methylphenylalanine (to inhibit maternal liver phenylalanine hydroxylase) at a dosage of 30 mg/100 g body weight plus phenylalanine supplementation (to increase maternal and fetal plasma phenylalanine) at a dosage of 60 mg/100 g body weight two times daily. In the second treatment, pregnant dams were injected with phenylalanine only at a dosage of 65 mg/100 g body weight three times daily. Treatment with alpha-methylphenylalanine/phenylalanine (mPhe/Phe) resulted in a 76% inhibition in the activity of maternal phenylalanine hydroxylase and a 25-fold increase in the mean daily concentration of phenylalanine in the maternal and fetal plasma. Phenylalanine treatment alone resulted in a 15-fold increase in plasma phenylalanine in the maternal and fetal animals. Significant reductions in body and brain weights in the fetal and neonatal rats were found in both treatment groups. Biochemical determinations indicated that the total DNA, RNA, and protein contents of the cerebra were reduced, with the reductions being greater in the mPhe/Phe- than the phenylalanine-treated rats. However, the retardation in body and brain growth of both treatment groups did not appear to be permanent because substantial recovery was noted in the rats after postnatal day 7. These results suggest that exposure of the fetus to high plasma concentrations of phenylalanine caused a delay in the biochemical maturation of the fetal rat brain.


Structural compartmentalization of MHC class II signaling function.
Major histocompatibility complex (MHC) class II molecules are critical restricting elements in the generation of thymus-dependent immune responses. Recent studies indicate that in addition to providing a composite epitope for recognition by T-cell antigen receptors, MHC class II molecules function in signal transduction through interaction with other cellular proteins. Mutational analyses indicate that structural information necessary for these functions is compartmentalized in different aspects of the molecular complex. Here, William Wade and colleagues review the structural basis of this MHC class II function as defined in the I-A alpha and -beta chains.


Weightlessness: a case history.
The facts presented represent, for convenience, a composite clinical picture of the three crewmen aboard Skylab II as observed by me.


Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. The Belgian Diabetes Registry.
Demographic and biological data were collected from all Caucasian Type 1 diabetic patients (n = 279) who were recruited at clinical onset by the Belgian Diabetes Registry over 34 months. The male/female ratio was significantly higher for onset between age 20 and 40 years (2.4) than before age 20 years (1.0); no age-or sex-differences were noticed in serum fructosamine concentration. Total and high concentrations of insulin autoantibodies and islet cell antibodies were preferentially associated with the HLA DQA1*0301-DQB1*0302 susceptibility haplotype. The occurrence of both types of antibodies was also correlated, irrespective of haplotype. At onset before age 10 years, the high risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 was more prevalent than all other DQA1-DQB1 genotypes taken together, leading to a higher prevalence of the DQA1*0301-DQB1*0302 haplotype in this age group (75%) than in the 10-39 years age group (54%). Under age 10 years, the presence of DQA1*0301-DQB1*0302 was strongly associated with insulin autoantibodies (90%) and islet cell autoantibodies (92% with 85% of high titre), whereas patients without this haplotype were less frequently positive for insulin autoantibodies (31%) or islet cell autoantibodies (38% high titre). In the group with onset at age 10-39 years, the DQA1*0301-DQB1*0302 haplotype presented a lower association with insulin autoantibodies (approximately 40%) and islet cell autoantibodies (50 to 65% high titre), prevalences which no longer differed from those in subjects lacking this haplotype.(ABSTRACT TRUNCATED AT 250 WORDS)


Thymic lymphocyte differentiation and thymic leukemogenesis.
Henry Kaplan helped establish the fields of lymphocyte biology and viral leukemogenesis by his early and continuing studies on radiation leukemogenesis. As one of Henry's students I carried on these dual preoccupations with thymic lymphocytopoiesis and thymic lymphomagenesis. This communication demonstrates that thymic lymphocytes are derived from bone marrow precursors which lack any T cell markers; these bone marrow cells (or their clonogenic subsets) can give rise to either thymic cortical plus medullary progeny, or medullary progeny alone; thymic lymphocytes mature in contact with 3-5 classes of nonlymphoid cells (thymic nurse cells, cortical dendritic epithelial cells, medullary epithelial cells, dendritic reticular cells, and macrophages), and one of these subsets, cortical dendritic epithelial cells, express an unusual distribution of MHC antigen (perhaps utilized in the maturation of T cell MHC restriction); the population of cells which are poised to emigrate from the thymus are a unique subset of cortical cells which possess peripheral lymphoid organ homing receptors; and the thymic target cells for retrovirus lymphomagenesis express highly specific retrovirus receptors that are analogous (and perhaps synonymous) with antigen-specific T cell receptors.


Childhood obesity.
The pediatrician's approach to overweight was best summarized by Bruch 25 years ago: The pediatrician plays an important role in the prevention of obesity. From birth on, feeding a child always involves a dual task--namely, offering food in appropriate amounts and gearing it to the child's expression of his needs. Only in this way can he develop discriminating awareness and become active in establishing self-regulation.... If a child is fed when he is hungry, played with when he needs attention, and encouraged to be active when he is restless, he is not likely to grow up inhibited and passive or overstuffed and helpless, unable to control his eating because every discomfort is misinterpreted as a need to eat.


Zinc oxide-montmorillonite hybrid influences diarrhea, intestinal mucosal integrity, and digestive enzyme activity in weaned pigs.
One hundred-eighty piglets (Duroc × Landrace × Yorkshire), with an average initial weight of 7.4 kg weaned at 27 ± 1 days of age, were used to evaluate the effects of dietary zinc oxide-montmorillonite hybrid (ZnO-MMT) on growth performance, diarrhea, intestinal mucosal integrity, and digestive enzyme activity. All pigs were allotted to five treatments and fed with the basal diets supplemented with 0, 250, 500, and 750 mg/kg of Zn as ZnO-MMT or 2,000 mg/kg of Zn as ZnO. The results showed that supplementation with 500 or 750 mg/kg of Zn from ZnO-MMT and 2,000 mg/kg of Zn from ZnO improved average daily gain, enhanced average daily feed intake, decreased fecal scores at 4, 8, and 14 days postweaning, reduced intestinal permeability which was evident from the reduced lactulose recovery and urinary lactulose/mannitol ratio, and improved the activities of protease, amylase, lipase, trypsin, and chymotrypsin both in pancreas and small intestinal contents of pigs as compared with the control. Supplemental 250 mg/kg of Zn from ZnO-MMT also decreased fecal scores at 8 and 14 days postweaning, decreased urinary lactulose/mannitol ratio, and improved chymotrypsin activity in pancreas and small intestinal contents as well as protease activity in small intestinal contents compared with control. Moreover, the above indexes of weanling pigs fed with 500 or 750 mg/kg of Zn as ZnO-MMT did not differ from those fed with 2,000 mg/kg of Zn as ZnO. The results demonstrated that supplementation with 500 or 750 mg/kg of Zn from ZnO-MMT was as efficacious as 2,000 mg/kg of Zn from ZnO in improving growth performance, alleviating postweaning diarrhea, and enhancing intestinal mucosal integrity and the digestive enzyme activities in pancreas and small intestinal contents of pigs. The results that feeding lower concentrations of ZnO-MMT to weanling pigs maintained performance will be beneficial for the environment and for sustaining swine production.


Comparison of the development of resistant strains of Type 1 herpes simplex virus to in vitro antiviral activity of 5-iodo-2'-deoxyuridine or ribavirin.
Exposure of HSV/1 to low concentrations of ribavirin during 4--5 passages does not produce ribavirin-resistant virus. IDU resistance was developed by HSV/1 while it was being passed simultaneously. This resistance was seen to develop in both KB and Vero cells. The IDU-resistant virus is also resistant to ribavirin in KB cells.


Functional dissociation between lateral and medial entorhinal cortex in memory processes in mice.
The effects of lesions of the medial or the lateral entorhinal cortex in mice were examined on acquisition, retention and extinction of an operant-conditioning task in a Skinner box. Compared with the control animals, lesions in the medial entorhinal had no behavioral effects whereas lesions in the lateral entorhinal enhanced retention and increased resistance to extinction but did not change acquisition of this task. These results suggest a functional dissociation between the two parts of the entorhinal cortex.


A novel driving assessment combining hazard perception, hazard prediction and theory questions.
A new hazard test was created using high-fidelity computer animation containing ten hazards. Sixty learner drivers and sixty experienced drivers sat either a hazard-perception version of this test (requiring timed responses to materialized hazards) or a hazard-prediction variant of the test (where the screen is occluded as the hazard begins to appear and drivers are asked 'What happens next?'). Recent studies have demonstrated that the prediction test format outperforms the hazard perception format using naturalistic video, but there has not yet been a study replicating this effect with computer-animated materials similar to the quality of those used in the official UK hazard perception test. The new test also included eleven theory questions designed to probe drivers' knowledge of the rules of the road. The results demonstrated that both test variants differentiated between driver groups with considerable effect sizes. Theory-question scores were comparable across learner and experienced driver groups, reflecting learners' preparation for the test and possible issues with memory decay and overwriting in the experienced group. As an interesting aside, driving-related video game play negatively correlated with hazard perception performance, but not with hazard prediction scores. Some individual hazards better suited the prediction or perception test format, raising the possibility of a future hybrid test that combines the two approaches.


Chronic obstructive pulmonary disease in the older patient.
Chronic obstructive pulmonary disease (COPD) is one of the most common chronic diseases in the world. It is a major cause of morbidity, mortality, and health care use, particularly in older adults. In the following sections, the authors review the diagnosis and management of COPD with a focus on special issues in older adults.


Immunoglobulins reduced oxidative stress in human microglial cells induced by high dose of acetoacetate.
Diabetic ketoacidosis (DKA) has been associated with cognitive impairment and structural alterations in the brain. There is increased evidence supporting the role of neuroinflammation in causing these alterations. In the present study, using human microglial cell line (CHME-5), we aimed to investigate the effect of immunoglobulins (IG) on survival, activation, reactive oxygen species (ROS) and cytokine production of microglia exposed to ketone bodies. We demonstrated that high and low dose of ketone bodies induced a significant increase in ROS within 1 h after exposure to CHME-5 cells with upregulation in mitochondrial superoxide level 5 min after exposure suggestive of early and selective impairment of mitochondrial function. A significant and delayed increase of apoptosis of CHME-5 cells was observed 4 days after ketone bodies exposure. Cytokine expression reached a peak within 1 h and persisted for 3 days after exposure to ketone bodies. IG significantly reduced ROS and transiently suppressed cytokine expression of CHME-5 cells after exposure to ketone bodies. However, no effect of IG on apoptosis was observed. Overall, these results supported that ketone bodies induced microglia activation with early and selective impairment of mitochondrial function, increased cytokines expression and delayed increase in apoptosis. IG suppressed microglia activation and transiently inhibited cytokines expression without affecting apoptosis. These results warrant further experimental work on the role of microglia and potential benefit of IG in brain structural changes induced by DKA.


Correlative study between computerized transverse scanning and stereoimpedoencephalography in space-occupying lesions of the brain.
Stereoimpedoencephalography (SIEG) is routinely used by the authors during stereotactic investigations of glial brain tumours prior to stereotactic implantation of isotopes or prior to conventional surgery: the brain tissue impedance is measured along a probe track according to the four electrodes impedance technique. The correlation between the tissue structures and the corresponding impedance values has been studied by comparison with the CATScan data reported on the stereotactic schedules; impedance values are influenced by changes in arterial pCO2 and also by other unknown factors; in order to avoid these uninterpretable changes of the impedance, the recorded values have been normalized with respect to the average impedance along a control track in the normal hemisphere. As a rule, the impedance profile exhibits a "hole" at the site of the pathological processes like tumours as well as surrounding oedema, and the delimitation of the pathological area is very similar to that obtained by the CATScan. There is a good linear correlation between the values of normalized impedance and the x-ray absorption as given by the computer listing of the CATScan. Lastly, statistical values of normalized impedances are determined for the main structures of the brain, showing that the tumour tissue has an impedance equal to half the impedance of the normal tissue.


Five-year results of surgical colorectal cancer treatment in rural Australia.
The incidence of colorectal cancer in Australia is among the highest worldwide. We investigate whether similar treatment results for colorectal cancer can be achieved in rural surgery as reported from metropolitan centres. Retrospective analysis of prospectively collected follow-up data in a rural surgical centre in South Australia has been carried out. Results of all patients undergoing surgical treatment for colorectal cancer are analysed, and all cancer stages and interventions over a 5-year period are included. Five-year survival of all patients (n = 194) treated for colorectal cancer independent of stage and cause of death was 56%, cancer-specific 5-year survival was 64%. Perioperative mortality was 1.7%. Overall survival was 96% in stage 1, 92% in stage 2, 58% in stage 3 and 0% for patients with metastatic disease at the time of diagnosis. Cancer-specific survival ranged from 100% in stage 1 to 0% for patients with metastatic disease. Assessment of overall and cancer-specific survival of all patients undergoing surgery for colorectal cancer over a 5-year time period in a rural South Australian centre shows that good long-term results can be achieved with low perioperative mortality. These findings compare well with the results of other groups.


HLA-B27 polymorphism in Turkish patients with ankylosing spondylitis.
The aim of this study was to determine the distribution of human leukocyte antigen (HLA)-B27 subtypes in serologically HLA-B27-positive ankylosing spondylitis (AS) patients and healthy controls from the Turkish population and to compare this with other reports from other populations. We subtyped HLA-B27 in 38 HLA-B27-positive Turkish patients with AS and 47 HLA-B27-positive healthy controls without AS by polymerase chain reaction with specific sequence primers (PCR-SSP). The results demonstrated that: B*2705 was the predominant subtype among both of the patients (71.1%) and controls (68.0%). B*2702 was observed in 26.3% and 32.0% of the patients and controls, respectively. B*2708 subtype was found in 2.6% of the patients but not among the control group. When the distribution of B27 subtypes in Turkish populations was compared with that in other populations, similar frequencies with the Caucasian-Europe groups were noted. However, this should be interpreted carefully because of the small number of individuals in our study.


Utilization of 2-nitrophenols in annulations with aryl isothiocyanates towards the synthesis of 2-aminobenzoxazoles.
A method for the annulation of 2-nitrophenols with aryl isothiocyanates is reported. The reactions proceeded in the presence of an iron(iii) acetylacetonate catalyst, elemental sulfur, NaOH as a base, and DMSO as a solvent. Derivatives of 2-aminobenzoxazoles bearing nitro, cyano, acetyl, sulfone, secondary amine, and pyrrolyl groups were successfully isolated.


Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) receptors.
Compounds 1-14 were synthesized in a search for high-affinity CRF1 receptor ligands that could be radiolabeled with (11)C or (18)F for use as positron emission tomography (PET) radiotracers. Derivatives of 2 were developed which contained amide N-fluoroalkyl substituents. Compounds [(18)F]24 and [(18)F]25 were found to have appropriate lipophilicities of logP7.4=2.2 but microPET imaging with [(18)F]25 demonstrated limited brain uptake.


Asymptomatic emphysematous cholecystitis.
Emphysematous cholecystitis (EC) is a life-threatening complication of acute cholecystitis. Its clinical manifestations are usually vague, but asymptomatic cases are very rare. We present such a case with an emphasis on sonographic (US) findings. In this case, detection of gas echoes in the gallbladder wall and the surrounding hepatic tissue led us to an appropriate treatment. US is now the technique of first choice for diagnosing gallbladder diseases, and knowledge of US findings encountered in this case can help prevent a hazardous delay in emergent treatment.


The long-term impact of footshock stress on addiction-related behaviors in rats.
We investigated the impact of electric shocks--frequently used to model post-traumatic stress disorder in rodents--on behaviors relevant to drug abuse in rats. Rats exposed to 10 shocks of 3 mA over 5 min showed a robust conditioned fear 28 days later, which confirms the traumatic nature of shock exposure. A different set of rats was studied in the conditioned place preference paradigm beginning with the 27th post-shock day. 10mg/kg morphine induced a marked place preference in both shocked and non-shocked rats. Although the magnitude of place preference was not affected, extinction was markedly delayed in shocked rats. We also investigated tolerance to the hyperthermic effects of morphine. A low dose (5mg/kg) that was administered 4 weeks after shock exposure robustly increased body temperature in both shocked and non-shocked rats. Repeated injections resulted in a mild tolerance in non-shocked controls; yet, morphine readily increased body temperature in these rats on the 5th day of injections. In contrast, the temperature-heightening effect of morphine was abolished in shocked rats after 2 days. Thus, shock exposure considerably delayed the extinction of place preference induced by, and dramatically accelerated the tolerance to the effects of, morphine. Our study shows that electric shocks durably affect behavior in tests relevant to drug abuse in conjunction with the development of post-traumatic stress disorder-like behavioral dysfunctions.


The impact of demographic and disease-specific variables on pain in cancer patients.
The aim of this study was to examine to what extent demographic and disease-specific variables affected pain in cancer patients. Two to three weeks after their last hospitalization, 1,453 cancer patients completed questionnaires measuring demographic variables, quality of life, and pain (EORTC-QLQ C-30). Response rate was 72.1%. Data on type of cancer and the severity of the disease were also compiled. Sixty percent of the sample reported some pain. Type of cancer, presence of metastases, and time until death were significant predictors of experienced pain. The patients' experience of pain was mainly associated with disease-specific variables. Sex, age, level of education, and co-habitation were not related to pain, but employment status was. The patients on disability pensions had significantly more pain than the patients who were working or studying. Special attention should be given to patients with advanced prostate cancer with a short time to live, as they reported the most pain.


The impact of recurrent throat infection on children and their families.
Recurrent throat problems in children are common and have an impact on the family. The appropriateness of surgery will depend on both clinical and social factors. The aim of this study was to assess the impact on the whole family when a child is suffering from recurrent throat problems, and investigate related parental attitudes. A total of 1190 parents of children in northern England for whom tonsillectomy or adeno-tonsillectomy was a possible treatment option were sent a questionnaire covering social and clinical issues such as children's symptoms, the impact on family life and parental attitudes. The majority of children had experienced more than four episodes in the previous year, had their sleep affected and time off school. Most parents were worried and reported disruption to the family, including taking time off work and cross-infection. Parental disruption, worry and eagerness for surgery were significantly associated with the duration of episodes of throat problems and the number of episodes in the previous year, but not with duration of tonsillitis. Time off school, or parental time off work was significantly associated with parental worry and disruption, but not with eagerness for surgery. This work highlights the impact of recurrent throat problems and related parental attitudes, and will aid in striking a balance between clinical requirements and the needs and wishes of the family.


28 novel mutations identified from 33 Chinese patients with cilia-related kidney disorders.
Cilia play an important role in cellular signaling pathways. Defective ciliary function causes a variety of disorders involve retina, skeleton, liver, kidney or others. Cilia-related kidney disorders are characterized by cystic renal disease, nephronophthisis and renal failure in general. In this study, we collected 33 families clinically suspected of cilia-related kidney disorders. Capture-based next-generation sequencing (NGS) of 88 related genes, Sanger sequencing, pedigree analysis and functional study were performed to analyze their genetic cause. 40 mutations in PKD1, PKD2, PKHD1, DYNC2H1 and TMEM67 genes were identified from 27 of 33 affected families. 70% (28/40) of the mutations were first found in patients. We reported a very early-onset autosomal dominant polycystic kidney disease (ADPKD) family caused by a novel heterozygous PKD1 mutation; another fetus with DYNC2H1 compound heterozygous missense mutations showed mainly kidney dysplasia instead of skeletal abnormalities; and a novel PKD1 mutation, c.12445-3C > G, was confirmed to cause two wrong splicing modes. As for previously reported mutations, such as PKD1, c.6395 T > G (p.F2132C) and c.6868G > T (p.D2290Y), we had new and different findings. The findings provided new references for genotype-phenotype analyses and broadened the mutation spectrum of detected genes, which were significantly valuable for prenatal diagnosis and genetic counseling.


Diversity of Clostridium perfringens isolates from various sources and prevalence of conjugative plasmids.
Clostridium perfringens is an important pathogen, causing food poisoning and other mild to severe infections in humans and animals. Some strains of C. perfringens contain conjugative plasmids, which may carry antimicrobial resistance and toxin genes. We studied genomic and plasmid diversity of 145 C. perfringens type A strains isolated from soils, foods, chickens, clinical samples, and domestic animals (porcine, bovine and canine), from different geographic areas in the United States between 1994 and 2006, using multiple-locus variable-number tandem repeat analysis (MLVA) and/or pulsed-field gel electrophoresis (PFGE). MLVA detected the genetic diversity in a majority of the isolates. PFGE, using SmaI and KspI, confirmed the MLVA results but also detected differences among the strains that could not be differentiated by MLVA. All of the PFGE profiles of the strains were different, except for a few of the epidemiologically related strains, which were identical. The PFGE profiles of strains isolated from the same domestic animal species were clustered more closely with each other than with other strains. However, a variety of C. perfringens strains with distinct genetic backgrounds were found among the clinical isolates. Variation was also observed in the size and number of plasmids in the strains. Primers for the internal fragment of a conjugative tcpH gene of C. perfringens plasmid pCPF4969 amplified identical size fragments from a majority of strains tested; and this gene hybridized to the various-sized plasmids of these strains. The sequences of the PCR-amplified tcpH genes from 12 strains showed diversity among the tcpH genes. Regardless of the sources of the isolates, the genetic diversity of C. perfringens extended to the plasmids carrying conjugative genes.


Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells.
Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-kappaB transcription factors that regulate several cell survival and anti-apoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-kappaB expression in androgen-refractory human prostate cancer cells exhibiting high constitutive NF-kappaB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-kappaB/p65. BetA-mediated NF-kappaB inhibition involved decreased IKK activity and phosphorylation of IkappaBalpha at serine 32/36 followed by its degradation. Reporter assays revealed that NF-kappaB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFalpha-induced activation of NF-kappaB via the IkappaBalpha pathway, thereby sensitizing the cells to TNFalpha-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF-kappaB activation and supports the rationale for targeting NF-kappaB through combination protocols with BetA in androgen-refractory prostate cancer.


Correction of blood drug levels for changes over the day.
A graph-based method is presented to compensate for the influence of variations in drug dosage schedules and blood sampling times upon the blood concentrations of drugs whose elimination half-life is between 7 and 48 hours. This method permits the clinician to interpret blood drug levels drawn at nonstandard times, and to correct blood drug levels for how the daily dose was divided. This method is expected to improve the convenience of monitoring blood drug levels.


Can a new antiseptic agent reduce the bacterial colonization rate of central venous lines in post-cardiac surgery patients?
Central venous (CV) catheters play an essential role in the management of critically ill patients in the Intensive Care Unit (ICU). CV lines are, however, allied to catheter-associated blood stream infections. Bacterial colonization of CV lines is deemed the main cause of catheter-associated infection. The purpose of our study was to compare bacterial colony counts in the catheter site before CV line insertion in two groups of post-cardiac surgery patients: a group receiving Sanosil (an antiseptic agent composed of H2O2 and silver) and a control group. This interventional prospective double-blinded clinical trial recruited the patients in three post-cardiac surgery ICUs of a heart center. The participants were divided into interventional (113 patients) and control (136 patients) groups. Sanosil was added to the routine preparation procedure (Chlorhexidine bath one day before and scrub with Povidone-Iodine just before the CV line insertion). After the removal of the CV lines, the catheters tips were sent for culture and evaluation of colony counts. Catheter colonization occurred in 55 (22.1%) patients: 26 (23%) patients in the Sanosil group and 29 (21.3%) in the control group; there was no significant statistical difference between the two groups (p value = 0.75, RR = 1.05, 95% CI: 0.76-1.45). The most common organism having colonized in the cultures of the catheter tips was staphylococcus epidermis: 20 cases in the control group and 16 cases in the intervention group. Catheter colonization frequently occurs in post-cardiac surgery patients. However, our results did not indicate the effectiveness of adding Sanosil to the routine preparation procedure with respect to reducing catheter bacterial colonization.


Influenza A/H1N1/09-10 infections in a NICU during the 2009-2010 H1N1 pandemic.
Few cases of the pandemic influenza A H1N1 have been reported in very low birth weight infants. We report here a small outbreak in our NICU of 3 cases of influenza A/H1N1/09-10 in very low birth weight infants during the 2009-2010 H1N1 pandemic and describe their clinical presentations and favorable outcomes despite the lack of treatment.


Comparison of clinical features in patients with pulmonary Mycobacterium-avium complex (MAC) disease treated before and after proposal for guidelines.
We aimed to investigate the transitional pattern of the clinical features of pulmonary Mycobacterium-avium complex (MAC) disease, especially with regard to the clinical effect of treatment, in patients treated before and after the implementation of the 1998 guidelines of the Japanese Society for Tuberculosis for combined chemotherapy for pulmonary MAC disease. The clinical findings and treatments of 220 patients with pulmonary MAC disease during the past 10 years were compared by dividing the patients into two groups, each encompassing a 5-year period. During the past 5 years, we have carried out combined chemotherapy with rifampicin, ethambutol, an aminoglycoside (streptomycin or kanamycin), and clarithromycin (CAM) following the guidelines for the treatment of pulmonary MAC disease proposed in 1998, and we have achieved positive results; both the sputum conversion rate and clinical improvement of the outcome in patients with primary infectious type rose significantly. Although there were no significant differences in the background or in microbiological and radiological findings in the two groups, significant improvement was seen in the sputum conversion rate and in improvement of the clinical effect of treatment. The results of this combined chemotherapy were unsatisfactory, however, when compared with its clinical effect on pulmonary tuberculosis. Therefore, we anticipate the development of new companion drugs for pulmonary MAC disease that are as active as CAM.


Diagnostic value of lymphopaenia and elevated serum ACE in patients with uveitis.
To evaluate the diagnostic worth of elevated serum ACE (sACE) and lymphopaenia, singly or combined, in diagnosing sarcoid uveitis. Monocentric retrospective study, on a cohort of 996 adult patients referred to our department between March 2001 and December 2018 for a diagnostic work-up of uveitis. The sensitivity (SE), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the two biomarkers were calculated in different contexts. Eight hundred and sixty-eight patient cases were reviewed. The mean age at uveitis onset was 49.4 (±18.6) years. Of them, 144 patients had a diagnosis of sarcoid uveitis. An elevated sACE had SE of 45.8%, Sp of 88.8%, PPV of 44.9% and NPV of 89.2% in diagnosing sarcoid uveitis. For lymphopaenia, SE was 15.3%, Sp was 96.7%, PPV was 47.8% and NPV was 85.2%. For the combination of elevated sACE and lymphopaenia, SE was 18.9%, Sp was 99.0%, PPV was 73.9% and NPV was 89.5%. The value of this combination varied according to patient age at diagnosis plus anatomoclinical entities: for patients aged ≤50 years, SE was 31.3%, Sp was 99.7%, PPV was 90.9% and NPV was 94.3%. For granulomatous uveitis, SE was 26.2%, Sp was 97.3%, PPV was 73.3% and NPV was 82.5%. A combination of elevated serum ACE and lymphopaenia more convincingly suggests sarcoid uveitis than these investigational tests used alone, especially in patients with granulomatous uveitis, while a lack of these markers corresponds to a high NPV. NCT03863782.


Formation of 3-Orsellinoxypropanoic Acid in Penicillum crustosum is Catalyzed by a Bifunctional Nonreducing Polyketide Synthase.
The heterologous expression of a nonreducing polyketide synthase gene oesA from Penicillium crustosum led to the identification of orsellinoylpropanoic acid (1). Domain deletion and recombination proved that OesA catalyzes not only the formation of orsellinic acid but also its transfer to 3-hydroxypropanoic acid. Both ACP domains contribute independently and complementarily to the product formation. Feeding experiments provided evidence that only the orsellinyl residue is derived from acetate.


Signs and Symptoms of Food Allergy and Food-Induced Anaphylaxis.
Food allergies are increasing in prevalence. In order for pediatric clinicians to appropriately diagnose and manage food allergies, the characteristic signs and symptoms of these potentially severe reactions must be recognized. Unlike nonimmunologic adverse food reactions (such as lactose intolerance and food poisoning), food allergies by definition are immune-mediated responses that occur reproducibly on food ingestion. The varying clinical presentations of food allergy include IgE-mediated disorders, mixed IgE- and cell-mediated disorders, and cell-mediated food allergies. This review describes the clinical manifestations of each of these categories of food allergy, with special emphasis on recognition of food-induced anaphylaxis.


Fiber Rearrangement and Matrix Compression in Soft Tissues: Multiscale Hypoelasticity and Application to Tendon.
It is widely accepted that the nonlinear macroscopic mechanical behavior of soft tissue is governed by fiber straightening and re-orientation. Here, we provide a quantitative assessment of this phenomenon, by means of a continuum micromechanics approach. Given the negligibly small bending stiffness of crimped fibers, the latter are represented through a number of hypoelastic straight fiber phases with different orientations, being embedded into a hypoelastic matrix phase. The corresponding representative volume element (RVE) hosting these phases is subjected to "macroscopic" strain rates, which are downscaled to fiber and matrix strain rates on the one hand, and to fiber spins on the other hand. This gives quantitative access to the fiber decrimping (or straightening) phenomenon under non-affine conditions, i.e. in the case where the fiber orientations cannot be simply linked to the macroscopic strain state. In the case of tendinous tissue, such an RVE relates to the fascicle material with 50 μm characteristic length, made up of crimped collagen bundles and a gel-type matrix in-between. The fascicles themselves act as parallel fibers in a similar matrix at the scale of a tissue-related RVE with 500 μm characteristic length. As evidenced by a sensitivity analysis and confirmed by various mechanical tests, it is the initial crimping angle which drives both the degree of straightening and the shape of the macroscopic stress-strain curve, while the final linear portion of this curve depends almost exclusively on the collagen bundle elasticity. Our model also reveals the mechanical cooperation of the tissue's key microstructural components: while the fibers carry tensile forces, the matrices undergo hydrostatic pressure.


Student Acceptance of Virtual Bedside Surgical Tutorials During COVID-19: A Randomized Controlled Trial.
The social distancing recommendations from the WHO during the pandemic has resulted in a pivot point in the delivery of medical education. With the medical student clinical experience constantly under threat; novel methods to maintain adequate surgical patient exposure and student interaction on a platform amenable to the interactive format required were devised using a virtual platform to compliment current pedagogical approaches. A parallel randomized controlled trial evaluated the perceived use of remote learning in place of bedside teaching. Participants were randomized to undergo surgical bedside teaching in person or virtually. Feedback questionnaires and exit interviews carried out following each session. Content analysis of transcripts was performed to evaluate the presence and quality of perceived learning, benefits and limitations to each modality. Feedback demonstrated greater engagement, satisfaction, involvement and learning (P < 0.001) in the bedside teaching group. Content analysis yielded three main themes; Technological, Interpersonal Component, Provision of Content. Participants in the virtual group reported a limited ability to elicit clinically relevant findings in surgical patients. Students however reported the virtual teaching was an acceptable method of learning with 90% satisfaction reported for learning via the virtual platform. The pandemic posed challenges to adequate student-patient exposure. Delivering surgical bedside teaching remotely is a method amenable to learning for students, with advantages including convenience, fewer reports of information fatigue, and decreased perceived pressure identified with this learning modality.


Bacillus tepidiphilus sp. nov., isolated from tepid spring.
A novel Bacillus strain, designated SYSU G01002T, was isolated from a sediment sample collected from tepid spring in Tengchong, Yunnan province, south-west PR China. The 16S rRNA gene sequence analysis showed that the strain SYSU G01002T shared the highest sequence identity with the type strain of Bacillus alkalitolerans (97.7%). Strain SYSU G01002T grew at pH 6.0-8.0 (optimum, pH 7.0), at 28-55 °C (optimum, 45 °C) and in the presence of 0-2.5% (w/v) NaCl (optimum in the absence of NaCl). It contained meso-2,6-diaminopimelic acid as the cell-wall diamino acid and MK-7 as isoprenoid quinone. The major cellular fatty acids were iso-C15:0, iso-C17:0 and C16:0. The polar were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, and unidentified phospholipid. The genomic DNA G + C content was 38.0 mol %. The digital DNA-DNA hybridization and average nucleotide identity values between SYSU G01002T and closely related members of the genus Bacillus were below the cut-off level recommended for interspecies identity. Based on the above results, strain SYSU G01002T represents a novel species of the genus Bacillus, for which the name Bacillus tepidiphilus sp. nov. is proposed. The type strain, SYSU G01002T (= KCTC 43131T = CGMCC 1.17491T).


Seasonal changes of ionic concentrations in the vacuolar sap of Chara vulgaris L. growing in a brackish water lake.
The composition of the vacuolar sap of Chara vulgaris growing in a brackish water lake was estimated weekly over 2 years (1984-1985). The ionic concentrations of the main cations Na+, K+, Ca2+, and Mg2+ and the anion Cl- varied depending on cell age, developmental state, and season. The average of all measurements (in mM) was Na+: 35, K+: 106, Ca2+: 7, Mg2+: 23, Cl-: 101, SO 2-4 : 20, and PO 3-4 : 5. At the onset of growth in May/June the ionic content was lower compared to the mean value for the year, steadily increasing until it reached its maximum above the annual mean in winter. During the period of fructification (sexual reproduction: formation of antheridia and oogonia), when up to 100 mM sucrose was accumulated in the vacuolar sap, ionic content was lowest. This resulted in a fairly constant osmotic potential throughout the year. Mg2+ and Ca2+ concentrations were correlated with the physiological age of the cells.


Use of Xenopus laevis as a model for investigating in vitro and in vivo endocrine disruption in amphibians.
The estrogenic activity of 17beta-estradiol (E2), alpha-zearalenol (alpha-ZEA), genistein (GEN), and 4-t-octylphenol (4-t-OP) was investigated using Xenopus laevis-based assays. All test compounds competed with [3H]E2 for binding to a recombinant Xenopus estrogen receptor (xER) with the following relative affinities: E2 > alpha-ZEA > 4-t-OP > GEN. The ability of these compounds to induce xER-mediated reporter gene expression was then assessed in MCF-7 human breast cancer cells cotransfected with a Gal4-xERdef chimeric estrogen receptor and a Gal4-regulated luciferase reporter gene. Luciferase activity was increased 30- to 50-fold by 10 nM E2 relative to that in solvent control. Maximal reporter gene activity induced by 10 nM alpha-ZEA was 54% of that induced by E2; however, the activity did not increase following doses of up to 10 microM. A dose of 1 microM 4-t-OP induced 23% of the maximal reporter gene activity induced by E2, whereas 10 microM GEN induced activity to the same level as E2. A dose-dependent increase in vitellogenin (VTG) mRNA expression was observed in Xenopus treated intraperitoneally with E2 at 0.05 to 5 mg/kg/d for three consecutive days, with the maximal induction observed in the group receiving 1 mg/kg/d. The alpha-ZEA, GEN, and 4-t-OP also significantly induced VTG mRNA expression, although at higher doses. These results demonstrate the utility of X. laevis as an amphibian model to assess the estrogenic activity of endocrine disruptors.