Nonocclusive coronary disease after chronic exposure to nitrates: evidence for physiologic nitrate dependence.
A 38-year-old man, exposed to notroglycerin in his work as an explosives expert, developed non-occlusive ischemic heart disease after withdrawal of exposure to organic nitrates. Despite the severity of his symptoms and the documented spasm of his right coronary artery, his electrocardiogram was at all times normal, as were results of a wide panel of laboratory tests. Sublingual nitroglycerin amerliorated the symptoms which have decreased with time.


Fractions of cardiovascular diseases, mental disorders, and musculoskeletal disorders attributable to job strain.
The aim of this study was to evaluate fractions of diseases attributable to job strain defined using Karasek's model among the French working population for cardiovascular diseases (CVD), mental disorders, and musculoskeletal disorders (MSD). Job strain was defined as the combination of high psychological demands and low decision latitude. The prevalence of exposure (P (e)) was estimated using the representative national sample of 24,486 employees of the French SUMER survey. Relative risks (RR) were estimated from a literature review (1990-2008) using the same inclusion criteria for the three health outcomes. P (e) and RR estimates were used to calculate attributable fractions (AF). P (e) estimates were 19.6% for men, 28.2% for women, and 23.2% for men and women combined. The literature review led to a selection of 13 studies for CVD, 7 studies for mental disorders, and 11 studies for MSD. RR estimates were 0.63-2.45 for CVD (morbidity and mortality), 1.2-3.3 for mental disorders, and 0.94-2.3 for MSD. AF estimates for CVD morbidity were 4.9-21.5% for men, 0-15.9% for women, and 6.5-25.2% for men and women combined, for CVD mortality 7.9-21.5% for men, 2.5% for women, and 6.5-25.2% for men and women combined, for mental disorders 10.2-31.1% for men, 5.3-33.6% for women, and 6.5% for men and women combined, and for MSD 0-19.6% for men, 0-26.8% for women, and 3.4-19.9% for men and women combined. This study is the first one to provide fractions of diseases attributable to job strain for three health outcomes in France on the basis of a systematic review of the literature. These results could contribute to the estimation of the economic cost of diseases attributable to job strain.


Combined tacrolimus and melatonin effectively protected kidney against acute ischemia-reperfusion injury.
Acute kidney injury (AKI) is commonly encountered and causes high mortality in hospitalized patients; however, effective therapies for AKI have still not been established. Accordingly, we performed a rodent model with acute renal ischemia-reperfusion (IR) and tested the hypothesis that combined tacrolimus and melatonin therapy could be superior to either one for protecting the kidney against IR injury. Adult-male SD rat (n = 30) were equally categorized into group 1 (receiving laparotomy only), group 2 (IR treated by 3.0 cc/normal-saline), group 3 [IR + tacrolimus/0.5 mg/kg by intravenous administration at 30 minutes and at days 1/2/3 after IR], group 4 (IR + melatonin/50 mg/kg by intra-peritoneal administration at 30 minutes and 25 mg/kg at days 1/2/3 after IR] and group 5 (IR + tacrolimus +melatonin). By day 3 after IR, the creatinine/BUN levels and ratio of urine protein to urine creatinine were highest in group 2, lowest in group 1 and significantly lower in group 5 than in groups 3/4 (all P < .0001), but they did not differ between the groups 3/4. The protein expressions of oxidative-stress (p47phox/NOX-1/NOX-2/NOX-4), upstream (TLR4/MAL/MyD88/TRAF6/ASK1/MKK4/MKK7/NF-κB) and downstream (IL-6/INF-γ/MMP-9/IL-1ß) inflammatory signaling, MAPK-family-signaling cascades(ERK1/2, JNK/p38/c-JUN), apoptotic/autophagic (p53/caspase 3/mitochondrial-Bax, ratio of LC3B-II/LC3B-I), and mitochondrial-damaged (cyclophilin D/cytochrome C/DRP1) biomarkers, and the expressions of inflammatory-immune cells (F4/80, CD14/CD3/CD8) as well as the kidney injured score exhibited an identical pattern of creatinine level (all P < .0001). In conclusion, combined tacrolimus and melatonin therapy was better than either single one on protecting the kidney functional and anatomical integrity against IR injury through suppressing inflammation and the generation of oxidative stress.


COVID-19 Vaccines Are Safely Tolerated in Adolescents with Cutaneous Mastocytosis.
The management of the COVID-19 vaccine in children with mastocytosis is unclear due to a lack of data. In the current study, we aimed to evaluate the adverse reactions following COVID-19 vaccination in adolescents with cutaneous mastocytosis (CM). This study included 27 paediatric patients who were diagnosed with CM and were followed up in the paediatric allergy department of a tertiary care children's hospital. The median (IQR) age of the patients at the time of COVID-19 vaccination was 180 (156-203) months. Forty-four per cent of patients were vaccinated with the COVID-19 vaccine. Among all participants, the vaccination rate was found to be higher in older children, those who had been diagnosed with MPCM, and those who had not been infected with COVID-19 (p = 0.019, p = 0.009, p = 0.002, respectively). A total of 23 doses of the COVID-19 vaccine, including two doses of Sinovac/CoronaVac and 21 doses of Pfizer/BioNTech, were administered to 12 paediatric patients with CM. One of the patients had a history of intense itch, erythematous urticarial plaques, and had an exacerbation of existing skin lesions within 24-48 h after both doses of Pfizer/BioNTech vaccination. The COVID-19 vaccination of patients with CM in this series seems to be safe, and the rate of adverse events was comparable to that in the general population. These results found in adolescents with CM are in line with the existing evidence that CM does not preclude vaccination in children.


Review: Trends in point-of-care diagnosis for Escherichia coli O157:H7 in food and water.
Escherichia coli O157:H7, a Shiga-producing E. coli is a major pathogenic E. coli strain which since the early 1980s has become a crucial food and water-borne pathogen. Several management strategies can be applied to control the spread of infection; however early diagnosis represents the optimum preventive strategy to minimize the infection. Therefore, it is crucial to detect this pathogen in a fast and efficient manner in order to reduce the morbidity and mortality. Currently used gold standard tests rely on culture and pre-enrichment of E. coli O157:H7 from the contaminated source; they are time consuming and laborious. Molecular methods such as polymerase chain reaction are sensitive; however, they require expensive instrumentation. Therefore, there is a requirement for Accurate, Sensitive, Specific, User friendly, Rapid, Equipment free and Deliverable (ASSURED) detection methods for use in the laboratory and in the field. Emerging technologies such as isothermal amplification methods, biosensors, surface enhanced Raman Spectroscopy, paper-based diagnostics and smartphone-based digital methods are recognized as new approaches in the field of E. coli O157:H7 diagnostics and are discussed in this review. Mobile PCR and CRISPR-Cas diagnostic platforms have been identified as new tools in E. coli O157:H7 POC diagnostics with the potential for implementation by industry. This review describes advances and progress in the field of E. coli O157:H7 diagnosis in the context of food and water industry. The focus is on emerging high throughput point-of-care (POC) E. coli O157:H7 diagnostics and the requirement for the transformation to service routine diagnostics in the food and water industry.


Human skeletal muscle proteins. The primary structure of troponin C.
The primary structure of the major component of human skeletal muscle troponin C has been established. The troponin C was purified by ammonium sulphate and isoelectric fractionation, followed by two chromatographic steps on DEAE Sephadex. The sequence was determined from the different overlapping enzymic peptides and by dansyl-Edman degradation. The only difference between rabbit skeletal muscle troponin C and the major component of human skeletal troponin C was found at position 112: Ala (rabbit), Pro (human). The partial amino acid sequence of the first 86 residues of the minor component of human skeletal troponin C was found to resemble the troponin C from bovine cardiac muscle. The only difference between them, has tentatively been located at position 62: Glu (human), Asp (bovine). These similarities suggest that troponin C is, from the point of view of molecular, one of the most conservative proteins so far studied.


Wild rats as urban detectives for latent sources of asbestos contamination.
Based on a large body of evidence asbestos minerals have been classified as carcinogens. Despite the Italian ban on asbestos in 1992 and the subsequent remediation activities, latent sources of contamination may still represent a hazard where asbestos were particularly used. Using wild rats as sentinel animals, this study aimed at uncovering sites with the greatest potential for non-occupational exposure to asbestos in the city of Casale Monferrato (Piedmont Region, Italy), where the largest Italian manufacturing plant of asbestos-cement had been active. During the study period (2013-2015) a total of 40 wild rats were captured from 16 sampling capture points. The lungs of wild rats have been investigated by using scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS). The SEM-EDS detected the presence of asbestos fibers (tremolite/actinolite, amosite, and chrysotile) in rats' lungs from 11 sampling points. The hypothetical rats' home-range and the observed site-specific concentration of asbestos fibers per gram of dry lung tissue were used to identify areas to be targeted by additional search of latent sources of asbestos. In conclusion, our results showed that the use of wild rats as sentinel animals may effectively integrate the strategies currently in use to reduce the exposure to asbestos.


Is patients' trust in clinicians related to patient-clinician racial/ethnic or gender concordance?
To examine the relationship between patient-clinician concordance (racial/ethnic and gender) and patients' trust in their regular clinician. This mixed methods study used the 2019 U.S. Health Reform Monitoring Survey to examine concordance and patient trust in clinicians, and semi-structured interviews with 24 participants to explore patients' perceptions of how concordance relates to trust in their clinician. Almost six in ten adults (59.8%) who had a regular clinician reported having trust in their clinician. White, Black, and Latino participants were similarly likely to report trust. Those with racial/ethnic concordant clinicians were 7.5 percentage points more likely to report trust than were those with non-concordant clinicians (62.4% vs 54.9%). This finding was consistent for men and women, and did not differ significantly across racial and ethnic groups. In interviews, while almost all participants described having trusted non-racial/ethnic concordant clinicians, several described immediately trusting concordant clinicians. In contrast, we did not observe a consistent relationship between patient-clinician gender concordance and trust. The findings underscore the importance of increasing the number of Black and Latino clinicians, and also highlight that all clinicians need to work hard to build trust with patients from different racial/ethnic backgrounds.


Ketogenic Diet for Malignant Gliomas: a Review.
In this review, we examine the postulated mechanisms of therapeutic effect of ketogenic diets in the treatment of gliomas, review the completed clinical trials, and discuss further directions in this field. Cancers including gliomas are characterized by derangements in cellular metabolism. In vitro and animal studies have revealed that dietary interventions to reduce glucose and glycolytic pathways in gliomas may have a therapeutic effect. Early trials in patients with malignant gliomas have shown feasibility, but are not robust enough yet to demonstrate clinical applicability. Therapies for malignant gliomas of the brain are increasingly using a multi-targeted approach. The use of ketogenic diets and its variants may offer a unique and promising anti-glioma treatment by exploiting metabolic alterations seen in cancers including gliomas seen at the cellular level, which may work in concert with other therapies.


Angiotensin II and aldosterone-induced neuronal damage in neurons through an astrocyte-dependent mechanism.
The contribution of the renin-angiotensin-aldosterone system (RAAS) to central nervous system (CNS) disorders is not yet fully understood. RAAS has been shown to be involved in the proliferation of astrocytes, which have a role in neuronal damage contributing to neurodegenerative diseases. However, the direct relationship between RAAS and neuronal damage is still unclear. We therefore examined the effect of angiotensin (Ang) II and aldosterone (Aldo) on damage to spinal ganglion neurons (SGNs) by regulating astrocytes. Ang II stimulation significantly increased DNA damage in SGNs in a time-dependent manner. This increase in DNA damage was further enhanced when SGNs were co-cultured with astrocytes. On the other hand, no significant increase was observed in SGNs co-cultured with astrocytes without Ang II stimulation. Moreover, the addition of conditioned medium from Ang II-treated astrocytes exacerbated SGN DNA damage. An Ang II type 1 receptor blocker, valsartan, inhibited Ang II-stimulated DNA damage but not DNA damage induced by conditioned medium prepared from astrocyte cultures. In contrast, an Aldo antagonist, eplerenone, significantly inhibited DNA damage induced by the culture medium from Ang II-treated astrocytes. Ang II-stimulated Aldo secretion in the conditioned medium from astrocytes. Furthermore, the administration of Aldo alone also enhanced DNA damage in SGNs. Finally, flow cytometric analysis showed that Ang II or Aldo treatment markedly increased the percentage of dead SGNs. In conclusion, Ang II- and Aldo-induced neuronal damage in SGNs through astrocytes regulation. Blocking Ang II and Aldo to target astrocytes might be useful for the treatment of CNS disorders.


Ligand induced stabilization of the melting temperature of the HSV-1 single-strand DNA binding protein using the thermal shift assay.
We have adapted the thermal shift assay to measure the ligand binding properties of the herpes simplex virus-1 single-strand DNA binding protein, ICP8. By measuring SYPRO Orange fluorescence in microtiter plates using a fluorescence-enabled thermal cycler, we have quantified the effects of oligonucleotide ligands on the melting temperature of ICP8. We found that single-stranded oligomers raise the melting temperature of ICP8 in a length- and concentration-dependent manner, ranging from 1°C for (dT)5 to a maximum of 9°C with oligomers ⩾10 nucleotides, with an apparent Kd of <1μM for (dT)20. Specifically, the results indicate that ICP8 is capable of interacting with oligomers as short as 5 nucleotides. Moreover, the observed increases in melting temperature of up to 9°C, indicates that single-strand DNA binding significantly stabilizes the structure of ICP8. This assay may be applied to investigate the ligand binding proteins of other single-strand DNA binding proteins and used as a high-throughput screen to identify compounds with therapeutic potential that inhibit single-strand DNA binding. As proof of concept, the single-strand DNA binding agent ciprofloxacin reduces the ligand induced stabilization of the melting temperature of ICP8 in a dose-dependent manner.


A comparison of children's behaviors following three types of stressors.
One purpose of this study was to examine the differences in behavior of children exposed to trauma versus no trauma. Another goal was to compare different types of traumatic events in terms of their effects on behaviors. Our analysis indicated significant differences between trauma and no trauma groups. Additional analyses indicated that those children who were allegedly sexually abused were rated as exhibiting higher levels of symptomatology on all three factors of the Pediatric Emotional Distress Scale (PEDS) as well as the Total PEDS score than the other three groups.


Interrelationship of nickel and cobalt contact sensitization.
The possible modulating effect of previous nickel sensitization on subsequent cobalt sensitization, and vice versa, was studied in a guinea pig model, using an open epicutanous induction protocol. Challenge tests were made by both topical and systemic routes. Controls included animals sensitized to only one of the metals. Animals sensitized with both metals seemed to react more readily in patch testing to either allergen, as compared to mono-sensitized animals. Systemic challenge with cobalt revealed a significantly (p less than 0.05) higher reaction rate (70%) in animals originally sensitized to cobalt and subsequently to nickel, as compared to the reaction rate (20%) in cobalt mono-sensitized animals. The reverse order of double-sensitization (nickel first, cobalt subsequently) led to an intermediate cobalt sensitization rate (50%). These experimental data corroborate clinical findings which have indicated a mutual enhancing effect of nickel and cobalt contact sensitization in man, and provide an animal model for studying the underlying immunological processes.


Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors.
Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARgamma activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA(1-3) receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA(3) agonist with an EC(50) of 692 nM. Interestingly, regardless of their LPA(1/2/3) ligand properties all of the Darmstoff analogs tested activated PPARgamma. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics.


Single-strand template repair: key insights to increase the efficiency of gene editing.
DNA double-strand breaks (DSBs) pose a serious hazard for the stability of the genome. CRISPR-Cas9-mediated gene editing intentionally creates a site-specific DSB to modify the genomic sequence, typically from an introduced single-stranded DNA donor. However, unlike typical forms of homologous recombination, single-strand template repair (SSTR) is Rad51-independent. Moreover, this pathway is distinct from other previously characterized Rad51-independent processes. Here, we briefly review the work characterizing this pathway, and how these findings can be used to guide and improve current gene editing strategies.


Invasive salmonellosis in urban Thai children: a ten-year review.
Invasive, extraintestinal salmonellosis carries a significant burden of childhood morbidity especially among infants and young children in developing countries. To determine the clinical manifestations, outcomes, laboratory findings and antimicrobial susceptibility patterns in patients with invasive salmonellosis. A retrospective chart review was conducted among children 0-18 years of age diagnosed with invasive salmonellosis receiving care at Queen Sirikit National Institute of Child Health, Bangkok, Thailand, from 2001 to 2010. We analyzed the records of 229 patients with culture-proven invasive salmonellosis. Sixty-three percent of cases had no documented underlying disease. Fever, diarrhea and respiratory symptoms were reported in 92%, 40% and 29% of cases, respectively. The spectrum of disease included isolated bacteremia (90%), clinical pneumonia (24.8%), bacteremia with meningitis (7.8%), septic arthritis (1.3%) and empyema thoracis (0.4%). Forty-seven of 57 cases presenting with clinical pneumonia had abnormal infiltrations on chest radiograph (20.5% of all cases). Despite the invasive nature of the illness, 53.1% of patients had a normal white blood cell count. Antimicrobial resistance was found among ampicillin (68.3%), chloramphenical (15.2%), trimethoprim-sulfamethoxazole (33.9%), ceftriaxone (17.4%) and ciprofloxacin (3%). The case fatality rate was 4.8%, 91% of whom had an underlying disease. Multivariate analysis indicated that age, underlying liver disease and presence of pneumonia were significant predictors of fatality. Fever, diarrhea and respiratory symptoms were among the most common presenting symptoms of invasive nontyphoidal salmonellosis. Older age, hepatobiliary disease and presence of pneumonia were associated with increased risk of fatality. Resistance to third-generation cephalosporins poses a major concern for its use as empiric antimicrobial therapy for this condition.


Using ontology-based semantic similarity to facilitate the article screening process for systematic reviews.
Systematic Reviews (SRs) are utilized to summarize evidence from high quality studies and are considered the preferred source of evidence-based practice (EBP). However, conducting SRs can be time and labor intensive due to the high cost of article screening. In previous studies, we demonstrated utilizing established (lexical) article relationships to facilitate the identification of relevant articles in an efficient and effective manner. Here we propose to enhance article relationships with background semantic knowledge derived from Unified Medical Language System (UMLS) concepts and ontologies. We developed a pipelined semantic concepts representation process to represent articles from an SR into an optimized and enriched semantic space of UMLS concepts. Throughout the process, we leveraged concepts and concept relations encoded in biomedical ontologies (SNOMED-CT and MeSH) within the UMLS framework to prompt concept features of each article. Article relationships (similarities) were established and represented as a semantic article network, which was readily applied to assist with the article screening process. We incorporated the concept of active learning to simulate an interactive article recommendation process, and evaluated the performance on 15 completed SRs. We used work saved over sampling at 95% recall (WSS95) as the performance measure. We compared the WSS95 performance of our ontology-based semantic approach to existing lexical feature approaches and corpus-based semantic approaches, and found that we had better WSS95 in most SRs. We also had the highest average WSS95 of 43.81% and the highest total WSS95 of 657.18%. We demonstrated using ontology-based semantics to facilitate the identification of relevant articles for SRs. Effective concepts and concept relations derived from UMLS ontologies can be utilized to establish article semantic relationships. Our approach provided a promising performance and can easily apply to any SR topics in the biomedical domain with generalizability.


Ischemia time and liver transplantation, today.
The aim of our study was to retrospectively evaluate the impact of ischemia time and other clinical factors on the development of liver allograft primary nonfunction (PNF). We enrolled 531 consecutive liver transplantations from 1998 to 2013, identifying 10 PNF (1.9%). PNF was found to be statistically related to 4 different variables: donor age>60 years (P=.01), female donor gender (P=.01), total ischemia time>10 hours (P=.03) and infusion of more than 30 fresh frozen plasma units during surgery (P=.02). The study focused on the clinical impact of total ischemia time. We grouped total ischemia time into 4 groups (Group 1: ≤7.5 hours; Group 2: between 7.5 and 10 hours; Group 3: between 10 and 12 hours; Group 4: >12 hours) and 2 groups (assigning a cut-off value of 10 hours): both these grouping systems significantly influenced the development of PNF and 1-year graft survival, with limited impact on long-term survival. We split total ischemia time in a "technical time," "hepatectomy time," and "warm ischemia time." Only the first 2 components were found to be statistically related to PNF development with P=.02 and P=.003, respectively. Further studies should focus on these aspects of PNF.


Halophiles, coming stars for industrial biotechnology.
Industrial biotechnology aims to produce chemicals, materials and biofuels to ease the challenges of shortage on petroleum. However, due to the disadvantages of bioprocesses including energy consuming sterilization, high fresh water consumption, discontinuous fermentation to avoid microbial contamination, highly expensive stainless steel fermentation facilities and competing substrates for human consumption, industrial biotechnology is less competitive compared with chemical processes. Recently, halophiles have shown promises to overcome these shortcomings. Due to their unique halophilic properties, some halophiles are able to grow in high pH and high NaCl containing medium under higher temperature, allowing fermentation processes to run contamination free under unsterile conditions and continuous way. At the same time, genetic manipulation methods have been developed for halophiles. So far, halophiles have been used to produce bioplastics polyhydroxyalkanoates (PHA), ectoines, enzymes, and bio-surfactants. Increasing effects have been made to develop halophiles into a low cost platform for bioprocessing with advantages of low energy, less fresh water consumption, low fixed capital investment, and continuous production.


Vidian nerve neurofibroma.
Vidian nerve is created from the connection of the greater petrosal nerve and the deep petrosal nerve (Giraddi et al., 2010). These two nerves transmit parasympathetic and sympathetic fibers respectively. Vidian nerve tumour is one of the rarest known tumours (Hong et al., 2014). Genetic changes effectively play a role in the development of nerve sheath tumors. Of course, due to the rarity of this type of tumor, there is not much information about its causes and risk factors (Yamasaki et al., 2015). The incidence rate of malignant peripheral nerve sheath tumors is about 0.001 % (Fortes et al., 2019). Considering the low prevalence of this tumor and the type of treatment performed on this patient, the investigation of the case presented in this study can lead to a better understanding and more correct treatment. This case report has been proposed due to the very low prevalence of neurofibroma of the Vidian nerve in the world. Vidian nerve supplies sympathetic and parasympathetic fibers to the lacrimal glands and nasopalatine mucosa. In many cases, involvement of the Vidian nerve by neurofibroma can be misleading for doctors. Due to the very low prevalence of neurofibroma of the Vidin nerve, the possibility of its being missed and not diagnosed during the examination of patients by doctors is very high. This case report is presented in order to familiarize scientists with this lesion due to its very low prevalence. This therapeutic approach that was used in this case requires longer follow-up periods, but it can prevent possible complications after surgery.


Modification of the Wise pattern breast reduction for oncological mammaplasty of upper outer and upper inner quadrant breast tumours: a technical note and case series.
The upper outer quadrant of the breast is the most common site for the incidence of breast cancer, and the upper inner quadrant the most cosmetically sensitive area. If an oncoplastic approach is considered however, these quadrants do not fall within the classical Wise pattern for oncological mammoplasty. We use a simple modification of the Wise pattern that facilitates oncological mammoplasty of tumours in these quadrants without the need for secondary or extended pedicles. In planning this modification excision of skin overlying the tumour is usually also possible. The modification of the Wise pattern technique that we use is described as a technical note, and a case series of 11 patients who underwent this procedure is presented. To date there have been no recurrences. This is a simple cosmetically acceptable modification of the Wise pattern breast reduction for oncological mammoplasty.


A Bibliometric Analysis of the Most-Cited Articles on Craniospinal Epidural Hematoma.
To analyze the most-cited articles on cranial and spinal epidural hematomas (EDHs). A title-specific search was performed on the Scopus database using the term ?epidural hematoma? in June 2020, with no publication date restrictions. The top 100 most-cited articles were collected, reviewed, and analyzed. A total of 2165 articles were published on EDH from 1949 to 2020, and the top 100 most-cited ones were published between 1966 and 2014, receiving an average citation of 84.7 per paper. Most papers were published in Neurosurgery and Journal of Neurosurgery (JNS). 48% of the most-cited articles on EDH originated from the United States of America (USA). Notably, studies on spinal EDH represented 75% of the most-cited articles in our review. The most-cited article on EDH was published by Lawton et al. in 1995, receiving a total of 412 citations at an annual citation rate of 16.4%. This report identifies the most influential publications on EDH as well as the publications trends over the last 70 years. Recognition of the most impactful work is an important tool for clinicians and researchers as it can reflect the enormous changes in the clinical practice. This report can serve as a guide for developing evidence-based practices and identifying areas of research inadequacy.


Monitoring respiration during sleep.
Monitoring of respiration during sleep allows the assessment of physiologic variables that are required to characterize SRBD events. The patency of the upper airway, the pattern of breathing, oxygenation, and ventilation usually can be inferred from simultaneous measurements of airflow, respiratory effort, thoracic volume, and blood gases. As new techniques of respiratory monitoring emerge, the respiratory therapist and sleep technologist must be familiar with the advantages and shortcomings of each modality.


Nature of nonenzymatically bound hexose in hemoglobin, albumin, and crystallin.
Glucose incorporated in vitro during nonenzymatic glucosylation into albumin and hemoglobin was fully reducible by sodium borohydride unlike native albumin. Further, a prior hydrolysis under mild conditions (1 M oxalic acid:2 M HCl, 4 hr) was not required for in vitro incorporated glucose to yield maximal color intensity in the phenol-sulfuric acid reaction. Glucosyl-albumin, glucosyl-crystallin, and hemoglobin A1 behaved similarly in this respect. Hexose bound to HbA0 which alone showed an enhanced color intensity on prior acid hydrolysis was also not easily reduced by sodium borohydride. L-Cysteine (0.023 M) enhanced the color yield of glucosyl-hemoglobin, glucosyl-albumin, and glucosyl-crystallin to a lesser extent compared to fructose in the phenol-sulfuric acid reaction. Urea (6 M) also marginally increased the color intensity of glucosyl proteins and fructose.


An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients.
As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients. Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.


MNU-induced mutant pools and high performance TILLING enable finding of any gene mutation in rice.
Mutant populations are indispensable genetic resources for functional genomics in all organisms. However, suitable rice mutant populations, induced either by chemicals or irradiation still have been rarely developed to date. To produce mutant pools and to launch a search system for rice gene mutations, we developed mutant populations of Oryza sativa japonica cv. Taichung 65, by treating single zygotic cells with N-methyl-N-nitrosourea (MNU). Mutagenesis in single zygotes can create mutations at a high frequency and rarely forms chimeric plants. A modified TILLING system using non-labeled primers and fast capillary gel electrophoresis was applied for high-throughput detection of single nucleotide substitution mutations. The mutation rate of an M(2) mutant population was calculated as 7.4 x 10(-6) per nucleotide representing one mutation in every 135 kb genome sequence. One can expect 7.4 single nucleotide substitution mutations in every 1 kb of gene region when using 1,000 M(2) mutant lines. The mutations were very evenly distributed over the regions examined. These results indicate that our rice mutant population generated by MNU-mutagenesis could be a promising resource for identifying mutations in any gene of rice. The modified TILLING method also proved very efficient and convenient in screening the mutant population.


Effects of seasonal variation on the biology and morphology of the dusky cotton bug, Oxcarenus laetus (Kirby).
The dusky cotton bug (Oxycarenus laetus, KIRBY) a pest of several crops. The effects of winter and summer on the biology and morphology was investigated. The sampled eggs of dusky cotton bug (DCB) were kept under controlled environment for biological and morphological investigations. In winter, the mating duration of DCB was observed longer significantly (74.2 days), egg development period (3.93 days), an egg laying period (3.6 days) and hatching period (6.66 days) noted longer in winter season. Interestingly, average number of hatched egg (16.8 days) observed significantly higher in summer and the percentage of the hatching of eggs (81.95%) were also observed higher in summer as compare to winter. Whereas, the longevity of all nymph stages in winter longer days as compare to summer nymph stages. Moreover, differences were also observed between male and female development days between winter and summer. In the winter, female DCB development was suggestively higher as compare to summer (24 days). Whereas, the developmental days were noted considerably more in winter for males as compare to summer (14.93 days). On other hand, for morphological parameters, no differences were observed between winter and summer population of DCB.


Variation in the 5'-flanking region of the neuropeptide Y2 receptor gene and metabolic parameters.
A previous report describes that neuropeptide Y (NPY)/NPY2 receptor (NPY2R) is involved in stress-induced visceral obesity. This is a report clarifying the effect on metabolic parameters of single nucleotide polymorphisms in the 5'-flanking region of NPY2R gene. Study participants are 317 people (98 men and 219 women, 40-79 years old) undergoing health checkups. The single nucleotide polymorphism typing of rs6857715 and rs6857530 located on the 5'-flanking region of the NPY2R gene was performed using allele-specific polymerase chain reaction method. Serum high-density lipoprotein cholesterol (HDL-C) level was significantly lower in men possessing rs6857715 TT genotype compared with CC and in men possessing rs6857530 GG genotype compared with AA. No significant difference was observed between each genotype and other metabolic parameters including body mass index, waist circumference, systolic and diastolic blood pressure, serum low-density lipoprotein cholesterol, triglyceride, and fasting plasma glucose. The variation in the 5'-flanking region of the NPY2R gene was associated with serum HDL-C level in men and was a predictor for serum HDL-C level independent of sex and serum triglyceride level.


The nicotinamide phosphoribosyltransferase antagonist FK866 inhibits growth of prostate tumour spheroids and increases doxorubicin retention without changes in drug transporter and cancer stem cell protein expression.
Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD) synthesis and is involved in cancer cell proliferation through regulation of energy production pathways. Therefore, NAMPT inhibitors are promising drugs for cancer therapy by limiting energy supply of tumours. Herein, we demonstrated that the NAMPT inhibitor FK866 ((E)-N-(4-(1-Benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) dose-dependently inhibited growth and cell motility of DU-145 prostate tumour spheroids and decreased the intracellular ATP concentration. The apoptosis marker cleaved caspase-3 remained unchanged, but the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) was upregulated. Growth inhibition was reversed upon co-administration of NAD to the cell culture medium. FK866 decreased calcein as well as pheophorbide A efflux from tumour spheroids and increased doxorubicin toxicity, indicating interference with function of drug efflux transporters. DU-145 multicellular tumour spheroids expressed the stem cell associated markers CD133, CD44, Oct4, Nanog, Sox2, and drug transporters ABCB1, ABCG2, and ABCC1 which are associated with stem cell properties in cancer cells. The ABCB1 inhibitor zosuquidar, the ABCG2 inhibitor Ko143, and the ABCC1 inhibitor MK571 increased calcein retention. Neither protein expression of stem cell markers, nor drug transporters was significantly changed upon FK866 treatment. In conclusion, our data suggest that FK866 inhibits prostate cancer cell proliferation by interference with the energy metabolism, and function of drug efflux transporters.


Functional genomics and epigenomics of atrial fibrillation.
Atrial fibrillation is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. Despite years of study, we still do not have a full comprehension of the molecular mechanism responsible for the disease. The recent implementation of large-scale approaches in both patient samples, population studies and animal models has helped us to broaden our knowledge on the molecular drivers responsible for AF and on the mechanisms behind disease progression. Understanding genomic and epigenomic changes that take place during chronification of AF will prove essential to design novel treatments leading to improved patient care.


[Amino acid makeup of the oocyst proteins of some species of coccidia of hens].
The composition of amino acids of sporocysts, membranes of oocysts and oocysts of four species of Coccidia from hens is reported. A considerable figgerence was found to exist in the quantitative composition of amino acids in oocysts of different Coccidia species and in different structures of oocysts. It is necessary to carry out a search of preparations breaking the inclusions of some amino acids into the protein molecule of oocysts of Coccidia from hens.


Discrepancy between perfusion- and diffusion-weighted images in ischemic stroke: A case report.
With the development of multi-slice computed tomography (CT) technology, perfusion CT angiography (p-CTA) is now widely used for the diagnosis of acute cerebral infarction. Although p-CTA has the advantage of distinguishing between an ischemic penumbra and an infarct core, more research is needed with respect to its clinical use. A healthy 36-year-old man experienced sudden dizziness while swimming. His dizziness persisted irrespective of the change in position, and then improved during transport. He had no neurological abnormality when he arrived at the emergency room. CT perfusion findings suggested left cerebellar infarction. P-CTA revealed a markedly delayed mean transit time, delayed time to peak, and increased cerebral blood volume in the left posterior inferior cerebellar artery territory at admission. However, the diffusion-weighted image (DWI) taken a few hours later revealed a large right cerebellar infarction. Because of the time window, thrombolysis could not be performed and anti-platelet therapy was started. Dysarthria and right-sided limb ataxia were newly developed before DWI (after p-CTA). Persistent foramen ovale was detected through transesophageal echography and identified as the cause of the stroke. This case report suggests that dynamic image changes can occur within a short period of time depending on the vascular status and hemodynamic changes of the patients.


Hyoid bone tenderness as a clinical indicator of laryngeal pathology.
Hyoid bone tenderness is an underemphasized clinical abnormality and is described as discomfort or pain on gentle palpation of the greater cornu. The primary outcome of this study is to assess if there is any association between hyoid tenderness and laryngeal pathology. This is a retrospective case-control study. Ninety-four subjects were identified. These were divided into two groups, those with hyoid tenderness and those without hyoid tenderness. Presenting complaints and findings on nasal laryngoscopy were compared to identify any association between hyoid tenderness and laryngeal pathology. There were a total of 76 (80.9%) female and 18 (19.1%) male patients in the study. Analysis of presenting complaints showed that dysphonia (P < 0.001, odds ratio = 4.82) and neck pain (P = 0.015, odds ratio = 10.9) were significantly associated with hyoid tenderness, more with these symptoms had hyoid tenderness than expected by chance. Findings on nasal laryngoscopy showed a significant association between hyoid tenderness and vocal fold nodules (P < 0.001). Nasopharyngitis (P = 0.065) and tense anterior neck muscles (P = 0.056) were almost significantly associated with hyoid tenderness. Hyoid tenderness has previously been reported as an early sign in acute epiglottitis. These results indicate that hyoid bone tenderness may be a useful clinical indicator of various other laryngeal pathologies or dysfunctions.


Role of D1- and D2-like receptors in age-specific regulation of juvenile hormone and 20-hydroxyecdysone levels by dopamine in Drosophila.
In Drosophila females, the precursor of 20-hydroxyecdysone (20E), ecdysone, is synthesized in the ovary follicular cells. Juvenile hormone (JH) is synthesized de novo in the specialized endocrine gland, corpus allatum (CA); JH degradation is carried out by the enzymes synthesized in the fat body (FB). Earlier we have shown that in Drosophila females, dopamine up- or down-regulates 20E and JH levels depending on the developmental stage. The present study focuses on the role of D1- and D2-like receptors in the age-specific regulation of 20E and JH metabolism by dopamine. We show that in Drosophila melanogaster females D1- and D2-like receptor genes (DopR and DD2R accordingly) are expressed in CA and FB, but not in follicular cells. The level of DopR expression in CA is much higher in the young than in the mature females, whereas DD2R expression is much higher in the mature than in the young females. The DopR and DD2R expression patterns in FB are opposite to those observed in CA. In addition, we obtained data suggesting that the age-specific changes of DopR and DD2R expression in FB are under the control of 20E.


Alginate-whey protein granular microspheres as oral delivery vehicles for bioactive compounds.
Alginate (AL)-whey protein isolate (WPI) microspheres of varied WPI/AL ratio, particle diameter and concentration of polymer bead forming solution (C(AL+WPI)) were prepared in order to develop a biocompatible vehicle for oral administration of bioactive compounds. Microscopy revealed a special matrix/granular structure for microspheres with a WPI/AL ratio of 8:2, 100 microm diameter and C(AL+WPI) of 5% (AL-WPI A2), featuring WPI granules 3-10 microm in diameter homogeneously distributed within an AL spherical matrix. The compound release properties of these microspheres were investigated in simulated gastric and intestinal fluids (SGF and SIF). They demonstrated the desirable property of retarding riboflavin release in SGF and underwent alginate matrix erosion together with liberation of WPI granules in SIF, followed by complete release of the riboflavin. Riboflavin release in SGF and in SIF without pancreatin followed the Higuchi diffusion model while release in SIF in the presence of pancreatin was attributed to WPI granule degradation.


Protective effect of protein hydrolysates from Litopenaeus vannamei waste on oxidative status, glucose regulation, and autophagy genes in non-alcoholic fatty liver disease in Wistar rats.
The effects of protein hydrolysates (FP) from Litopenaeus vannamei on oxidative stress, and autophagy gene expression was investigated in the NAFLD-induced rats. For this purpose, twenty-four male rats were divided into four groups: Control, High-fat diet (HFD), FP20+HFD, and FP300+HFD (20 and 300 mg FP /kg rat body weight) and fed for 70 days. The results indicated that the rat body and relative weight of the liver were not affected by experimental treatments (P>0.05) although the highest relative weight of the liver was observed in HFD treatment. The highest and lowest values for antioxidant enzymes and MDA concentration were observed in FP treatments (P<0.05). Also, the results showed that FP significantly decreased liver enzymes (ALT, AST) in the liver in comparison with HFD treatment (P<0.05). Plasma biochemical indices were investigated and the lowest amylase, ALP, fasting glucose, insulin, HOMA-IR, triglycerides, cholesterol, and inflammation cytokines (TNF-α, IL-6) were seen in the FP treatments which had a significant difference with HFD (P<0.05). Autophagy gene expression in the liver cells was affected by experimental diets and the lowest expression of Beclin-1 and Atg7 was observed in HFD and FP300 treatments. Interestingly, the highest expression of LC3-ɪ and P62 was seen in HFD and FP treatments, not in the control. Overall, the results of this experiment indicated that FPs extracted from Whiteleg shrimp at 50 °C improve the oxidative status, glucose metabolism, and autophagy gene expression and could be used as a useful nutritional strategy in fatty liver prevention.


Postoperative biochemical recurrence of pathologically localized high-grade prostate cancer in adjuvant treatment-naïve patients.
To evaluate biochemical recurrence (BCR) risk in men with localized prostate cancer (PC) of pathological Gleason score (pGS) 8-10. Although such patients have low BCR-free survival (BCRFS) following radical prostatectomy (RP), they are not recommended for adjuvant radiation therapy (ART) as per current guidelines. Among an adjuvant treatment-naïve cohort between 1995 and 2015, 1272 men were identified and categorized into group 1 [pGS7 (3 + 4) and pT3; n = 654], group 2 [pGS7 (4 + 3) and pT3; n = 408], and group 3 (pGS 8-10 and pT2; n = 210). The BCR risk of group 3 was compared with that of groups 1 and 2 who are the candidates for ART. At a median follow-up of 60 months (interquartile range: 39-86), 432 men experienced BCR. BCRFS was lower in group 3 than in groups 1 and 2 (p < 0.001 and p = 0.021, respectively). In multivariate analysis, this association persisted and surgical margin (SM) was found to be a significant BCR predictor. Although statistically not significant, BCRFS was lower in group 3 with positive SM (PSM) than in group 2 with PSM (p = 0.101). BCRFS was significantly worse in group 3 with negative SM (NSM) than in group 1 with PSM (p = 0.038), while it was better in group 2 with PSM (p = 0.297). Localized high-grade PC with PSM showed lower BCRFS and that with NSM showed better BCRFS without statistical significance than locally advanced GS 7 PC with PSM that are eligible for ART.


The biological significance of angiotensin-converting enzyme inhibition to combat kidney fibrosis.
Both angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker have been recognized as renin-angiotensin system (RAS) inhibitors. These two RAS inhibitors are rarely recognized as drugs with distinct pharmacological effects in the clinic or most clinical trials. Some preclinical basic research and clinical trials indicate that ACE-I might display superior organ-protective effects, especially anti-fibrotic effects. Such anti-fibrotic effects of ACE-I could be associated with an endogenous anti-fibrotic peptide, N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). In this review, we focused on the anti-fibrotic effects of RAS inhibition and the endogenous anti-fibrotic peptide AcSDKP.


Bacterial colonization of a power-driven water flosser during regular use. A proof-of-principle study.
The present proof-of-principle study assessed whether daily use of a power-driven water flosser (Sonicare AirFloss; SAF) leads to bacterial colonization in the nozzle and/or the device, resulting in contaminated water-jet. In five participants, saliva samples at baseline and water-jet samples of devices used daily with bottled water for 3 weeks (test) were collected. Additionally, water-jet samples from devices used daily with bottled water extra-orally for 3 weeks (positive control) and from brand new devices (negative control), as well as samples from newly opened and 1- and 3-week opened water bottles were collected. Colony forming units (CFU) were recorded after 48 h culturing and 20 oral pathogens were assessed by polymerase chain reaction-based analysis. Distinct inter-individual differences regarding the number of detected bacteria were observed; water-jet samples of test devices included both aerobic and anaerobic bacterial species, with some similarities to the saliva sample of the user. Water-jet samples from positive control devices showed limited number of aerobic and anaerobic bacterial species, while the samples from negative control devices did not show any bacterial species. Very few aerobic bacteria were detected only in the 3-week-old bottled water samples, while samples of newly and 1-week opened water bottles did not show any bacterial growth. The present proof-of-principle study showed that daily use of a power-driven water flosser for 3 weeks resulted in bacterial colonization in the nozzle and/or device with both aerobic and anaerobic, not only oral, species, that are transmitted via the water-jet.


A comparison between male and female parasuicides in Hong Kong.
The epidemiological, social and clinical characteristics of 259 male and 475 female parasuicides in Hong Kong were compared. The majority are young adults, with an overall female: male ratio of 1.83. Compared to male subjects, females are more likely to be married or cohabiting, of higher social-economic status, born in places in the Far East apart from Mainland China, and of lower educational level. Their parasuicidal acts are more often motivated by interpersonal difficulties, especially with spouses or friends of the opposite sex, and take the form of self-poisoning. Male subjects on the other hand are more often single, immigrants from Mainland China, and of lower socio-economic status. Their problems are more often personal, and they are more likely to employ physical methods in their parasuicidal acts. In both sexes, age specific parasuicidal rates showed a second peak in senescence. Both the overall prevalence of psychiatric disorders and the rate of repeated parasuicide 2 years following the index admissions were low. The implications of these findings are explored.


One cell at a time: droplet-based microbial cultivation, screening and sequencing.
Microbes thrive and, in turn, influence the earth's environment, but most are poorly understood because of our limited capacity to reveal their natural diversity and function. Developing novel tools and effective strategies are critical to ease this dilemma and will help to understand their roles in ecology and human health. Recently, droplet microfluidics is emerging as a promising technology for microbial studies with value in microbial cultivating, screening, and sequencing. This review aims to provide an overview of droplet microfluidics techniques for microbial research. First, some critical points or steps in the microfluidic system are introduced, such as droplet stabilization, manipulation, and detection. We then highlight the recent progress of droplet-based methods for microbiological applications, from high-throughput single-cell cultivation, screening to the targeted or whole-genome sequencing of single cells.


Underrepresentation of vulnerable older patients with cancer in phase II and III oncology registration trials: A case-control study.
We aimed to determine the proportion of "fit" versus "vulnerable" older patients with cancer included in phase II and III oncology registration trials, as compared to the proportions in a real life oncology setting. Trial and patient characteristics of older (≥70years) patients treated at the OECI-designated clinical cancer centre in Kortrijk and included in a phase II or III oncology registration trial were collected retrospectively. These patients were matched individually with randomly-selected patients from the general oncology setting, based on gender, age, tumour type, tumour stage, and treatment intent. Patients' fitness, based on routine Geriatric-8 (G8) screening, was retrieved from prospectively constructed databases. Between November 2012 and October 2018, 218 older patients with cancer were included in a phase II or III oncology registration trial. Of those, 41 cases with a mean age of 76.0years were included in the analyses. A Fisher's Exact Test revealed a statistical significant difference between cases and matched controls, with a higher proportion of "fit" patients included in phase II or III oncology registration trials compared to the proportion in the matched control group (respectively 70.7% and 41.5%, p<.010). We provide evidence for the hypothesis that older patients included in phase II or III oncology trials are significantly fitter than the real life oncology population. Some form of geriatric evaluation should be integrated in future cancer clinical trials to enable stratification according to this parameter and allow subgroup analysis. This will broaden the application and interpretation of trial results.


Major prognostic factors of patients with adult T-cell leukemia-lymphoma: a cooperative study. Lymphoma Study Group (1984-1987).
A total of 854 patients with anti-HTLV-I antibody positive ATL, newly diagnosed from 1983 to 1987, were analyzed for prognostic factors. There were 466 males and 388 females with a mean age of 57.1. Of these 269 (31.5%) were alive with a median follow-up time of 14 months from diagnosis, while 585 (65.5%) were dead with a median survival time (MST) of 6 months. MST, and projected 2- and 4-year survival rates of all patients were 10 months, 28% and 12%, respectively. A Cox proportional hazards model analysis revealed that five factors, advanced performance status, high lactic dehydrogenase value, age of 40 years or more, increased number of total involved lesions and hypercalcemia, were associated with shortened survival at P less than 0.01. These factors were used to construct a model to identify patients at three different risks for shortened survival. A group of 178 patients (21.8%) with a hazard ratio of less than 0.5 were classified into the low risk (LR) group, 492 (60.4%) with hazard ratio of less than or equal to 0.5 and less than 2.5 into standard high risk (SHR) group, and 145 (17.8%) with hazard ratio of 2.5 or more extremely high risk (EHR) group. MST, and projected 2- and 4-year survival rates were 37 months, 66.3% and 41.2% for LR, 8 months 20.6%, and 4.5% for SHR, and 2.4 months, 5.6% and 0% for EHR, respectively. The risk grouping is of interest in determining the therapeutic strategy of ATL at diagnosis.


Ureteral injuries during vascular surgery.
The rapid increase in the number of vascular surgical procedures done has led to a new class of iatrogenic ureteral injuries. Vena caval ligation, bilateral lumbar sympathectomy, bypass procedures and abdominal aortic aneurysmectomy produce the majority of these injuries. Established principles useful in the repair of iatrogenic injuries following a gynecologic or colonic operation often are inapplicable.


Identification of a novel mutation in the factor XIII A subunit in a patient with inherited factor XIII deficiency.
Inherited factor XIII (FXIII) deficiency is an extremely rare and under-diagnosed autosomal recessive inherited coagulopathy, which is caused by genetic defects in the F13A1 or F13B gene. More than 200 genetic mutations have been identified since the first case of inherited FXIII deficiency was reported. This study aimed to identify underlying gene mutations in a patient with inherited FXIII deficiency who presented with recurrent intracerebral hemorrhage. Levels of plasma FXIII-A antigen were measured, F13A1 and F13B genes were sequenced, mutation information was analyzed, and the mutated protein structure was predicted using bioinformatics methods. Molecular genetic analysis identified four mutations of FXIII-related genes in the proband, including three previously reported mutations inherited from his parents (c.631G>A, p.Gly210Arg and c.1687G>A, p.Gly562Arg of F13A1 gene and c.344G>A, p.Arg115His of F13B gene) and a novel spontaneous mutation of F13A1 gene (c.2063C>G, p.Ser687Cys). Molecular structural modeling demonstrated that the novel Ser687Cys mutation may cause changes in the spatial structure of FXIII-A and increase its instability. In conclusion, we identified a novel and likely pathogenic mutation of the F13A1 gene, which enriched the gene mutation spectrum of inherited FXIII deficiency. The findings may provide promising targets for diagnosis and treatment of inherited FXIII deficiency.


A meta-analysis of prognostic indicators to predict seizures, arrhythmias or death after tricyclic antidepressant overdose.
To systematically review and summarize studies on the accuracy of ECG and tricyclic antidepressant (TCA) concentration as prognostic indicators of the risk of seizures, ventricular arrhythmia (VA) or death in patients with TCA overdose. Articles were identified with MedLine and Cochrane register of controlled clinical trials searches and review of medical toxicology textbooks. Quality of the included studies was assessed. Pooled estimates of sensitivity, specificity, likelihood ratios and Summary Receiver Operating Characteristics (SROC) curves were generated. A total of 18 studies were included in the analysis. The pooled sensitivity (Se) and specificity (Sp) of the QRS for predicting seizures were 0.69 [95% CI 0.57-0.78] and 0.69 [95% CI 0.58-0.78] as compared to 0.75 [95% CI 0.61-0.85] and 0.72 [95% CI 0.61-0.81] for the TCA concentration. The Se and Sp of the QRS to predict VA were 0.79 [95% CI 0.58-0.91] and 0.46 [95% CI 0.35-0.59] compared to 0.78 [95% CI 0.56-0.90] and 0.57 [95% CI 0.46-0.67] for the TCA concentration. The Se and Sp of the QRS to predict death were 0.81 [95% CI 0.54-0.94] and 0.62 [95% CI 0.55-0.68] compared to 0.76 [95% CI 0.49-0.91] and 0.60 [95% CI 0.47-0.72] for the TCA concentration. Very few studies evaluated the accuracy of QTc, T 40 ms axis and the R/S ratio. Overall, the studies suggested that the ECG and TCA concentration have similar but relatively poor performance for predicting complications, such as seizures, VA or death, associated with TCA overdose.


Anatomy of the posterior branch of the medial antebrachial cutaneous nerve: A cadaveric study.
The posterior branch of the medial antebrachial cutaneous nerve (MACN) is at risk to be damaged during cubital tunnel surgery. The purpose of this study was to identify the location of the posterior branch of the MACN (PBMACN) in relation to surgical landmarks pertinent in cubital tunnel surgery. We performed an anatomical study on 20 limbs from 13 fresh cadavers. The nerve was dissected from 10cm proximal to 10cm distal of the medial epicondyle. We measured the distance between the nerve and the medial epicondyle, and also the distance separating the PBMACN from the ulnar nerve passage between the two heads of the flexor carpi ulnaris. Measurements were performed with the elbow at 45° and 90° of flexion, as well as in full pronation and supination. After its emergence from the main trunk of the MACN, the posterior branch ran anteriorly to the medial epicondyle, taking an oblique direction toward the ulnar shaft. The PBMACN was in average 2.53cm under the medial epicondyle when the elbow was flexed at 45°, and 2.96cm when the elbow was flexed at 90°. Average distance between the PBMACN and the penetrating point of the ulnar nerve within the flexor carpi ulnaris was 1.54cm when the elbow was flexed at 45°, and 1.62cm when the elbow was flexed at 90°. Pronation and supination positions of the forearm did not significantly modify our measurements. Understanding the position of MACN posterior branch during ulnar nerve release surgery at the elbow may help in preventing iatrogenic injury. According to our measurements, incision and superficial dissection anterior to the medial epicondyle or distal to the ulnar nerve penetrating point between the two heads of the flexor carpi ulnaris should be avoided or done with an elbow flexed at 90°.


Pharmacokinetics and tissue distribution of iv injection of polyphase liposome-encapsulated cisplatin (KM-1) in rats.
The pharmacokinetics and biodistribution of cisplatin encapsulated in polyphase liposome (KM-1) were compared with those of free drug in rats. The platinum levels in serum and normal organs, after a single dose of iv injection of free or encapsulated cisplatin to rats, were determined by induced coupled plasma atomic emission spectrometry. Serum platinum concentration-time curve after a single iv dose of KM-1 4.5 mg/kg in rats was fitted with an open three-compartment model. The pharmacokinetic parameters were as follows: Vc=0.10 L/kg, T1/2pai=0.3 h, T1/2alpha=3.5 h, T1/2beta=2.7 h, AUC=265 mg.h.L(-1), and CL(s) =0.02 g.L.h(-1). KM-1 was cleared from the circulation much more slowly than free cisplatin. Liver and spleen had the highest concentration of platinum after KM-1 treatment. KM-1 remained in the bloodstream longer than its free drug, and was taken mainly by the reticuloendothelial system.


Enhanced dermal and retinal vascular permeability in streptozotocin-induced type 1 diabetes in Wistar rats: blockade with a selective bradykinin B1 receptor antagonist.
The vascular complications associated with type 1 diabetes are to some extent related to the dysfunction of the endothelium leading to an increased vascular permeability and plasma extravasation in the surrounding tissues. The various micro- and macro-vascular complications of diabetes develop over time, leading to nephropathy, retinopathy and neuropathy and cardiomyopathy. In the present study, the effect of a novel selective bradykinin B1 receptor (BKB1-R) antagonist, R-954, was investigated on the changes of vascular permeability in the skin and retina of streptozotocin (STZ)-induced type 1 diabetic rats. Plasma extravasation increased in the skin and retina of STZ-diabetic rats after 1 week and persisted over 4 weeks following STZ injection. Acute treatment with R-954 (2 mg/kg, bolus s.c.) highly reduced the elevated vascular permeability in both 1- and 4-week STZ-diabetic rats. These results showed that the inducible BKB1-R subtype modulates the vascular permeability of the skin and retina of type 1 diabetic rats and suggests that BKB1-R antagonists could have a beneficial role in diabetic neuropathy and retinopathy.


Gastric GDF15 levels are regulated by age, sex, and nutritional status in rodents and humans.
Growth differentiation factor 15 (GDF15) is a stress response cytokine that has been proposed as a relevant metabolic hormone. Descriptive studies have shown that plasma GDF15 levels are regulated by short term changes in nutritional status, such as fasting, or in obesity. However, few data exist regarding how GDF15 levels are regulated in peripheral tissues. The aim of the present work was to study the variations on gastric levels of GDF15 and its precursor under different physiological conditions, such as short-term changes in nutritional status or overfeeding achieved by HFD. Moreover, we also address the sex- and age-dependent alterations in GDF15 physiology. The levels of gastric and plasma GDF15 and its precursor were measured in lean and obese mice, rats and humans by western blot, RT-PCR, ELISA, immunohistochemistry and by an in vitro organ culture system. Our results show a robust regulation of gastric GDF15 production by fasting in rodents. In obesity an increase in GDF15 secretion from the stomach is reflected with an increase in circulating levels of GDF15 in rats and humans. Moreover, gastric GDF15 levels increase with age in both rats and humans. Finally, gastric GDF15 levels display sexual dimorphism, which could explain the difference in circulating GFD15 levels between males and females, observed in both humans and rodents. Our results provide clear evidence that gastric GDF15 is a critical contributor of circulating GDF15 levels and can explain some of the metabolic effects induced by GDF15.


Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease.
Acute kidney injury (AKI) may lead to the development of chronic kidney disease (CKD), i.e. AKI-CKD transition, but the underlying mechanism remains largely unclear. Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded or misfolded proteins in ER resulting in a cellular stress response. The role of ER stress in AKI-CKD transition remains unknown. In this study, we examined ER stress in the mouse model of AKI-CKD transition after unilateral renal ischemia-reperfusion injury (uIR). To determine the role of ER stress in AKI-CKD transition, we tested the effects of two chemical chaperones: Tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). uIR led to the induction of ER stress in kidneys, as indicated by increased expression of UPR molecules CHOP (C/EBP homologous protein) and BiP(binding immunoglobulin protein; also called GRP78-78 kDa glucose-regulated protein). Given at 3 days after uIR, both TUDCA and 4-PBA blocked ER stress in post-ischemic kidneys. Notably, both chemicals promoted renal recovery and suppressed tubulointerstitial injury as manifested by the reduction of tubular atrophy, renal fibrosis and myofibroblast activation. Inhibition of ER stress further attenuated renal tubular epithelial cell apoptosis, inflammation and autophagy in post-ischemic kidneys. These findings suggest that ER stress contributes critically to the development of chronic kidney pathologies and CKD following AKI, and inhibition of ER stress may represent a potential therapeutic strategy to impede AKI-CKD transition.


Estimation of Platelet Counts and Other Hematological Parameters in Pseudothrombocytopenia Using Alternative Anticoagulant: Magnesium Sulfate.
The platelet count, mean platelet volume, and other hematological parameters were compared in blood samples anticoagulated with MgSO4 and EDTA. A total of 15 samples were taken, and the platelet counts were observed to be significantly high in MgSO4-anticoagulated blood samples ranging from 53 × 103 to 499 × 103/μL, whereas in EDTA-anticoagulated blood samples, the counts ranged from 10 × 103 to 353 × 103/μL. This increased platelet count was also statistically significant with the P value being .005. The morphology of red blood cells and white blood cells in Leishman-stained smears from MgSO4-anticoagulated blood was below average. In conclusion, MgSO4 can be used as an alternative anticoagulant only to estimate the platelet counts in EDTA-induced pseudothrombocytopenia.


Clinical significance of erythromycin-resistant Campylobacter jejuni in children.
Campylobacter has been recognized as the common cause of bacterial gastroenteritis in many countries. Increasing erythromycin resistance in Campylobacter jejuni infection is noted recently, but severe case was rarely reported. In this study, we aimed to clarify the clinical significance of the resistant strain of C jejuni in children. We reviewed the charts of children who were diagnosed with C jejuni enteritis in our hospital from January 2000 to December 2005, including 326 patients (117 males and 209 females). All the cases had positive stool culture. We divided them into two groups, the sensitive group (a total of 306 cases) and resistant group (a total of 20 cases), according to the drug sensitivity. We analyzed the clinical manifestations and laboratory data between the two groups. The mean age was 3.79 ± 3.24 years in the sensitive group and 3.03 ± 2.84 years in the resistant group. There was no significant difference between the two groups in clinical presentations and laboratory examinations. No mortality was found, and one case was initially presented with colonic perforation. This report demonstrates that infection by erythromycin-resistant strains of C jejuni has no clinical significance in children, despite the probably increased emergence of erythromycin resistance.


Combining segmental systolic pressures and plethysmography to diagnose arterial occlusive disease of the legs.
Computer-assisted analysis of the data from SLP and PVR study of the legs with angiographically documented arterial occlusive disease, projected against a background of normal limbs, was used to assess the diagnostic value of each study, including its individual variables, as well as their varied combinations. The accuracy of both SLP and PVR interpretation was significantly improved by standarization against brachial values, but even with the aid of superimposed physician interpretation, each only reached 86 per cent when cases with multilevel occlusive disease were included. The combination of these two studies, which compensate for each other's limitations in several respects, achieved an overall accuracy of 97 per cent, with no errors observed in diagnosing either normal limbs or those with isolated occlusive disease. Objective diagnostic criteria for both SLP and PVR interpreatation are presented in algorithmic form.


The effect of mitochondrial energization on cytochrome c oxidase kinetics as measured at low temperatures. I. The reaction with carbon monoxide.
The kinetics of CO binding by the cytochrome c oxidase of pigeon heart mitochondria were studied as a function of membrane energization at temperatures from 180 to 280 degrees K in an ethylene glycol/water medium. Samples energized by ATP showed acceleration of CO binding compared to those untreated or uncoupled by carbonylcyanide p-trifluoromethyoxyphenylhydrazone but only at relatively low temperatures and high CO concentrations. Experiments using samples in a "mixed valency" (partially oxidized) state showed that the acceleration of ligand binding is not due to the formation of a partially oxidized state via reverse electron transport. It is concluded that in the deenergized state one CO molecule can be closely associated with the cytochrome a3 heme site without actually being bound to the heme iron; in the energized state, two or more ligand molecules can occupy this intermediate position. The change in the apparent ligand capacity of a region near the heme iron in response to energization is evidence for an interaction between cytochrome oxidase and the ATPase system. Furthermore, these results suggest a control mechanism for O2 binding.


Early initiation of breast feeding and associated factors among mother-baby dyads with immediate skin-to-skin contact: cross-sectional study based on the 2016 Ethiopian Demographic and Health Survey data.
The study aimed to assess the practice of early initiation of breast feeding (EIBF) and associated factors among mother-baby dyads who practiced immediate skin-to-skin contact in Ethiopia. Cross-sectional study. The study was conducted nationally in nine regional states and two city administrations. In the study, 1420 mother-baby dyads with last-born children (children born in the 2 years preceding the survey, children <24 months old) and children put on the mother's bare skin. The data of the study participants were extracted from the Ethiopian Demographic and Health Survey 2016. The outcome measure of the study was the proportion of EIBF among mother-baby dyads and associations. EIBF among mothers and newborns with skin-to-skin contact was 88.8% (95% CI 87.2 to 90.4). EIBF among mother-baby dyads with immediate skin-to-skin contact was more likely among mothers from wealthy families (adjusted OR (AOR)=2.37, 95% CI 1.38 to 4.08), attended secondary and above education (AOR=1.67, 95% CI 1.12 to 2.57), living in Oromia (AOR=2.87, 95% CI 1.11 to 7.46), Harari (AOR=11.60, 95% CI 2.48 to 24.34) and Dire Dawa (AOR=2.93, 95% CI 1.04 to 8.23) regions, gave birth by non-caesarean section (AOR=3.34, 95% CI 1.33 to 8.39), gave birth at hospital (AOR=2.02, 95% CI 1.02 to 4.00), and health centre (AOR=2.19, 95% CI 1.21 to 3.98), and gave birth by midwifery assistance (AOR=1.62, 95% CI 1.06 to 2.49). Nine in ten mother-baby dyads with immediate skin-to-skin contact early initiate breast feeding. The EIBF was affected by educational status, wealth index, region, mode of delivery, place of delivery and delivery assisted by midwifery. Improving healthcare service, institutional delivery and the competency of maternal healthcare providers may aid the EIBF in Ethiopia.


Route of exposure influences pesticide body burden and the hepatic metabolome in post-metamorphic leopard frogs.
Pesticides are being applied at a greater extent than in the past. Once pesticides enter the ecosystem, many environmental factors can influence their residence time. These interactions can result in processes such as translocation, environmental degradation, and metabolic activation facilitating exposure to target and non-target species. Most anurans start off their life cycle in aquatic environments and then transition into terrestrial habitats. Their time in the aquatic environment is generally short; however, many important developmental stages occur during this tenure. Post-metamorphosis, most species spend many years on land but migrate back to the aquatic environment for breeding. Due to the importance of both the aquatic and terrestrial environments to the life stages of amphibians, we investigated how the route of exposure (i.e., uptake from contaminated soils vs. uptake from contaminated surface water) influences pesticide bioavailability and body burden for four pesticides (bifenthrin (BIF), chlorpyrifos (CPF), glyphosate (GLY), and trifloxystrobin (TFS)) as well as the impact on the hepatic metabolome of adult leopard frogs (Gosner stage 46 with 60-90 days post-metamorphosis). Body burden concentrations for amphibians exposed in water were significantly higher (ANOVA p < 0.0001) compared to amphibians exposed to contaminated soil across all pesticides studied. Out of 80 metabolites that were putatively identified, the majority expressed a higher abundance in amphibians that were exposed in pesticide contaminated water compared to soil. Ultimately, this research will help fill regulatory data gaps, aid in the creation of more accurate amphibian dermal uptake models and inform continued ecological risk assessment efforts.


Xylosandrus crassiusculus (Motschulsky) on Cocoa Pods (Theobroma cacao L.): Matter of Bugs and Fungi.
Exudation of mucilage from pinhead-sized boreholes in cocoa pods was recorded in Karnataka, India, during 2021. Further investigations showed the association of scolytine beetles with infested pods. The identity of the pest, Xylosandrus crassiusculus, was confirmed through morphological characterization and sequencing of the mitochondrial COI gene. We studied the predisposing factors for its infestation, visible and concealed damaging symptoms, and fungal symbionts. In addition to its well-known symbiotic fungus, Ambrosiella roeperi, a new association of yeast, Ambrosiozyma monospora, was discovered. We also traced the possible role of the mirid bug, Helopeltis theivora, in host selection by X. crassiusculus. Overall results indicated that a 'mirid bug-ambrosia beetle-pathogen complex' is responsible for the severe damage to cocoa pods in South India.


Work-related recovery opportunities: testing scale properties and validity in relation to health.
Recovery opportunities allow employees to recuperate from work and diminish load effects. The aims of this study are to present a scale for measuring recovery opportunities, study its psychometric properties and its relationship with health. Data from three Dutch worker samples were used with response rates over 60%. Sample 1 contained 6,863 employees working in a wide variety of jobs in 114 organizations. Sample 2 contained data from 992 mental health care workers from ten different organizations. Sample 3 were 436 employees working in several specialized health care clinics. Internal consistency of the nine-item recovery opportunities scale is good. Content validity of recovery opportunities, especially how it discriminates from other aspects of job control, is also good. Recovery opportunities show significant effects on work-related fatigue (need for recovery), sleep complaints, and health complaints, but not on future absenteeism. The recovery opportunities scale has good reliability and shows good content-, construct- and criterion-related validity in three samples of workers that differ in amount of heterogeneity.


Robotic assisted laparoscopic prostatectomy in a patient with prostate cancer and complex urinary tract malformation.
We present a case of prostate cancer with abnormal renal and ureteric anatomy who underwent robotic assisted laparoscopic prostatectomy. This is a 59-year-old European patient who presented with lower urinary tract symptoms (LUTS) and pelvic pain. Investigations revealed prostate cancer as well as a supernumerary right kidney and an atrophic horseshoe left kidney draining into the left seminal vesicle. He was managed with robotic assisted laparoscopic prostatectomy (RALP) using a modified technique. Selective pre-operative investigations and patient counselling led to proper operative planning and good surgical technique and outcome.


High cell density cultivation of Corynebacterium glutamicum on bio-based lignocellulosic acetate using pH-coupled online feeding control.
Acetate represents a promising alternative carbon source for future industrial biotechnology. In this study, the high potential of Corynebacterium glutamicum for utilizing acetate as sole carbon source was demonstrated. Batch culture studies revealed that C. glutamicum ATCC 13032 naturally exhibits high acetate tolerance with maximum growth rates (µmax = 0.47 h-1) similar to those on D-glucose. Based on a simple and auto-regulated pH-coupled feeding strategy which utilizes bio-acetic acid in pure form, a novel and high-efficient fed-batch process was developed in a 42 L stirred-tank bioreactor. By optimizing the carbon-to-nitrogen (C/N) feeding ratio, maximum biomass concentrations of 80.2 gCDW/L were achieved with a space-time yield of 66.6 gCDW/L·d. In addition, a process model was implemented describing the time-courses of biomass growth and substrate concentrations. This is the first study in which an industrial platform organism was grown to high cell densities using green, lignocellulosic acetate as an alternative carbon source.


Trypsin/chymotrypsin inhibitors from millets.
Properties of purified proteinase inhibitors from the small-seeded grains, finger millet, sorghum, pearl millet, Italian millet, and barnyard millet are compared. The changes in the levels of inhibitory activities during germination and plant growth of finger millet and barnyard millet are discussed. The action of millet proteinase inhibitors on human and other animal pancreatic enzymes is detailed. The role of substrates in determining the magnitude of the inhibition of proteolytic enzymes by the millet inhibitors is emphasized.


The Effects of Vitamin D Supplementation During Infancy on Growth During the First 2 Years of Life.
The relationship between maternal and infant vitamin D and early childhood growth remains inadequately understood. This work aimed to investigate how maternal and child 25-hydroxyvitamin D (25[OH]D) and vitamin D supplementation affect growth during the first 2 years of life. A randomized, double-blinded, single-center intervention study was conducted from pregnancy until offspring age 2 years. Altogether 812 term-born children with complete data were recruited at a maternity hospital. Children received daily vitamin D3 supplementation of 10 μg (group 10) or 30 μg (group 30) from age 2 weeks to 2 years. Anthropometry and growth rate were measured at age 1 and 2 years. Toddlers born to mothers with pregnancy 25(OH)D greater than 125 nmol/L were at 2 years lighter and thinner than the reference group with 25(OH)D of 50 to 74.9 nmol/L (P < .010). Mean 2-year 25(OH)D concentrations were 87 nmol/L in group 10 and 118 nmol/L in group 30 (P < .001). When group 30 was compared with group 10, difference in body size was not statistically significant (P > .053), but group 30 had slower growth in length and head circumference between 6 months and 1 year (P < .047), and more rapid growth in weight and length-adjusted weight between 1 and 2 years (P < .043). Toddlers in the highest quartile of 25(OH)D (> 121 nmol/L) were shorter (mean difference 0.2 SD score [SDS], P = .021), lighter (mean difference 0.4 SDS, P = .001), and thinner (in length-adjusted weight) (mean difference 0.4 SDS, P = .003) compared with the lowest quartile (< 81.2 nmol/L). Vitamin D and early childhood growth may have an inverse U-shaped relationship.


Crafting the Future-Opportunities for Students by the Reinvigorated IEEE EMBS Student Activities Committee.
"As we look ahead into the next century, leaders will be those who empower others."-Bill Gates.


Genetics of sensitivity of Salmonella species to colicin M and bacteriophages T5, T1, and ES18.
Nearly all of 62 strains of Salmonella paratyphi B were sensitive to colicin M and phage T5 but resistant to phages T1 and ES18 and to colicin B. All tested S. typhimurium strains were resistant to colicin M and phage T5, and many were sensitive to phage ES18. A rough S. typhimurium LT2 strain given the tonA region of Escherichia coli or S. paratyphi B became sensitive to colicin M and phage T5. We infer that the tonA allele of S. paratyphi B, like that of E. coli, determines an outer membrane protein that adsorbs T5 and colicin M but not phage ES18, whereas the S. typhimurium allele determines a protein able to adsorb only ES18. The partial T1 sensitivity of a rough LT2 strain with a tonA allele from E. coli or S. paratyphi B and also the tonB(+) phentotype of an E. coli B trp-tonB Delta mutant carrying an F' trp of LT2 origin showed that S. typhimurium LT2 has a tonB allele like that of E. coli with respect to determination of sensitivity to colicins and phage T1. Rough S. paratyphi B, although T5 sensitive, remained resistant to T1 even when given F' tonB(+) of E. coli origin. Classes of Salmonella mutants selected as resistant to colicin M included: T5-resistant mutants, probably tonA(-); mutants unchanged except for M resistance, perhaps tolerant; and Exb(+) mutants, producing a colicin inhibitor (presumably enterochelin). Some Exb(+) mutants were resistant to a bacteriocin inactive on E. coli but active on all tested S. paratyphi B and S. typhimurium strains (and on nearly all other tested Salmonella). A survey showed sensitivity to colicin M in several other species of Salmonella.


Hypofractionated boost with high-dose-rate brachytherapy and open magnetic resonance imaging-guided implants for locally aggressive prostate cancer: a sequential dose-escalation pilot study.
To evaluate the feasibility, tolerance, and preliminary outcome of an open MRI-guided prostate partial-volume high-dose-rate brachytherapy (HDR-BT) schedule in a group of selected patients with nonmetastatic, locally aggressive prostatic tumors. After conventional fractionated three-dimensional conformal external radiotherapy to 64-64.4 Gy, 77 patients with nonmetastatic, locally aggressive (e.g., perineural invasion and/or Gleason score 8-10) prostate cancer were treated from June 2000 to August 2004, with HDR-BT using temporary open MRI-guided (192)Ir implants, to escalate the dose in the boost region. Nineteen, 21, and 37 patients were sequentially treated with 2 fractions of 6 Gy, 7 Gy, and 8 Gy each, respectively. Neoadjuvant androgen deprivation was given to 62 patients for 6-24 months. Acute and late toxicity were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring system. All 77 patients completed treatment as planned. Only 2 patients presented with Grade > or =3 acute urinary toxicity. The 3-year probability of Grade > or =2 late urinary and low gastrointestinal toxicity-free survival was 91.4% +/- 3.4% and 94.4% +/- 2.7%, respectively. Rates of 3-year biochemical disease-free survival (bDFS) and disease-specific survival were 87.1% +/- 4.1% and 100%, respectively. Boosting a partial volume of the prostate with hypofractionated HDR-BT for aggressive prostate cancer was feasible and showed limited long-term toxicity, which compared favorably with other dose-escalation methods in the literature. Preliminary bDFS was encouraging if one considers the negatively selected population of high-risk patients in this study.


Kawasaki disease presenting after intussusception: a case report.
Kawasaki disease is a common vasculitis of unknown etiology that occurs mainly in preschool children. It manifests as a self-limited acute febrile illness with other features including extremity changes, cervical lymphadenopathy, oropharyngeal changes, truncal rash, and conjunctivitis. Intestinal involvement is not uncommon, with abdominal pain and vomiting being the most frequently reported symptoms. Intussusception has been described as a manifestation or complication of this disease, but few reports exist in literature. A 7-month-old boy of Asian origin who presented with vomiting and passage of bloody mucoid stool was diagnosed with intussusception that was successfully reduced during emergency laparotomy. The baby was discharged home post-surgery following clinical improvement. He was readmitted on the fourth postoperative day with fever, irritability, and diarrhea. He was investigated and treated for presumed intraabdominal sepsis with multiple antibiotics with no improvement. He gradually developed the mucocutaneous features of Kawasaki disease and was treated with intravenous immunoglobulin and aspirin with good outcome. Intussusception and Kawasaki disease both commonly occur in children less than 2 years old. It is important to include Kawasaki disease as a differential diagnosis in children of this age who present with an acute febrile illness and gastrointestinal symptoms. A common underlying pathologic process could be contributing to both conditions.


Alterations in expression and chromatin configuration of the alpha hemoglobin-stabilizing protein gene in erythroid Kruppel-like factor-deficient mice.
Erythroid Krüppel-like factor (EKLF) is an erythroid zinc finger protein identified by its interaction with a CACCC sequence in the beta-globin promoter, where it establishes local chromatin structure permitting beta-globin gene transcription. We sought to identify other EKLF target genes and determine the chromatin status of these genes in the presence and absence of EKLF. We identified alpha hemoglobin-stabilizing protein (AHSP) by subtractive hybridization and demonstrated a 95 to 99.9% reduction in AHSP mRNA and the absence of AHSP in EKLF-deficient cells. Chromatin at the AHSP promoter from EKLF-deficient cells lacked a DNase I hypersensitive site and exhibited histone hypoacetylation across the locus compared to hyperacetylation of wild-type chromatin. Wild-type chromatin demonstrated a peak of EKLF binding over a promoter region CACCC box that differs from the EKLF consensus by a nucleotide. In mobility shift assays, the AHSP promoter CACCC site bound EKLF in a manner comparable to the beta-globin promoter CACCC site, indicating a broader recognition sequence for the EKLF consensus binding site. The AHSP promoter was transactivated by EKLF in K562 cells, which lack EKLF. These results support the hypothesis that EKLF acts as a transcription factor and a chromatin modulator for the AHSP and beta-globin genes and indicate that EKLF may play similar roles for other erythroid genes.


Self-perceived versus physician documented adverse events in patients with multiple sclerosis REGIMS-a pharmacovigilance registry for patients with multiple sclerosis in Germany.
Post-marketing studies, including registries, mark an indispensable step in the establishment of drug side-effect profiles. In recent years, the inclusion of the patients' perspective has gained increasing relevance regarding pharmacovigilance. Primary objective of this study was to analyse the concordance of subjectively experienced symptoms by multiple sclerosis (MS) patients treated with immunotherapy and the adverse events reported by their treating physicians. REGIMS, the data source of this study, is a prospective registry investigating the long-term drug safety in the treatment of MS in Germany. Patients included had to meet the revised McDonald criteria (2005) and be treated with immunotherapy. Concordance of adverse events documented six and 12 months after baseline presentation in 642 MS patients from 46 different neurologic outpatient centres all over Germany was analysed. Physicians' documentation was done either on paper or electronically during routine visits, while patients' self-reports were based on mailed questionnaires. Regression models were used to analyse factors influencing reporting. During one year of follow-up patients reported a total number of 4,841 events per 1,000 patient-years (PYs) while physicians reported 467 events/1,000 PYs. Patients' and physicians' reports focused on different body functions and categories, respectively. Factors increasing patients' likeliness to report were female gender (ß-coefficient: 1.52, 95% CI: 0.96-2.09), a history of smoking (ß: 0.80, 95% CI: 0.13-1.47), a higher EDSS score (ß: 0.28, 95% CI: 0.10-0.46) and previous MS therapies (ß: 0.35, 95% CI: 0.11-0.59) increased the patients' reporting of AEs. Physicians were more likely to report an AE for Fingolimod than for Interferon beta preparations (OR = 3.22, 95% CI: 1.22-8.52). Underreporting of adverse events has been a known problem in clinical routine for several years without signs of substantial improvement. Encouraging patients' involvement in adverse event reporting offers the possibility to a more holistic approach to pharmacovigilance. Further investigations in patients' and physicians' strategies when it comes to causality assessment of adverse events related to MS medication may be insightful.


Inactivation of metalloenzymes by lysinoalanine, phenylethylaminoalanine, alkali-treated food proteins, and sulfur amino acids.
Synthetic lysinoalanine (LAL) may be a more effective inhibitor of the zinc-containing enzyme carboxypeptidase A than is ethylenediamine tetraacetic acid (EDTA). The enzyme is also inactivated by alkali-treated, lysinoalanine-containing food proteins such as casein, high-lysine corn protein, lactalbumin, soy protein isolate, and wheat gluten, and by alkali-treated zein, which contains no lysinoalanine. Zinc sulfate regenerates only part of the enzymatic activity after exposure to the treated proteins. The extent of inhibition increases with protein concentration and time of treatment. Any inhibition due to phytate is distinct from that due to the treatment. Phenylethylaminoalanine (PEAA), derived from biogenic phenylethylamine, inhibited enzymatic activity of the metalloenzyme carboxypeptidase A (CPA). The inhibition was maximal at pH 7.0 in the pH range 7 to 8.5. The extent of inhibition increased with time of treatment and PEAA concentration. N-acetyl-PEAA did not inhibit the enzyme, suggesting that the free alpha-NH2 group is required for inhibition. PEAA, LAL, sodium phytate, and cysteine also inactivated the copper enzyme, polyphenol, oxidase (tyrosinase) which plays a major role in enzymatic (oxidative) browning of foods. Analogous comparative studies with LAL, EDTA, and sodium phytate suggest that the potency of PEAA as an inhibitor of CPA is similar to that of sodium phytate, and that of the four compounds tested, PEAA is least effective against tyrosinase. Related studies of the iron and copper containing enzyme cytochrome C oxidase showed that EDTA was not inhibitory, PEAA was slightly inhibitory, and LAL and sodium phytate were stronger inhibitors. Mechanistic explanations are offered to account for some of these observations. The possible relevance of these findings to in vivo protein digestion, enzymatic (oxidative) browning of foods, and the mechanism of the lysinoalanine effect on kidney cells are also discussed.


Mutations in the binding site of TNFR1 PLAD reduce homologous interactions but can enhance antagonism of wild-type TNFR1 activity.
The tumour necrosis factor receptor superfamily (TNFRSF) members contain cysteine-rich domains (CRD) in their extracellular regions, and the membrane-distal CRD1 forms homologous interactions in the absence of ligand. The CRD1 is therefore termed a pre-ligand assembly domain (PLAD). The role of PLAD-PLAD interactions in the induction of signalling as a consequence of TNF-TNFR binding led to the development of soluble PLAD domains as antagonists of TNFR activation. In the present study, we generated recombinant wild-type (WT) PLAD of TNFR1 and mutant forms with single alanine substitutions of amino acid residues thought to be critical for the formation of homologous dimers and/or trimers of PLAD (K19A, T31A, D49A and D52A). These mutated PLADs were compared with WT PLAD as antagonists of TNF-induced apoptosis or the activation of inflammatory signalling pathways. Unlike WT PLAD, the mutated PLADs showed little or no homologous interactions, confirming the importance of particular amino acids as contact residues in the PLAD binding region. However, as with WT PLAD, the mutated PLADs functioned as antagonists of TNF-induced TNFR1 activity leading to induction of cell death or NF-κB signalling. Indeed, some of the mutant PLADs, and K19A PLAD in particular, showed enhanced antagonistic activity compared with WT PLAD. This is consistent with the reduced formation of homologous multimers by these PLAD mutants effectively increasing the concentration of PLAD available to bind and antagonize WT TNFR1 when compared to WT PLAD acting as an antagonist. This may have implications for the development of antagonistic PLADs as therapeutic agents.


Innervation of the serotonin-immunoreactive cells distributed in the wall of the common carotid artery and its branches in the chicken.
In the chicken, serotonin-immunoreactive cells were widely distributed not only in the carotid body but also in the wall of the common carotid artery and around each artery arising from the common carotid artery. Almost all of the serotonin cells in the wall of the common carotid artery were intensely immunoreactive to the neuropeptide Y, met- and leu-enkephalin antisera, whereas in the carotid body only a few cells were immunoreactive to these antisera. Innervation of the serotonin cells in and around arteries of chickens was investigated by immunohistochemistry and electron microscopy, in comparison with that of the carotid body. The serotonin cell groups in and around arteries, as well as the carotid body, received numerous peptidergic nerve fibers. Calcitonin gene-related peptide (CGRP)- and substance P-immunoreactive varicose nerve fibers were densely distributed, and somatostatin-immunoreactive fibers were moderately distributed in the serotonin cell groups. Galanin- and vasoactive intestinal peptide (VIP)-immunoreactive fibers were sparsely distributed in the cell groups. By electron microscopy, the serotonin cells in and around arteries were characterized by the presence of numerous dense-cored vesicles, 70-220 nm in diameter. The granule-containing cells were in close association with numerous axons. Naked axons regarded axon terminals were frequently apposed on the granular cells. The axon terminals were usually long and often partly invested the granular cells. Numerous synaptic junctions were detected along the contact between the granular cells and axon terminals. Most of the synaptic junctions showed afferent morphology; the secretory granules were accumulated near and attached to the asymmetrical membrane thickenings. Thus, the serotonin cells in and around arteries, like the carotid body, constitute chemoreceptive tissue.