Epidermal Growth Factor-labeled liposomes as a way to target the toxicity of silver nanoparticles into EGFR-overexpressing cancer cells in vitro.
Silver nanoparticles (AgNPs) are the most toxic nanostructures for both cancer and healthy cells. Thus, their usefulness in the anticancer therapy is limited. Interestingly, the epidermal growth factor receptor (EGFR) is overexpressed in many cancer cells, e.g. in lung and tongue cancers. Therefore, the aim of this study was to develop a way to direct the cytotoxic effect of AgNPs against cancer cells, saving healthy ones by entrapping these NPs inside liposomes labeled with the epidermal growth factor (EGF-LipoAgNPs) and directing these structures into EGFR-overexpressing cancer cells. The obtained results showed spherical structures with a 107.9 nm size and - 16.60 mV zeta-potential. The UV-Vis scan and TEM images did not show free AgNPs in the solution. The obtained complexes were able to decrease the metabolic activity in the A549 and SCC-15 cells more effectively than native AgNPs. Furthermore, the ROS production, lactate dehydrogenase release, and caspase-9 and -3 activity were significantly increased after the treatment with EGF-LipoAgNPs for 24 and 48 h. The expression of genes encoding catalase, superoxide dismutase, and p53 protein increased significantly, while the KI67 gene expression decreased, especially in the A549 and SCC-15 cells. Moreover, the KI67 protein expression was lower than in the cells treated with native AgNPs, while catalase activity was decreased significantly after the treatment with the obtained complexes. In turn, SOD activity increased more efficiently in the EGFR-overexpressing cancer cells. In all tested parameters, EGF-LipoAgNPs exerted a lower toxic effect on the BJ cells than native AgNPs. Summarizing, the created liposomal system reduces the toxicity of AgNPs against normal human fibroblasts and enhances the toxic and proapoptotic effect of these NPs, which may be caused by improvement of their uptake by EGFR-overexpressing cancer cells.


Carboxymethylcellulose/layered double hydroxides bio-nanocomposite hydrogel: A controlled amoxicillin nanocarrier for colonic bacterial infections treatment.
In this work, a pH-sensitive carboxymethylcellulose based bio-nanocomposite hydrogel beads with different content of layered double hydroxides (LDHs) as a nanoparticle was prepared (CMC/LDH(Cu/Al)). EDX spectroscopy was used to confirm the successful composition of LDH(Cu/Al) with CMC and its presence in the hydrogel matrix. The prepared CMC/LDH(Cu/Al) bio-nanocomposite hydrogel bead characterized by XRD, FT-IR, and SEM analysis. The swelling results showed the pH-sensitive properties for all of the prepared CMC/LDH(Cu/Al). Amoxicillin (AMX) as a model of the antibiotic drug was selected to study the ability of the prepared systems as an oral drug delivery vehicle. The obtained results showed that the CMC/LDH(Cu/Al 7.5) bio-nanocomposite hydrogel bead has a good performance compared to the other prepared bio-nanocomposites. MTT assay approved the safety of this bio-nanocomposite hydrogel bead against HUVEC cells. Consistent with the obtained results, the prepared hydrogel beads could be potentially proposed as an efficient safe drug carrier for AMX oral delivery.


The source of SYBR green master mix determines outcome of nucleic acid amplification reactions.
Quantitative (q) PCR by amplification of nucleic acid with a fluorescent dye is widely used. Selection of adequate PCR reagents and devices is relevant to achieve reliable and consistent data. Our main objective was to test the robustness of different commercial SYBR green PCR mixes with respect to specificity and sensitivity of the PCR assay, across various PCR machines (Light Cycler 96, ViiA7) and amplification protocols. Herein, we applied PCR protocols for determining mRNA transcript levels, DNA copy numbers, and DNA genotype. First, we set up 70 primer-based assays that targeted immune-related mRNA transcripts. Of the 70 assays 66 (94.3 %) resulted in a single melting curve peak, indicating specificity of the amplification, with PCR mixes from large vendors (Roche, ABI, Bio-Rad). But this was only seen when the PCR protocol that was indicated in the vendor's guidelines for each particular mix was applied. When deviating from the prescribed protocol, suboptimal melting curves were most often seen when using Roche SYBR green. With respect to PCR yields, the use of ABI mix more often led to lower Cq values. Second, we set up 20 primer-selective PCR assays to target different insertion-deletion and single nucleotide polymorphism regions throughout the genome. The variation in delta Cq between positive and negative DNA samples among the PCR assays was the lowest when using ABI master mix. Finally, the quality of high resolution melting (HRM) assays for DNA genotyping was compared between four commercial HRM PCR mixes (Roche, Bioline, PCR Biosystems, ABI). Only Roche and ABI mixes produced optimal clusters of melting profiles that clearly distinguished genotype variants. The current results show a preference for the use of ABI mix when it comes to obtaining higher sensitivity in cDNA analysis and a higher consistency among assays in distinguishing DNA genotypes among different individuals. For HRM assays, it is advisable to use master mix from a relatively large vendor.


Double-blind food challenge in the diagnosis of food sensitivity in the adult.
This study is an attempt to determine the role of double-blind food challenge (DBFC) in suspected food sensitivity in the adult as compared wih established tests of food allergy, including the skin test, RAST, and leukocyte histamine release (LHR) to specific food antigens. Twenty-two subjects (ages 18 to 67) with histories of reactions to foods were challenged with freeze-dried food or placebo in opaque dye-free capsules, in increasing doses over a 90 min span to a total of 13 to 15 gm. This was repeated twice at weekly intervals by similar DBFC. DBFC was preceded by skin testing and venapuncture for RAST and LHR studies. Patients were kept under observation for 2 hr, after which each was asked to maintain a detailed diary of related symptoms and food ingested over the following week. Of 46 DBFCs, 13 (21%) were positive. The correlation with positive skin tests and positive DBFC was 4/13 (30%). The correlation with positive LHR and positive DBFC was lower at 2/13 (15%), and 1/13 (7.6%) with RAST. We concluded that DBFC is an effective test of adult food sensitivity compared with tests usually performed and should be used when the diagnosis is in doubt.


The progression of thyroid cartilage calcification as it relates to the utilization of laryngeal ultrasound.
The purpose of this study is to review the computed tomography (CT) scans of infants, children, and adults to assess the degree of calcification of the thyroid cartilage at various ages in order to understand in which age group laryngeal ultrasound can be utilized. Retrospective. Two hundred patients from newborn to 50 years who received a CT scan of the neck were identified. The Hounsfield units (HU) of the thyroid cartilage were calculated at one o'clock, four o'clock, eight o'clock, and eleven o'clock at the level of the true and false vocal fold. The Spearman correlation coefficient was calculated to evaluate the correlation between each measure and age, then a linear regression with a logarithmic transformation was applied to further study how the measures were related to age. The Spearman correlation coefficients ranged from 0.58 to 0.75. The P values of these coefficients were all < 0.0001, showing a significant relationship to age. The age increase by 1 year resulted in increased calcification by 1.5% to 4%. The Wilcoxon signed rank test compared the rate of calcification at each site measured. This showed that the two posterolateral sites calcify faster than the two anteromedial sites. The thyroid cartilage calcifies at a rate that is significantly related to increasing age and calcifies in a posterolateral to anteromedial direction. Based on the HU, the thyroid cartilage is not consistently denser than soft tissue until greater than 40 years of age, which would make laryngeal ultrasound feasible for this population. 4.


Obtaining accreditation by the pharmacy compounding accreditation board, part 4: tips for "last minute" preparations.
One of the most exciting new developments in the world of compounding is the opportunity for a pharmacy to obtain accreditation. Other healthcare organizations have had that opportunity for years. Compounding pharmaies now have an external standard-setting entity to which they can apply for accreditation-the Pharmcy Compounding Accreditaion Board-and they are encouraged to do so. The pharmacy staff may have extra anxiety the few days before a survey is conducted by the Pharmacy Compounding Accreditation Board, but, by following the pre-survey tips included in this article, compounding pharmacists and their staff can channel the extra energy into productive activites that will help in achieving accreditation.


Management of cancer pain.
Pain secondary to cancer in animals should be promptly addressed to alleviate suffering, stress, and anxiety and to improve quality of life. Uncontrolled cancer pain can have a negative effect on the owners and caregivers of affected animals. The pathophysiology of cancer pain is discussed in this article, along with pain evaluation and monitoring. Treatment of cancer pain should be individualized, and a step-wise approach to the management of cancer pain is presented. The use of opioids, nonsteroidal anti-inflammatory drugs, and adjuvant medications are also reviewed.


A comparison of single-dose and fractionated total-body irradiation on the development of pneumonitis following bone marrow transplantation.
A review of 132 consecutive patients who received bone marrow transplant for various malignancies was conducted to determine factors associated with increased risk in developing interstitial pneumonitis (IP) as the result of total body irradiation (TBI). Twenty-four patients were excluded because 22 did not receive TBI and two had insufficient records. Patients were conditioned with TBI and various drug regimens. Eighteen patients received a single 6.0 Gy dose of x-rays. The remaining 90 were treated with three doses of 3.33 Gy separated by 24 h. All patients were followed for at least 18 months for the purposes of determining the IP incidence. Twenty-seven of these 108 (25%) patients developed IP; 19 (17.6%) died. The 2-year estimated incidence of IP was 24 and 18.6% for fatal IP. The etiology was determined to be idiopathic in 12 patients, the result of cytomegalovirus in 6 patients, and caused by a variety of other infectious organisms in 9 patients. We were unable to demonstrate a statistically significant increase in IP with age (adults vs. children), dose regimen, use of methotrexate for graft-vs.-host disease prophylaxis, the presence of acute graft-vs.-host disease, time from diagnosis to transplant, or transplant type (allogeneic vs. autologous). The incidence of fatal IP reported here is similar to that reported by other institutions utilizing hyperfractionated TBI protocols. Our data do not support the need for hyperfractionation to reduce the risk of IP.


[Possibility of the nonbiological binding of CO2 and CO by the components of Martian soil].
A mixture of carbon dioxide and carbon monoxide was irradiated in the presence of limonite and hydrogen peroxide at 340 nm. As has been demonstrated by gas chromatography, chemical reactions occurring in this case yield organic compounds which could be synthesized in the experiments conducted by the Viking stations. Consequently, this method cannot discriminate between the chemical and biological processes which possibly accounted for positive signals registered in the experiments of the Viking stations.


Metabolite Sensing by Colonic ILC3s: How Far Is Too Ffar2 Go?
It is poorly understood how group 3 innate lymphoid cells (ILC3s) recognize metabolites produced by the gut microbiota. In this issue of Immunity, Chun et al. show that short-chain fatty acids sensed through the G protein-coupled receptor Ffar2 promote ILC3 function in the colon.


Obstructive sleep apnea is associated with increased arterial stiffness in severe obesity.
Obstructive sleep apnea is associated with obesity and metabolic syndrome, leading to greater cardiovascular risk. Severely obese patients with obstructive sleep apnea may still be at risk of adverse health outcomes, even without previous cardiovascular disease. Pulse wave analysis non-invasively measures peripheral pulse waveforms and derives measures of haemodynamic status, including arterial stiffness, augmentation pressure and subendocardial viability ratio. We hypothesized that the presence of obstructive sleep apnea in severe obesity, even in the absence of an antecedent history of cardiovascular disease, would affect measurements derived from pulse wave analysis. Seventy-two severely obese adult subjects [obstructive sleep apnea 47 (body mass index 42 ± 7 kg m(-2) ), without obstructive sleep apnea (non-OSA) 25 (body mass index 40 ± 5 kg m(-2) )] were characterised using anthropometric, respiratory and cardio-metabolic parameters. Groups were similar in age, body mass index and gender. More subjects with obstructive sleep apnea had metabolic syndrome [obstructive sleep apnea 60%, without obstructive sleep apnea (non-OSA) 12%]. Those with obstructive sleep apnea had greater arterial stiffness, augmentation pressure and decreased subendocardial viability ratio (all P < 0.001), with significantly higher systolic (P = 0.003), diastolic (P = 0.04) and mean arterial pressures (P = 0.004) than patients without obstructive sleep apnea (non-OSA). Arterial stiffness correlated with mean arterial blood pressure (P = 0.003) and obstructive sleep apnea severity (apnea-hypopnea index; P < 0.001). apnea-hypopnea index significantly predicted arterial stiffness in multiple regression analysis, but components of the metabolic syndrome did not. Thus, patients with obstructive sleep apnea with severe obesity have increased arterial stiffness that may potentially influence cardiovascular risk independently of metabolic abnormalities. The presence of obstructive sleep apnea in severe obesity identifies a group at high cardiovascular risk; clinicians should ensure that risk factors are managed appropriately in this group whether or not treatment of obstructive sleep apnea is offered or accepted by patients.


Evidence that the COMTVal158Met polymorphism moderates subclinical psychotic and affective symptoms in unaffected first-degree relatives of patients with schizophrenia.
Psychotic patients with COMT(Val158Met) Met alleles were recently found to display more intense psychotic and affective responses to daily life stressors. We aimed to test the hypothesis that the Met allele is implicated in the development of affective and psychotic symptomatology in subjects genetically at risk for schizophrenia, by testing if unaffected first-degree relatives of patients with schizophrenia who share a Met allele have greater concordance of symptomatology than relatives not sharing a Met allele. Unaffected relatives (n=38) were arranged in as many genetically related pairs as possible (n=26), and Met-sharing between Index Unaffected Subject (IUS) and Related Unaffected Subject (RUS) was assessed. Symptomatology was assessed with the Brief Psychiatric Rating Scale (BPRS) total score. Multilevel regression revealed an interaction between RUS BPRS score and Met-sharing in the model of IUS BPRS score (interaction chi(2)=3.78, p=0.05). Stratified analyses revealed that IUS-RUS total BPRS scores were significantly associated in the case of Met-sharing (B=0.57, 95% CI: 0.22-0.93, p=0.002), but were not when there was no Met-sharing. These findings support the hypothesis that the Met allele may be involved in the causation of psychopathology, at least in populations with a genetic predisposition to psychosis.


Proteolysis of SNAP-25 isoforms by botulinum neurotoxin types A, C, and E: domains and amino acid residues controlling the formation of enzyme-substrate complexes and cleavage.
Tetanus toxin and the seven serologically distinct botulinal neurotoxins (BoNT/A to BoNT/G) abrogate synaptic transmission at nerve endings through the action of their light chains (L chains), which proteolytically cleave VAMP (vesicle-associated membrane protein)/synaptobrevin, SNAP-25 (synaptosome-associated protein of 25 kDa), or syntaxin. BoNT/C was reported to proteolyze both syntaxin and SNAP-25. Here, we demonstrate that cleavage of SNAP-25 occurs between Arg198 and Ala199, depends on the presence of regions Asn93 to Glu145 and Ile156 to Met202, and requires about 1,000-fold higher L chain concentrations in comparison with BoNT/A and BoNT/E. Analyses of the BoNT/A and BoNT/E cleavage sites revealed that changes in the carboxyl-terminal residues, in contrast with changes in the amino-terminal residues, drastically impair proteolysis. A proteolytically inactive BoNT/A L chain mutant failed to bind to VAMP/synaptobrevin and syntaxin, but formed a stable complex (KD = 1.9 x 10(-7) M) with SNAP-25. The minimal essential domain of SNAP-25 required for cleavage by BoNT/A involves the segment Met146-Gln197, and binding was optimal only with full-length SNAP-25. Proteolysis by BoNT/E required the presence of the domain Ile156-Asp186. Murine SNAP-23 was cleaved by BoNT/E and, to a reduced extent, by BoNT/A, whereas human SNAP-23 was resistant to all clostridial L chains. Lys185Asp or Pro182Arg mutations of human SNAP-23 induced susceptibility toward BoNT/E or toward both BoNT/A and BoNT/E, respectively.


Characterizing interactions between cardiac shape and deformation by non-linear manifold learning.
In clinical routine, high-dimensional descriptors of the cardiac function such as shape and deformation are reduced to scalars (e.g. volumes or ejection fraction), which limit the characterization of complex diseases. Besides, these descriptors undergo interactions depending on disease, which may bias their computational analysis. In this paper, we aim at characterizing such interactions by unsupervised manifold learning. We propose to use a sparsified version of Multiple Manifold Learning to align the latent spaces encoding each descriptor and weighting the strength of the alignment depending on each pair of samples. While this framework was up to now only applied to link different datasets from the same manifold, we demonstrate its relevance to characterize the interactions between different but partially related descriptors of the cardiac function (shape and deformation). We benchmark our approach against linear and non-linear embedding strategies, among which the fusion of manifolds by Multiple Kernel Learning, the independent embedding of each descriptor by Diffusion Maps, and a strict alignment based on pairwise correspondences. We first evaluated the methods on a synthetic dataset from a 0D cardiac model where the interactions between descriptors are fully controlled. Then, we transfered them to a population of right ventricular meshes from 310 subjects (100 healthy and 210 patients with right ventricular disease) obtained from 3D echocardiography, where the link between shape and deformation is key for disease understanding. Our experiments underline the relevance of jointly considering shape and deformation descriptors, and that manifold alignment is preferable over fusion for our application. They also confirm at a finer scale the characteristic traits of the right ventricular diseases in our population.


Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2.
Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction. CYLD expression was dramatically upregulated in the cardiomyocytes of hypertrophic and failing human and murine hearts. Knockout of CYLD improved survival rate and alleviated cardiac hypertrophy, fibrosis, apoptosis, oxidative stress, and dysfunction in mice that were subjected to sustained pressure overload induced by transverse aortic constriction. Deep sequencing and gene array analyses revealed that the most dramatically changed genes are those involving in the free radical scavenging pathway and cardiovascular disease, including fos, jun, myc, and nuclear factor erythroid-2 related factor 2 (Nrf2) in the heart. Moreover, knockdown of CYLD enhanced mitogen-activated protein kinase (MAPK) ERK- and p38-mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes. The CYLD deficiency-induced suppression of reactive oxygen species (ROS) formation, death and hypertrophy in cardiomyocytes was blocked by additional knockdown of Nrf2. Taken together, our findings demonstrate for the first time that CYLD mediates cardiac maladaptive remodeling and dysfunction, most likely via enhancing myocardial oxidative stress in response to pressure overload. At the molecular level, CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart.


Lifetime risk of cardiometabolic mortality according to vitamin D status of middle and older-aged adults: NHANES III mortality follow-up.
The predictive value of total 25-hydroxyvitamin D (25(OH)D, a biomarker of vitamin D status) in relation to lifetime risk of cardiometabolic mortality is not known. The purpose of this study was to determine the association between standardized and annualized total 25(OH)D levels and lifetime risk for cardiometabolic mortality in middle- to older-aged adults. In this study, we followed up 7958 participants in the Third National Health and Nutrition Examination Survey from 1988 to 1994 (NHANES III) until the occurrence of cardiometabolic death or attainment of 95 years of age (median follow-up 17.9 years, 1371 cardiometabolic-deaths). Lifetime risks were estimated according to recommended total 25(OH)D cutoffs by national guidelines, and a combination of total 25(OH)D status and traditional risk factor burden. We also explored variation in lifetime risk estimates by levels of body mass index (BMI). The results of this study showed that annualized total 25(OH)D <30 nmol/L was associated with high lifetime risk of cardiometabolic mortality (40%). Lifetime risks of cardiometabolic mortality were similar for annualized levels between 30-< 50 nmol/L, 50-< 75 nmol/L and ≥75 nmol/L (31-33%). Lifetime risk was highest among participants with annualized total 25(OH)D <30 nmol/L and ≥2 major traditional risk factors (45%), whereas lifetime risk was lowest among participants with annualized 25(OH)D ≥30 nmol/L and low-intermediate risk factors (28%). Lifetime risk estimates were similar across BMI categories. In conclusion, a single measurement of vitamin D deficiency (annualized levels <30 nmol/L) in middle- to older-aged adults is a strong predictor of high lifetime risk for cardiometabolic mortality, particularly among those with high burden of traditional risk factors.


Spontaneous rupture of the spleen as the presenting feature of the blastoid variant of mantle cell lymphoma.
Spontaneous splenic rupture is rare, and particularly so as the initial presentation of a lymphoproliferative disorder. Although rare cases of splenic rupture have been reported in mantle cell lymphoma there has not been a report of the blastoid variant presenting in this manner. We report such a case in a 64-year-old man.


[Tubercular fibrosing conjunctivitis associated with facial cutaneous tuberculosis].
Tuberculous conjunctivitis has been described only rarely during the course of lupus vulgaris. We report a case of hemifacial cutaneous tuberculosis, diagnosed as atypical lupus vulgaris, associated with homolateral fibrosing tuberculous conjunctivitis. An 83-year-old woman presented inflammatory conjunctivitis without bullous involvement in the left eye leading to corneal neovascularisation, symblepharons and ptosis. Erythematous and atrophic papules were seen on the left side of the face. Biopsy of the skin and conjunctiva revealed a tuberculoid granulomatous infiltrate. Bacterial culture and PCR were both positive for Mycobacterium tuberculosis. This case illustrates the need to consider tuberculosis when faced with an atypical facial eruption and ocular involvement.


Reverse submandibular gland flap: An alternative for reconstruction of medium-sized oral defects.
Despite the development of microsurgery, local flaps still play an essential role in the reconstruction of head and neck defects. The submandibular gland flap (SMGF) has proven to be a reliable method for repairing medium-sized defects. It requires a shorter duration of general anesthesia and has fewer donor site complications compared to the free flap. However, the restricted vascular pedicle length limits its application. Retrograde flow is one solution. The authors describe a novel technique of using reverse submandibular gland flap (RSMGF) for the reconstruction of oral cavity defects. Additional vascular pedicle length was obtained by ligating the proximal end and dissecting the distal end of the facial vessels, thus extending its application range. The RSMGF is technically feasible and suitable for repairing medium-sized defects of the oral cavity (cT2 stage tumor) like buccal mucosa, especially for the elderly in poor general condition, for whom free flaps are not applicable.


Advances in processing of surface myoelectric signals: Part 2.
The paper focuses on the analysis of myoelectric evoked potentials and their progressive scaling, as well as morphological changes using orthogonal basis functions with essentially finite time support; and the compression of the information content using principal component analysis. The application of the Hermite-Rodriguez and the associated Hermite functions is discussed as a means to provide compact information about the shape of the M-wave or of the power spectral density function of either voluntary or electrically elicited myoelectric signals; a means to estimate scaling factors; and a means to describe and classify nonstationarities. The principal component analysis shows the possibility of a compression ratio of at least 10:1 in the storage of M-wave sequences. The paper also describes three methods for the estimation of delay between similar signals, and therefore for estimation of conduction velocity. They are based on normalised integrals. Fourier transform matching and matching in the time domain. In particular conditions they provide different results for the same pair of signals. The concept of delay and the performance of these methods are reviewed and discussed. The paper is not exhaustive. It has the main objective of making the reader aware of the wealth of methods available for nonstationary myoelectric signal analysis and conduction velocity estimation, and of the need to use them with knowledge of their respective advantages, disadvantages, peculiarities and limitations.


Reliability and validity of a Chinese computerized diagnostic instrument.
This paper reports on the development and testing of a new Chinese diagnostic instrument--the Adult Diagnostic Interview Schedule-Present (ADIS-P). This instrument uses a selection of items adapted from DIS and SADS. It is administered within approximately 25 min by a trained clinician using a small portable computer that provides an immediate diagnosis. The instrument was tested on 1,331 patients from six large mental hospitals across the country. The concurrent validity was good: compared to the concensus diagnosis of two senior clinicians (who were blinded to the ADIS-P result), the overall diagnostic accuracy was 83% and the weighted Kappa value was 0.60. The 1 month test-retest reliability was satisfactory (weighted Kappa = 0.55). We conclude that ADIS-P is a convenient, reliable and valid diagnostic instrument.


[Treatment of the acute diverticulitis: A systematic review].
Acute diverticulitis is a common disease with increasing incidence. In most of cases, diagnosis is made at an uncomplicated stage offering a curative attempt under medical treatment and use of antibiotics. There is a risk of diverticulitis recurrence. Uncomplicated diverticulitis is opposed to complicated forms (perforation, abscess or fistula). Recent insights in the pathophysiology of diverticulitis, the natural history, and treatments have permitted to identify new treatment strategies. For example, the use of antibiotics tends to decrease; surgery is now less invasive, percutaneous drainage is preferred, peritoneal lavage is encouraged. Treatments of the diverticulitis are constantly evolving. In this review, we remind the pathophysiology and natural history, and summarize new recommendations for the medical and surgical treatment of acute diverticulitis.


Stationary Distribution of Telomere Lengths in Cells with Telomere Length Maintenance and its Parametric Inference.
Telomeres are nucleotide caps located at the ends of each eukaryotic chromosome. Under normal physiological conditions as well as in culture, they shorten during each DNA replication round. Short telomeres initiate a proliferative arrest of cells termed 'replicative senescence'. However, cancer cells possessing limitless replication potential can avoid senescence by the telomere maintenance mechanism, which offsets telomeric loss. Therefore, cancer cells have sufficiently long telomeres even though their lengths are significantly shorter than their normal counterparts. This implies that the attrition and elongation rates play crucial roles in deciding whether and when cells ultimately become carcinogenic. In this research, we propose a concise mathematical model that shows the shortest telomere length at each cell division and prove mathematical conditions related to the attrition and elongation rates, which are necessary and sufficient for the existence of stationary distribution of telomere lengths. Moreover, we estimate the parameters of the telomere length maintenance process based on frequentist and Bayesian approaches. This study expands our knowledge of the mathematical relationship between the telomere attrition and elongation rates in cancer cells, which is important because the telomere length dynamics is a useful biomarker of cancer diagnosis and prognosis.


Hidden cargo: The impact of historical shipping trade on the recent-past and contemporary non-native flora of northeastern United States.
Understanding establishment and spread of non-native plants is important in the face of a homogenizing global flora. While many studies focus on successful, invasive species, fewer have studied failed plant introductions. Until the early 1900s, large quantities of ship ballast, often containing foreign plant propagules, were deposited in New Jersey (USA). The resulting ballast flora is documented in extensive herbarium records, providing us a unique opportunity to analyze successes and failures of novel plant species introductions. We used digitized specimens from 75 herbaria to study 264 non-native species introduced into New Jersey through 19th century ballast deposition. We used spatial (density-based clustering; HDBSCAN) and temporal analyses of species retention and geographic spread to quantify disappearance rate, survival, and dispersion through time and define trajectory groups. Four distinct trajectory groups were identified: waif (only present during import; 32% of species), short-term (disappeared quickly; 20%), established-limited spread (survives locally, 30%), and established-widespread (widespread, 18%). Species disappearance rate was highest during ballast deposition and decreased soon after deposition stopped around 1900. Spatial patterns showed a strong association with 19th century railroads for inland dispersal from ports. The disappearance rate and spatial analyses are robust to herbarium collection bias. This study using New Jersey as a model is one of the few documenting multispecies successes and failures in inadvertent plant introductions. Results reveal distinct trends in species establishment and geographic spread and highlight the utility of herbarium specimens in answering questions that span large time scales.


Telemedicine and Community Health Projects in Asia.
Telemedicine has the potential to deliver high-quality, affordable health care to underserved populations that otherwise would not have adequate access to care. The authors provide a snapshot of several telemedicine initiatives that have used information and communication technologies to connect patients with health care providers across various Asian countries with differing socioeconomic statuses. They highlight several factors thought to contribute to the success of telemedicine programs, such as financial sustainability, ease of use, and utilization of existing resources. Challenges these programs have faced include lack of technological infrastructure, limitations in funding, and conflicting health system priorities.


Effect of complexes of apolipoprotein A-I with tetrahydrocortisol and pregnenolone on protein biosynthesis in rat hepatocytes culture.
Complexes of apolipoprotein A-I with tetrahydrocortisol and pregnenolone exhibit high biological activity and increase the rate of protein biosynthesis in the culture of rat hepatocytes. An important role in this process is played by reduced delta44-3-keto group in the A-ring of steroid hormones. A complex of apolipoprotein A-I and pregnenolone modulated the rate of protein biosynthesis in liver cells. Hence, the observed changes are not organ-specific for this steroid. Our results suggest that this mechanism of regulation play an important role in intracellular regeneration and proliferation.


Photoaffinity-labeling peptide substrates for farnesyl-protein transferase and the intersubunit location of the active site.
--CAAX motif peptides, which are substrates for isoprenylation, were synthetically derivatized with the light-sensitive benzophenone (Bz) group in order to determine their potential use as catalytic site-directed covalent photocross-linking ligands for one of the enzymes catalyzing protein isoprenylation, farnesyl-protein transferase (FPTase). Bz-peptides could be synthesized with [3H]benzophenone and possessed eiter one or two benzophenone groups located at or near the peptide's NH2 terminus (e.g. the mono-Bz probes Bz-ACVIM and Bz-LPCVVM, and the di-Bz derivatized probe Bz-GY-(Bz)PCVVM, referred to as Bz2-GYPCVVM). Each type of derivatized peptide behaved as a substrate for farnesylation in vitro without irradiation, while under 366-nm irradiation each demonstrated covalent cross-linking ability as a catalytic site-directed photoaffinity ligand with tissue-purified or enriched but impure fractions from rat and bovine brain FPTase, as well as with a recombinant human FPTase variant, FPTase (beta alpha t) expressed in Escherichia coli. Without photoactivation, Bz-ACVIM yielded a Kd of 37 nM for the cloned variant of human FPTase. Pseudo first-order photolytic inhibition of FPTase preparations with Bz-peptides, as well as protection from photoinactivation by unmodified -CAAX motif peptides, supported the capacity of these Bz-peptides to serve as co-substrates and their specificity for seeking the catalytic site of the enzyme. SDS-polyacrylamide gel electrophoresis analysis subsequent to photolysis indicated that the mono-Bz-derivatized peptides (e.g. [3H]Bz-LPCVVM or 3H]Bz-ACVIM) became covalently cross-linked preferentially to the approximately 49-kDa beta subunit of the alpha beta dimeric FPTase. The farnesyl-PP cosubstrate bound equally well to unmodified and Bz-ACVIM-labeled enzyme. The di-Bz derivative, [3H]Bz2-GYPCVVM, in contrast, revealed exclusive photocovalent cross-linking with a species of molecular mass approximately 95-97 kDa, indicating that both FPTase subunits were tethered together covalently by the di-Bz probe. Similar differential SDS-polyacrylamide gel electrophoresis cross-linking patterns were obtained with homogeneous FPTases as well as with partially purified rat or bovine brain enzyme preparations. The absence of nonspecific photolabeling of any proteins in the partially purified rat or bovine brain enzyme preparations other than FPTase independently attested to the high efficiency of photocross-linking of the FTPase, and the selective catalytic site-seeking ability of these Bz-derivatized peptide substrates, verifying their potential as structural probes for the active site domain on the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)


Thermal acclimation in the perch (Perca fluviatilis L.) immunity.
Fish immune systems must be able to cope with pathogens over a wide temperature range. Earlier research suggest that fish are more dependent on innate immune responses based on pattern recognition than acquired functions with specific recognition. If this applies to phagocytes, then opsonins (serum factors that augment phagocytosis e.g. immunoglobulins and complement proteins) attached on zymosan (Z) particles should be recognized better at higher temperatures than Z only. Z is recognized by glucan receptor representing pattern recognition. In this study perch were acclimated to 5 °C or 16 °C for 3-5 weeks. The recognition and activation of respiratory burst reaction of peripheral blood phagocytes was examined at seven different measurement temperatures (5, 10, 16, 20, 24 27, and 30 °C) when the cells were stimulated with Z and serum opsonized zymosan (OZ). Respiratory burst was measured as luminol chemiluminescence (CL) from diluted whole blood. OZ-induced CL per volume of blood was on average approximately 4.6 times higher in 16 °C acclimated fish than 5 °C acclimated perch (P<0.0001). Z-induced CL was approximately 3 times higher at lower temperatures in 16 °C acclimated perch than 5 °C acclimated fish and 6-9 times higher at 27 °C and 30 °C (P<0.001), respectively. CL reaction kinetics were faster in perch acclimated to 5 °C than 16 °C -acclimated fish, especially at low temperatures (P<0.001). Thermal acclimation caused a 3-4 °C shift in temperature response curves of CL towards the acclimation temperature (P<0.0001 and P<0.053 in Z and OZ-induced CL, respectively). Serum opsonins activated perch phagocytes substantially better at higher temperatures in both acclimation groups, which is consistent with an earlier study in rainbow trout (O. mykiss). However, opsonin recognition was significantly better in 16 °C acclimated perch than 5 °C acclimated fish, which was seen as higher CLs for OZ compared to Z, especially at higher temperatures. This is opposite to previously reported results in rainbow trout. Differences between rainbow trout and perch in opsonin recognition by blood phagocytes suggest that the living habits of perch, which prefers approximately a 10 °C higher temperature than rainbow trout, may be reflected in immune cell functions. Results of the present examination suggest that also in fish phagocytes pattern recognition is the prevailing system at low temperatures, and specific recognition is more effective at high temperatures.


Relationship between intraneural vascular flow measured with sonography and carpal tunnel syndrome diagnosis based on electrodiagnostic testing.
The purpose of this study was to document and analyze intraneural vascular flow within the median nerve using power and spectral Doppler sonography and to determine the relationship of this vascular flow with diagnosis of carpal tunnel syndrome based on electrodiagnostic testing. Power and spectral Doppler sonograms in the median nerve were prospectively collected in 47 symptomatic and 44 asymptomatic subjects. Doppler studies were conducted with a 12-MHz linear transducer. Strict inclusion criteria were established for postexamination assessment of waveforms; routine quality assurance was completed; electrodiagnostic tests were conducted on the same day as sonographic measurements; and the skin temperature was controlled. Included waveforms were categorized by location and averaged by individual for comparative analysis to electrodiagnostic testing. A total of 416 waveforms were collected, and 245 were retained for statistical analysis based on strict inclusion criteria. The mean spectral peak velocity among all waveforms was 4.42 (SD, 2.15) cm/s. At the level of the pisiform, the most consistent data point, mean peak systole, was 3.75 cm/s in symptomatic patients versus 4.26 cm/s in asymptomatic controls. Statistical trending showed an initial increase in the mean spectral peak velocity in symptomatic but diagnostically negative cases, with decreasing velocity as diagnostic categories progressed from mild to severe. An inverse relationship may exist between intraneural vascular flow in the median nerve and an increasing severity of carpal tunnel syndrome based on nerve conduction results. Randomized controlled trials are needed to determine whether spectral Doppler sonography can provide an additive benefit for diagnosing the severity of carpal tunnel syndrome.


Detection of SARS-CoV-2 in tissue: the comparative roles of RT-qPCR, in situ RNA hybridization, and immunohistochemistry.
The emergence of SARS-CoV-2, the causative agent the COVID-19 pandemic, has led to a rapidly expanding arsenal of molecular diagnostic assays for the detection of viral material in tissue specimens. We review the value and shortcomings of available tissue-based assays for SARS-CoV-2 detection in formalin-fixed paraffin-embedded (FFPE) tissue, including immunohistochemistry, in situ hybridization, and quantitative reverse transcription PCR (RT-qPCR). The validation, accuracy, and comparative utility of each method is discussed. Subsequently, we identify commercially available antibodies which render the greatest specificity and reproducibility of staining in FFPE specimens. We offer expert opinion on the efficacy of such techniques and guidance for future implementation, both clinical and experimental.


Selective deposition of dietary α-lipoic acid in mitochondrial fraction and its synergistic effect with α-tocoperhol acetate on broiler meat oxidative stability.
The use of bioactive antioxidants in feed of broiler to mitigate reactive oxygen species (ROS) in biological systems is one of promising nutritional strategies. The aim of present study was to alleviate ROS production in mitochondrial fraction (MF) of meat by supplemented dietary antioxidant in feed of broiler. For this purpose, mitochondria specific antioxidant: α-lipoic acid (25 mg, 75 mg and 150 mg) with or without combination of α-tocopherol acetate (200 mg) used in normal and palm olein oxidized oil (4%) supplemented feed. One hundred and eighty one day old broiler birds were randomly divided into six treatments and provided the mentioned feed from third week. Feed intake, feed conversion ratio (FCR) remained statistically same in all groups while body weight decreased in supplemented groups accordingly at the end of study. The broiler meat MF antioxidant potential was significantly improved by feeding supplemented feed estimated as 1,1-di phenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, 2,2-azinobis-(3- ethylbenzothiazoline-6-sulphonic acid) (ABTS+) and thiobarbituric acid reactive substances (TBARS). The maximum antioxidant activity was depicted in group fed on 150 mg/kg α-lipoic acid (ALA) and 200 mg/kg α-tocopherol acetate (ATA) (T4) in both breast and leg MF. Moreover, TBARS were higher in leg as compared to breast MF. Although, oxidized oil containing feed reduced the growth, lipid stability and antioxidant potential of MF whilst these traits were improved by receiving feed containing ALA and ATA. ALA and ATA showed higher deposition in T4 group while least in group received oxidized oil containing feed (T5). Positive correlation exists between DPPH free radical scavenging activity and the ABTS + reducing activity. In conclusion, ALA and ATA supplementation in feed had positive effect on antioxidant status of MF that consequently diminished the oxidative stress in polyunsaturated fatty acid enriched meat.


The Complete Genome Sequences of 19 Species of Snipes (Scolopacidae, Charadriiformes, Aves).
We present the complete genome sequences of 19 species of snipes from 7 genera. Illumina sequencing was performed on genetic material from museum specimens. The reads were assembled using a de novo method followed by a finishing step. The raw and assembled data are publicly available via Genbank.


Variable reduction in Norrin signaling activity caused by novel mutations in FZD4 identified in patients with familial exudative vitreoretinopathy.
To identify novel mutations in FZD4 and to investigate their pathogenicity in a cohort of Chinese patients with familial exudative vitreoretinopathy (FEVR). Next-generation sequencing was performed in patients with a clinical diagnosis of FEVR. Wide-field angiography was performed in probands and family members if available. Clinical data were collected from patient charts. The effect of the mutations in FZD4 on its biologic activity in the Norrin/β-catenin signaling pathway was analyzed with the luciferase reporter assay. Four novel mutations in FZD4 (c.1188_1192del/p.F396fs, c.1220delC/p.A407Vfs*24, c.905G>A/p.C302Y, c.1325T>A/p.V442E) were identified in four unrelated families. The mutations were not detected in 200 healthy individuals. The variability of the ocular phenotypes was not only observed in the probands and parents harboring the same mutation but also between two eyes in one individual. All four novel mutations introduced reduction in luciferase activity. Compared with the wild-type, the FZD4 level of the four mutants also decreased variably. Four novel mutations in FZD4 were identified in Chinese patients with FEVR. No correlation in the reduced luciferase activity and the ocular phenotype was observed in this study. This study further emphasized the complexity of the FEVR-causing machinery.


Pamidronate is effective for Paget's disease of bone refractory to conventional therapy.
Paget's disease of bone is characterized by primary osteoclastic dysfunction and prolonged treatment with conventional medications including calcitonin and etidronate, results in a number of patients becoming refractory to treatment. We have evaluated the effectiveness of three dosage regimes of aminohydroxypropylidene bisphosphonate (pamidronate) in 15 patients with extensive Paget's disease who had become refractory to conventional therapy. Nine patients had pamidronate (intravenous infusion of 30 mg over 4-5 hours at monthly intervals) for 6 months. A further four patients received 30 mg of pamidronate infusion daily for 6 consecutive days and another two patients, 60 mg on 3 consecutive days (total dose of 180 mg/patient). In all three groups the bone-specific alkaline phosphatase and urinary hydroxyproline excretion both fell by 75% (P < 0.001). All but one patient showed a marked improvement in clinical symptomatology (pain and mobility) and biochemical parameters indicating decreased bone turnover. Remissions achieved (> 12 months) with all three regimens were comparable. The pagetic bone pain was reduced and the mobility was significantly improved after 3 months of therapy and was continued for up to 1 year. Currently, it may be difficult to justify the use of intravenous bisphosphonate as the first line of therapy for Paget's disease, but it does seem to have a definite place in patients with severe Paget's disease who do not respond to other therapeutic agents. Here we demonstrate that pamidronate is highly effective in patients with extensive Paget's disease who became refractory to conventional treatment. Further studies are necessary to optimize the dosage and frequency of administration of pamidronate.


Comparison of corneal measurements in normal and keratoconus eyes using Anterior Segment Optical Coherence Tomography (AS-OCT) and Pentacam HR topographer.
Keratoconus (KC) is easily recognized by its unique topographic pattern, but it can be difficult to distinguish subclinical form of the disease from the normal cornea. Optovue anterior segment optical coherence tomography (AS-OCT) helps diagnose KC. To assess and the level of agreement of Keratometry-readings (K), Central Corneal Thickness (CCT) and Thinnest Corneal Thickness (TCT) measurements obtained by Optovue AS-OCT and Wavelight Oculyzer Pentacam HR in two groups: KC eyes and normal eyes. This is a prospective clinical observational study. The study included 110 eyes divided into two groups. The study group included 62 eyes with topographic evidence of KC. The control group included 48 eyes of normal subjects with no topographic evidence of KC. All of the participants underwent full cycloplegic refraction, spectacle best-corrected distance visual acuity, comprehensive slit-lamp biomicroscopy and fundoscopy. All participants underwent corneal topography by Pentacam HR and AS-OCT. There were highly significant differences between the studied groups as regarding BCVA, intraocular pressure and CCT measurements which were found to be lower among KC group compared to the control one. There were highly significant differences between the studied groups regarding TCT measurement detected by Pentacam HR and AS-OCT which was found to be lower among the keratoconus group compared to the control one (470.9, 455.7 versus 541.9 and 518.7 respectively). Both Scheimpflug-based imaging and AS-OCT provide comparable readings with a good agreement regarding corneal pachymetry in keratoconus group with accurate identification of KC eyes and healthy ones. However, there was a significant difference in K readings between both devices in Keratoconus and control group.


Additional vinyl ketones and their pyranyl ketones in gonyleptid harvestmen (Arachnida: Opiliones) suggest these metabolites are widespread in this family.
Four species of gonyleptid harvestmen, Acanthogonyleptes pulcher, Gonyleptes saprophilus (Gonyleptinae), Sodreana barbiellini, and Sodreana leprevosti (Sodreaninae), were examined by GC-MS and ¹³H NMR. All of these species release vinyl ketones, and three of them produce the corresponding pyranyl ketones, which are presumed hetero-Diels-Alder (HDA) dimers. The vinyl ketones 5-methyl-1-hexen-3-one, rac-4-methyl-1-hexen-3-one, and (S)-4-methyl-1-hexen-3-one were synthesized. Natural 4-methyl-1-hexen-3-one is present as a single stereoisomer and has the R-configuration. Vinyl ketone dimers (HDA dimers) were also observed in the scent gland exudate and characterized by HRMS, ¹³C NMR, and ¹H NMR chemical shifts of the pyranyl moiety.


MR imaging of coarctation of the aorta and its postoperative complications in adults: assessment with spin-echo and cine-MR imaging.
To evaluate the ability of ECG-gated spin-echo (SE)-MR imaging vs. cine-MR imaging to assess coarctation of the aorta, 11 patients aged 15-45 years, with known or suspected coarctation of the aorta, and five patients suspected of re-stenosis or postoperative false-aneurysms after coarctation repair were examined by multisection SE-MR imaging and single-section multiphase cine-MR imaging on a 1.0 Tesla device. Aortography was performed in 15, and surgery in 14 of these 16 patients. Qualitatively, the location, severity, and length of the coarctation were shown in all cases with MR imaging, as well as the relationship with the arteries arising from the aortic arch. The respective sensitivities and specificities in the assessment of severity of stenoses were 86% and 100% for SE MR images, and 100% and 100% for cine-MR images. Cine-MR imaging was superior to SE imaging in stenosis diameter assessment with contrast angiography as reference, as well as to identify the site of leakage in cases of postoperative pseudoaneurysm. Pre-stenotic dilation or post-stenotic aneurysm, collateral channels, and associated malformations were better identified on SE images. Quantitatively, a better stenosis diameter correlation was found between cine-MR images and angiography than between SE-MR images and angiography (r=0.99 vs. r=0.78; p=0.001 vs. p=0.004), related to overestimation of stenoses with SE-MR imaging. The use of a combination of spin-echo and cine-MR imaging correlates well with conventional angiographic findings in this small series of patients with coarctation of aorta or postoperative pseudoaneurysmal complications. Cine-MRI can provide anatomic information that is equivalent to angiography for surgical planning.


Interactions between lead(II) ions and dissolved organic matter derived from organic fertilizers incubated in the field.
This work was to study composition characteristics and the subsequent effect on the lead (Pb) binding properties of dissolved organic matter (DOM) derived from seaweed-based (SWOF) and chicken manure organic fertilizers (CMOF) during a one-year field incubation experiment using the excitation-emission matrix-parallel factor (EEM-PARAFAC) and two-dimensional correlation spectroscopy (2DCOS) analysis. Results showed that high aromatic and hydrophobic fluorescent substances were enriched in CMOF-derived DOM and SWOF-derived DOM and enhanced over time. And phenolic groups in the fulvic-like substances for SWOF-derived DOM and carboxyl groups in the humic-like substances for CMOF-derived DOM had the fastest responses over time, respectively. Moreover, both non-fluorescent polysaccharides and fluorescent humic-like substances or fulvic-like substances with aromatic (C=C) groups first participated in the binding process of Pb to SWOF-derived DOM on day 0 and 180 during the lead binding process. In contrast, humic-like substances associated with aromatic (C=C) and phenolic groups gave a faster response to Pb binding on day 360. Regarding CMOF-derived DOM, the fulvic-like substances associated with aromatic (C=C) and carboxylic groups displayed a faster response to Pb ions on day 0. Nonetheless, polysaccharides and humic-like associated with phenolic groups had a faster response on days 180 and 360. It is noteworthy that the polysaccharides, which participated in Pb binding to CMOF-derived DOM, posed a higher risk of Pb in the environment after 360 days. Therefore, these findings gave new insights into the long-term applications of commercial organic fertilizers for the amendment of soil.


Rebuilding MTOCs upon centriole loss during mouse oogenesis.
The vast majority of animal cells contain canonical centrosomes as a main microtubule-organizing center defined by a central pair of centrioles. As a rare and striking exception to this rule, vertebrate oocytes loose their centrioles at an early step of oogenesis. At the end of oogenesis, centrosomes are eventually replaced by numerous acentriolar microtubule-organizing centers (MTOCs) that shape the spindle poles during meiotic divisions. The mechanisms involved in centrosome and acentriolar MTOCs metabolism in oocytes have not been elucidated yet. In addition, little is known about microtubule organization and its impact on intracellular architecture during the oocyte growth phase following centrosome disassembly. We have investigated this question in the mouse by coupling immunofluorescence and live-imaging approaches. We show that growing oocytes contain dispersed pericentriolar material, responsible for microtubule assembly and distribution all over the cell. The gradual enlargement of PCM foci eventually leads in competent oocytes to the formation of big perinuclear MTOCs and to the assembly of large microtubule asters emanating from the close vicinity of the nucleus. Upon meiosis resumption, perinuclear MTOCs spread around the nuclear envelope, which in parallel is remodelled before breaking-down, via a MT- and dynein-dependent mechanism. Only fully competent oocytes are able to perform this dramatic reorganization at NEBD. Therefore, the MTOC-MT reorganization that we describe is one of key feature of mouse oocyte competency.


Metabolic regulation of trisporic acid on Blakeslea trispora revealed by a GC-MS-based metabolomic approach.
The zygomycete Blakeslea trispora is used commercially as natural source of â-carotene. Trisporic acid (TA) is secreted from the mycelium of B. trispora during mating between heterothallic strains and is considered as a mediator of the regulation of mating processes and an enhancer of carotene biosynthesis. Gas chromatography-mass spectrometry and multivariate analysis were employed to investigate TA-associated intracellular biochemical changes in B. trispora. By principal component analysis, the differential metabolites discriminating the control groups from the TA-treated groups were found, which were also confirmed by the subsequent hierarchical cluster analysis. The results indicate that TA is a global regulator and its main effects at the metabolic level are reflected on the content changes in several fatty acids, carbohydrates, and amino acids. The carbon metabolism and fatty acids synthesis are sensitive to TA addition. Glycerol, glutamine, and ã-aminobutyrate might play important roles in the regulation of TA. Complemented by two-dimensional electrophoresis, the results indicate that the actions of TA at the metabolic level involve multiple metabolic processes, such as glycolysis and the bypass of the classical tricarboxylic acid cycle. These results reveal that the metabolomics strategy is a powerful tool to gain insight into the mechanism of a microorganism's cellular response to signal inducers at the metabolic level.


Autoreactivity and altered immune responses in inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a poorly understood condition that is associated with a wide variety of immunologic alterations. Because its pathogenesis is unknown, these immunologic alterations have been investigated with an eye toward unraveling the complex mechanism of injury in the bowels of these patients. There are several lines of evidence suggesting that IBD is related to immunologic events. The histopathology of active disease resembles the Arthus reaction, whereas the presence of antiepithelial cell antibodies is reminiscent of Goodpasture's disease. Antibodies against many microorganisms and autoantibodies to mucosal components are commonly found in these patients. Further, there is a marked increase in plasma cells in the lamina propria of patients with active IBD. It is important to keep these findings in perspective. No studies to date have been able to determine whether the features are entirely primary events, that is, related to the initial damage to the intestinal mucosa. If the surface mucosa is injured by an as-yet-unidentified agent, the immunologic findings in IBD may be secondary events. Nonetheless, the similarity in histopathology of the experimental immunologic models of IBD to the human disease encourages investigators to pursue the etiology of this complex disease.


Persistent Viral Presence Determines the Clinical Course of the Disease in COVID-19.
The clinical management of coronavirus disease 2019 (COVID-19) is dependent on understanding the underlying factors that contribute to the disease severity. In the absence of effective antiviral therapies, other host immunomodulatory therapies such as targeting inflammatory response are currently being used without clear evidence of their effectiveness. Because inflammation is an essential component of host antiviral mechanisms, therapies targeting inflammation may adversely affect viral clearance and disease outcome. To understand whether the persistent presence of the virus is a key determinant in the disease severity during COVID-19 and to determine whether the viral reactivation in some patients is associated with infectious viral particles. The data for patients were available including the onset of the disease, duration of viral persistence, measurements of inflammatory markers such as IL-6 and C-reactive protein, chest imaging, disease symptoms, and their durations among others. Follow-up tests were performed to determine whether the viral negative status persists after their recovery. Our data show that patients with persistent viral presence (>16 days) have more severe disease outcomes including extensive lung involvement and requirement of respiratory support. Two patients who died of COVID-19 were virus-positive at the time of their death. Four patients demonstrated virus-positive status on the follow-up tests, and these patient samples were sent to viral culture facility where virus culture could not be established. These data suggest that viral persistence is the key determining factor of the disease severity. Therapies that may impair the viral clearance may impair the host recovery from COVID-19.


Laccase-Catalyzed Heterocoupling of Dihydroquercetin and p-Aminobenzoic Acid: Effect of the Reaction Product on Cultured Cells.
Derivatization of the natural flavonoid dihydroquercetin with p-aminobenzoic acid was carried out in an ethyl acetate/citric buffer biphasic system using laccase from the fungus Trametes hirsuta. The main reaction product yield was ~68 mol %. The product was characterized by 1H NMR, 13C NMR, and liquid chromatography-mass spectroscopy, and its structure was elucidated. The reaction product affected viability of cultured human rhabdomyosarcoma cells (RD cell line) in a dose-dependent manner and, therefore, can be of interest to pharmaceutical industry.


Synthesis, stereochemical assignment, and enantioselective catalytic activity of late transition metal planar chiral complexes.
Planar chirality is an important form of molecular chirality that can be utilized to induce enantioselectivity when incorporated into transition metal catalysts. However, due to synthetic constraints, the use of late transition metal planar chiral complexes to conduct enantioselective transformations has been limited. Additionally, the published methods surrounding the stereochemical assignment of planar chiral compounds are sometimes conflicting, making proper assignment difficult. This review aims to provide clarity on the methods available to assign planar chirality and provide an overview on the synthesis and use of late transition metal planar chiral complexes as enantioselective catalysts.


Mitochondrial evolution: Gene shuffling, endosymbiosis, and signaling.
Genes for cardiolipin and ceramide synthesis occur in some alphaproteobacterial genomes. They shed light on mitochondrial origin and signaling in the first eukaryotic cells.


Long-Term Treatment with Olanzapine in Hospital Conditions: Prevalence and Predictors of the Metabolic Syndrome.
The risk of metabolic abnormalities is greatly increased in schizophrenic patients started on an atypical antipsychotic medication. Patients with psychiatric disorders exceed mortality ranges resulting from, among others, increased risk of cardiovascular events. Other factors contributing to the development of metabolic syndrome include prolonged duration of illness, increasing age, female sex and lifestyle factors. OBJECTIVE This cross-sectional study was taken up to assess the prevalence of the metabolic syndrome (MetS) in schizophrenic patients receiving olanzapine monotherapy for at least six months and to determine the most important risk factors associated with metabolic syndrome presence in these patients. METHODS A total of 93 long term hospitalized schizophrenic patients (71 men, 22 women), had a screening of the following: case-history data, psychiatric scales, anthropometric measures, blood (fasting glucose, lipid status, C-reactive protein--CRP) and urine samples (microalbuminuria). Prevalence of MetS according to International Diabetes Federation criteria in our study was 34.4%. The multivariate analysis distinguished the following significant predictors of MetS presence (in order of appearance): data about diabetes mellitus in family history (p = 0.002), body mass index > 25 kg/m2 (p = 0.002), hyperlipidemia in family history (p = 0.008), and elevated CRP value (p = 0.042). High rate of MetS in patients treated with olanzapine in this study exceeds MetS prevalence in general population. Among observed parameters, our study pointed to several "high risk" predictors associated with MetS presence. Regular monitoring of cardiometabolic risk factors is highly recommended. Positive heredity distress mentioned above may direct a psychiatrist to prescribe some other drug than olanzapine in the long term treatment of schizophrenia.


Isolation and characterization of orbivirus genotypic variants.
Orbivirus variants containing either RNA deletions or concatemeric RNAs have been isolated. A variant of Ibaraki virus (a member of the epizootic hemorrhagic disease of deer serogroup) contained an RNA 9 segment which had terminal sequences identical to RNA 9 of wild type virus but was approximately 140 base pairs (bp) shorter. In vitro translation showed that whereas RNA 9 of wild type virus generated the minor structural protein VP6 (molecular weight 38 K), the variant RNA 9 coded for a 32 K protein. Analysis of hybrid molecules formed after melting and reannealing mixtures of [32P]-pCp-labeled wild type and variant RNA 9 molecules indicated that generation of variant RNA 9 may have involved the loss of approximately 150 bp at a location 148 bp from one end of the wild type RNA molecule. Analysis of minor proteins generated by premature termination during in vitro translation of wild type and variant RNA 9 suggested that the deletion occurred towards the 3' end of the positive strand of wild type RNA 9. RNA genome segments 10 and 9 of bluetongue virus type 21 and Bunyip Creek (a Palyam serogroup member) respectively, were observed to form concatemers. Molecular weight estimates and T1 RNase mapping suggested that the concatemers were dimers in a 5'-3' to 5'-3' orientation. In vitro translation of dimeric RNAs yielded products apparently identical to those generated by monomeric RNAs. The possible ramifications of these results with respect to orbivirus evolution are discussed.


Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study.
Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan that acts on different receptors (e.g. those of N-methyl-D-aspartate (NMDA) and presynaptic α7 nicotinic acetylcholine (nACh)), exerts fundamentally antiglutamatergic effects. In view of its antiglutamatergic properties, an elevation of the KYNA level within the brain might result in neuroprotection. However, the use of KYNA as a neuroprotective agent is rather limited, because it crosses the blood-brain barrier (BBB) to only a poor extent. During recent years, new KYNA derivatives have been developed which can readily traverse the BBB and also exert neuroprotection. However, as KYNA and its derivatives are able to interfere with glutamatergic and cholinergic transmission, the potential risks of interfering with cognitive functions cannot be excluded. This in vivo study on anesthetized rats therefore tested the effects of the administration of KYNA and a KYNA derivative (SZR72) (in a dosage that exerted neuroprotection) on long-term potentiation (LTP) and pure field excitatory postsynaptic potentials induced by contralateral CA3 region stimulation and recorded in the pyramidal layer of the CA1 region of the hippocampus. Surprisingly, KYNA and this derivative did not reduce, but rather increased the induceability of LTP. The possible explanation is discussed in detail. In brief: an elevated KYNA level in the perisynaptic area produced, for example, by exogenous prodrug or derivative administration exerts preferential effects on the extrasynaptic NMDA receptors and the nACh receptors on presynaptic glutamatergic terminals, while sparing the currents mediated by synaptic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors. This might be the explanation why the treatment with the prodrug of KYNA or the KYNA derivative in a dosage which induced neuroprotection did not reduce the cognitive functions or the LTP.


Synthesis of hierarchically porous structured CaCO3 and TiO2 replicas by sol-gel method using lotus root as template.
Intensive attention has been put in mimicking the morphologies in nature owing to their uniqueness, complexity, and diversity. One of the effective approaches to mimic bio-morphologies is through biotemplating - the technique of using biological structures as template to reproduce intricate structure in other forms of materials. This work presents a facile sol-gel technique that can be widely used to convert various carbon-rich bio-structures into different materials. Lotus root, a biomorphic template with high porosity at varying length scales, was selected as the example to demonstrate this approach. The experiment was conducted by infiltrating precursors - titanium (IV) n-butoxide (TnBT) and acetic acid calcium solution - into the lotus root template under vacuum system, followed by calcination. After the treatment, the replicas were calcite CaCO3 and anatase TiO2. In both CaCO3 and TiO2 replicas, the intact structure of the template was preserved. In spite of the overall similarity of the CaCO3 and TiO2 lotus root replicas, some respective differences were found. TiO2 replica was covered with nanowire bundles of 100-200nm in diameter, formed by preferable crystallization of particles, while CaCO3 replica presented the gradient-distributed pores of 10-100μm, which greatly resembled the microstructure of lotus root template. In the BET result, TiO2 replica was mesoporous structure with pores centralizing in 3-4nm. On the other hand, CaCO3 replica had pores in a wider distribution ranging from micro to macro scale. In addition, the surface area was greatly enhanced in both cases. The synthesized materials with hierarchical biomorphic structures may have great potential for purification applications due to their large specific surface area, photocatalytic property, and high adsorption rate.


Genetic analysis of the bicarbonate secreting anion exchanger SLC26A6 in chronic pancreatitis.
Pancreatic ductal HCO3(-) secretion is critically dependent on the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) and the solute-linked carrier 26 member 6 anion transporter (SLC26A6). Deterioration of HCO3(-) secretion is observed in chronic pancreatitis (CP), and CFTR mutations increase CP risk. Therefore, SLC26A6 is a reasonable candidate for a CP susceptibility gene, which has not been investigated in CP patients so far. As a first screening cohort, 106 subjects with CP and 99 control subjects with no pancreatic disease were recruited from the Hungarian National Pancreas Registry. In 60 non-alcoholic CP cases the entire SLC26A6 coding region was sequenced. In the Hungarian cohort variants c.616G > A (p.V206M) and c.1191C > A (p.P397=) were further genotyped by restriction fragment length polymorphism analysis. In a German replication cohort all exons were sequenced in 40 non-alcoholic CP cases and variant c.616G > A (p.V206M) was further analyzed by sequencing in 321 CP cases and 171 controls. Sequencing of the entire coding region revealed four common variants: intronic variants c.23 + 78_110del, c.183-4C > A, c.1134 + 32C > A, and missense variant c.616G > A (p.V206M) which were found in linkage disequilibrium indicating a conserved haplotype. The distribution of the haplotype did not show a significant difference between patients and controls in the two cohorts. A synonymous variant c.1191C > A (p.P397=) and two intronic variants c.1248 + 9_20del and c.-10C > T were detected in single cases. Our data show that SLC26A6 variants do not alter the risk for the development of CP.


Safe hemostasis by application of a new strict graft inclusion technique for replacement of the aortic root.
Bleeding from a coronary anastomosis and aortic annulus is sometimes a problem in the technique for aortic root replacement described by Bentall and DeBono and Cabrol and colleagues. Exposure and repair of these suture lines may be quite difficult after the termination of bypass. This article describes a new technique for aortic root replacement. In our experience to date, 6 patients with aneurysm of the ascending aorta and root and a calcified aortic valve stenosis as well as 1 patient with aortic dissection type A have benefited from this new procedure.


Palladium nanoparticles synthesis, characterization using glucosamine as the reductant and stabilizing agent to explore their antibacterial & catalytic applications.
Low cost and an easy technique for the synthesis of palladium nanoparticles (PdNPs) was developed. Glucosamine was used to stabilize palladium precursor (PdCl2) into palladium nanoparticles. Several analytical techniques were used for the determination of morphology, crystalline structure; size, capping, and composition of synthesize palladium nanoparticles. The UV-visible spectroscopy SPR peak (Surface Plasmon Resonance) at 284 nm revealed synthesis of PdNPs. Energy dispersive X-ray (EDX) and X-ray diffraction (XRD) studies proved the elemental composition and crystalline structure of the synthesized palladium nanoparticles respectively. The average particle sizes (5.5 nm) were obtained by using the 1 M glucosamine solution, with a fixed amount of PdCl2 (4 mM). Moreover, the as synthesized PdNPs was evaluated against Gram negative bacterial E. which shows tremendous antibacterial activity as compare to tobramycin standard antibiotics. It's mechanistically found that PdNPs damage cell membrane and caused imbalance of metabolism system of the cell as a result production of reactive oxygen species (ROS). Thus, these finding revealed that cells become leaky and all organelles come out from cells, finally caused death of the E. coli. Addition, the as prepared PdNPs also showed excellent catalytic activities toward reduction of methylene blue and 4-nitrophenol.Thus, glucosamine mediated PdNPs having dual functions biomedical as well as intoxicating catalyst for industries.


Trophoblast concept as applied to therian mammals.
Available evidence provides little support for a recent proposal that the term "trophoblast" be applied solely to eutherian mammals. Arguments for such a restricted usage are based on a dichotomous interpretation of therian reproduction that underestimates the developmental, structural, and functional diversity of trophoblastic tissues occurring within the infraclass Eutherian. The occurrence of developmental patterns that are phenotypically intermediate between those of commonly studied eutherians and metatherians suggests that blastocyst development is not fundamentally different in marsupials and eutherians. The trophoblast of marsupials accomplishes most or all of the major functions of the eutherian trophoblast, including maternal-fetal physiological exchange, implantation, contribution to placental membranes, steroid metabolism, and possibly, immunological protection of the conceptus. Furthermore, application of the term "trophoblast" to marsupials is consistent with present and past usage, as well as with the original definition and etymological derivation of the term. Therefore, we recommend that the term "trophoblast" continue to be applied in a functional-morphological sense to the appropriate extraembryonic tissues of marsupials. Such use of functional (rather than taxonomic) criteria for application of this term avoids biasing interpretations of mammalian reproductive evolution.


The organic matrix of urinary uric acid crystals.
We have demonstrated that urinary uric acid crystals contain an organic matrix within the crystalline boundaries, morphologically similar to that of uric acid stones. Among several glycosaminoglycans in urine, heparan sulfate was almost exclusively identified in this matrix, as in that of uric acid stones. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that several proteins in urine were incorporated in this matrix on a selective basis; two of which were albumin and Tamm-Horsfall mucoprotein. An affinity of uric acid or urate for selective urinary macromolecules in a liquid phase was supposed to be the origin of this matrix. But the proteins in the uric acid stone matrix were not separated by SDS-PAGE. Therefore we could not conclude whether the organic matrix of urinary uric acid crystals is similar to that of uric acid stones.


Viral prevalence and laboratory investigations of gastroenteritis in institutions for dependent people.
Viruses are recognized as important agents of gastroenteritis outbreaks in institutions caring for dependent people. We aimed to define norovirus (NoV) and rotavirus (RV) immunochromatographic tests (ICT) and reverse transcription-polymerase chain reaction (RT-PCR) used in gastroenteritis investigations. Fourteen sites were monitored from 2010 to 2015, with 360 laboratory investigations. Twenty-two outbreaks and 44 sporadic case patients were investigated with ICTs (114 NoVs and 80 RVs) and RT-PCRs (114 NoVs and 52 RVs). ICTs were useful during outbreaks (identification of NoVs and RVs in respectively 76.5% and 75.0% of episodes) despite the NoV sensitivity limit (55.1%) and the four RV false positive results observed for 10 samples. Given the NoV ICT performance and the observed variations of the NoV and RV prevalence (between 20.0% and 5.0%), ICTs are not appropriate to identify sporadic gastroenteritis case patients. Positive predictive values <60.0% were observed when the prevalence of RV and NoV was low (<5.0%). NoV and RV RT-PCR indications are sporadic gastroenteritis case patients, negative NoV and RV ICT during outbreaks, control of positive RV ICT in cases of suspected NoV and RV co-circulation, patients with long symptom duration, and NoV genogroup and genotype identifications (infection control and epidemiological surveillance). Inclusion of patients with specific clinical symptoms is recommended irrespective of the technique. On the basis of the ICT limits identified in this work, RT-PCR development seems essential to improve viral gastroenteritis investigations in institutions caring for dependent people.


Functional relationship between CgMyD88-1 and CgMyD88-2 in the Pacific oyster.
MyD88 is a universal adapter protein for the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling pathway. Since invertebrates are believed to lack MyD88-independent pathways, MyD88 appears more critical in oyster TLR signaling pathway. In the Pacific oyster (Crassostrea gigas), two complete paralogues, named as CgMyD88-1 and CgMyD88-2, have been identified. In the current study, we indicated that CgMyD88-1 and CgMyD88-2 might act synergistically to increase the efficiency of immune signaling by activating NF-κB transcription factor. However, we found that upon stimulation with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid [poly (I:C)], CgMyD88-1 and CgMyD88-2 show differences in their response: CgMyD88-1 accumulated as large spots in the cytoplasm, while CgMyD88-2 assembled in the cytoplasm and in the membrane. Our results support the theory that expansion of these immune genes is associated with functional diversity.


Effect of donor/recipient body weight mismatch on patient and graft outcome in living-donor kidney transplantation.
There have been conflicting reports showing that kidneys from small donors may be at risk for graft loss if they are transplanted into large recipients. The aim of this work was to examine the donor/recipient body weight ratio (D/RBWR) on patient and graft outcome. During the period from January 1990 to January 2002, 856 kidney transplants were performed. Of these, 776 kidney transplant recipients were selected after exclusion of pediatric, second transplant patients and those with a body mass index of 35. All patients achieved a minimum follow-up of 1-year. According to D/RBWR, patients were divided into 3 groups: low (0.9), medium (0.91-1.2) and high (1.2). Data were collected on graft function, acute and chronic rejection, post-transplant complications, and 1- and 5-year graft and patient survival. There was a statistically significant increase in the incidence of chronic rejection, post-transplant hypertension and diabetes mellitus in the low group. The incidence and frequency of acute rejection episodes were nearly the same in the 3 groups. Graft function, estimated by serum creatinine at 1 year, was significantly lower in the low group. The 5-year graft and patient survival was 71, 80, 88 and 81, 85 and 92%, in the low, medium and high groups, respectively. We conclude that a low D/RBWR may contribute to inferior long-term renal allograft survival. The hyperfiltration hypothesis due to low nephron mass in the low D/RBWR group may explain these findings.


[CT evaluation of response to chemotherapy and/or radiotherapy in primary lung cancer: comparison of response evaluation criteria in solid tumors (RECIST) and the WHO criteria, and comparison of both methods with the histological evaluation].
The new RECIST criteria for evaluation of tumor response to chemotherapy and/or radiotherapy were proposed in 1999. We compared RECIST with the WHO criteria and also compared both methods with the histological findings, to evaluate RECIST. The subjects were 32 primary lung cancer patients operated on after chemotherapy and/or radiotherapy. Two radiologists measured the diameter of the tumors and compared the RECIST and WHO criteria using the McNemar test. We also compared both criteria with the histological results. Using RECIST, partial response (PR) was assessed in 12 cases, stable disease (SD) in 18, and progressive disease (PD) in 2. With the WHO criteria, PR was seen in 15, no change (NC) in 15, and PD in 2. The two evaluations corresponded in 29 of 32 cases, and the p-value was 0.2500. Ef.1b-2 (good histological effect) was much higher in PR, and to evaluate the size of the tumors was useful, although more than half of SD was Ef.1b-2. RECIST criteria corresponded almost perfectly with the WHO criteria, suggesting that RECIST is accurate and useful.


TP53 and outcome in DLBCL: not only the coding region.
In this issue of Blood, Li et al report mutations in the 3′ untranslated region (3′UTR) of TP53 that modify the expression of p53 and thus its effect on response to therapy in diffuse large B-cell lymphoma (DLBCL) patients.


The anti-invasive flavonoid (+)-catechin binds to laminin and abrogates the effect of laminin on cell morphology and adhesion.
To study the effect of the flavonoid (+)-catechin on cell-matrix interactions two cell types with a different morphology on and adhesion to laminin were used. MO4 virally transformed fetal mouse cells adhere and spread when cultured on top of laminin-coated coverslips or on human amnion basement membrane. M5076 mouse reticulum cell sarcoma cells poorly adhere to these substrates and remain round. Both cell types are invasive in confronting cultures with embryonic chick heart fragments. (+)-Catechin binds to laminin in a pH-dependent way. Pretreatment of laminin-coated coverslips or amnion basement membrane with 0.5 mM (+)-catechin abrogates the effect of laminin on cell morphology and adhesion. MO4 cells do not adhere to the pretreated substrates and remain round, while M5076 cells now adhere and spread. (+)-Catechin inhibits the invasion of MO4 cells but not of M5076 cells into embryonic chick heart in vitro. We speculate that the anti-invasive activity of the flavonoid to MO4 cells is the result of its interference with MO4 cell adhesion to laminin. Invasion of M5076 cells does not imply adhesion to and spreading on laminin.


Effect of glucocorticoid deficiency after adrenalectomy on antitumor immunity.
We studied the effect of corticosterone after adrenalectomy on antitumor immunity in immunogenic tumors in mice. Antitumor immunity in the glucocorticoid deficient adrenalectomized mice (ADX mice) examined via comitant immunity and cytotoxic activity of spleen cells was compromised. Antitumor immunity was detected in ADX mice receiving sufficient supplementary doses of corticosterone. Loaded stress compromised the cytotoxic activity of the spleen cells in the ADX mice receiving adequate corticosterone, and the failure also contributed to the glucocorticoid deficiency because the activity was not affected by stress in the sham ADX mice. A matured effector cell activity was transferred to the glucocorticoid deficient ADX mice. We conclude that glucocorticoid deficiency compromises the antitumor immune response and that glucocorticoid might play an important role in the maturation of immunocompetent cells.


PGE2 and PGF2alpha biosynthesis in stimulated and nonstimulated peritoneal preparations containing macrophages.
The biosynthesis of PGE2 and PGF2alpha was measured in intact peritoneal exudate preparations obtained from C. parvum-treated and control C3H mice. Although both the control and stimulated preparations biosynthesized PGF2alpha and PGE2 from [1-14C] arachidonic acid, the stimulated preparations generated more of both prostaglandins than did nonstimulated preparations, probably as a result of increased synthesis within macrophages. Increased transformation of PGE2 into PGF2alpha by PGE2 9-ketoreductase was noted in stimulated preparations when compared to that in control cells. The data suggest that stimulated macrophages are capable of generating increased quantities of PGF2alpha and therefore might function as one source of this substance in resolving inflammatory reactions.


The operational impact of deploying SARS-CoV-2 vaccines in countries of the WHO African Region.
When available, SARS-CoV-2 vaccines will be deployed to countries with limited immunization systems. We conducted an immunization capacity assessment of a simulated WHO African Region country using region-specific data on immunization, population, healthcare workers (HCWs), vaccine cold storage capacity (quartile values for national and subnational levels), and characteristics of influenza vaccines to represent future SARS-CoV-2 vaccines. We calculated monthly increases in vaccine doses, doses per vaccinator, and cold storage volumes for four-month SARS-CoV-2 vaccination campaigns targeting risk groups compared to routine immunization baselines. Administering SARS-CoV-2 vaccines to risk groups would increase total monthly doses by 27.0% for ≥65 years, 91.7% for chronic diseases patients, and 1.1% for HCWs. Assuming median nurse density estimates adjusted for absenteeism and proportion providing immunization services, SARS-CoV-2 vaccination campaigns would increase total monthly doses per vaccinator by 29.3% for ≥65 years, 99.6% for chronic diseases patients, and 1.2% for HCWs. When we applied quartiles of actual African Region country vaccine storage capacity, routine immunization vaccine volumes exceeded national-level storage capacity for at least 75% of countries, but subnational levels had sufficient storage capacity for SARS-CoV-2 vaccines for at least 75% of countries. In the WHO African Region, SARS-CoV-2 vaccination campaigns would substantially increase doses per vaccinator and cold chain capacity requirements over routine immunization baselines. Pandemic vaccination campaigns would add volume to national-level stores already at their limits, but sufficient capacity exists at subnational levels. Immediate attention to strengthening immunization systems is essential to support pandemic responses. None.


Enhanced trabeculectomy in a UK district general hospital setting: is selective use of 5-fluorouracil all that is required?
To determine whether primary trabeculectomies performed in a UK district general hospital, specifically without making use of mitomycin-C augmentation but with selective use of the low potency anti-metabolite 5-fluorouracil, produce an acceptable long-term intraocular pressure (IOP)-lowering effect for an unselected patient group. Retrospective analysis of the outcomes of all the trabeculectomies (53 eyes) performed by a single surgeon in a UK district hospital with or without 5-fluorouracil enhancement. The mean follow-up period was 5.04 years. Mean IOP preoperatively was 26.4 mm Hg while postoperatively the mean was ≤14.9 at all the time periods examined. Intraoperative complications occurred in two eyes (3.8 %) including one suprachoroidal haemorrhage and one hyphema. Postoperative complications that occurred during the follow-up period included choroidal effusions in seven patients (13 %), early postoperative bleb leak in four patients (8 %) and immediate postoperative hypotony not requiring intervention in 18 patients (34 %). Five patients (9 %) developed postoperative hyphema (all <30 % anterior chamber height) and one patient (1.9 %) developed blebitis and endophthalmitis. None of our patients developed hypotony maculopathy. When trabeculectomy is performed on unselected patients attending a UK district general hospital, selective 5-fluorouracil augmentation is probably all that is required to obtain acceptable surgical outcomes.


Detection of telomerase activity in saliva from oral squamous cell carcinoma patients.
Tumor markers have been detected in saliva from patients with oral cancers. In order to investigate the expression of telomerase in saliva and its clinical significance. Sixty-two saliva specimens were collected from 32 patients with oral squamous cell carcinoma and 30 normal persons, the telomerase activity was assayed by telomerase PCR-ELISA method. It was detected positively in 75.0% (24/32) of patients with oral squamous cell carcinoma, while it was positive in 6.67% (2/30) of normal persons, the statistical difference was significant with P < 0.001. But the difference of expression of telomerase activity between the patients in clinical early and late stage was not significant with P > 0.05, the same to that between the patients with and without lymph nodes metastasis with P > 0.05. The results suggest that the telomerase in saliva could be used as an assistant marker for oral squamous cell carcinoma, however, a larger study is encouraged to confirm the value of judgement on clinical stage and lymph nodes metastasis.


Aronia melanocarpa polysaccharide ameliorates liver fibrosis through TGF-β1-mediated the activation of PI3K/AKT pathway and modulating gut microbiota.
The purpose of this experiment was to investigate the anti-hepatic fibrosis effect of Aronia melanocarpa polysaccharide (AMP) on TAA-induced liver fibrosis mice and its mechanism, as well as the changes in intestinal flora in vivo. This was established with a dose of 200 mg/kg TAA (i.p) once every three days, lasting for eight weeks. Colchicine with 0.4 mg/kg, and AMP (200 and 400 mg/kg) were given by intragastric administration (i.g) after 28 days of intraperitoneal injection of TAA. AMP treatment significantly inhibited the activities of liver injury markers ALT and AST in serum. Histopathological staining demonstrated that AMP significantly reversed TAA-induced hepatocyte necrosis and collagen deposition. In addition, AMP treatment block TGF- β1/Smads pathway inhibited the production of ECM and alleviates liver fibrosis. Furthermore, AMP treatment enhanced the phosphorylation of PI3K/AKT and decreased the expression of its downstream apoptosis-related proteins in liver, thus effectively alleviating TAA-induced liver fibrosis. In addition, 16S rDNA gene sequencing analysis showed that AMP treatment helped restore the imbalanced ecosystem of gut microbes, increased the proportion of Bacteroidetes and Proteobacteria, and increased species richness. Above findings clearly show that AMP is an effective method for treating liver fibrosis, possibly by improving the gut microbiota.


The effects of trans trans methyl linoleate on the concentration of prostaglandins and their precursors in rat.
Four groups of weanling male rats were fed a diet containing hydrogenated coconut oil (Treatment A); 9-trans, 12-trans linoleate (trans linoleate, (Treatment B); an equal mixture of 9-cis, 12-cis linoleate (cis linoleate) and trans linoleate (Treatment C); and cis linoleate (Treatment D); respectively for 12 weeks. The level of dietary fat was 11% of calories. Only trace amount of eicosatrienoic acid (C20:3w6) was detected in tissues, (liver, platelets) of rats in Treatments A and B. The level of C20:3w6 in platelet lipids of Treatments C and D was 0.1 and 0.33% respectively. The level of arachidonic acid in rats on Treatments A, B, C and D was 2.0, 1.4, 14.1 and 17.6% for platelet lipids, respectively. The serum levels of prostaglandin PGE1 for Treatments A, B, C and D were 1.10 +/- 0.24, 0.22 +/- 0.02, 3.51 +/- 0.58 and 5.69 +/- 0.59 ng/ml, respectively and 2.19 +/- 0.85, 0.15 +/- 0.03, 11.64 +/- 2.63 and 24.89 +/- 4.35 ng/ml for PGE2, respectively. Thus feeding trans linoleate to rats apparently caused decreased biosynthesis of PGs resulting from decreased levels of precursor acids. This was apparently due to the inhibition of conversion of cis linoleate to longer chain polyunsaturated fatty acids. The results indicate that the availability of precursor acids is one limiting factor in PG biosynthesis in rats, and small differences in the level of precursor acids, affected by dietary trans fatty acids may cause large variations in amounts of PGs synthesized.


Neurotensin secretion by fibrolamellar carcinoma of the liver.
Serum neurotensin concentrations were supranormal in 5 out of 20 patients with carcinoma of the liver. Liver specimens from 4 of these 5 patients demonstrated features typical of fibrolamellar carcinoma. Neurotensin may be suitable as a tumour marker for fibrolamellar carcinoma and may be useful for the detection of recurrences after treatment.


Semantic access in second-language visual word processing: evidence from the semantic Simon paradigm.
The present study investigated whether visually presented second-language words activate their meaning during low-level word processing, just as native-language words do. Using the semantic Simon paradigm (De Houwer, 1998) with a letter-case judgment task, Dutch-English bilingual participants were instructed to classify targets' letter case using verbal labels (e.g., by saying "animal" to uppercase targets or "occupation" to lowercase targets). Results showed that both native-language and second-language targets yielded faster responses if the verbal response corresponded to the targets' semantic category (e.g., the response "animal" to the target leeuw or lion) than when it did not (e.g., lawyer), even though the meaning of target words was irrelevant for the task. These results show that second-language word forms may quickly and automatically activate their meaning through strong form-to-meaning mappings, which is consistent with theories of bilingual lexicosemantic organization, such as that of Duyck and Brysbaert (2004).


Interfacial energetics of globular-blood protein adsorption to a hydrophobic interface from aqueous-buffer solution.
Adsorption isotherms of nine globular proteins with molecular weight (MW) spanning 10-1000 kDa confirm that interfacial energetics of protein adsorption to a hydrophobic solid/aqueous-buffer (solid-liquid, SL) interface are not fundamentally different than adsorption to the water-air (liquid-vapour, LV) interface. Adsorption dynamics dampen to a steady-state (equilibrium) within a 1 h observation time and protein adsorption appears to be reversible, following expectations of Gibbs' adsorption isotherm. Adsorption isotherms constructed from concentration-dependent advancing contact angles theta(a) of buffered-protein solutions on methyl-terminated, self-assembled monolayer surfaces show that maximum advancing spreading pressure, Pi(a)max, falls within a relatively narrow 10 < Pi(a)max < 20 mN m(-1) band characteristic of all proteins studied, mirroring results obtained at the LV surface. Furthermore, Pi(a) isotherms exhibited a 'Traube-rule-like' progression in MW similar to the ordering observed at the LV surface wherein molar concentrations required to reach a specified spreading pressure Pi(a) decreased with increasing MW. Finally, neither Gibbs' surface excess quantities [Gamma(sl)-Gamma(sv)] nor Gamma(lv) varied significantly with protein MW. The ratio {[Gamma(sl)-Gamma(sv)]/Gamma(lv)} approximately 1, implying both that Gamma(sv) approximately 0 and chemical activity of protein at SL and LV surfaces was identical. These results are collectively interpreted to mean that water controls protein adsorption to hydrophobic surfaces and that the mechanism of protein adsorption can be understood from this perspective for a diverse set of proteins with very different composition.


Bayesian inference with Stan: A tutorial on adding custom distributions.
When evaluating cognitive models based on fits to observed data (or, really, any model that has free parameters), parameter estimation is critically important. Traditional techniques like hill climbing by minimizing or maximizing a fit statistic often result in point estimates. Bayesian approaches instead estimate parameters as posterior probability distributions, and thus naturally account for the uncertainty associated with parameter estimation; Bayesian approaches also offer powerful and principled methods for model comparison. Although software applications such as WinBUGS (Lunn, Thomas, Best, & Spiegelhalter, Statistics and Computing, 10, 325-337, 2000) and JAGS (Plummer, 2003) provide "turnkey"-style packages for Bayesian inference, they can be inefficient when dealing with models whose parameters are correlated, which is often the case for cognitive models, and they can impose significant technical barriers to adding custom distributions, which is often necessary when implementing cognitive models within a Bayesian framework. A recently developed software package called Stan (Stan Development Team, 2015) can solve both problems, as well as provide a turnkey solution to Bayesian inference. We present a tutorial on how to use Stan and how to add custom distributions to it, with an example using the linear ballistic accumulator model (Brown & Heathcote, Cognitive Psychology, 57, 153-178. doi: 10.1016/j.cogpsych.2007.12.002 , 2008).