Checkpoint protein Rad9 plays an important role in nucleotide excision repair.
Rad9, an evolutionarily conserved checkpoint gene with multiple functions for preserving genomic integrity, has been shown to play important roles in homologous recombination repair, base excision repair and mismatch repair. However, whether Rad9 has an impact on nucleotide excision repair remains unknown. Here we demonstrated that Rad9 was involved in nucleotide excision repair and loss of Rad9 led to defective removal of the UV-derived photoproduct 6-4PP (6,4 pyrimidine-pyrimidone) and the BPDE (anti-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide)-DNA adducts in mammalian cells. We also demonstrated that Rad9 could co-localize with XPC in response to local UV irradiation. However, our data showed that Rad9 was not required for the photoproducts recognition step of nucleotide excision repair. Further investigation revealed that reduction of Rad9 reduced the UV-induced transcription of the genes of the nucleotide excision repair factors DDB2, XPC, DDB1 and XPB and DDB2 protein levels in human cells. Interestingly, knockdown of one subunit of DNA damage recognition complex, hHR23B impaired Rad9-loading onto UV-damaged chromatin. Based on these results, we suggest that Rad9 plays an important role in nucleotide excision repair through mechanisms including maintaining DDB2 protein level in human cells.


Transient response of the calcium homeostatic system: effect of calcitonin.
With the use of an intravenous step load of calcium, a rapid (less than 30 min) process that helps regulate plasma calcium has been identified in pigs. The process appears to be calcitonin dependent, may not involve simple equilibration, and varies inversely with age, as it is virtually absent in old sheep compared with its intensity in young sheep. Based on these findings and a general model of calcium homeostasis, five classes of regulatory processes are proposed. Grade I (half time, t1/2, congruent to 15 min) is a transient and saturable response present only in young individuals and is calcitonin dependent. Grade II (1/2 congruent to 60-90 min) is parathyroid hormone and possibly calcitonin dependent. Grade III (t1/2 = 3-4 h) is parathyroid hormone dependent and probably renal in nature. Grade IV (t1/2, several hours) is vitamin D dependent and intestinal in nature. Grade V (t1/2, hours or days) is parathyroid hormone and calcitonin dependent and skeletal in nature.


Analysis of time-resolved argon line spectra from OMEGA direct-drive implosions.
We discuss the observation and data analysis of argon K-shell line spectra from argon-doped deuterium-filled OMEGA direct-drive implosion cores based on data recorded with two streaked crystal spectrometers. The targets were 870 microm in diameter, 27 microm wall thickness plastic shells filled with 20 atm of deuterium gas, and a tracer amount of argon for diagnostic purposes. The argon K-shell line spectrum is primarily emitted at the collapse of the implosion and its analysis provides a spectroscopic diagnostic of the core implosion conditions. The observed spectra includes the He alpha, Ly alpha, He beta, He gamma, Ly beta, and Ly gamma line emissions and their associated He- and Li-like satellites thus covering a broad photon energy range from 3100 to 4200 eV with a spectral resolution power of approximately 500. The data analysis relies on detailed atomic and spectral models that take into account nonequilibrium collisional-radiative atomic kinetics, Stark-broadened line shapes, and radiation transport calculations.


Do Spaniards know their rights as patients?
In 2002, Spain introduced new legislation regulating the rights of patients. Spaniards have thus seen an increase in their capacity for decision-making, bringing them into line with many other countries. However, the law changes do not mean to be acquainted with the new legislation and therefore, putting it into practice. To analyse whether the rules governing patients' rights in Spain are sufficiently well known among patients and to identify the profile of those patients most aware of their rights. Cross-sectional quota-sampled survey study. A total of 790 patients discharged from hospitals or attended in primary care took a telephone survey, 773 replayed. Twenty per cent had some knowledge of the rules governing patients' rights. Respondent characteristics that were associated with better knowledge of basic rights included: age of medical responsibility (P < 0.001), cases in which a doctor may inform family members (P < 0.001), whether or not a patient can refuse treatment (P < 0.001) and what is constituted by advance directives (P < 0.001). Patients who opt for a more active role in consultations with medical professionals show greater knowledge of their rights (P < 0.01). Age was related to greater ignorance of these rights (P < 0.01). Patients' knowledge of their rights is quite limited, making it difficult for them to assert those rights in specific medical encounters. The youngest patients, the most demanding, and those who prefer to have the last word in decisions are those with the best knowledge of their rights as patients.


A hydrogel material for plastic and reconstructive applications injected into the subcutaneous space of a sheep.
Soft tissue reconstruction using tissue-engineered constructs requires the development of materials that are biocompatible and support cell adhesion and growth. The objective of this study was to evaluate the use of macroporous hydrogel fragments that were formed using either unmodified alginate or alginate covalently linked with the fibronectin cell adhesion peptide RGD (alginate-RGD). These materials were injected into the subcutaneous space of adult, domesticated female sheep and harvested for histological comparisons at 1 and 3 months. In addition, the alginate-RGD porous fragments were seeded with autologous sheep preadipocytes isolated from the omentum, and these cell-based constructs were also implanted. The results from this study indicate that both the alginate and alginate-RGD subcutaneous implants supported tissue and vascular ingrowth. Furthermore, at all time points of the experiment, a minimal inflammatory response and capsule formation surrounding the implant were observed. The implanted materials also maintained their sizes over the 3-month study period. In addition, the alginate-RGD fragments supported the adhesion and proliferation of sheep preadipocytes, and adipose tissue was present within the transplant site of these cellular constructs, which was not present within the biomaterial control sites.


[The prevalence of otitis media with effusion of kindergarten children in Wuhan city].
To investigate the prevalence of otitis media with effusion (OME) of kindergarten children in Wuhan City. The study subjects were 3-6-year-old children in some kindergarten children in Wuhan City . All subjects were assessed with routine otorhinolaryngologic examination, otoscopic examination and tympanometry. Chi-square test were used to analyse the difference of data. The prevalence of children of some kindergarten in Wuhan City is 6.67%. There was no statistical difference were found between sexuality. The prevalence of OME in 3 years old group is obviously higher than that in 4-6 years old group. Previous acute otitis media episodes, feeding, high-arched palate, and nasal obstruction are risk factors of OME. Children with previous acute otitis media episode and nasal obstruction should be suggested to have otorhinolaryngologic examination regularly. It is necessary to have routine otoscopic examination and tympanometry in children of kindergarten.


Investigation of two variants in the DOPA decarboxylase gene in patients with autism.
Though genetic risk factors are important for the development of autism, no specific risk alleles have yet been identified. DOPA decarboxylase (DDC) is involved in both the catecholaminergic and serotonergic pathways and may be considered a functional candidate gene for autism. The present study is the first to test if two new variants of possible functional significance in the DDC gene increase the susceptibility to autism. A total of 90 parent-offspring trios recruited in Denmark and France were investigated using the transmission disequilibrium test (TDT). We found no evidence of linkage disequilibrium between autism and either of the two polymorphisms. Nor did we find linkage disequilibrium between autism and haplotypes of the two variants using a multiallelic TDT. These findings suggest that the DDC gene is unlikely to play a major role in the development of autism in our data set.


On the racemization of chiral imidazolines.
Racemization of chiral imidazolines with base has been studied for the first time following an unexpected finding in the synthesis of chiral imidazoline ligands. Amine bases do not cause racemization. Strong inorganic bases can induce racemization, yet this occurs only when the nitrogen is unsubstituted, in agreement with a symmetry-allowed thermal disrotatory ring opening and closure from a diazapentadienyl anion. Surprisingly, even with electron-withdrawing N-substituents, no racemization is observed. Conditions which allow for the racemization-free manipulations of this important compound class have been defined and developed.


Endoscopic versus surgical resection for early colorectal cancer-a systematic review and meta-analysis.
To investigate the available data on the treatment of early colorectal cancer (CRC), either endoscopically or surgically. Two independent reviewers searched MEDLINE, EMBASE, CENTRAL COCHRANE, LILACS and EBSCO for articles published up to August 2015. No language or dates filters were applied. Inclusion criteria were studies with published data about patients with early colonic or rectal cancer undergoing either endoscopic resection (i.e., mucosectomy or submucosal dissection) or surgical resection (i.e., open or laparoscopic). Extracted data items undergoing meta-analysis were en bloc resection rate, curative resection rate, and complications. A complementary analysis was performed on procedure time. The risk of bias among studies was evaluated with funnel-plot expressions, and sensitivity analyses were carried out whenever a high heterogeneity was found. The risk of bias within studies was assessed with the Newcastle score. A total of 12,819 articles were identified in the preliminary search. After applying inclusion and exclusion criteria, three cohort studies with a total of 768 patients undergoing endoscopic resection and 552 patients undergoing surgical resection were included. The en bloc resection rate risk difference was -11% [-13%, -8% confidence interval (CI)], demonstrating worse outcome results for the endoscopic resection group as compared to the surgical resection group [number need to harm (NNH) =10]. The curative resection rate risk difference was -9% [(-12%, 6% CI)] after a sensitivity analysis was performed, which also demonstrated worse outcomes in the intervention group (NNH =12). The complications rate exhibited a -7% risk difference [(-11%, -4% CI)], denoting a lesser number of complications in the endoscopic group [Number Need to Treat (NNT =15). A complementary analysis of procedure time with two of the selected studies demonstrated a mean difference of -118.32 min [(-127.77, -108.87 CI)], in favor of endoscopic resection, even though such data lacks homogeneity across studies, and could be heavily influenced by local expertise. Long-term results were found in only one study and therefore were not included in the final analysis. According to the current available data, the treatment of early CRC by surgical resection is associated with higher curative resection rates and higher en bloc resection rates, despite of higher complications rates, as compared to endoscopic resection. Shorter procedure times are associated with the endoscopic methods of treatment, however high heterogeneity levels limit this conclusion.


Freud's brain: toward a unified neuropsychodynamic model of personality and psychotherapy.
Neuropsychological findings and principles are not by themselves sufficient to provide definitive answers to broad questions of personality, psychopathology, or psychodynamics, nor should they be seen as attempting to usurp other approaches. This review has briefly noted some of the directions in which neuropsychology is being applied to psychoanalysis and psychodynamic personality theory, as well as to clinical practice. The purpose of any model is to try to weave disparate observations and findings into a coherent theoretical framework that can be productively employed for further clinical and research purposes. To this end, the neuropsychodynamic approach can contribute. Man--as Freud recognized--is neither "organic" or "functional." He is both, and our commitment to psychological knowledge must entail a search for unities.


Automated Optical Tweezers Manipulation to Transfer Mitochondria from Fetal to Adult MSCs to Improve Antiaging Gene Expressions.
Mitochondrial dysfunction is considered to be an important factor that leads to aging and premature aging diseases. Transferring mitochondria to cells is an emerging and promising technique for the therapy of mitochondrial deoxyribonucleic acid (mtDNA)-related diseases. This paper presents a unique method of controlling the quality and quantity of mitochondria transferred to single cells using an automated optical tweezer-based micromanipulation system. The proposed method can automatically, accurately, and efficiently collect and transport healthy mitochondria to cells, and the recipient cells then take up the mitochondria through endocytosis. The results of the study reveal the possibility of using mitochondria from fetal mesenchymal stem cells (fMSCs) as a potential source to reverse the aging-related phenotype and improve metabolic activities in adult mesenchymal stem cells (aMSCs). The results of the quantitative polymerase chain reaction analysis show that the transfer of isolated mitochondria from fMSCs to a single aMSC can significantly increase the antiaging and metabolic gene expression in the aMSC. The proposed mitochondrial transfer method can greatly promote precision medicine for cell therapy of mtDNA-related diseases.


Sedation and mechanical antinociception after intravenous administration of detomidine in donkeys: a dosage-effect study.
There is limited, useful, scientific information on detomidine in donkeys. This study compared the effects of intravenous saline, detomidine (10, 13.5, 17 and 20 μg/kg) and acepromazine (50 μg/kg) in donkeys by computing areas under the curve for 0-30, 30-60 and 60-120 minutes (AUC0-30, AUC30-60 and AUC60-120) for sedation scores, head heights and mechanical nociceptive thresholds (MNTs). For sedation scores, all detomidine treatments, except 10 μg/kg, increased AUC0-30 values compared with saline, and AUC0-30 values were larger for 17 μg/kg detomidine than for acepromazine. All head height AUC values were lower for detomidine than for saline (except AUC60-120 for 10 μg/kg detomidine) and acepromazine (except AUC0-30 for 10 and 20 μg/kg detomidine, and AUC60-120 for 10 μg/kg detomidine). For MNTs, all detomidine treatments increased AUC0-30 and AUC30-60 values compared with saline and acepromazine; AUC30-60 values were smaller for 10 μg/kg than for 17 and 20 μg/kg detomidine. MNT AUC60-120 values were larger for 20 μg/kg detomidine than for saline, 10 μg/kg detomidine and acepromazine. Detomidine induced sedation and antinociception, but only antinociception was dosage dependent. Selection of detomidine dosage for donkeys may depend on the required duration of sedation and/or degree of analgesia.


Collodictyon triciliatum and Diphylleia rotans (=Aulacomonas submarina) form a new family of flagellates (Collodictyonidae) with tubular mitochondrial cristae that is phylogenetically distant from other flagellate groups.
Comparative electron microscopic studies of Collodictyon triciliatum and Diphylleia rotans (=Aulacomonas submarina) showed that they share a distinctive flagellar transitional zone and a very similar flagellar apparatus. In both species, the basic couple of basal bodies and flagella #1 and #2 are connected to the dorsal and ventral roots, respectively. Collodictyon triciliatum has two additional basal bodies and flagella, #3 and #4, situated on each side of the basic couple, each of which also bears a dorsal root. The horseshoe-shaped arrangement of dictyosomes, mitochondria with tubular cristae and the deep ventral groove are very similar to those of Diphylleia rotans. These two genera have very specific features and are placed in a new family, Collodictyonidae, distinct from other eukaryotic groups. Electron microscopic observation of mitotic telophase in Diphylleia rotans revealed two chromosomal masses, surrounded by the nuclear envelope, within the dividing parental nucleus, as in the telophase stage of the heliozoan Actinophrys and the helioflagellate Dimorpha. Spindle microtubules arise from several MTOCs outside the nucleus, and several microtubules penetrate within the dividing nucleus, via pores at the poles. This semi-open type of orthomitosis is reminiscent of that of actinophryids. The SSU rDNA sequence of Diphylleia rotans was compared with that of all the eukaryotic groups that have a slow-evolving rDNA. Diphylleia did not strongly assemble with any group and emerged in a very poorly resolved part of the eukaryotic phylogenetic tree.


Efficacy of immune checkpoint inhibitors in the treatment of non-small cell lung cancer patients with different genes mutation: A meta-analysis.
Latest clinical trials have proved the better overall survival (OS) for the use of immune checkpoint inhibitors verse chemotherapy in non-small cell lung cancer (NSCLC) patients. However, we still have no clear ideas of the factors which could affect the efficacy of immune checkpoint inhibitors. Cancer, essentially, is a disease related to genes mutation. Therefore, we conducted a systematic review and meta-analysis to compare efficacy of immune checkpoint inhibitors for NSCLC patients with different genes mutation. PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched for all clinical trials in NSCLC until December 16, 2019. The hazard ratio (HR) and 95% confidence intervals (CIs) of OS or progression-free survival (PFS) were used. A total of 4453 patients from 7 randomized controlled trials (RCTs) were included. Immune checkpoint inhibitors significantly prolonged the OS (HR, 0.67; 95% CI, 0.60-0.67) in NSCLC patients having epidermal growth factor receptor (EGFR) wild-type versus chemotherapy. Meanwhile, they prolonged the OS (HR, 0.61; 95% CI, 0.39-0.94) in NSCLC patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. No matter PD-L1 tumor proportion scores were >1% or <1%, immune checkpoint inhibitors were more effective than chemotherapy (HR, 0.64; 95% CI, 0.55-0.75). Immune checkpoint inhibitors are more efficacious than chemotherapy in NSCLC patients with EGFR wild-type, KRAS mutation, and any PD-L1 tumor proportion scores.


Porcine alveolar macrophage CD163 abundance is a pivotal switch for porcine reproductive and respiratory syndrome virus infection.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a problematic virus that is difficult to control. The principal target cells for PRRSV infection are porcine alveolar macrophages (PAMs). Increasing evidence has demonstrated that CD163 is the determinant receptor for PRRSV infection. However, the relationship between CD163 abundance and PRRSV infection is unclear. In this study, we first generated primary immortalized PAMs (iPAMs) using SV40 large T antigen and demonstrated that CD163 expression is suppressed by the alternative splicing of mRNA in iPAMs. Two forms of CD163 transcripts were discovered, and most iPAMs expressed a short-form CD163 transcript that lacked from scavenger receptor cysteine-rich tandem repeat 1 (SRCR1) to SRCR5 of the functional domain. More importantly, using flow cytometric cell sorting technology, we isolated CD163-positive single-cell-derived clones with varying CD163 abundances to investigate the relationship between CD163 abundance and PRRSV infection. For the first time, we showed that cells with low CD163 abundance (approximately 20%) do not initiate PRRSV infection, while cells with moderate CD163 abundance display limited infection. PRRSV initiated efficient infection only in cells with high CD163 abundances. Our results demonstrate that CD163 abundance is a pivotal switch for PRRSV replication.


Luminescent nanoparticles for rapid monitoring of endogenous acetylcholine release in mice atria.
The present work introduces for the first time a nanoparticulate approach for ex vivo monitoring of acetylcholinesterase-catalyzed hydrolysis of endogenous acetylcholine released from nerve varicosities in mice atria. Amino-modified 20-nm size silica nanoparticles (SNs) doped by luminescent Tb(III) complexes were applied as the nanosensors. Their sensing capacity results from the decreased intensity of Tb(III)-centred luminescence due to the quenching effect of acetic acid derived from acetylcholinesterase-catalyzed hydrolysis of acetylcholine. Sensitivity of the SNs in monitoring acetylcholine hydrolysis was confirmed by in vitro experiments. Isolated atria were exposed to the nanosensors for 10 min to stain cell membranes. Acetylcholine hydrolysis was monitored optically in the atria samples by measuring quenching of Tb(III)-centred luminescence by acetic acid derived from endogenous acetylcholine due to its acetylcholinesterase-catalyzed hydrolysis. The reliability of the sensing was demonstrated by the quenching effect of exogenous acetylcholine added to the bath solution. Additionally, no luminescence quenching occurred when the atria were pre-treated with the acetylcholinesterase inhibitor paraoxon.


Selective chemical inhibition as a tool to study Cdk1 and Cdk2 functions in the cell cycle.
Cyclin-dependent kinases are highly conserved among all eukaryotes, and have essential roles in the cell cycle. However, these roles are still only poorly understood at a molecular level, partly due to the functional redundancy of different Cdk complexes. Indeed, mice knockouts have even thrown into some doubt the assumed essential roles for Cdk2-cyclin E in triggering S-phase, but this is almost certainly due to compensation by Cdk1 complexes. By combining both knockout approaches and chemical Cdk inhibition in Xenopus egg extracts, we have shown that one reason for functional redundancy of Cdk control of S-phase is that Cdk activity required to trigger S-phase is very low. Cdk1 contributes to this activity even in the presence of Cdk2, and Cdk activity at this stage does not show "switch-like" regulation, as at the onset of mitosis. It is important to try to confirm and extend these findings to other cell-types, and to explain why different cells might have evolved different requirements for Cdk activity. In this paper, we present data that suggest that selective chemical Cdk inhibition will be a useful tool towards achieving this goal.


[The role of the state of protein-lipid interactions in stimulated membranes in the conformation of C40-carotenoids].
It was shown by Raman spectroscopy that conformation of carotenoid in the frog nerve membranes at rest and at propagation of rhythmic excitation depends on the state of protein-lipid interaction modified by exposition of the nerve in solution with trypsin, alpha-chymotrypsin, urea, glutaraldehyde, SH-reagents, isopropanol and system "Fe-ascorbate". It is suggested that the level of the protein-lipid interactions in excitable membranes with the intramembrane potential determines C40-carotenoid conformation at the propagation of rhythmic excitation by he nerve.


Investigating the impact of Echinococcus multilocularis vesicular fluid on human cells from healthy blood donors.
Alveolar echinococcosis (AE) is a severe chronic helminthic disease that mimics slow-growing liver cancer. Previous studies using murine models suggest that Echinococcus multilocularis (Em) metacestodes have developed mechanisms which impair the natural inflammatory host response. The aim of this study was to investigate in vitro the impact of Em vesicular fluid (VF) on monocytes, monocytes derived dendritic cells and lymphocytes from healthy blood donors. First, assays were performed to investigate whether or not Em-VF influences monocyte-derived dendritic cell (MoDC) differentiation and maturation. Monocytes during differentiation and immature MoDCs were exposed to Em-VF. The effect of Em-VF was assessed using flow cytometry (CD86, CD83, CD80) and immune assays (IL-10 and TGFβ). Second, assays were performed to investigate the interaction between Em-VF, peripheral blood monocyte cells (PBMC) and Toll-like Receptor (TLR) agonists (LPS, PolyIC, R848 and CpG). PBMC were stimulated by each of the TLR agonists with and without Em-VF. The subsequent TGFβ production was assessed. Exposure to Em-VF had bearing on both differentiation and maturation of MoDC, but only partially. A decrease in the expression of co-stimulatory molecules was observed; however, levels of immune-regulatory cytokines were stable. PBMC exposed simultaneously to Em-VF and LPS induced a significant increase of TGFβ (p<0.05, Wilcoxon signed-rank test). Further experiments showed that TGFβ production was lymphocyte-dependent. The assays performed confirmed that Em-VF influences the host immune response. However, only minor changes were observed when investigating the Em-VF impact on cells from healthy blood donors. Assays with TLR agonists suggested that co-stimulation with LPS reinforces the response of healthy blood donors exposed to Em-VF.


Patient isolation in chronic benign pain.
Over the years, nurses, doctors and scientists have sought ways of assessing the impact of pain on patients. While many of the instruments devised have been extremely useful in identifying the nature and intensity of pain, defining the effect it has on people's lives and perceptions has proved much more problematic. Based on the work she carried out with patients suffering from chronic benign pain, Karen Rose explores one aspect of these effects--the feeling of isolation. By using a four-step anthropological approach to identify the impact of pain, she argues, nurses can arrive at a realistic and accurate assessment of how patients are coping.


Electronically reconfigurable unit cell for transmit-reflect-arrays in the X-band.
This paper proposes an electronically reconfigurable unit cell for transmit-reflect-arrays in the X-band, which makes it possible to control the reflection or transmission phase independently by combining the mechanisms of reconfigurable transmitarrays and reconfigurable reflectarrays. The fabricated unit cell was characterized in a waveguide simulator. The return loss in the reflection mode and insertion loss in the transmission mode are smaller than 1.8 dB for all states at 10.63 GHz, and a 1-bit phase shift for both modes is achieved within 180° ± 10°. When compared to full-wave electromagnetic simulation results, the proposed unit cell shows good results and is thus verified.


Chelation of cadmium.
The toxicity of cadmium is determined by chelation reactions: in vivo, Cd2+ exists exclusively in coordination complexes with biological ligands, or with administered chelating agents. The Cd2+ ion has some soft character, but it is not a typical soft ion. It has a high degree of polarizability, and its complexes with soft ligands have predominantly covalent bond characteristics. Cd2+ forms the most stable complexes with soft donor atoms (S much greater than N greater than 0). The coordination stereochemistry of Cd2+ is unusually varied, including coordination numbers from 2 to 8. Even though the Cd2+ ion is a d10 ion, disturbed coordination geometries are often seen. Generally, the stability of complexes increases with the number of coordination groups contributed by the ligand; consequently, complexes of Cd2+ with polydentate ligands containing SH groups are very stable. Cd2+ in metallothionein (MT) is coordinated with 4 thiolate groups, and the log stability constant is estimated to 25.5. Complexes between Cd2+ and low molecular weight monodentate or bidentate ligands, e.g., free amino acids (LMW-Cd), seem to exist very briefly, and Cd2+ is rapidly bound to high molecular weight proteins, mainly serum albumin. These complexes (HMW-Cd) are rapidly scavenged from blood, mainly by the liver, and Cd2+ is redistributed to MT. After about 1 day the Cd-MT complex (MT-Cd) almost exclusively accounts for the total retained dose of Cd2+, independent of the route of exposure. MT-Cd is slowly transferred to and accumulated in kidney cortex. The acute toxicity and interorgan distribution of parenterally administered Cd2+ are strongly influenced by preceding MT induction, or decreased capacity for MT synthesis; however, the gastrointestinal (GI) uptake of Cd2+ seems unaffected by preceding MT induction resulting in considerable capacity for Cd2+ chelation in intestinal mucosa, and this finding indicates that endogenous MT is not involved in Cd2+ absorption. The toxicity of parenterally administered Cd2+ is strongly enhanced when administered as complexes with NTA or STPP , but it is much decreased when administered as a complex with EDTA. In chronic oral exposure the toxicity and GI uptake of Cd2+ is not changed when Cd2+ is administered as a complex with the detergent formula chelating agents NTA, EDTA and STPP . The uptake of Cd2+ from ligated intestine in vivo was not affected by administration of Cd2+ as complexes with CYS or GSH, but significantly reduced by complexation with EDTA or BAL. The acute toxicity of orally administered Cd2+ is reduced when Cd2+ is administered as a complex with EDTA.(ABSTRACT TRUNCATED AT 400 WORDS)


Paraburkholderia lacunae sp. nov., isolated from soil near an artificial pond.
A Gram-stain-negative, strictly aerobic bacterial strain, designated strain S27T, was isolated from soil near an artificial pond in South Korea. Cells were non-motile short rods showing oxidase- and catalase-positive activities. Growth of strain S27T was observed at 20-40°C (optimum, 30°C), pH 5.0-7.0 (optimum, pH 6.0), and 0-0.5% (w/v) NaCl (optimum, 0%). Ubiquinone-8 was detected as the sole respiratory quinone and the major fatty acids were C16:0, cyclo-C17:0, and cyclo-C19:0ω8c. The G + C content of the genomic DNA was 62.4 mol%. Phosphatidylglycerol, phosphatidylethanolamine, and an unidentified aminophospholipid were detected as the major polar lipids. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain S27T formed a clearly distinct phyletic lineage from closely related Paraburkholderia species within the genus Paraburkholderia. Strain S27T was most closely related to Paraburkholderia rhynchosiae WSM3937T, Paraburkholderia ginsengiterrae DCY85T, Paraburkholderia fungorum NBRC 102489T, and Paraburkholderia graminis C4D1MT with 98.8%, 98.4%, 98.4%, and 97.7% 16S rRNA gene sequence similarities, respectively. The DNA-DNA relatedness level between strain S27T and the type strain of P. rhynchosiae was 36.8 ± 2.6%. On the basis of phenotypic, chemotaxonomic and molecular properties, strain S27T represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia lacunae sp. nov. is proposed. The type strain is S27T (KACC 19714 T = JCM 32721T).


[Early gastric cancer and precancerous conditions diagnostics with confocal laser endomicroscopy].
To develop endomicroscopic criteria of early gastric cancer and precancerous conditions 157 suspected for early gastric cancer patients were included in our study. In all cases complex endoscopic examination (narrow-band imaging NBI-HD endoscopy, endosonography (EUS) and endoscope-based confocal laser endomicroscopy (CLE) with precise biopsy) was performed. CLE images compared to pathology data. Precise criteria of intestinal metaplasia in CLE was presence of oval gray goblet cells in epithelium. Gastric adenoma with moderate dysplasia appeared on CLE images as glandular structures in mucosa surface layers. The signs of high-grade dysplastic changes in adenoma were appearing of different shape and size cells with lost polarity. Well-differentiated carcinoma featured destruction of some glands and forming dark cell clusters. Revealed criteria of poor-differentiated carcinoma was total disintegration of glandular structures. Overall accuracy of CLE in early gastric cancer and precancerous conditions diagnostics reached 95,6% (P < 0.001). Selected accuracy in different condition was: 100% in intestinal metaplasia identifying, 86.1%--in adenoma with moderate dysplasia, 96.2% in high-grade dysplasia and cancer in situ, and 100%--in poor-differentiated gastric carcinoma types). As the result of our study we have developed precise endomicroscopic criteria of intestinal metaplasia in stomach, gastric adenoma with moderate and high-grade dysplasia and early gastric cancer--as well-differentiated, as poor-differentiated.


Seminal vesicle metastasis after liver transplantation for hepatocellular carcinoma: A case report.
Cancer recurrence and metastasis after liver transplantation (LT) is common in some hepatocellular carcinoma (HCC) patients. The most common sites of extrahepatic metastases are lung, regional lymph node, adrenal gland, and bone. To our knowledge, HCC metastasis to the seminal vesicle after LT has not been reported in the literature. A 56-year-old Asian man presented at hospital with a 9-year history of orthotopic LT because of HCC. The patient underwent surgery and radiotherapy for HCC metastasis to adrenal gland and 1 year later, chemotherapy for peritoneal metastasis. A few months later, the patient presented with computed tomography (CT) image showing masses in right lobe of liver, seminal vesicle, and space occupying mass between the spleen and stomach. Combination of clinical and pathological features revealed the seminal vesicle mass as metastasis from HCC. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for liver and seminal vesicle lesions was performed and the postoperative pathology revealed malignancy. Thus, the patient underwent surgery and the diagnosis of seminal vesicle metastasis of HCC was confirmed by pathology and immunohistochemical analysis. The patient died due to systemic failure. Seminal vesicle metastasis from HCC after LT is rare and there is no consensus on its treatment. Further research into the pathogenesis and therapy of seminal vesicle from HCC after LT is needed to improve outcomes in the rare disease.


A retrospective study of Pupingqinghua prescription versus Lianhuaqingwen in Chinese participants infected with SARS-CoV-2 Omicron variants.
Background: Coronavirus disease (COVID-19) seriously endangers global public health. Pupingqinghua prescription (PPQH) is an herbal formula from traditional Chinese medicine used for treatment of SARS-CoV-2 infection. This study aims to evaluate the clinical efficacy and safety of PPQH in Chinese participants infected with the SARS-CoV-2 Omicron variant. Methods: A total of 873 SARS-CoV-2 (Omicron)-infected patients were included. Among them, the patients were divided into the PPQH group (653 cases) and LHQW group (220 cases) according to different medications. The effectiveness indicators (hematological indicators, Ct values of novel Coronavirus nucleic acid tests, and viral load-shedding time) and safety indicators (liver and kidney function and adverse events) were analyzed. Results: There was no significant difference in baseline characteristics between the PPQH group and the LHQW group, except the gender; After the treatment, the levels of IL-5, IL-6, IL-10, NK cells, and INF-α of the patients in the PPQH group showed a downward trend (p < 0.05); The viral load shedding time was 5.0 (5.0, 7.0) in the PPQH group and 5.0 (4.0, 7.0) in the LHQW group; both PPQH and LHQW can shorten the duration of symptoms of fever, cough, and sore throat. The re-positive rate of COVID-19 test was 1.5 % in the PPQH group and 2.3 % in the LHQW group. In terms of safety, the levels of γ-GTT decreased significantly (p < 0.01); gastrointestinal reaction was the primary adverse reaction, and the reaction rate was 4.7 % in the PPQH group and 9.5 % in the LHQW group. Conclusion: PPQH can shorten the length of hospital stay and improve clinical symptoms of patients with SARS-COV-2 (Omicron), and it also has a good safety profile.


Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer.
Tumour lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Previous reviews did not find clear evidence of benefit of urate oxidase in children with cancer. This review is the second update of a previously published Cochrane review. To assess the effects and safety of urate oxidase for the prevention and treatment of TLS in children with malignancies. In March 2016 we searched CENTRAL, MEDLINE, Embase, and CINAHL. In addition, we searched the reference lists of all identified relevant papers, trials registers and other databases. We also screened conference proceedings and we contacted experts in the field and the manufacturer of rasburicase, Sanofi-aventis. Randomised controlled trials (RCT) and controlled clinical trials (CCT) of urate oxidase for the prevention or treatment of TLS in children under 18 years with any malignancy. Two review authors independently extracted trial data and assessed individual trial quality. We used risk ratios (RR) for dichotomous data and mean difference (MD) for continuous data. We included seven trials, involving 471 participants in the treatment groups and 603 participants in the control groups. No new studies were identified in the update. One RCT and five CCTs compared urate oxidase and allopurinol. Three trials tested Uricozyme, and three trials tested rasburicase for the prevention of TLS.The RCT did not evaluate the primary outcome (incidence of clinical TLS). It showed no clear evidence of a difference in mortality (both all-cause mortality (Fisher's exact test P = 0.23) and mortality due to TLS (no deaths in either group)), renal failure (Fisher's exact test P = 0.46), and adverse effects between the treatment and the control groups (Fisher's exact test P = 1.0). The frequency of normalisation of uric acid at four hours (10 out of 10 participants in the treatment group versus zero out of nine participants in the control group, Fisher's exact test P < 0.001) and area under the curve of uric acid at four days (MD -201.00 mg/dLhr, 95% CI -258.05 mg/dLhr to -143.95 mg/dLhr; P < 0.00001) were significantly better in the treatment group.One CCT evaluated the primary outcome; no clear evidence of a difference was identified between the treatment and the control groups (RR 0.77, 95% CI 0.44 to 1.33; P = 0.34). Pooled results of three CCTs showed significantly lower mortality due to TLS in the treatment group (RR 0.05, 95% CI 0.00 to 0.89; P = 0.04); no clear evidence of a difference in all-cause mortality was identified between the groups (RR 0.19, 95% CI 0.01 to 3.42; P = 0.26). Pooled results from five CCTs showed significantly lower incidence of renal failure in the treatment group (RR 0.26, 95% CI 0.08 to 0.89; P = 0.03). Results of CCTs also showed significantly lower uric acid in the treatment group at two days (three CCTs: MD -3.80 mg/dL, 95% CI -7.37 mg/dL to -0.24 mg/dL; P = 0.04), three days (two CCTs: MD -3.13 mg/dL, 95% CI -6.12 mg/dL to -0.14 mg/dL; P = 0.04), four days (two CCTs: MD -4.60 mg/dL, 95% CI -6.39 mg/dL to -2.81 mg/dL; P < 0.00001), and seven days (one CCT: MD -1.74 mg/dL, 95% CI -3.01 mg/dL to -0.47 mg/dL; P = 0.007) after therapy, but not one day (three CCTs: MD -3.00 mg/dL, 95% CI -7.61 mg/dL to 1.60 mg/dL; P = 0.2), five days (one CCT: MD -1.02 mg/dL, 95% CI -2.24 mg/dL to 0.20 mg/dL; P = 0.1), and 12 days (one CCT: MD -0.80 mg/dL, 95% CI -2.51 mg/dL to 0.91 mg/dL; P = 0.36) after therapy. Pooled results from three CCTs showed higher frequency of adverse effects in participants who received urate oxidase (RR 9.10, 95% CI 1.29 to 64.00; P = 0.03).Another included RCT, with 30 participants, compared different doses of rasburicase (0.2 mg/kg versus 0.15 mg/kg). The primary outcome was not evaluated. No clear evidence of a difference in mortality (all-cause mortality (Fisher's exact test P = 1.0) and mortality due to TLS (no deaths in both groups)) and renal failure (no renal failure in both groups) was identified. It demonstrated no clear evidence of a difference in uric acid normalisation (RR 1.07, 95% CI 0.89 to 1.28; P = 0.49) and uric acid level at four hours (MD 8.10%, 95% CI -0.99% to 17.19%; P = 0.08). Common adverse events of urate oxidase included hypersensitivity, haemolysis, and anaemia, but no clear evidence of a difference between treatment groups was identified (RR 0.54, 95% CI 0.12 to 2.48; P = 0.42).The quality of evidence ranks from very low to low because of imprecise results, and all included trials were highly susceptible to biases. Although urate oxidase might be effective in reducing serum uric acid, it is unclear whether it reduces clinical TLS, renal failure, or mortality. Adverse effects might be more common for urate oxidase compared with allopurinol. Clinicians should weigh the potential benefits of reducing uric acid and uncertain benefits of preventing mortality or renal failure from TLS against the potential risk of adverse effects.


Zeolite-catalyzed hydrogenation of carbon dioxide and ethene.
Ab initio molecular orbital theory and density functional theory calculations have been used to study the three-stage zeolite-catalyzed hydrogenation of CO2 to methanol and the hydrogenation of C2H 4 to ethane, with the aim of designing an effective zeolite catalyst for these reactions. Both Brønsted acid (XH) and alkali metal (XM) sites in model zeolites (-X-Al-XH- or -X-Al-XM-) have been examined. It is found that appropriately designed zeolites can provide excellent catalysis for these reactions, particularly for the hydrogenation of CO2, HCO2H and CH2O, with uncatalyzed barriers of more than 300 kJ mol(-1) being reduced to as little as 17 kJ mol(-1) (in the case of CH2O). The reaction barrier depends on the acidity of the XH moiety or the nature of the metal cation M in the XM moiety, and the basicity of the adjacent X group in the catalyst. For a catalyst based on alkali metal zeolites (XM), the catalytic activity is relatively insensitive to the nature of X in the XM group. As a result, the catalytic activity for these types of zeolites increases as X becomes more basic. We propose that alkali metal zeolites with Ge and N incorporated into the framework could be very effective catalysts for hydrogenation processes.


The privilege paradox: Geographic areas with highest socio-economic advantage have the lowest rates of vaccination.
The present study is the first to examine associations between area-level socio-demographic factors and uptake of vaccination among 5-year old children throughout Australia. A public-health focused ecological methodology was used that combined postcode-level socio-demographic variables from the 2016 Census with postcode-level vaccination data. Analyses included one-way analysis of variance and assessment of linear trends for each socio-demographic variable across five categories of vaccination rate; ranging from lowest (≤90%) to highest (96.1-100%), as well as using vaccination rate as a continuous variable. Multiple regression analysis was also conducted using select indicators to predict vaccination rates in postcodes from major cities. The results of the univariate analyses showed that communities with lower rates of vaccination had relatively less disadvantage, and had relatively greater education and occupation status, as measured by SEIFA (ABS [4]). When we looked at the ASGS Remoteness Areas, we saw that the vaccination rates were lowest in postcodes from the major cities of Australia, and vaccination rates increased as communities became more remote. When the community is further refined to postcodes located in the major cities, and to the target group of parents/partners in a family with children aged 4-7, we found that postcodes with lower vaccination rates were characterised as having a relatively greater proportion of people with: a high education level (bachelor degree level or higher); having white-collar jobs as managers; having no religion, having people in the older age category (50-54); and conversely being unemployed.


Infection prediction in swine populations with machine learning.
The pork industry is an essential part of the global food system, providing a significant source of protein for people around the world. A major factor restraining productivity and compromising animal wellbeing in the pork industry is disease outbreaks in pigs throughout the production process: widespread outbreaks can lead to losses as high as 10% of the U.S. pig population in extreme years. In this study, we present a machine learning model to predict the emergence of infection in swine production systems throughout the production process on a daily basis, a potential precursor to outbreaks whose detection is vital for disease prevention and mitigation. We determine features that provide the most value in predicting infection, which include nearby farm density, historical test rates, piglet inventory, feed consumption during the gestation period, and wind speed and direction. We utilize these features to produce a generalizable machine learning model, evaluate the model's ability to predict outbreaks both seven and 30 days in advance, allowing for early warning of disease infection, and evaluate our model on two swine production systems and analyze the effects of data availability and data granularity in the context of our two swine systems with different volumes of data. Our results demonstrate good ability to predict infection in both systems with a balanced accuracy of [Formula: see text] on any disease in the first system and balanced accuracies (average prediction accuracy on positive and negative samples) of [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] on porcine reproductive and respiratory syndrome, porcine epidemic diarrhea virus, influenza A virus, and Mycoplasma hyopneumoniae in the second system, respectively, using the six most important predictors in all cases. These models provide daily infection probabilities that can be used by veterinarians and other stakeholders as a benchmark to more timely support preventive and control strategies on farms.


[Diagnosis of liver tumors--when is scintigraphy of value?].
This paper illustrates the importance of utilizing radionuclide techniques to characterize in vivo benign liver masses. Examining the physiologic tumor function cholescintigraphy offers a highly specific pattern for identifying focal nodular hyperplasia (FNH): hypervascularisation, hepatocellular uptake and impaired transport of the bilirubin like tracer documented as trapping in later images. An hemangioma is diagnosed with high probability in case of a positive bloodpoolscintigraphy. But false-positive results have been reported. Therefore, a second unrelated examination, e.g. ultrasound, magnetic resonance imaging or dynamic computerized tomography is necessary to establish this diagnose in a sufficient certainty. If complications due to tumor growth are not expected, both, FNH and hemangioma need no further therapy. High sensitivity is necessary to establish resectability or tumor spread. Scintigraphic techniques are advantageous in scanning completely the whole body. On the other hand, there are limitations as low resolution and anatomical orientation, low specific activity in the tumor and artificial activity near by the tumor. To measure therapy effects and to detect recurrencies especially in borderline-cases positron emission computed tomography (PET)-technology is recommended, because PET offers a specific-parametric evaluation.


Nasal carriage of Staphylococcus aureus: frequency and molecular diversity in a randomly sampled Norwegian community population.
A randomly selected, healthy Norwegian community population was studied for nasal carriage of Staphylococcus aureus (S. aureus) to describe frequency and molecular diversity in a non-hospital cohort (n = 95). Multilocus sequence typing revealed 31 sequence types (STs) belonging to 15 clonal complexes (CCs). The majority of isolates (71%) were classified as CC 15, 30 or 45. This clustering was confirmed by spa typing. There was no statistically significant difference in the distribution of CCs between this community population and a previously studied group of orthopaedic health care workers from a hospital in the same community. The study may indicate that microbial and host factors may be stronger determinants for S. aureus colonization than exposures associated with the hospital environment.


Pattern formation during vasculogenesis.
Vasculogenesis, the assembly of the first vascular network, is an intriguing developmental process that yields the first functional organ system of the embryo. In addition to being a fundamental part of embryonic development, vasculogenic processes also have medical importance. To explain the organizational principles behind vascular patterning, we must understand how morphogenesis of tissue level structures can be controlled through cell behavior patterns that, in turn, are determined by biochemical signal transduction processes. Mathematical analyses and computer simulations can help conceptualize how to bridge organizational levels and thus help in evaluating hypotheses regarding the formation of vascular networks. Here, we discuss the ideas that have been proposed to explain the formation of the first vascular pattern: cell motility guided by extracellular matrix alignment (contact guidance), chemotaxis guided by paracrine and autocrine morphogens, and sprouting guided by cell-cell contacts.


Aging: changes in cardiac alpha 1-adrenoceptor responsiveness and expression.
Several investigators have reported a diminished responsiveness of senescent cardiac muscle to norepinephrine and beta-adrenoceptor agonists. In contrast, relatively little is known regarding the effects of aging on myocardial actions mediated specifically by alpha-adrenoceptor stimulation. Thus, the current study examined aging-dependent changes in: (a) the inotropic response to methoxamine, an alpha-adrenoceptor agonist; (b) characteristics of myocardial alpha 1-adrenoceptors as monitored by specific [3H]prazosin binding; and (c) steady state levels of alpha 1-adrenoceptor mRNA as determined by Northern blot analysis. Cardiac preparations were isolated from 4-, 14-, and 25-month-old F344 rats. An aging-associated decline was observed in the maximum positive inotropic effect elicited by methoxamine in right ventricular strips (160 +/- 23, 134 +/- 13 and 79 +/- 26% increase above control developed tension in 4, 14 and 25 months, respectively) with no change in ED50 values. [3H]Prazosin binding to ventricular sarcolemmal membranes revealed a reduction in receptor number (82 +/- 7, 69 +/- 6 and 59 +/- 5 fmol/mg protein in 4, 14 and 25 months, respectively); the apparent dissociation constant was not affected. Steady state levels of alpha 1-adrenoceptor mRNA decreased progressively between 4 and 25 months of age (14- and 25-month levels were approximately 71 and 38% of 4 months, respectively), while steady state levels of beta-actin mRNA did not change with age. These results suggest that the aging-related decline in alpha 1-adrenergic responsiveness in rat ventricular muscle is mediated, at least in part, by a decrease in cardiac alpha 1-adrenoceptor density.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of anti-malarial effects of mass chemoprophylaxis in the Republic of Korea army.
Vivax malaria was endemic on the Korean peninsula for many centuries until the late 1970's when the Republic of Korea (ROK) was declared "malaria free". Since its re-emergence in 1993, the number of malaria cases in the military increased exponentially through 2000 near the demilitarized zone. Chemoprophylaxis with chloroquine and primaquine has been used in the ROK Army since 1997 in an attempt to reduce the number of the malaria cases throughout the ROK. Data show that chemoprophylaxis contributed, in part, to the decrease in the number of malaria cases among military personnel. However, mass chemoprophylaxis on a large scale in the ROK Army is unprecedented and extensive supervision and monitoring is warranted to determine its effectiveness and to monitor the appearance of chloroquine tolerant/resistant strains of Plasmodium vivax.


Common Electrolyte and Metabolic Abnormalities Among Thyroid Patients.
The prevalence of thyroid diseases is high in the general population and causes serious abnormalities and disorders that can affect the quality of life. Many complications can result from poor or inappropriate management of the disease, leading to serious cardiovascular and metabolic complications. In the present review study, we aim to discuss the effect of thyroid diseases on metabolic and electrolyte abnormalities and the potential correlation with some common disorders. Evidence from previous studies has demonstrated that thyroid dysfunctions hugely affect the metabolism of glucose in the bodies of the affected patients, which can lead to the development of both type 1 and 2 diabetes mellitus (DM). Hyperthyroidism can lead to the development of impaired glucose tolerance and secondary diabetes mellitus. These include an increased glycogenolysis and gluconeogenesis process, increased intestinal absorption of glucose, and secondary ketogenesis and lipolysis, which will subsequently affect the functions of the insulin-secreting cells of the pancreas. Evidence showed that thyroid diseases are associated with the development of obesity and metabolic syndrome, and the management for these modalities should involve prior management of underlying thyroid diseases. Efforts should be made to adequately manage these cases with concomitant approaches to achieve the best clinical outcomes.


Bilateral isolated mylohyoid groove fracture progressing as submandibular abscess: an usual fracture pattern of mandible.
The mylohyoid ridges or lines are pairs of anatomical bony structures located on the internal or lingual surface of mandible. They are the origin for the mylohyoid muscle. These bony structures are distinct in the mandibular molar region, well protected and gradually become undiscernible towards anterior mandible. Bilateral, isolated fracture of the mylohyoid ridges without concomitant mandibular fracture is rare and, to the best of the authors knowledge, was never previously described. This case report describes an isolated bilateral mylohyoid groove fracture, where one side of a necrotic bone fragment at the fracture site progress to became a nidus of infection, which later caused submandibular space abscess requiring emergency surgical intervention. Diagnosis, possible theory to explain the occurrence of isolated mylohyoid groove fracture and management of these condition are explained in this report.


Structural insight into precursor ribosomal RNA processing by ribonuclease MRP.
Ribonuclease (RNase) MRP is a conserved eukaryotic ribonucleoprotein complex that plays essential roles in precursor ribosomal RNA (pre-rRNA) processing and cell cycle regulation. In contrast to RNase P, which selectively cleaves transfer RNA-like substrates, it has remained a mystery how RNase MRP recognizes its diverse substrates. To address this question, we determined cryo-electron microscopy structures of Saccharomyces cerevisiae RNase MRP alone and in complex with a fragment of pre-rRNA. These structures and the results of biochemical studies reveal that coevolution of both protein and RNA subunits has transformed RNase MRP into a distinct ribonuclease that processes single-stranded RNAs by recognizing a short, loosely defined consensus sequence. This broad substrate specificity suggests that RNase MRP may have myriad yet unrecognized substrates that could play important roles in various cellular contexts.


Use of nasal cells in micronucleus assays and other genotoxicity studies.
Genotoxicity experiments with exfoliated nasal mucosa cells are a promising minimally invasive approach for the detection of DNA-damaging compounds in ambient air. Results of single cell gel electrophoresis (SCGE) assays with individual cells and organ cultures from bioptic material show that DNA damage caused by compounds such as nitrosamines, polycyclic aromatic hydrocarbons and pesticides can be detected. Biochemical studies indicate that enzymes involved in the metabolism of environmental mutagens are represented in nasal cells. Several protocols for experiments with nasal cells have been developed and it was shown that formaldehyde, metals, styrene and crystalline silica induce DNA damage in SCGE and/or in micronucleus studies; furthermore, it was also found that polluted urban air causes DNA instability in nasal epithelial cells. Comparisons of these data with results obtained in lymphocytes and buccal cells indicate that nasal cells are in general equally sensitive. Broad variations in the baseline levels, differences of results obtained in various studies as well as the lack of information concerning the impact of confounding factors on the outcome of experiments with these cells indicate the need for further standardisation of the experimental protocols.


Premarket evaluation of Monofluor reagent for detecting Chlamydia trachomatis in adolescent outpatients.
A new direct fluorescent antibody reagent, Monofluor, was evaluated for detecting Chlamydia trachomatis in fresh specimens. Monofluor was compared with Micro Trak and with cultivation in McCoy cells. Both direct systems were slightly less sensitive than culture, but no significant differences in specificity or sensitivity were noted between culture, Monofluor, or Micro Trak results.


Successful treatment of recurrent Helicobacter fennelliae bacteraemia by selective digestive decontamination with kanamycin in a lung cancer patient receiving chemotherapy.
Helicobacter fennelliae is an enterohepatic Helicobacter species causing bacteraemia in immunocompromised hosts. Only a few cases of recurrent H. fennelliae bacteraemia have been reported in Japan and there are no guidelines regarding antimicrobial treatment for H. fennelliae infection. H. fennelliae bacteraemia was observed in a patient receiving platinum-based chemotherapy for lung cancer. To prevent recurrence, the patient received antibiotic therapy with cefepime, amoxicillin and doxycycline for 6 weeks, which is similar to the therapy for Helicobactercinaedi bacteraemia. Bacteraemia recurred despite the long-term antibiotic therapy. We hypothesized that the H. fennelliae bacteraemia originated from endogenous infection in the intestinal tract due to the long-term damage of the enteric mucosa by platinum-based drugs and performed selective digestive decontamination (SDD) with kanamycin. Bacteraemia did not recur after SDD. Our observations indicate that clinicians should be aware of possible recurrent H. fennelliae bacteraemia, which could be effectively prevented by SDD with kanamycin.


Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial.
Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce. An open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop®) to AL (Coartem®) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured. The day 42 genotyping-adjusted cure rate estimates were 97.3% [95% CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier survival estimates). The difference in day 42 cure rates was -3.1% [upper limit 95% CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 [95% CI: 0.46-0.63] (ASAQ) and 0.66 [0.57-0.73] (AL) (p = 0.017). Both ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended. The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713, ISRCTN40020296.


Compounded Bioidentical Menopausal Hormone Therapy: ACOG Clinical Consensus No. 6.
Many compounding pharmacies use the phrase "bioidentical hormone" as a marketing term to imply that these preparations are natural and, thus, safer and more effective than U.S. Food and Drug Administration (FDA)-approved menopausal medications that use bioidentical or synthetic hormones or both. However, evidence to support marketing claims of safety and effectiveness is lacking. Compounded bioidentical menopausal hormone therapy should not be prescribed routinely when FDA-approved formulations exist. Clinicians should counsel patients that FDA-approved menopausal hormone therapies are recommended for the management of menopausal symptoms over compounded bioidentical menopausal hormone therapy. If a patient requests the use of compounded bioidentical menopausal hormone therapy, clinicians should educate them on the lack of FDA approval of these preparations and their potential risks and benefits, including the risks specific to compounding. To truly understand the benefits and harms of compounded bioidentical menopausal hormone therapy, high quality placebo-controlled randomized controlled trials with long-term follow-up comparing custom-compounded products with FDA-approved menopausal hormone therapy are needed.


Paroxetine induced mania in pre-adolescence.
Selective serotonin reuptake inhibitor induced mania has been described in adults, and more recently in adolescents. To the authors' knowledge a case in pre-adolescents has not yet been published in the literature. The authors would like to report two cases of SSRI-induced mania. Both cases were pre-adolescent girls, A and B, who had a DSM-IV diagnosis of panic disorder, and were treated with paroxetine.


Synthesis and properties of 2-S-(N,N-dialkylamino)ethyl)thio-1,3,2-dioxaphosphorinane 2-oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents.
A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.220.127.116.11)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.


Cyclic AMP regulates NCAM expression and phosphorylation in cultured mouse astrocytes.
The neural cell adhesion molecule (NCAM) plays a key morphoregulatory role during neural development. Patterns of NCAM expression were investigated in cultured astrocytes exhibiting distinct states of morphological differentiation. In vitro differentiation of confluent primary cultures of astrocytes was enhanced by a long-term (7 days) treatment with dibutyryl cyclic AMP (dBcAMP). The diversity of NCAM mRNAs arising from alternative splicing of a single primary transcript was analyzed by Northern blotting. Synthetic DNA-oligonucleotide probes, designed to recognize selected exons (exons 7, 15, and VASE) or exon combinations (exons 7/8, exons 12/13, and exons 12/a/AAG/13), revealed NCAM mRNA classes of 6.7, 5.2, and 2.9 kilobases (kb) in both control and dBcAMP-treated astrocytes. Although long-term treatment of astrocytes with dBcAMP did not change the qualitative pattern of NCAM transcripts, the relative abundance of individual mRNA species appeared to be altered: in morphologically differentiated astrocytes, a general elevation of NCAM mRNA as well as preferential accumulation of the 6.7 kb message were found. The quantitative rise within this size class may primarily be accounted for by a dramatic upregulation of exon VASE-containing NCAM transcripts. In dBcAMP-treated astrocytes, immunoblot analysis revealed an unexpected expression of the 190 kDa NCAM-A isoform as well as an intense staining of bands corresponding to NCAM-B (135 kDa) and NCAM-C (115 kDa), as compared to the control pattern of untreated astrocytes. Furthermore, NCAM-A and NCAM-B were shown to be phosphorylated in astrocytes subjected to long-term treatment with dBcAMP, whereas no incorporation of [32P]phosphate into NCAM was demonstrated in untreated astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)


Anti-inflammatory, anti-diarrheal, thrombolytic and cytotoxic activities of an ornamental medicinal plant: Persicaria orientalis.
Persicaria orientalis, an ornamental medicinal plant, has been used in traditional medicine for the treatment of various diseases. Although the plant is reported to have some important pharmacological effects, many medicinal values remain unidentified. Our objective was to evaluate the anti-inflammatory, anti-diarrheal, thrombolytic, and cytotoxic properties of the methanol extract of P. orientalis leaves (Po-MeOH). Anti-inflammatory activity was measured by the inhibition of hypotonicity-induced human red blood cell hemolysis and albumin denaturation technique in vitro of Po-MeOH. Diarrheal episodes were examined in mice with castor oil-induced diarrhea. The clot lysis and brine shrimp lethality bioassay in vitro were used to evaluate the thrombolytic and cytotoxic activities of the plant extract, respectively. Using in vitro anti-inflammatory models, the results demonstrated that Po-MeOH at the five different dose ranges from 31.25 to 500 μg/mL significantly (p<0.05) protected (0.98%-50.71%) the erythrocyte membrane against lysis induced by hypotonic medium solution and protein denaturation (38.27%-79.22%) of bovine albumin, respectively. The extract exhibited a significant reduction of severity (75.17%) of castor oil-induced diarrhea in mice at the highest dose of 400 mg/kg compared to loperamide (82.06%) at 5 mg/kg. Po-MeOH also showed 33.14% clot lytic activity in the thrombolytic test and cytotoxicity with LC50 value 58.91 μg/mL in the brine shrimp bioassay. These findings suggest that Po-MeOH has significant anti-inflammatory and anti-diarrheal effects along with moderate thrombolytic and lower cytotoxic properties that may warrant the further exploration.


CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response.
CD4+ T cell help to CD8+ T cell responses requires that CD4+ and CD8+ T cells interact with the same antigen presenting dendritic cell (Ag+DC), but it remains controversial whether helper signals are delivered indirectly through a licensed DC and/or involve direct CD4+/CD8+ T cell contacts and/or the formation of ternary complexes. We here describe the first in vivo imaging of the intact spleen, aiming to evaluate the first interactions between antigen-specific CD4+, CD8+ T cells and Ag+DCs. We show that in contrast to CD4+ T cells which form transient contacts with Ag+DC, CD8+ T cells form immediate stable contacts and activate the Ag+DC, acquire fragments of the DC membranes by trogocytosis, leading to their acquisition of some of the DC properties. They express MHC class II, and become able to present the specific Marilyn peptide to naïve Marilyn CD4+ T cells, inducing their extensive division. In vivo, these CD8+ T cells form direct stable contacts with motile naïve CD4+ T cells, recruiting them to Ag+DC binding and to the formation of ternary complexes, where CD4+ and CD8+ T cells interact with the DC and with one another. The presence of CD8+ T cells during in vivo immune responses leads to the early activation and up-regulation of multiple functions by CD4+ T lymphocytes. Thus, while CD4+ T cell help is important to CD8+ T cell responses, CD8+ T cells can interact directly with naïve CD4+ T cells impacting their recruitment and differentiation.


Electrochemically Induced Nanobubbles between Graphene and Mica.
We present a new method to create dynamic nanobubbles. The nanobubbles are created between graphene and mica by reducing intercalated water to hydrogen. The nanobubbles have a typical radius of several hundred nanometers, a height of a few tens of nanometers and an internal pressure in the range of 0.5-8 MPa. Our approach paves the way to the realization of nanobubbles of which both size and internal pressure are tunable.


Practitioners' experiences of deteriorating personal hygiene standards in people living with depression in Australia: A qualitative study.
Functional impairment in people diagnosed with depression is common, although the domain of personal hygiene and grooming has received limited attention in the scholarly literature. While issues concerning personal hygiene and grooming by those experiencing depression have been reported in personal narratives, they are rarely included in symptom lists or treatment guidelines, or as an outcome indicator in research studies. The aim of this research was to better understand how mental health practitioners assessed, understood and worked with, service users diagnosed with depression who had previously exhibited declining personal hygiene and grooming standards. In-depth interviews (n = 16) explored the views of professionals experienced in this area of mental health practice. A qualitative descriptive methodology was utilised. Findings indicated that for some service users, personal hygiene and grooming issues were an integral aspect of their depression, which negatively impacted recovery, particularly in areas concerned with overall functioning, mood, social and vocational engagement, motivation, self-worth and esteem, and engagement with treatment. Study results supported the benefits of a person-centred approach to assess, engage with and intervene effectively when a decline in personal hygiene and grooming was noted. However, lack of pertinent research is a barrier to appropriately assessing specific skill or performance difficulties when declining standards are observed. This impedes the provision of interventions which might support the person to develop and maintain of personal hygiene routines, which conform to socially acceptable standards. Difficulties with personal hygiene and grooming presented both a barrier to recovery and an opportunity for timely and salient intervention. Further investigation is needed to build the research evidence needed to develop appropriate and acceptable interventions, and to inform effective treatment strategies.


H2 blockers in chronic urticaria.
Two hundred unselected patients with chronic idiopathic urticaria were treated with adequate doses of conventional antihistamines given at frequent intervals; 98.5% were completely freed of disease while on therapy. In three cases, the lesions subsided but did not clear completely. The addition of 800 mg of cimetidine in divided doses cleared the lesions in two cases, and in the third case the dose of H1 blocker was increased, which resulted in complete clearance of wheals and symptoms. Addition of H2 blockers play a role, but only in a very small percentage of patients with chronic idiopathic urticaria who do not completely respond to adequate doses of H1 blockers.


Fragile X phenotype in a patient with a large de novo deletion in Xq27-q28.
A 2-year-old boy with manifestations of the fragile X syndrome was found to have a cytogenetically visible deletion of Xq27-q28 including deletion of FMR-1. Molecular analysis of the patient was recently described in Tarleton et al. [1993: Hum Mol Genet 2(11): 1973-1974] and the deletion was estimated to be at least 3 megabases (Mb). His mother had 2 FMR-1 alleles with normal numbers of CGG repeats, 20 and 32, respectively. Thus, the deletion occurred as a de novo event. The patient does not appear to have clinical or laboratory findings other than those typically associated with fragile X syndrome, suggesting that the deletion does not remove other contiguous genes. This report describes the phenotype of the patient, including psychological studies.


From non-adherence to adherence: Can innovative solutions resolve a longstanding problem?
Non-adherence to medication is a longstanding problem, profoundly affecting patient outcomes and sustainability of healthcare systems. Historically, non-adherence has been observed since the time of Hippocrates, however, when potent drugs became available in the midst of the 20th century, it became a pivotal concern. Despite numerous studies and interventions designed, medication adherence rates remain suboptimal, currently reaching about 50 % still, as described in WHO report two decades ago. What is worse, many healthcare professionals feel neither responsible nor able to change it. Enhancing adherence requires in-depth understanding of the concept, as many intuitive approaches fail to work. For example, contrary to expectations, patient education alone proves insufficient when addressing this issue. Both behavioural models and recent experience reflecting low acceptance of COVID-19 vaccinations strongly suggest that patients' decisions are driven by emotions, which often results in intentional non-adherence. Several technical innovations, such as smart inhalers and electronic pill dispensers, offer potential solutions. However, their effectiveness varies, and standardized certification procedures are lacking. Altogether, technical solutions do not eliminate the problem entirely. To move forward, social and health system innovation is equally needed. Multiple stakeholders could benefit from improved adherence, therefore their greater involvement is advisable to create an adherence-supporting environment. In conclusion, despite available evidence-based interventions, non-adherence remains a complex challenge. Technical and social innovations, combined with a shift in policy priorities, could lead to improved medication adherence and better patient outcomes. The global tide of non-communicable chronic conditions, and aging of societies urges us to take this problem seriously.


Seasonality of nitrogen partitioning (non-structural vs structural) in the leaves and woody tissues of tropical eucalypts experiencing a marked dry season.
Numerous studies have shown that internal nitrogen (N) translocation in temperate tree species is governed by photoperiod duration and temperature. For tropical tree species, the seasonality of rainfall is known to affect growth and foliage production, suggesting that efficient internal N recycling also occurs throughout the year. We tested this hypothesis by comparing the N budgets and N partitioning (non-structural vs structural N) in the different organs of 7-year-old Eucalyptus urophylla (S.T. Blake) × E. grandis (W. Hill ex Maiden) trees from a plantation in coastal Congo on poor sandy soil. The trees were sampled at the end of the dry season and late in the rainy season. Lower N concentrations and N investment in the non-structural fraction were observed in leaves during the dry season, which indicates resorption of non-structural N from senescing leaves. Stem wood, which contributes to about 60% of the total biomass of the trees, accumulated high amounts of non-structural N at the end of the dry season, most of which was remobilized during the following rainy season. These results support the hypothesis of efficient internal N recycling, which may be an important determinant for the growth potential of eucalypts on N-poor soils. Harvesting trees late in the rainy season when stem wood is depleted in non-structural N should be recommended to limit the export of nutrients off-site and to improve the sustainability of tropical eucalypt plantations.


Origin of multiplexing capabilities of multifrequency magnetic ratchets.
Through a combination of theory, numerical simulation, and experiment, we investigate the motion of magnetic beads on the surface of a magnetic ratchet driven by multifrequency fields. Here, we focus on the influence of static forcing terms, which were not included in previous models, and we derive analytical models that show why the static forcing terms are responsible for inducing beads of two different sizes to move in opposite directions on the same ratchet potential. We begin our analysis with the simplest possible forcing model, and we show that the main effect of the static forcing terms is to delay the phase of flux reversal. From there, we move onto the full analysis and theoretically derive the phase range for which opposite motion among two different bead types is achieved. Based on these theoretical results, we conduct experimental investigations that explore the effects of bead size and static forcing coefficient on the direction of bead motion, which confirm most of the expected trends. These results shed light both on past experimental work both by ourselves and others, as well as elucidate the more general multiplexing capabilities of ratchets.


Effects of moderate exercise and oat beta-glucan on innate immune function and susceptibility to respiratory infection.
Both moderate exercise and the soluble oat fiber beta-glucan can increase immune function and decrease risk of infection, but no information exists on their possible combined effects. This study tested the effects of moderate exercise and oat beta-glucan on respiratory infection, macrophage antiviral resistance, and natural killer (NK) cell cytotoxicity. Mice were assigned to four groups: exercise and water, exercise and oat beta-glucan, control water, or control oat beta-glucan. Oat beta-glucan was fed in the drinking water for 10 days before intranasal inoculation of herpes simplex virus type 1 (HSV-1) or euthanasia. Exercise consisted of treadmill running (1 h/day) for 6 days. Macrophage resistance to HSV-1 was increased with both exercise and oat beta-glucan, whereas NK cell cytotoxicity was only increased with exercise. Exercise was also associated with a 45 and 38% decrease in morbidity and mortality, respectively. Mortality was also decreased with oat beta-glucan, but this effect did not reach statistical significance. No additive effects of exercise and oat beta-glucan were found. These data confirm a positive effect of both moderate exercise and oat beta-glucan on immune function, but only moderate exercise was associated with a significant reduction in the risk of upper respiratory tract infection in this model.


Intrathecal Injection of Resveratrol Attenuates Burn Injury Pain by Activating Spinal Sirtuin 1.
The present study sought to detect spinal sirtuin 1 (SIRT1) and acetylation of histone H3 (Ac-H3) expression in rats with burn injury pain (BIP model). A BIP model was first established. BIP rats showed lower paw withdrawal threshold (PWT) from day 1, which persisted for 21 days following the burn injury. Spinal SIRT1/Ac-H3 expression increased following burn injury. The intrathecal use of resveratrol increased PWT and SIRT1 expression but induced down-regulation of Ac-H3 expression. We first demonstrated that the inhibition of SIRT1 significantly induced mechanical allodynia in naïve rats. The preinjection of SIRT1 inhibitor partly antagonized the analgesic effects of resveratrol in BIP rats. Inhibition of SIRT1 produces pain facilitation in the naïve rats. The expression of spinal SIRT1 increased after burn injury in the BIP model. The activation of spinal SIRT1 might mediate the resveratrol-induced analgesic effects. Burn injury resulted in pain facilitationResveratrol attenuates pain facilitation induced by burn injuryIntrathecal injection of resveratrol attenuates burn injury pain by increasing spinal sirtuin 1 (SIRT1) expressionInhibition of SIRT1 by selisistat, an SIRT1 inhibitor attenuated analgesic effects of resveratrol Abbreviations used: SIRT1: Sirtuin 1, Ac-H3: Acetylation of histone H3, SD: Sprague-Dawley, EX527: Selisistat, an SIRT1 inhibitor, BIP: Burn injury pain, DMSO: Dimethyl sulfoxide, PWTs: Paw withdrawal thresholds.


Proliferation, macrophage colony-stimulating factor, and macrophage colony-stimulating factor-receptor expression of alveolar macrophages in active sarcoidosis.
Alveolar macrophages (AM) in sarcoidosis display an enhanced mitotic activity. Immunocytochemical detection of the proliferation-associated Ki-67 antigen revealed significant increase in the number of proliferating AM in active sarcoidosis as compared with inactive stages of disease. Macrophage proliferation may provide an additional marker of disease activity. Since growth of macrophages is regulated by hematopoietic growth factors, we examined the expression of macrophage colony-stimulating factor (M-CSF), granulocyte M-CSF, and interleukin-3 by bronchoalveolar lavage cells in active sarcoidosis. Expression of granulocyte M-CSF or interleukin-3 genes could not be detected. AM in active sarcoidosis displayed M-CSF RNA to a comparable level like normal AM. They differed, however, in about 50% of cases analyzed, from normal AM by an enhanced level of c-fms proto-oncogene (M-CSF-receptor) expression. The enlarged proportion of proliferating AM in active sarcoidosis may be the result of an increased influx of strongly fms expressing macrophage precursors into the alveoli and autostimulation of macrophages by M-CSF.


Detection of antibodies against Trypanosoma cruzi in donors from a blood bank in Cuernavaca, Morelos, Mexico.
Surveys carried out in the Mexican state of Morelos indicate the presence of Chagas' disease. The aim of this work was to perform a pilot study to detect the presence of antibodies against Trypanosoma cruzi in donors from the Blood Bank at the Regional Hospital of Cuernavaca, Morelos. From March-September 1993, blood samples from 318 donors (284 men and 34 women) were collected. The of age range donors was from 18-45 years. Antibodies against T. cruzi were determined using a commercial ELISA kit. Fifty-four (17%) serum samples had antibodies against T. cruzi: 34 out of 284 men, and 20 out of 34 women were positive (11.9 and 58.8%, respectively). Of the 128 individuals who donated blood more than once, 9 (7%) were positive and had previously donated blood from 1-4 times. Antibodies against Leishmania sp. and T. rangeli were not determined. Based on the results of this study, procedures to detect antibodies against T. cruzi in blood donors and the application of a questionnaire inquiring into risk factors for T. cruzi infection should be implemented.


Inhibition of lovastatin on proliferation and expression of proinflammatory cytokines in cultured human glomerular mesangial cells.
To study the effects and mechanism of lovastatin on cell proliferation and expression of proinflammatory cytokines in cultured human glomerular mesangial cells. The influence of lovastatin on HMC proliferation was evaluated with 3H-thymidine incorporation. mRNA expression of proinflammatory cytokines (IL-1 beta, IL-6, TNF-alpha, and MCP-1) and activation of NF-kappa B of HMC were measured using Reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA) respectively. Lovastatin was found to have inhibitory effects on human mesangial cell (HMC) proliferation and lipopolysaccharide (LPS)-mediated human mesangine cell HMC mRNA expression of proinflammatory cytokines via activation of NF-kappa B. The effect of lovstatin on HMC could be prevented when the mevalonate and farnesol were added to the culture. Lovastatin may decrease HMC proliferation and production of proinflammatory cytokines through the inhibition of NF-kappa B activation. This provided experimental evidence for further evaluation of the renal protective effect of HRI, suggesting that it may be a potent agent for prevention of progressive renal diseases aside from its lipid-lowering effect.


Amino acid supplementation for enhancing recombinant protein production in E. coli.
Recombinant protein production (RPP) in Escherichia coli (E. coli) often induces metabolic burden to the cells that compromise their overall growth and productivity. Amino acid starvation due to RPP is a major contributor of the metabolic burden on the cells and induces global stress response known as a stringent-like response. In this study, the effect of amino acid supplementation in a chemically defined medium on cellular growth and recombinant pramlintide production was investigated. Based on the consumption profile, few amino acids were categorized as growth-promoting (GP1) and protein production promoting (GP2). Feeding strategies of GP1 and GP2 were tested in shake flasks followed by scale up into the bioreactor. A 40% increase in the recombinant pramlintide (rPramlintide) production (protein concentration of 3.09 ± 0.12 g/L and yield of 227.69 ± 19.72 mg pramlintide per gram dry cell weight) was realized. Furthermore, transcriptomics data indicated the downregulation of several genes associated with global stress response and genes involved in amino acid biosynthesis in test culture, supported by proteomics analysis. These results signify that the external supply of critical amino acids decreases cellular stress during RPP and improves process productivity.


Optical and photophysical properties of indolocarbazole derivatives.
We present a study of the optical and photophysical properties of five ladder indolo[3,2-b]carbazoles, namely, M1, M2, M3, M4, and M5. The ground-state optimized structures were obtained by B3LYP/6-31G* density functional theory (DFT) calculations, whereas the optimization (relaxation) of the first singlet excited electronic state (S1) was performed using the restricted configuration interaction (singles) (RCIS/6-31G*) approach. The excitation to the S1 state does not cause important changes in the geometrical parameters of the compounds, as corroborated by the small Stokes shifts. The excitation and emission energies have been obtained by employing the time-dependent density functional theory (TDDFT). For all the compounds, excitation to the S1 state is weakly allowed, whereas the S2 <-- S0 electronic transition of each oligomer possesses a much larger oscillator strength. The absorption and fluorescence spectra of the compounds have been recorded in chloroform. A reasonable agreement is obtained between TDDFT vertical transition energies and the (0,0) absorption and fluorescence bands. On one hand, the pattern of the aliphatic side chains does not affect the absorption and fluorescence maxima of the compounds. On the other hand, the replacement of aliphatic chains by phenyl or thiophene rings induces hypsochromic shifts in the absorption and fluorescence spectra. Finally, the fluorescence quantum yield and lifetime of the compounds in chloroform have been obtained. From these data, the radiative and nonradiative rate constants of the deactivation of the S1 state have been determined.


The Italian version of the "frailty index" based on deficits in health: a validation study.
Several measurements were taken for frailty classification in geriatric population. "Frailty index" is based on "deficits in health," but it is still not available in Italian version. Thus, the aim of the present work was to validate a version of "frailty index" for the Italian geriatric community. The validation of Italian frailty index (IFi) is based on a cohort study that enrolled 1077 non-disabled outpatients aged 65 years or older (81.3 ± 6.5 years) in Naples (Italy). IFi has been expressed as a ratio of deficits present/deficits considered after a comprehensive geriatric assessment. IFi was stratified in light, moderate and severe frailty. Mortality, disability (considering an increase in ADL lost ≥1 from the baseline) and hospitalization were considered at 3, 6, 12, 18 and 24 months of follow-up. Area under curve (AUC) was evaluated for both Fried's and IFi frailty index. At the end of follow-up, mortality increased from 1.0 to 30.3%, disability from 40.9 to 92.3% and hospitalization from 0.0 to 59.0% (p < 0.001 for trend). Multivariate analysis shows that the relative risk for unit increase in IFi is 1.09 (95% CI = 1.01-1.17, p = 0.013) for mortality, 1.04 (95% CI = 1.01-1.06, p = 0.024) for disability and 1.03 (95% CI = 1.01-1.07, p = 0.041) for hospitalization. AUC is higher in IFi with respect to Fried's frailty index when considering mortality (0.809 vs. 0.658, respectively), disability (0.800 vs. 0.729, respectively) and hospitalization (0.707 vs. 0.646, respectively). IFi is a valid measure of frailty after the comprehensive geriatric assessment in an Italian cohort of non-institutionalized patients.


The treatment of adolescents presenting with a varicocele.
In the last 10 years there have been many reports of children and adolescents with varicocele, but virtually none from the UK. There is an increasing incidence with age, to 19% by the age of 19 years. There is some evidence that a varicocele impairs the development of the affected testis; 9.3% of boys of 19 years old have a small testis as a result. Some aspects of testicular function are compromised. Treatment of the varicocele allows compensatory growth and testicular function. The surgical technique must be meticulous to avoid complications, particularly the formation of a hydrocele. Despite much research, the effect on fertility is unknown. The incidence of varicocele is much higher than that of male factor infertility. It is not known whether varicocele in adolescence impairs fertility or whether surgery restores fertility. At present the main indications for surgery are persistent delay in growth of >20%, bilateral varicocele and impaired spermatogenesis persisting beyond 18 years old.


mFOLFOX6 Plus Panitumumab Versus 5-FU/LV Plus Panitumumab After Six Cycles of Frontline mFOLFOX6 Plus Panitumumab: A Randomized Phase II Study of Patients With Unresectable or Advanced/Recurrent, RAS Wild-type Colorectal Carcinoma (SAPPHIRE)-Study Design and Rationale.
In Japan, oxaliplatin (OXA)/5-fluorouracil (5-FU)/leucovorin (LV)-the mFOLFOX6 regimen-is the most frequently used first-line chemotherapy backbone for metastatic colorectal cancer. However, peripheral nerve disorders caused by OXA during mFOLFOX6 therapy can decrease patients' quality of life. OXA can be safely discontinued from a FOLFOX regimen after 6 cycles during first-line therapy. Also, for patients who discontinue OXA without having experienced peripheral nerve disorders, reintroducing OXA in the later stages of treatment could remain an option. The study is a phase II, multicenter, open-label, parallel-group, randomized, controlled exploratory study comparing the efficacy and safety of mFOLFOX6 plus panitumumab and 5-FU/LV plus panitumumab in patients with chemotherapy-naïve, unresectable, advanced or recurrent colorectal carcinoma of RAS wild-type (SAPPHIRE; ClinicalTrials.gov identifier, NCT02337946). Eligible patients will receive 6 cycles of mFOLFOX6 plus panitumumab combination therapy, followed by 1:1 randomization to either further treatment with mFOLFOX6 plus panitumumab or discontinuation of OXA and treatment with 5-FU/LV plus panitumumab. Up to 100 randomized patients will receive treatment for approximately 12 months or until any of the criteria for treatment discontinuation have been met. The primary endpoint is progression-free survival rate at 9 months after the day of randomization. The secondary endpoints are progression-free survival, overall survival, response rate, and interval to treatment failure. Safety will be evaluated according to the incidence and severity of adverse events, including the incidence of peripheral nerve and skin disorders. Additional endpoints will include maintenance of performance status, continuation of OXA in the mFOLFOX6 plus panitumumab group, and continuation of panitumumab in both groups.


Electrical connection between the right atrium and the superior vena cava, and the extent of myocardial sleeve in a patient with atrial fibrillation originating from the superior vena cava.
We describe a case in which the superior vena cava (SVC) was electrically isolated by an application of radiofrequency energy to a point with electrical connection between the right atrium and the SVC in a patient with atrial fibrillation (AF) originating from the SVC. The connection was located in the posteroseptal region between the right atrium and the myocardial sleeve extending into the SVC. Local AF occurred after radiofrequency ablation and rapid activities were recorded all around the SVC, whereas the atrium was still in sinus rhythm. It is suggested that focal AF in the SVC contributes not only to the initiation but also to the maintenance of AF, and the myocardial sleeve extends into the SVC through a connection point to cover the entire internal lumen.


Surgical treatment for ventricular aneurysm.
The results of 110 patients with ventricular aneurysm treated surgically are discussed. The overall mortality in this group was 11.8 per cent. Since the use of coronary bypass operation and the intra-aortic balloon pump, the mortality has been significantly reduced.


Co-expression of bacterial hemoglobin overrides high glucose-induced repression of foreign protein expression in Escherichia coli W3110.
Co-expression of Vitreoscilla hemoglobin (VHb) can enhance production of foreign proteins in several microorganisms, including Escherichia coli. Production of foreign proteins [green fluorescent protein (GFP) and organophosphorous hydrolase (OPH)] has been examined in two typical industrial E. coli strains, W3110 (a K12 derivative) and BL21 (a B derivative). In particular, we investigated the effects of VHb co-expression and media glucose concentration on target protein production. We employed the nar O(2)-dependent promoter for self-tuning of VHb expression based on the natural changes in dissolved O(2) levels over the duration of culture. Foreign protein production in strain BL21 was decreased by a high glucose concentration but co-expression of VHb had no effect on this. In contrast, co-expression of VHb in strain W3110 overrode the glucose-induced repression and resulted in steady expression of foreign proteins.


At what degree of belief in a research hypothesis is a trial in humans justified?
Randomized controlled trials (RCTs) have emerged as the most reliable method of assessing the effects of health care interventions in clinical medicine. However, RCTs should be undertaken only if there is substantial uncertainty about which of the trial treatments would benefit a patient most. The purpose of this study is to determine the degree of uncertainty in a research hypothesis before it can empirically be tested in an RCT. We integrated arguments from three independent lines of research - on ethics, principles of the design and conduct of clinical trials, and medical decision making - to develop a decision model to help solve the dilemma of under which circumstances innovative treatments should be tested in an RCT. We showed that RCTs are the preferable option to resolve uncertainties about competing treatment alternatives whenever we desire reliable, undisputed, high-quality evidence with a low likelihood of false-positive or false-negative results. When the expected benefit:risk ratio of a new treatment is small, an RCT is justified to resolve uncertainties over a wide range of prior belief (e.g. 10-90) in the accuracy of the research hypothesis. Randomized controlled trials represent the best means for resolving uncertainties about health care interventions.


[Cost-benefit relationship between endoscopic resection (TURP) and open surgery (Millen) in prostatic hypertrophy ].
Evaluation of the cost/benefit relationship between TURP (50 cases) and Millin (30 cases). The factors considered are as follows: average post-operative hospitalization, average catheterisation time, average operation time, cost of materials, number of operators employed, number of transfused blood units. The post-operative hospitalization relating to the two kinds of operation varies considerably with a difference of 5.15 days less for the TURP, while the average catheterisation time doesn't seem to be affected. Blood transfusion was necessary in the 43.3% (0.75 unit/patient) of cases for the Millin compared to the 14% (0.26 unit/patient) for the TURP. Evaluation of economical advantages between TURP and Millin shows a relationship of 1:2.3 in favour for of TURP.


Biodegradable silicon nanoneedles for ocular drug delivery.
Ocular drug delivery remains a grand challenge due to the complex structure of the eye. Here, we introduce a unique platform of ocular drug delivery through the integration of silicon nanoneedles with a tear-soluble contact lens. The silicon nanoneedles can penetrate into the cornea in a minimally invasive manner and then undergo gradual degradation over the course of months, enabling painless and long-term sustained delivery of ocular drugs. The tear-soluble contact lens can fit a variety of corneal sizes and then quickly dissolve in tear fluid within a minute, enabling an initial burst release of anti-inflammatory drugs. We demonstrated the utility of this platform in effectively treating a chronic ocular disease, such as corneal neovascularization, in a rabbit model without showing a notable side effect over current standard therapies. This platform could also be useful in treating other chronic ocular diseases.