Rapid and reversible control of human metabolism by individual sleep states.
Sleep is crucial to restore body functions and metabolism across nearly all tissues and cells, and sleep restriction is linked to various metabolic dysfunctions in humans. Using exhaled breath analysis by secondary electrospray ionization high-resolution mass spectrometry, we measured the human exhaled metabolome at 10-s resolution across a night of sleep in combination with conventional polysomnography. Our subsequent analysis of almost 2,000 metabolite features demonstrates rapid, reversible control of major metabolic pathways by the individual vigilance states. Within this framework, whereas a switch to wake reduces fatty acid oxidation, a switch to slow-wave sleep increases it, and the transition to rapid eye movement sleep results in elevation of tricarboxylic acid (TCA) cycle intermediates. Thus, in addition to daily regulation of metabolism, there exists a surprising and complex underlying orchestration across sleep and wake. Both likely play an important role in optimizing metabolic circuits for human performance and health.


Isoprenylated proteins in myelin.
Incubation of rat brainstem slices with [3H]-mevalonate ([3H]MVA) in the presence of lovastatin resulted in the incorporation of label into three groups of myelin-associated proteins with molecular masses of 47, 21-27, and 8 kDa, as revealed on sodium dodecyl sulfate-polyacrylamide rod gel electrophoresis. Although the gel patterns of [3H]MVA-derived prenylated proteins were similar, the relative level of 3H incorporated into each protein species differed between myelin and the brainstem homogenate. Immunoprecipitation studies identified the 47-kDa prenylated protein as a 2'-3'-cyclic nucleotide phosphodiesterase, whereas the 8-kDa protein proved to be the gamma subunit of membrane-associated guanine nucleotide regulatory protein. The 3H-labeled 21-27-kDa group in myelin corresponds to the molecular mass of the extensive Ras-like family of monomeric GTP-binding proteins known to be prenylated in other tissues. Increase in lovastatin concentration resulted in reduced levels of [3H]MVA-labeled species in myelin and concomitantly increased levels in the cytosol. A cold MVA chase restored to normality the appearance of [3H]MVA-labeled proteins in myelin. Furthermore, a high lovastatin concentration in the brainstem slice incubation mixture altered the appearance of newly synthesized nonprenylated myelin proteins, including proteolipid protein and the 17-kDa subspecies of myelin basic protein. Because other myelin proteins were unaffected by the high lovastatin concentration, restricting the availability of MVA in myelin-forming cells may selectively alter processes required for myelinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)


Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy.
Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition.


Future hydrological regimes and glacier cover in the Everest region: The case study of the upper Dudh Koshi basin.
Assessment of future water resources under climate change is required in the Himalayas, where hydrological cycle is poorly studied and little understood. This study focuses on the upper Dudh Koshi river of Nepal (151km(2), 4200-8848ma.s.l.) at the toe of Mt. Everest, nesting the debris covered Khumbu, and Khangri Nup glaciers (62km(2)). New data gathered during three years of field campaigns (2012-2014) were used to set up a glacio-hydrological model describing stream flows, snow and ice melt, ice cover thickness and glaciers' flow dynamics. The model was validated, and used to assess changes of the hydrological cycle until 2100. Climate projections are used from three Global Climate Models used in the recent IPCC AR5 under RCP2.6, RCP4.5 and RCP8.5. Flow statistics are estimated for two reference decades 2045-2054, and 2090-2099, and compared against control run CR, 2012-2014. During CR we found a contribution of ice melt to stream flows of 55% yearly, with snow melt contributing for 19%. Future flows are predicted to increase in monsoon season, but to decrease yearly (-4% vs CR on average) at 2045-2054. At the end of century large reduction would occur in all seasons, i.e. -26% vs CR on average at 2090-2099. At half century yearly contribution of ice melt would be on average 45%, and snow melt 28%. At the end of century ice melt would be 31%, and snow contribution 39%. Glaciers in the area are projected to thin largely up to 6500ma.s.l. until 2100, reducing their volume by -50% or more, and their ice covered area by -30% or more. According to our results, in the future water resources in the upper Dudh Koshi would decrease, and depend largely upon snow melt and rainfall, so that adaptation measures to modified water availability will be required.


Studies directed toward the total synthesis of lancifodilactone G: an expeditious route to the ABC subunit.
An efficient entry to the ABC network of lancifodilactone G is outlined. The C ring is constructed by way of enyne ring-closing metathesis. The AB component is established via a base-mediated biomimetic oxy-Michael addition--lactonization sequence.


Micro-replication platform for studying the structural effect of seed surfaces on wetting properties.
Biological surfaces in plants are critical for controlling essential functions such as wettability, adhesion, and light management, which are linked to their adaptation, survival, and reproduction. Biomimetically patterned surfaces replicating the microstructures of plant surfaces have become an emerging tool for understanding plant-environment interactions. In this study, we developed a two-step micro-replication platform to mimic the microstructure of seed surfaces and demonstrated that this initial platform can be used to study seed surface-environment interactions. The two-step process involved the extraction of a simplified seed surface model from real seeds and micro-replication of the simplified seed surface model using nanoimprint lithography. Using Allium seeds collected from Mongolia and Central Asia as the model system, we studied the wettability of biological and synthetic seed surfaces. We could independently control the material properties of a synthetic seed surface while maintaining the microstructures and, thereby, provide clear evidence that Allium seed surfaces were highly wettable owing to the high surface energy in the epidermal material rather than a microstructural effect. We expect that this platform can facilitate study of the independent effect of microstructure on the interaction of seed surfaces with their surroundings and contribute to research on the evolution of plant-environment interactions.


The monoclonal antibody directed to difucosylated type 2 chain (Fuc alpha 1 leads to 2Gal beta 1 leads to 4[Fuc alpha 1 leads to 3]GlcNAc; Y Determinant).
One of the monoclonal (AH-6) antibodies prepared by hybridoma technique against human gastric cancer cell line MKN74 was found to react with a series of glycolipids having the Y determinant (Fuc alpha 1 leads to 2Gal beta 1 leads to 4[Fuc alpha 1 leads to 3]GlcNAc). The structure of one such glycolipid isolated from human colonic cancer and from dog intestine was identified as lactodifucohexaosyl-ceramide (Fuc alpha 1 leads to 2Gal beta 1 leads to 4[Fuc alpha 1 leads to 3]GlcNAc beta 1 leads to 3Gal beta 1 leads to 4Glc beta 1 leads to 1-ceramide; IV3,III3Fuc2nLc4Cer). The hapten glycolipid did not react with monoclonal antibodies directed to Lea, Leb, and X-hapten structures, and the AH-6 antibody did not react with the X-hapten ceramide pentasaccharide (Gal beta 1 leads to 4[Fuc alpha 1 leads to 3]GlcNAc beta 1 leads to 3Gal beta 1 leads to 4Glc beta 1 leads to 1-ceramide), H1 glycolipid (Fuc alpha 1 leads to 2Gal beta 1 leads to 4GlcNAc beta 1 leads to 3Gal beta 1 leads to 4Glc beta 1 leads to 1-ceramide), nor with glycolipids having the Leb (Fuc alpha 1 leads to 2Gal beta 1 leads to 3[Fuc alpha 1 leads 4]GlcNAc beta 1 leads to R) determinant. The antibody reacted with blood group O erythrocytes, but not with A erythrocytes. Immunostaining of thin layer chromatography with the monoclonal antibody AH-6 indicated that a series of glycolipids with the Y determinant is present in tumors and in O erythrocytes.


Isolation of genes highly expressed in early and late stages of Friend virus-induced erythroleukemia in mice.
We isolated two genes that are highly expressed in Friend erythroleukemia. The first one, expressed at an extremely high level in a late-stage tumorigenic cell line F5-5, was found to be a species of intracisternal A-particle. Most of those genomes in F5-5 DNA were not amplified nor rearranged compared with those in the normal cell DNA, suggesting transcriptional activation. Another late-stage cell line T3K showed similar results. The second gene, highly expressed in early-stage cells but weaker in late-stage cells, was identified as one of the heme-synthesizing enzymes, uroporphyrinogen decarboxylase. Usefulness of these two genes for the analysis of erythroid transformation and differentiation will be discussed.


Safety and efficacy of prolonged levofloxacin inhalation solution (APT-1026) treatment for cystic fibrosis and chronic Pseudomonas aeruginosa airway infection.
Levofloxacin inhalation solution (LIS) is the first aerosolized fluoroquinolone licensed for treatment of patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infection. This study evaluated the safety and efficacy of extended LIS treatment. Patients completing a multinational, randomized study comparing LIS and tobramycin inhalation solution (TIS) were enrolled in an open-label extension in which all patients received three additional cycles of 28days of LIS 240mg twice daily followed by 28days off drug. Endpoints included mean relative change in percent predicted forced expiratory volume in 1s (FEV1), time to pulmonary exacerbation, and patient-reported quality of life. Extended treatment with LIS in 88 patients was well tolerated with no new safety signals and evidence of positive effects on FEV1 and quality of life. Patients receiving extended LIS treatment continued to show favorable efficacy with no additional safety concerns.


Phenotypic heterogeneity of vascular endothelial cells in the human kidney.
To clarify the structural base of immune response occurring in the kidney, we investigated the antigenic and functional properties of vascular endothelial cells. Peritubular capillary endothelial cells exhibited the same immunohistochemical characteristics (OKM5-positive, HLA-DR-positive, Factor VIII/von Willebrand factor antigen-negative, Interleukin 1-positive) as a peripheral blood macrophage subset capable of presenting soluble antigens and triggering the autologous mixed lymphocyte reaction. On the other hand, endothelial cells of glomerular capillary loops, considered to be involved in blood coagulation, were OKM5-negative, HLA-DR-positive, Factor VIII/von Willebrand factor antigen-positive, Interleukin 1-positive. Thus the results of this study suggest that vascular endothelial cells in different anatomic compartments of the kidney express surface antigens heterogenously and may play different roles in the immune reaction.


Novel protein Callipygian defines the back of migrating cells.
Asymmetric protein localization is essential for cell polarity and migration. We report a novel protein, Callipygian (CynA), which localizes to the lagging edge before other proteins and becomes more tightly restricted as cells polarize; additionally, it accumulates in the cleavage furrow during cytokinesis. CynA protein that is tightly localized, or "clustered," to the cell rear is immobile, but when polarity is disrupted, it disperses throughout the membrane and responds to uniform chemoattractant stimulation by transiently localizing to the cytosol. These behaviors require a pleckstrin homology-domain membrane tether and a WD40 clustering domain, which can also direct other membrane proteins to the back. Fragments of CynA lacking the pleckstrin homology domain, which are normally found in the cytosol, localize to the lagging edge membrane when coexpressed with full-length protein, showing that CynA clustering is mediated by oligomerization. Cells lacking CynA have aberrant lateral protrusions, altered leading-edge morphology, and decreased directional persistence, whereas those overexpressing the protein display exaggerated features of polarity. Consistently, actin polymerization is inhibited at sites of CynA accumulation, thereby restricting protrusions to the opposite edge. We suggest that the mutual antagonism between CynA and regions of responsiveness creates a positive feedback loop that restricts CynA to the rear and contributes to the establishment of the cell axis.


African trypanosomiasis: treatment-induced invasion of brain and encephalitis.
Histological sections of the brain from Microtus montanus infected with Trypanosoma rhodesiense and treated after the initial infection period showed that trypanosomes promptly invade the brain tissue and induce a severe encephalitis within a very short time. These findings suggest that the brain invasion and encephalitis that occur after treatment in sleeping sickness must be considered an effect of the treatment. The results illustrate that the brain invasion is probably not hematogenic but rather due to a process of parasite migration from the subarachnoidal space over the Virchow-Robin spaces into the brain.


[Behçet's syndrome. Apropos of 12 cases].
Twelve observations of Behcet's syndrome are described, which comply with the diagnostic criteria of O'DUFFY. The clinic symptomatology is reviewed and compared with those found by other authors.


Congenital anomalies of the seminal ducts.
The frequency of individual congenital anomalies of the deferens, the seminal vesicles, the ejaculatory ducts and the utricle in 158 patients treated for sterility was determined by the method of deferentovesiculography by punction. Congenital anomalies were found in 14 patients (8.8%). Anomalies of rare occurrence are demonstrated in detail. The relation of such anomalies to sterility of patients is described.


Linking soil organic carbon stock to microbial stoichiometry, carbon sequestration and microenvironment under long-term forest conversion.
Forest conversion can drastically impact carbon (C) and nutrient processes and microbial stoichiometry, which will modify soil organic C (SOC) stock. However, SOC stock dynamics and its underlying mechanisms induced by long-term forest conversion remain unclear. Three well-protected plantations converted from natural forests for 36 years were compared, i.e., Cryptomeria fortunei (CF), Metasequoia glyptostroboides (MG) and Cunninghamia lanceolata (CL), with a natural forest (NF) as a control. SOC stock size and stability across three soil depths (0-10, 10-30 and 30-60 cm) were examined with aggregate-based method. Forest floors and fine roots were treated as C and nutrient inputs while soil respiration (Rs) was treated as C output. Soil microbial biomass C, nitrogen and phosphorus were measured to calculate microbial stoichiometry, as well as microenvironment and soil physicochemical properties. The relationships between SOC stock (size and stability) and these factors were explored using structural equation model. The results showed that microbial stoichiometry had strong or strict homeostasis at each soil depth. At 0-10 cm soil deep, SOC stock size varied with tree species (following the rank of CL > NF ≈ CF > MG) but its stability increased in all forest conversion types, regulated by forest floor quantity and quality associated with Rs; at 10-30 cm soil deep, the SOC stock sizes decreased in CF and MG, but SOC stock stability increased in MG, jointly driven by fine root quality and microenvironment; at 30-60 cm soil deep, SOC stock size decreased but its stability increased in MG, whereas both its size and stability had few changes in CF or CL, modified by soil physicochemical property associated with microbial stoichiometry and Rs. Overall, the effects of microbial stoichiometry and microenvironment on SOC stock were not pronounced. Thus, SOC stock size changed with soil depth and tree species but its stability tended to be steady at all depths varying with tree species. These results suggest that SOC stock size and stability are mainly determined by self-regulation process of forest ecosystems over more than three-decade after forest conversion, which will help us more accurately assess C sequestration strategies regarding long-term forest conversion.


Cationic crosslinked carbon dots-adjuvanted intranasal vaccine induces protective immunity against Omicron-included SARS-CoV-2 variants.
Mucosal immunity plays a significant role in the first-line defense against viruses transmitted and infected through the respiratory system, such as SARS-CoV-2. However, the lack of effective and safe adjuvants currently limits the development of COVID-19 mucosal vaccines. In the current study, we prepare an intranasal vaccine containing cationic crosslinked carbon dots (CCD) and a SARS-CoV-2 antigen, RBD-HR with spontaneous antigen particlization. Intranasal immunization with CCD/RBD-HR induces high levels of antibodies with broad-spectrum neutralization against authentic viruses/pseudoviruses of Omicron-included variants and protects immunized female BALB/c mice from Omicron infection. Despite strong systemic cellular immune response stimulation, the intranasal CCD/RBD-HR vaccine also induces potent mucosal immunity as determined by the generation of tissue-resident T cells in the lungs and airway. Moreover, CCD/RBD-HR not only activates professional antigen-presenting cells (APCs), dendritic cells, but also effectively targets nasal epithelial cells, promotes antigen binding via sialic acid, and surprisingly provokes the antigen-presenting of nasal epithelial cells. We demonstrate that CCD is a promising intranasal vaccine adjuvant for provoking strong mucosal immunity and might be a candidate adjuvant for intranasal vaccine development for many types of infectious diseases, including COVID-19.


hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer.
The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. The lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1) as an important zinc transporter involved in zinc accumulation in prostate cells. Therefore, we investigated the possibility that down-regulation of hZIP1 gene expression might be involved in the inability of malignant prostate cells to accumulate zinc. To address this issue, the expression of hZIP1 and the depletion of zinc in malignant versus non-malignant prostate glands of prostate cancer tissue sections were analyzed. hZIP1 expression was also determined in malignant prostate cell lines. hZIP1 gene expression, ZIP1 transporter protein, and cellular zinc were prominent in normal peripheral zone glandular epithelium and in benign hyperplastic glands (also zinc accumulating glands). In contrast, hZIP1 gene expression and transporter protein were markedly down-regulated and zinc was depleted in adenocarcinomatous glands and in prostate intra-epithelial neoplastic foci (PIN). These changes occur early in malignancy and are sustained during its progression in the peripheral zone. hZIP1 is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1. The studies clearly establish that hZIP1 gene expression is down regulated and zinc is depleted in adenocarcinomatous glands. The fact that all the malignant cell lines express hZIP1 indicates that the down-regulation in adenocarcinomatous glands is likely due to in situ gene silencing. These observations, coupled with the numerous and consistent reports of loss of zinc accumulation in malignant cells in prostate cancer, lead to the plausible proposal that down regulation of hZIP1 is a critical early event in the development prostate cancer.


A simple computer-based method for performing and analyzing intracranial self-stimulation experiments in rats.
Intracranial self-stimulation (ICSS) in the rat is a useful tool for studying the importance of various brain monoamines in positive reinforcement. The effects of compounds interacting with dopaminergic neurotransmission is measurable by studying the changes of reward thresholds. By computerisation of the analysis of these thresholds, standardisation and reproducibility is greatly enhanced. The use of an object-oriented programming language simplifies the programming of a specific application and it provides scientists without formal training in computer programming the means to create their own software. A system for the acquisition, execution, analysis and storage of ICSS experiments is described. The hardware is based on Apple Macintosh computers, interfaced to the test chambers and physiological stimulators using a plug-in card supporting A/D, D/A, digital I/O and timer functions. The software written in G (LabVIEW) provides the user with a graphically based 'Virtual Instrument' performing all aspect of the ICSS experiment. The software performs threshold analysis immediately after completion of the ICSS experiment, thereby greatly reducing the total time previously needed to evaluate these experiments. The graphical approach used in LabVIEW allows the programmer to make fast and simple alterations to suit different experimental problems.


Electrosurgical fundamentals.
Electrosurgery is used regularly by physicians in the performance of minor outpatient surgery. Most dermatologists are familiar with the electrosurgical methods used to treat many common skin lesions. Many practitioners, however, are unfamiliar with the electrophysical fundamentals underlying these modalities. The basic principles necessary for the safe and optimal use of these methods are presented herein.


The effect of treatment with Corynebacterium parvum on the development and growth of experimental hematogenic metastases of schwannoma in the rat.
Single i.v. administration of Corynebacterium parvum 5 days before i.v. injection of 10(6) tissue cultured syngeneic schwannoma cells in Lewis rats resulted in extension of survival time (P less than 0.05). There was a significant decrease in metastatic tumor incidence for lung, heart, and kidney and decreased lung tumor growth with approximately 50% of the lung tumor burden of untreated controls (P less than 0.05). Rats treated similarly with C. parvum 10 days after tumor cell injection showed no enhanced survival; to the contrary, their survival was shortened. Moreover, tumor incidence in the post-treated group was not significantly different from the control but significantly increased in comparison to the pretreated group. Enhanced lung tumor growth resulted in a final tumor burden about twice that of untreated controls (P less than 0.05).


Nanotechnology, nanotoxicology, and neuroscience.
Nanotechnology, which deals with features as small as a 1 billionth of a meter, began to enter into mainstream physical sciences and engineering some 20 years ago. Recent applications of nanoscience include the use of nanoscale materials in electronics, catalysis, and biomedical research. Among these applications, strong interest has been shown to biological processes such as blood coagulation control and multimodal bioimaging, which has brought about a new and exciting research field called nanobiotechnology. Biotechnology, which itself also dates back approximately 30 years, involves the manipulation of macroscopic biological systems such as cells and mice in order to understand why and how molecular level mechanisms affect specific biological functions, e.g., the role of APP (amyloid precursor protein) in Alzheimer's disease (AD). This review aims (1) to introduce key concepts and materials from nanotechnology to a non-physical sciences community; (2) to introduce several state-of-the-art examples of current nanotechnology that were either constructed for use in biological systems or that can, in time, be utilized for biomedical research; (3) to provide recent excerpts in nanotoxicology and multifunctional nanoparticle systems (MFNPSs); and (4) to propose areas in neuroscience that may benefit from research at the interface of neurobiologically important systems and nanostructured materials.


Use of yeast two-hybrid system for detection of Bacillus subtilis FtsZ protein partners.
Yeast two-hybrid system was modified to allow easy detection of prokaryotic protein-protein interactions. Three plasmids (pGBR1, pGBR2, pGBR3) with the ClaI restriction site shifted in the three possible reading frames in fusion with GAL4 activating domain were constructed. The modified plasmids were used for identification of protein partners of FtsZ from Bacillus subtilis. Among partners of FtsZ the FtsA protein and a globular part of the SpoIIE protein were identified. The protein interactions were quantified by measurements of beta-galactosidase activity in yeast cells using 4-methylumbelliferyl beta-D-galactopyranoside as fluorogenic substrate.


Association between gait speed as a measure of frailty and risk of cardiovascular events after myocardial infarction.
This study sought to determine the additional clinical value of gait speed to Framingham risk score (FRS), cardiac function, and comorbid conditions in predicting cardiovascular events in patients with ST-segment elevation myocardial infarction. There is growing evidence that gait speed is inversely associated with all-cause mortality, particularly cardiovascular mortality, among the elderly. We undertook a single-center prospective observational study of gait speed in 472 patients with ST-segment elevation myocardial infarction in Japan, between 2001 and 2008. Gait speeds were measured using a 200-m course before discharge in all patients, and we followed up cardiovascular events, which consist of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal ischemic strokes. During the 2,596 person-years of follow-up, 83 patients (17.6%) experienced cardiovascular events. Cardiovascular events increased across decreasing tertiles of gait speed (fastest tertile: n = 5, 3.2%; middle tertile: n = 20, 12.6%; slowest tertile, n = 58, 36.7%). By multiple adjusted Cox proportional hazards analysis, gait speed was a significant and independent predictor of cardiovascular events (hazard ratio for increasing 0.1 m/s of gait speed: 0.71, 95% confidence interval [CI]: 0.63 to 0.81, p < 0.001). The addition of gait speed to the model incorporating FRS, B-type natriuretic peptide levels, and comorbidity index improved reclassification (net reclassification index: 32.8%, 95% CI: 17.4 to 48.3, p < 0.001) and the C-statistics with a reasonable global fit and calibration (C-statistics: from 0.703 [95% CI: 0.636 to 0.763] to 0.786 [95% CI: 0.738 to 0.829]). Among patients with ST-segment elevation myocardial infarction, slow gait speed was significantly associated with an increased risk of cardiovascular events. (Gait Speed for Predicting Cardiovascular Events After Myocardial Infarction; NCT01484158).


COLIGENTA treatment of small intestinal bacterial overgrowth. Results of an open study.
The treatment of small intestinal overgrowth (SIBO) varies according to the center. The present study aimed to evaluate the efficacy of COLIGENTA, an association of colimycin and gentamycin, on SIBO symptomatology and breath test normalization PATIENTS AND METHODS: In this prospective cross-sectional open study, 150 patients with functional bowel disorders and SIBO diagnosed by lactulose hydrogen breath test (LHBT) underwent COLIGENTA oral treatment. A new HLBT was performed 4 weeks after the first HLBT. The patients were mainly female (74%), with a mean age of 47.4 ± 16.2 years and a body mass index of 26.2 ± 5.9 kg/m². After treatment, a decrease of expired hydrogen concentration (P<0.001) was found in the entire population. Improvement of gastrointestinal symptoms was found in 129 patients (86%), while the breath test's normalization was found in 62 patients (42%). Logistic regression showed that normalization of bowel symptoms was not associated with demographics, clinical, or hydrogen breath concentration. In contrast, normalization of LHBT was associated with an increase of breath hydrogen concentration at time 100 min during the first test (P = 0.003; OR=1.072; 95%CI= [1.023-1.123]). The present study shows that 10-days of COLIGENTA treatment has a high SIBO clinical improvement rate and can be used as the first or second treatment line.


Mesenchymal stem cell-derived exosomes in cardiovascular and cerebrovascular diseases: From mechanisms to therapy.
Cardiovascular and cerebrovascular diseases (CVDs) remain an intractable problem and have high morbidity and mortality worldwide, as well as substantial health and economic burdens, representing an urgent clinical need. In recent years, the focus of research has shifted from the use of mesenchymal stem cells (MSCs) for transplantation to the use of their secretory exosomes (MSC-exosomes) for the treatment of numerous CVDs, including atherosclerosis, myocardial infarction (MI), heart failure (HF), ischemia/reperfusion (I/R), aneurysm, and stroke. MSCs are pluripotent stem cells with multiple differentiation pathways that exert pleiotropic effects by producing soluble factors, the most effective components of which are exosomes. MSC-exosomes are considered to be an excellent and promising cell-free therapy for CVDs due to their higher circulating stability, improved biocompatibility, reduced toxicity, and immunogenicity. In addition, exosomes play critical roles in repairing CVDs by inhibiting apoptosis, regulating inflammation, ameliorating cardiac remodeling, and promoting angiogenesis. Herein, we describe knowledge about the biological characteristics of MSC-exosomes, investigate the mechanism by which MSC-exosomes mediate therapeutic repair, and summarize recent advances in the efficacy of MSC-exosomes in CVDs, with a view toward future clinical applications.


Settling of buoyant microplastic in estuaries: The importance of flocculation.
Rivers and estuaries are regarded as major pathways of microplastic (MP) transport from terrestrial areas to marine ecosystems. Despite this knowledge on the transport dynamics and fate of MP in freshwater riverine and brackish estuarine waters is limited. Via ex situ settling experiments emulating the Msimbazi River and Estuary in Dar es-Salaam, Tanzania, we demonstrate that flocculation and subsequent settling of positively buoyant MP and fine-grained suspended sediment in riverine and estuarine waters are important for the environmental fate of the plastic particles. Our results show that settling velocities of MP and fine-grained sediment in estuarine water were between five and 21 times larger than in freshwater, explained by the increase in ionic strength that occurs when particles enter saline water. This confirms the concept of increased flocculation and settling of fine-grained particles as they are transported from freshwater to estuarine and marine waters. The implication is that land-based sources of small positively buoyant high-density polyethylene (HDPE) MP transported by rivers will tend to settle and accumulate in estuarine environments and thereby lead to a decrease in the overall load of MPs delivered to the wider marine environment. Thereby our results support the notion of estuaries as MP traps and that flocculation explains the trapping of large quantities of MP debris. Based on these findings we recommend that the interaction of MP with fine-grained sediment should be taken into account when transport models of this pollutant are established.


Current status of bioassays in genetic toxicology--the dominant lethal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program.
The term dominant lethal may be defined as death of the heterozygote arising through multiple chromosomal breaks. The assay is generally conducted by treating male animals, usually mice or rats, acutely (1 dose), subacutely (5 doses), or over the entire period of spermatogenesis. Animals treated acutely or subacutely are mated at weekly intervals to females for a sufficient number of weeks to cover the period of spermatogenesis. Those treated for the entire spermatogenic cycle are mated for 1 or 2 successive weeks at the termination of treatment. Females usually are killed at 14 days of pregnancy and examined for the number of total implantations in the uterus, the number of implantations classified as early deaths, and, in some cases, the number of corpora lutea. The category of early death is the most significant index of dominant lethality. A total of 249 papers were reviewed and 140 chemicals were evaluated. Of the 140 chemicals, 65 were positive by the criteria used by the Work Group in evaluating each publication. The category of "positive" includes those responses of a borderline nature. 99 chemicals were declared negative. There is considerable overlap of chemicals in both categories, which accounts for the incongruity in the total number of chemicals tested and the number considered positive and negative. A total of 44 animal carcinogens have been tested in the dominant lethal assay, 26 of which were positive and 18 negative for a correlation of 59%. The role of the assay should be that of confirming positive results from lower tier chromosomal aberration-detecting systems (confirming in the sense of indicating the ability of the chemical to penetrate gonadal tissue and to produce cytogenetic damage). The dominant lethal assay should not be used as a risk assessment method.


Development of a multiplex panel with 31 multi-allelic InDels for forensic DNA typing.
Insertion/Deletion (InDel) polymorphic genetic markers are abundant in human genomes. Diallelic InDel markers have been widely studied for forensic purposes, yet the low polymorphic information content limits their application and current InDel panels remain to be improved. In this study, multi-allelic InDels located out of low complexity sequence regions were selected in the datasets from East Asian populations, and a multiplex amplification system containing 31 multi-allelic InDel markers and the Amelogenin marker (FA-HID32plex) was constructed and optimized. The preliminary study on sensitivity, species specificity, inhibitor tolerance, mixture resolution, and the detection of degraded samples demonstrates that the FA-HID32plex is highly sensitive, specific, and robust for traces and degraded samples. The combined power of discrimination (CPD) of 31 multi-allelic InDel markers was 0.999 999 999 999 999 999 85, and the cumulative probability of exclusion (CPE) was 0.999 920 in a Chinese Han population, which indicates a high discrimination power. Altogether, the FA-HID32plex panel could provide reliable supplements or stand-alone information in individual identification and paternity testing, especially for challenging samples.


Biological properties of human melanoma cells in culture.
Three human melanoma cell lines derived from one primary and two metastatic tumors from three different patients were characterized for growth properties usually associated with malignant transformation; these include cell morphology, growth rate, saturation density, growth in semisolid media, colony-forming ability on contact-inhibited monolayers of normal fibroblasts and epithelial cells, and tumorigenicity in immunosuppressed mice. Variations in expression of aberrant properties were evident among the lines. One of the metastatic lines satisfied all the parameters of malignancy tested and the other showed a number of these properties, whereas the primary essentially fulfilled only one. These results suggest that cultured melanoma cells reflect the clinical variability often observed among melanoma patients and that metastatic melanoma seems to display a higher degree of malignant transformation than the primary.


Laccase Encapsulation in ZIF-8 Metal-Organic Framework Shows Stability Enhancement and Substrate Selectivity.
CgL1 laccase from Corynebacterium glutamicum was encapsulated into the metal-organic framework (MOF) ZIF-8 which was synthesized in a rapid enzyme friendly aqueous synthesis, the fastest in situ encapsulation of laccases reported to date. The obtained enzyme/MOF, i. e. laccase@ZIF-8 composite showed enhanced thermal (up to 70 °C) and chemical (N,N-dimethylformamide) stability, resulting in a stable heterogenous catalyst, suitable for high temperature reactions in organic solvents. Furthermore, the defined structure of ZIF-8 produced a size selective substrate specificity, so that substrates larger than the pore size were not accepted. Thereby, 2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) was used to verify that the enzyme is immobilized inside the MOF versus the outside surface. The enzyme@MOF composite was analyzed by atomic absorption spectroscopy (ASS) to precisely determine the enzyme loading to 2.1 wt%.


Moderate and Severe Inflammatory Acne Vulgaris Effectively Treated with Single-Agent Therapy by a New Fixed-Dose Combination Adapalene 0.3 %/Benzoyl Peroxide 2.5 % Gel: A Randomized, Double-Blind, Parallel-Group, Controlled Study.
A need exists for topical treatments in managing more severe inflammatory acne. The objectives of this study were to evaluate the efficacy and safety of adapalene 0.3 %/benzoyl peroxide 2.5 % (0.3 % A/BPO) topical gel in subjects with moderate and severe inflammatory acne. This was a multicenter, randomized, double-blind, parallel-group study. Randomization was stratified by acne severity (50 % moderate and 50 % severe). Subjects received 0.3 % A/BPO, 0.1 % A/BPO (benchmark), or vehicle (comparator) once daily for 12 weeks. Co-primary efficacy endpoints were success rate at week 12 (the percentage of subjects rated 'clear' or 'almost clear' with at least a 2-grade improvement on Investigator's Global Assessment [IGA]) and change in inflammatory (IN) and noninflammatory (NIN) lesion counts from baseline to week 12. Secondary efficacy endpoints were percent changes in IN and NIN lesion counts. Safety endpoints were incidence of adverse events (AEs) and local tolerability signs/symptoms. A total of 503 subjects were randomized: 217, 217, and 69 subjects in the 0.3 % A/BPO, 0.1 % A/BPO, and vehicle groups, respectively. For success rate (subjects rated 'clear' or 'almost clear' with ≥2-grade improvement in IGA), 0.3 % A/BPO was superior to vehicle, with a treatment difference of 22.7 % (33.7 vs. 11.0 %; 95 % confidence interval [CI] 12.8-32.6, p < 0.001). At week 12, 0.3 % A/BPO was superior to vehicle for mean reduction from baseline in IN (27.0 vs. 14.4) and NIN lesion counts (40.2 vs. 18.5), as well as for percentage reduction from baseline in IN (68.7 vs. 39.2 %) and NIN lesion counts (68.3 vs. 37.4 %) (all p < 0.001). Among subjects with severe inflammatory acne (IGA = 4), 0.1 % A/BPO did not reach statistical significance for success rate compared with vehicle (p = 0.443), whereas 0.3 % A/BPO demonstrated significantly greater efficacy (p = 0.029, requiring ≥3-point IGA improvement). Additionally, 0.3 % A/BPO was safe and well-tolerated. Results of this clinical trial demonstrate the significantly greater efficacy of adapalene 0.3 % A/BPO topical gel compared with vehicle as well as a good safety profile in the treatment of moderate to severe inflammatory non-nodulocystic acne, which increases patients' treatment options. CLINICALTRIALS. NCT01880320.


Interchangeability of transthoracic and transesophageal echocardiographic right heart measurements in the perioperative setting and correlation with hemodynamic parameters.
Reduction of right ventricular (RV) function after cardiac surgery has been shown to impact outcomes. Conventional indices for right ventricular dysfunction are validated using transthoracic echocardiogram (TTE) which has limited use compared to transesophageal echocardiogram (TEE) in the perioperative settings. The aim of this study was to assess the agreement of RV systolic function assessment with TEE compared to TTE and assess the association of echocardiographic parameter with hemodynamic indices of RV dysfunction. This was a single center prospective observational study in an academic institution. Fifty adult patients undergoing elective cardiac surgery were included. TTE, TEE and stroke volume measurements pre-cardiopulmonary bypass (CPB) and post-CPB were performed. The variables of interest were anatomical M-mode tricuspid annular plane systolic excursion (AMM-TAPSE), fractional area change (FAC), tricuspid annular velocity (S') and myocardial performance index (MPI). FAC and AMM-TAPSE measured at the mid-esophageal 4 chamber view had substantial agreement with the TTE acquired parameters (Lin's concordance correlation coefficient (CCC) = 0.76, 95%CI 0.59-0.86 and CCC = 0.85, 95%CI 0.76-0.91). S' was significantly underestimated by TEE (CCC = 0.07, 95%CI 0.04-0.19) and MPI showed moderate agreement (CCC = 0.45 95%CI 0.19-0.65). Despite the significant changes in echocardiographic parameters, there were no corresponding changes in stroke volume (SV) or pulmonary artery pulsatility index at the post-CPB period. TEE acquired FAC and AMM-TAPSE had substantial agreement with pre-operative TTE values and no significant differences between the pre-CPB and post-CPB period. Systolic RV echocardiographic parameters decreased post-CPB but this was not accompanied by significant hemodynamic changes.


Nanozyme-assisted ratiometric photoelectrochemical aptasensor over Cu2O nanocubes mediated photocurrent-polarity-switching based on S-scheme FeCdS@FeIn2S4 heterostructure.
The controllable modulation of the response mode is highly attractive for the construction of photoelectrochemical (PEC) sensors with improved sensitivity and anti-interference ability in complex real samples matrix. Here, we present a charming proof-of-concept ratiometric PEC aptasensor of enrofloxacin (ENR) analysis via the controllable signal transduction. Different with the traditional sensing mechanism, this ratiometric PEC aptasensor integrates the anodic PEC signal induced by PtCuCo nanozyme-catalyzed precipitation reaction and the polarity-switching cathodic PEC response mediated by Cu2O nanocubes on S-scheme FeCdS@FeIn2S4 heterostructure. Taking advantages of the photocurrent-polarity-switching signal response model and the superior performance of the photoactive substrate material, the proposed ratiometric PEC aptasensor displays a good detection linear range for ENR analysis from 0.01 pg mL-1 to 10 ng mL-1, with a detection limit of 3.3 fg mL-1. This study provides a general platform for detecting interested trace analytes in real samples and expands the diversity of sensing strategy design.


HSP70 localization in Podarcissiculus embryos under natural thermal regime and following a non-lethal cold shock.
The Heat Shock Proteins (HSPs) are a superfamily of molecular chaperones that maintain cellular homeostasis under stress. HSP70 represents the major stress-inducible family member, often activated in response to changes in thermal ranges of organisms, and therefore playing an important role enhancing thermal tolerance limits in ectothermic animals. The present study aimed to investigate the presence and the localization of HSP70 through the development of Podarcis siculus, an oviparous lizard inhabiting temperate Mediterranean regions, showing a limited potential to tolerate thermal changes during embryogenesis. Immunohistochemical analysis demonstrated that HSP70 protein is constitutively present in early embryonic stages, abundantly distributed in eye, in encephalic domains (predominantly in ventricular areas and in grey matter), in grey matter of spinal cord, in lung, gut mucosa, hepatic cords and kidney tubules. Interestingly, a severe drop in incubation temperature (5°C for 3 days) does not induce enhancements in HSP70 levels nor changes in tissues localization. These results suggest that the HSP70 found in P. siculus embryos represents a non-inducible, constitutive molecular chaperone that should be better called Heat Shock Cognate 70 (HSC70); the presence of stress-induced members of the HSP family in P. siculus has yet to be proven.


Multi-drug-resistant chronic endometritis in infertile women with repeated implantation failure: trend over the decade and pilot study for third-line oral antibiotic treatment.
To evaluate the yearly prevalence and annual transition of multi-drug-resistant-chronic endometritis (MDR-CE) in infertile women with a history of repeated implantation failure (RIF) and to establish the third-line antibiotic treatment regimen against MDR-CE. This retrospective/prospective cohort and pilot study included 3473 RIF women between April 2010 and September 2021. The endometrial stromal plasmacyte density index (ESPDI) was calculated in 3449 CD138-immunostained endometrial sections to evaluate CE. The microbiota in the vaginal secretions and endometrial fluid was compared between 17 patients with MDR-CE and 16 patients with antibiotics-sensitive CE. In a pilot study, oral moxifloxacin (400 mg/day, 10 days, n = 24) or azithromycin (500 mg/day, 3 days, n = 24) was administered to eligible patients with MDR-CE. From April 2010 to March 2020, CE was detected in 31.4% of RIF women and MDR was detected in 7.8% of CE. While the prevalence of CE was stable for a decade, MDR in CE increased steadily (OR 8.27, 95% CI 2.58-26.43, p trend < 0.001). The bacterial species/communities unique to MDR-CE were not found. The histopathologic cure rate of MDR-CE was similar between the moxifloxacin and azithromycin groups (79.2% vs 75.0%, OR 1.27, 95% CI 0.32-4.89, p value 0.73), as well as reproductive outcomes in subsequent embryo transfer cycles. In RIF women, MDR in CE increased over the decade. As a third-line treatment for MDR-CE, azithromycin may have a clinical advantage due to its shorter time administration periods. ClinicalTrials.gov Identifier: UMIN-CTR 000029449/000031909.


Phase I/II study of amrubicin in combination with S-1 as second-line chemotherapy for non-small-cell lung cancer without EGFR mutation.
Both amrubicin (Am) and S-1 are effective against non-small-cell lung cancer (NSCLC), and preclinical studies have demonstrated that the effect of tegafur/uracil, the original compound of S-1, in combination with Am significantly inhibits tumor growth. We conducted a phase I/II study of Am and S-1 against pretreated NSCLC without EGFR mutation. We fixed the dose of S-1 at 40 mg/m(2) on days 1-14 and escalated the Am dose in increments of 5 mg/m(2) from a starting dose of 30 mg/m(2)/day on days 1-3 and repeated the cycle every 4 weeks. Twenty-six patients were registered. In phase I, at an Am dose of 35 mg/m(2)/day, three patients experienced grade 2 leukopenia during S-1 administration, and S-1 was withdrawn. Another patient developed grade 2 serum bilirubin in the first cycle. DLTs were observed in four of six patients at this dose level, and therefore, 30 mg/m(2)/day was set as the recommended dose for Am. Twenty patients received this recommended Am dose. Febrile neutropenia was observed in two patients, and one patient developed a grade 4 increase in serum creatinine. Grade 3 vomiting, infection, hypotension, and urinary retention were observed in one patient each, respectively. Other toxicities were mild, and there were no treatment-related deaths. Two patients showed a CR, three showed a PR, and the overall response rate was 25.0%. The median progression-free and the median survival times were 3.8 and 15.6 months, respectively, and the 1-year survival rate was 60%. Am and S-1 every 4 weeks is an effective combination for pretreated NSCLC without EGFR mutation.


Acculturation and post-disaster mental health problems among affected and non-affected immigrants: a comparative study.
It is unknown to what extent acculturation among disaster-affected immigrants is associated with mental health problems (MHP) compared to non-affected immigrants. We examined the associations between acculturation and post-disaster MHP among affected and non-affected immigrants in The Netherlands. Among the affected group, keeping norms and values of original culture and limited skills to cope with the demands of the new society were independently associated with PTSD-symptomatology, anxiety, depression, hostility, and somatic problems at 18 months post-event. In the non-affected comparison group no associations were found. Interestingly, levels of acculturation did not differ between both groups, in contrast to MHP. The acculturation levels could be influenced by the experience of a disaster. However, levels did not differ statistically between the study groups. Furthermore, the groups were reasonably small and the response rates were, although not uncommon in health studies among immigrants, relatively low. The findings of this unique study clearly suggest that post-disaster mental health policies should target low levels of skills to survive in the new society. Furthermore, the acculturation domain of keeping traditional norms and values can be contrary to the Dutch care after a disaster where self-efficacy and individualistic, cognitive functioning are the central goals. Further research is warranted to explore and examine post-event interventions aimed at increasing the levels of acculturation that may facilitate recovery.


Combined exposure to multiple dioxins and dioxin-like polychlorinated biphenyls on hypertension among US adults in NHANES: a cross-sectional study under three statistical models.
Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are mainly released as by-products of human activities, often in the form of mixtures, and the potential harm on human health deserves attention. Therefore, our study aimed to analyze the combined effect of dioxins and DL-PCB exposures on hypertension (HTN) among US adults. Data of eligible participants were acquired from the National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression models with adjustment for covariates were applied to explore the associations between 13 persistent organic pollutants (POPs) and HTN. Stratified analyses and interaction analyses were then conducted by age and gender. Finally, the combined effects of dioxins and DL-PCBs on HTN were assessed by the weighted quantile sum (WQS) model and the Bayesian kernel machine regression (BKMR) model. A total of 976 adults were included in our study, of whom 397 had HTN. Spearman correlations indicated positive correlations among 13 POPs. And most of them (except PCB28, PCB66, and 1,2,3,4,7,8,9-hpcdf) had significant effects on HTN. The result of WQS revealed that mixed exposure to dioxins and DL-PCBs was significantly associated with increased risk of HTN (OR: 2.205; 95% CIs: 1.555, 3.127). The BKMR model also presented a positive trend of HTN risk with exposure to multiple dioxins and DL-PCBs. And 1,2,3,4,6,7,8,9-ocdd may be the main factor for this positive association. Considering the limitations of our cross-sectional study with the small sample, further prospective studies are necessary to validate our findings.


"It's Been Ugly": A Large-Scale Qualitative Study into the Difficulties Frontline Doctors Faced across Two Waves of the COVID-19 Pandemic.
This study aimed to gain an uncensored insight into the most difficult aspects of working as a frontline doctor across successive COVID-19 pandemic waves. Data collected by the parent study (CERA) was analysed using conventional content analysis. Participants comprised frontline doctors who worked in emergency, anaesthetic, and intensive care medicine in the UK and Ireland during the COVID-19 pandemic (n = 1379). All seniority levels were represented, 42.8% of the sample were male, and 69.2% were white. Four themes were identified with nine respective categories (in parentheses): (1) I'm not a COVID hero, I'm COVID cannon fodder (exposed and unprotected, "a kick in the teeth"); (2) the relentlessness and pervasiveness of COVID ("no respite", "shifting sands"); (3) the ugly truths of the frontline ("inhumane" care, complex team dynamics); (4) an overwhelmed system exacerbated by COVID (overstretched and under-resourced, constant changes and uncertainty, the added hinderance of infection control measures). Findings reflect the multifaceted challenges faced after successive pandemic waves; basic wellbeing needs continue to be neglected and the emotional impact is further pronounced. Steps are necessary to mitigate the repeated trauma exposure of frontline doctors as COVID-19 becomes endemic and health services attempt to recover with inevitable long-term sequelae.


CREB expression in cardiac fibroblasts and CREM expression in ventricular myocytes.
Activation of gene expression by the cAMP-dependent signaling pathway is regulated by members of the cAMP response element binding protein (CREB) family consisting of CREB, CREM, and ATF-1. It is decisively for the understanding of the heart function as to which type of heart cells expresses CREB and/or CREM. Ventricular myocytes and fibroblasts of young (3 months) and old (24 months) rat hearts were separately investigated to analyse CREB, CREM, and phospho-CREB. Western blot showed CREB expression exclusively in fibroblasts but CREM was predominantly detected in ventricular myocytes. CREB-positive nuclei in heart sections were only revealed in fibroblasts. CREB was activated by forskolin (10 microM), PMA (500 nM), and cyclical mechanical strain (1 Hz, 5% elongation) in fibroblasts. The number of CREB-positive myocytes in old rats was larger than in young rats. But CREB could not be activated by forskolin (10 microM) in all myocytes. Our results suggest that the expression of CREB depends on the cell type and the age of the animal. We discuss that modulation of gene expression as it occurs with a age could be affected by the change within the CREB family members.


Empirie und Dogma in den <<Jahreszeiten>> medizinischer Wissenschaft.
Empiric and Dogmatic 'Seasons' in the Progress of Medical ScienceThe current 'postmodern' times are not simply permissive towards any theory whatever. In medicine, the 'external validity' of theories and the exact place of various healing schools has become an important subject. 'Critical appraisal' of the empiric evidence for treatment benefit in all areas of medicine, conventional or unconventional, will separate the wheat from the chaff. Pluralistic evidence-based medicine constitutes the flail for achieving this task. This happens in late summer. Later in winter, the chaff of useless medicine will decay; a new therapeutic spring will only be possible when the current task of identifying effective and beneficial treatments in all areas and of abandoning useless therapies will be fulfilled. The current primacy of the empiric study of medicine, rather than the dogmatic, should not be misunderstood as a pure empirism. Rather, we are in the empiric 'season'. Questions about mechanisms of action will remain, but will retreat to the back of the mind for some time.


Dissemination of pHK01-like incompatibility group IncFII plasmids encoding CTX-M-14 in Escherichia coli from human and animal sources.
Few studies have compared CTX-M encoding plasmids identified in different ecological sources. This study aimed to analyze and compare the molecular epidemiology of plasmids encoding CTX-M-14 among strains from humans and animals. The CTX-M-14 encoding plasmids in 160 Escherichia coli isolates from animal faecal (14 pigs, 16 chickens, 12 cats, 8 cattle, 5 dogs and 3 rodents), human faecal (45 adults and 20 children) and human urine (37 adults) sources in 2002-2010 were characterized by molecular methods. The replicon types of the CTX-M-14 encoding plasmids were IncFII (n=61), I1-Iγ (n=24), other F types (n=23), B/O (n=10), K (n=6), N (n=3), A/C (n=1), HI1 (n=1), HI2 (n=1) and nontypeable (n=30). The genetic environment, ISEcp1 -bla(CTX-M-14) - IS903 was found in 89.7% (52/58), 87.7% (57/65) and 86.5% (32/37) of the animal faecal, human faecal and human urine isolates, respectively. Subtyping of the 61 IncFII incompatibility group plasmids by replicon sequence typing, plasmid PCR-restriction fragment length polymorphism and marker genes (yac, malB, eitA/eitC and parB/A) profiles showed that 31% (18/58), 30.6% (20/65) and 37.8% (14/37) of the plasmids originating from animal faecal, human faecal and human urine isolates, respectively, were pHK01-like. These 52 pHK01-like plasmids originated from diverse human (20 faecal isolates from 2002, 2007 to 2008, 14 urinary isolates from 2004) and animal (all faecal, 1 cattle, 1 chicken, 5 pigs, 9 cats, 1 dog, 1 rodent from 2008 to 2010) sources. In conclusion, this study highlights the importance of the IncFII group, pHK01-like plasmids in the dissemination of CTX-M-14 among isolates from diverse sources.


Draft Genome Sequence of Megasphaera sp. Strain DJF_B143, an Isolate from Pig Hindgut Unable to Produce Skatole.
The butyrate-producing Megasphaera spp. predominate in the pig hindgut and may play important roles in gut health. Moreover, one Megasphaera isolate has been reported to produce the boar taint compound, skatole. Here, we provide a 2.58-Mbp draft genome of a pig hindgut isolate, Megasphaera sp. DJF_B143, unable to produce skatole.


A synonymous (c.3390C>T) or a splice-site (c.3380-2A>G) mutation causes exon 26 skipping in four patients with von Willebrand disease (2A/IIE).
We characterized four unrelated patients with von Willebrand disease type 2A/IIE, sharing the same von Willebrand factor (VWF) in-frame deletion (p.[P1127_G1180delinsR];[=]) resulting from exon 26 skipping (Δ26). To identify the VWF mutations and how they caused the mRNA splicing alteration, to evaluate the deletion by in vitro expression studies, and to assess whether or not the heterogeneity of the patients' phenotype might be related to a different degree of expression of the deleted subunit in patient plasma VWF. Sequence analysis was performed with patient genomic DNA and platelet mRNA. Semiquantitative RT-PCR was also carried out to compare the expression of the wild-type (WT) and Δ26 alleles in the four patients. In silico analysis was performed with prediction splicing programs. Expression studies were performed to evaluate mutant recombinant VWF (rVWF) (Δ26 and Δ26/WT) as compared with WT rVWF. Three patients shared the synonymous single-nucleotide substitution (SSS) c.[3390C>T];[=], whereas the novel mutation c.[3380-2A>G];[=] was present in the fourth patient. Semiquantitative RT-PCR of platelet mRNA revealed a different ratio of the WT and Δ26 alleles in the patients, consistent with the different VWF:FVIIIB values present in patient plasma. Expression studies confirmed reduced VWF-FVIII binding of rVWF-Δ26/WT. SSS can induce alternative splicing, and those like c.3390C>T, which impact on the poorly conserved splicing regulatory elements, are difficult to predict, so that their role can be evaluated only by mRNA analysis. Moreover, these mutations seem to have different effects on the efficiency of alternative splicing, producing heterogeneous VWF variants among the four patients.


Absorbable staples in abdominal hysterectomy.
A technique is illustrated wherein the vaginal vault is closed with absorbable staples before the cervix is excised. The resulting minimal contamination of the pelvis and small avascular pedicles improves the postoperative course of the patient.


Effect of charge density of polysaccharide on self-assembly behaviors of ovalbumin and sodium alginate.
Similarities and differences of assembly for ovalbumin (OVA) and two kinds of sodium alginate (SA1 and SA2) varying in charge densities (λSA1: λSA2 ≈ 2:1) were investigated. The assembly processes of OVA/SA mixtures were characterized by phase diagram, particle size, and microstructure. Two differences between OVA/SA1 and OVA/SA2 mixtures in the phase diagram were distinctly observed. First, due to the higher charge density of SA1, the strong interaction between OVA and SA1 caused only pHφ1 to be recorded. A higher linear charge density of SA1 narrowed the pHφ1-pHφ2 range at ratios of 2:1 and 1:1. Second, OVA/SA1 complexes formed a coacervate with a relatively strong resistance to ion-induced shielding effects. This maintained the smaller size (tighter structure) with a larger number of complexes in the coacervate without 250 mM NaCl. The regulating polysaccharides with different charge densities could control the soluble region of complexes and endow various size or morphology of the coacervate assembled by proteins and polysaccharides.


Interactions between herbs and conventional drugs: overview of the clinical data.
This article provides an overview of the clinical evidence of interactions between herbal and conventional medicines. Herbs involved in drug interactions--or that have been evaluated in pharmacokinetic trials--are discussed in this review. While many of the interactions reported are of limited clinical significance and many herbal products (e.g. black cohosh, saw palmetto, echinacea, hawthorn and valerian) seem to expose patients to minor risk under conventional pharmacotherapy, a few herbs, notably St. John's wort, may provoke adverse events sufficiently serious to endanger the patients' health. Healthcare professionals should remain vigilant for potential interactions between herbal medicines and prescribed drugs, especially when drugs with a narrow therapeutic index are used.


Murine alloantigen acquisition by schistosomula of Schistosoma mansoni: further evidence for the presence of K, D, and I region gene products on the tegumental surface.
Previous studies have demonstrated that shistosomula, recovered from the lungs of Schistosoma mansoni-infected mice, acquire H-2Kk and both Ik and Is gene products. We confirmed and extended those observations by identifying several individual antigenic specificities mapping not only to H-2Kk and I-Ak (Sher, Hall & Vadas 1978), but to H-2Dk, I-Ek, H-2Kb, H-2Db and I-Ab as well. Private H-2 specificities 23 (H-2Kk) and 32 (H-2Dk) were identified on the tegumental surface of schistosomula isolated from C3H/Crgl mice (H-2k). Larvae isolated from C57Bl/10Sn (B10) mice (H-2b) were shown to acquire private specificities 33 and 2, which map to H-2Kb and H-2Db respectively. I region associated (Ia) antigens coded for by genes mapping in the I-A subregion (Ia.2 and 3) and I-E subregion (Ia.7) were also acquired from C3H/Crgl mice. Schistosomula from B10 donors were shown to acquire Ia specificities 3 and 8, which are under I-A subregion control. Evidence that monoclonal antibodies recognize H-2 antigens on the larval surface is also demonstrated.


The Therapeutic Potential of Nanobodies.
Today, bio-medical efforts are entering the subcellular level, which is witnessed with the fast-developing fields of nanomedicine, nanodiagnostics and nanotherapy in conjunction with the implementation of nanoparticles for disease prevention, diagnosis, therapy and follow-up. Nanoparticles or nanocontainers offer advantages including high sensitivity, lower toxicity and improved safety-characteristics that are especially valued in the oncology field. Cancer cells develop and proliferate in complex microenvironments leading to heterogeneous diseases, often with a fatal outcome for the patient. Although antibody-based therapy is widely used in the clinical care of patients with solid tumours, its efficiency definitely needs improvement. Limitations of antibodies result mainly from their big size and poor penetration in solid tissues. Nanobodies are a novel and unique class of antigen-binding fragments, derived from naturally occurring heavy-chain-only antibodies present in the serum of camelids. Their superior properties such as small size, high stability, strong antigen-binding affinity, water solubility and natural origin make them suitable for development into next-generation biodrugs. Less than 30 years after the discovery of functional heavy-chain-only antibodies, the nanobody derivatives are already extensively used by the biotechnology research community. Moreover, a number of nanobodies are under clinical investigation for a wide spectrum of human diseases including inflammation, breast cancer, brain tumours, lung diseases and infectious diseases. Recently, caplacizumab, a bivalent nanobody, received approval from the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for treatment of patients with thrombotic thrombocytopenic purpura.


Posterior Segment Characterization in Children With Pierson Syndrome.
Pierson syndrome is a rare genetic disease defined by congenital nephrotic syndrome in association with microcoria. The authors aim to describe the posterior segment and retinal features in Pierson syndrome. A retrospective chart review of nine patients diagnosed with Pierson syndrome was ascertained. Details of ophthalmic history, ocular examination, retinal imaging, and surgical interventions were obtained during a median duration of 17 months of follow-up (range: 6 to 60 months). Retinal interventions included scatter laser photocoagulation and surgical retinal repair. Sixteen eyes of nine patients were included. The axial length of five eyes with flat retina was 26.59 mm ± 0.99 mm. Highly myopic features including tessellated fundus with accompanying optic disc pallor, unidentifiable cup, and abnormal retinal vascular emanation from the disc were observed in all eyes (100%), whereas 12 eyes (75%) had parapapillary chorioretinal atrophy. Features of abnormal retinal vascularization included avascular peripheral retina on fluorescein angiography, aberrant course of the temporal arcades in 13 eyes (81.3%), and straightened nasal retinal blood vessels in 12 eyes (75%). Tortuous retinal blood vessels were observed in three eyes (18.75%). Surgical repair was performed in five out of seven eyes with rhegmatogenous retinal detachment (RRD). Recurrence was observed in all eyes, which required two to three procedures to achieve final reattachment. Combined features of high axial myopia with incomplete peripheral vascular maturation characterize the posterior segment in Pierson syndrome. Careful posterior segment examination is essential to detect RRD or retinal neovascularization. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:618-627.].


Impaired control of information transfer at an isolated synapse treated by aluminum: is it related to dementia?
Information transfer across an isolated cholinergic synapse exposed to aluminum was investigated using conventional electrophysiological techniques and computer-assisted analysis. Spontaneous and stimulation-induced release of neurotransmitter from frog motor nerve endings was augmented in the presence of aluminum (6-200 micrograms/ml). The release-enhancing effect of aluminum was dose-dependent and it was independent of the concentration of calcium ions in the extracellular solution. These results indicate that aluminum at concentrations similar to those found in the diseased brain of demented patients modulates synaptic transmission.


RHEGMATOGENOUS RETINAL DETACHMENT: A RARE OCULAR MANIFESTATION OF PROTEUS SYNDROME.
To present a case report of a rare ocular manifestation of Proteus syndrome-rhegmatogenous retinal detachment. Retrospective review of the patient's medical record and a review of the literature. A 16-year-old boy with Proteus syndrome who presented with a total retinal detachment because of an operculated retinal tear. This patient underwent successful surgical repair of the retinal detachment and subsequent cataract surgery. Proteus syndrome may be complicated by the development of rhegmatogenous retinal detachment, which can present in childhood.


Comparative efficacy of oral sotalol and procainamide in patients with chronic ventricular arrhythmias: a multicenter study.
In an open, randomized, crossover study, the efficacy of sotalol and procainamide was compared in 33 patients with frequent, chronic premature ventricular contractions (PVCs). A 75% reduction in PVCs/24 hours (two 24-hour recordings) was arbitrarily considered to constitute an adequate therapeutic effect. Sotalol was started at a dose of 160 mg once daily for 1 week, followed by a 24-hour recording. In the absence of any therapeutic effect, the same procedure was repeated with 320 mg, 480 mg, and 640 mg daily. Procainamide, 1 gm three times/day, was given or, if plasma concentrations were insufficient, 1.5 gm three times/day for 1 week. PVC control was obtained in 22 (67%) patients on sotalol, including all 12 with ischemic heart disease. Procainamide was successful in 13 (39%) patients. Effects on the number of attacks of ventricular tachycardia were achieved by both drugs in those patients where PVCs were reduced by at least 75%. Sotalol caused side effects in five patients, who therefore could not accept planned increases in dosage. Side effects were noted by 12 patients with procainamide. Nine patients responded to both drugs, seven to neither. Thirteen responded to sotalol only and four to procainamide only. We conclude that sotalol is a useful alternative to procainamide in controlling chronic PVCs, especially in patients with ischemic heart disease.


Anesthesia of the Equine Neonate in Health and Disease.
Anesthetizing the neonatal foal presents significant challenges as a result of physiologic differences from the adult equine. This article gives the reader an overview of these differences and the impact they have on anesthetic drug selection, monitoring, and support of the equine neonate. Special emphasis is directed to the sick neonate and appropriate preparation and maintenance of anesthesia in the face of commonly presented disease conditions.


Intracisternal granules in the somatotrophs in the anterior pituitary of the mouse.
A detailed study of the anterior pituitaries of pregnant and lactating mice revealed changes occurring in the ultrastructure of the somatotrophs. The rough endoplasmic reticulum cisternae become greatly dilated forming channels that are continuous with the perivascular space. This occurrence expands the membrane surface available for the release of hormone. Individual granules and cytoplasmic islands containing numerous granules appear in these channels. This suggests an alternative mechanism for granule release which would facilitate a rapid response to increased hormone requirement.


Identification of glaucomatous optic nerve head changes in Indian donor eyes without clinical history.
The purpose of this study is to develop methods to identify glaucoma by examining the optic nerve head (ONH) of donor's eyes when information on the preexisting ocular disease is unavailable. The ONH of the donor's eyes was evaluated under a stereomicroscope for the cup-disc ratio (CDR) and focal retinal rim thinning. The vertical diameter of the cup and disc was also measured using a precalibrated eyepiece micrometer. The suspect eyes were subjected to histological analysis to confirm the presence of specific glaucomatous changes. A total of 202 eyes from 119 donors (68 males and 51 females, aged 42-96) were evaluated for glaucoma. Among them, 190 (94%) eyes showing vertical CDR in the of 0.0-0.6 range were considered nonglaucomatous and the remaining eyes with >0.6 as glaucoma suspect. The calculated mean CDR of the two groups (0.3 ± 0.16, 0.62 ± 0.27) was highly significant (P = 0.0003). Of 12 eyes suspected of glaucoma, 7 eyes from 5 donors showed specific glaucomatous changes by histology. The prevalence of glaucoma was 4.2% among the donors studied. A simple method of screening fresh donor eyes for selecting those with glaucoma features using CDR and histological analysis was reported. This method helps to obtain biologically active human ocular tissue for glaucoma research on gene expression, ultrastructural/proteome changes, and outflow mechanism.


The role of tyrosine in the binding of steroid by progesterone binding globulin from the guinea pig.
Treatment of progesterone binding globulin (PBG) with tetranitromethane (TNM) resulted in a loss of steroid binding activity (inactivation) which was dependent on both time and concentration of reagent. Scatchard analysis of binding revealed that inactivation was due to a decrease in binding site number with no effect upon the affinity of PBG for steroid. Incorporation studies demonstrated that the loss of binding activity correlated with the incorporation of 1.3 nitro groups per molecule of PBG. The involvement of the steroid binding site in the reaction was shown by the ability of progesterone, but not cortisol, to protect against inactivation. Treatment with N-acetylimidazole did not inactivate PBG nor did the conversion of nitrotyrosyl residues to amino-tyrosines regenerate binding activity, suggesting that the pheolic hydroxyl is not involved in steroid binding. These studies suggest that inactivation was due to the incorporation of a bulky group into the aromatic ring of a tyrosine present at the steroid binding site thus blocking its ability to participate in hydrophobic interactions with the ligand.


Metagenomic and proteomic analysis of bacterial retting community and proteome profile in the degumming process of kenaf bast.
Data on the microbial community and functional proteins associated with degumming in kenaf remains scant. Here, we analyzed the microbial communities associated with kenaf (Hibiscus cannabinus) bast fibers during retting to identify potential candidate degumming bacteria. Retting liquids were collected and analyzed at 0 days, 10 days, and 34 days and then evaluated the yield and quality of kenaf fiber at the different retting times. Besides, the microbial communities were characterized using metagenomic and proteomic analysis by LC-MS/MS technology. The data showed that increase in the retting time significantly improves the softness, dispersion, and fiber whiteness of the kenaf fiber. The relative abundance of Acinetobacter increased from 2.88% at the baseline to 6.64% at the 34th retting. On the other hand, some members of Clostridium were reduced from 3% at the baseline to 2% at the 34th retting. Analysis of carbohydrate active enzymes showed constant changes in the utilization of carbohydrates. Besides, benzoquinone reductase, cellobiose dehydrogenase, glucose 1-oxidase, aryl alcohol oxidase and alcohol oxidase were the top five most abundant enzymes in the retting liquids. This present results demonstrated that the expressions of B7GYR8, Q6RYW5 and Q6FFK2 proteins were suppressed in Acinetobacter with the retting time. On the contrary, P05149 was upregulated with the retting time. In Clostridium, P37698, P52040 and P54937 proteins were upregulated with the retting time. In addition, bacteria Acinetobacter and Clostridium might be playing important roles in the kenaf degumming process. Similarly, up-regulation of P37698, P52040 and P54937 proteins is an important manifestation and mediates important roles in the degumming process.


The fusiform skin excision: one recipe for success.
The fusiform skin excision is commonly performed by dermatologists. This brief review presents a stepwise approach to this procedure and discusses recent evidence related to dermatologic minor surgery.


Erratum: The study of service dogs for veterans with Post-Traumatic Stress Disorder: a scoping literature review.
[This corrects the article DOI: 10.1080/20008198.2018.1503523.].


Phosphate selective recovery by magnetic iron oxide impregnated carbon flow-electrode capacitive deionization (FCDI).
The recovery of phosphorus (P) from wastewaters is a worthy goal considering the potential environmental and economic benefits. Flow-electrode capacitive deionization (FCDI), which employs flowable carbon electrodes instead of the static electrodes used in conventional CDI, has been demonstrated to be a promising P recovery technology. FCDI outperforms CDI and other competitive technologies in a number of aspects including (i) large salt adsorption capacity and (ii) extremely high water recovery rate. In this study, magnetic (Fe3O4 impregnated) activated carbon particles were prepared and applied as FCDI electrodes. The magnetic carbon electrodes were found to have a strong affinity towards P, facilitating the selective adsorption of P to the magnetic particles through a ligand exhange mechanism. Continuous operation of the FCDI system could be achieved with only three minutes required to separate the electrode particles from the brine stream on application of an external magnetic field. A P-rich stream was produced on regeneration of the exhausted magnetic electrodes using alkali solution. We envision that the use of magnetic carbon enhanced flow-electrodes will pave the way for efficient operation of FCDI as well as the preferential recovery of P.


The in vitro effect of temperature on motility and antioxidant response of common carp Cyprinus carpio spermatozoa.
The effect of temperature on Cyprinus carpio spermatozoa in vitro was investigated with spermatozoa activated at 4, 14, and 24°C. At 30s post-activation, motility rate was significantly higher at 4°C compared to 14 and 24°C, whereas highest swimming velocity was observed at 14°C. The thiobarbituric acid-reactive substance (TBARS) content was significantly higher at 14°C and 24°C than at 4°C in motile spermatozoa. No significant differences in catalase and superoxide dismutase activity relative to temperature were observed. This study provides new information regarding effect of temperature on lipid peroxidation intensity and spermatozoon motility parameters in carp. The elevation of TBARS seen at higher temperatures could be due to inadequate capacity of antioxidant enzymes to protect the cell against the detrimental effects of oxidative stress induced by higher temperatures.


New assay for the measurement of selenoprotein P as a sepsis biomarker from serum.
Selenium (Se) is incorporated into selenoproteins as the 21st proteinogenic amino acid selenocysteine. Serum Se concentrations decline during critical illness and are indicative of poor prognosis. Serum Se is mainly contained in the hepatically derived selenoprotein P (SePP) which controls the expression of antioxidative selenoproteins. Here, we describe the development of an immunoluminometric sandwich assay that uses two polyclonal sheep antihuman SePP antibodies. After assessing the stability of the analyte, we determined SePP concentrations in samples from healthy individuals and patients with sepsis. The analytical detection limit was 0.016 mg SePP/L serum. The assay was linear on dilution. SePP was stable in serum at room temperature for at least 24 h and resistant to six freeze-thaw cycles. Median SePP concentration in healthy individuals was 3.04 mg SePP/L serum (25th-75th percentiles, 2.6-3.4 mg/L) which corresponded to 98.4 microg Se/L serum. The interlaboratory CV was <20% for SePP values >0.06 mg/L. There was no association with gender, but concentrations differed between young and older individuals. Median SePP concentrations were significantly (P<0.0001) decreased in patients with sepsis (n=60) compared to healthy controls (n=318). Since SePP contains the major fraction of serum Se, we conclude that downregulation of SePP biosynthesis or removal of circulating SePP from blood underlies the negative acute phase response of serum Se in critical illness.


Current clinical practice of subcutaneous implantable cardioverter-defibrillator: Analysis using the JROAD-DPC database.
Current evidence describing the characteristics of subcutaneous implantable cardioverter-defibrillator (S-ICD) therapy, its trend, and perioperative outcomes compared with transvenous implantable cardioverter-defibrillator (TV-ICD) based on a real-world, large-scale database is scarce. The purpose of this study was to identify the characteristics of current S-ICD therapy using a nationwide database. A retrospective analysis of ICD implantation was performed using a nationwide database obtained between 2016 and 2020. A total of 8690 patients implanted with ICD (median age 65 [52-72] year; 6902 men; 2021 S-ICD recipients) were analyzed. Younger patients were more prone to have S-ICD (P <.001). A history of ventricular fibrillation (VF) (odds ratio [OR] 2.45; 95% confidence interval [CI] 2.04-2.93), nonsustained ventricular tachycardia (VT) (OR 1.73; 95% CI 1.36-2.21), Brugada syndrome (BrS) (OR 3.14; 95% CI 2.48-4.00), and dialysis treatment (OR 2.02; 95% CI 1.44-2.82) were independent predictors of S-ICD selection on mixed-model logistic analysis. The proportion of S-ICD implantations has been increasing (P <.001), especially in patients with BrS (P <.001) and dialysis (P = .04). The proportion of combined complications after S-ICD implantation was low (1.3%) in the unmatched cohort and was comparable to TV-ICD in the 1:1 propensity-matched cohort of 3354 patients (1.5% vs 2.3%; OR 0.65; 95% CI 0.38-1.10). S-ICD was more likely to be implanted in younger patients and those with a history of VF, nonsustained VT, BrS, and dialysis treatment. The proportion of S-ICD implantation increased, especially in patients with BrS. The incidence of in-hospital complications was low in S-ICD recipients.


[Radiological aspects of gastric localizations of malignant non-Hodgkin's lymphoma. Apropos of 50 cases].
The authors describe radiological features of non Hodgkin's gastric lymphomas based on a study of 50 cases, with endoscopic correlation in 43 cases. Radiographic appearance is categorized as infiltrative (40 per cent), ulcerative (26 per cent), polypoid (10 per cent) and polymorphic (24 per cent). Gastric carcinoma is the most important differential diagnosis. Since staging, therapy and prognostic are different in these two diseases, accurate radiologic diagnosis is of particular importance. Combination of several peculiar radiologic signs suggest gastric lymphoma in 56 per cent of all the cases (16 per cent for endoscopy alone); this fact demonstrate the necessity of barium meal for a more accurate diagnosis of gastric lymphomas.


Managing advanced-stage cervical cancer.
The current staging methods and the definition of advanced cervical cancer are discussed. The clinical International Federation of Gynaecology and Obstetrics (FIGO) staging system has been found to be inaccurate and this limits treatment planning. More accurate management could be based on surgicopathological features of the tumour. However, the latest imaging techniques have the potential to give us this information in a non-invasive way. To deliver optimal treatment in advanced cervical cancer, we need to optimize the way we categorize the prognostic groups. Accurately delineating the extent of the disease will potentially minimize treatment morbidity and improve survival. The techniques of chemoradiation are also discussed in detail.


Pyrimidine-5-carbonitriles II: synthesis and antimicrobial activity of novel 6-alkyl-2,4-disubstituted pyrimidine-5-carbonitriles.
New series of 6-alkyl-2,4-disubstituted pyrimidine-5-carbonitriles namely, 6-alkyl-2-thiouracil-5-carbonitriles 4c,d, 6-alkyl-2-arylmethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 5a-p, 6-alkyl-2-(2-methoxyethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 6a-d, 6-alkyl-2-benzyloxymethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 7a-c, 6-alkyl-2-(5-nitrofuran-2-ylmethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 8a-d, 6-alkyl-4-arylthio-2-(benzylsulfanyl)pyrimidine-5-carbonitriles 10a, b and 2-benzylsulfanyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-6-pentylpyrimidine-5-carbonitrile 11, were synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 4d, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5 l, 5p, 7a, 7b, 7c, 8a, 8b, 8c, 8d and 11 -displayed marked antibacterial activity particularly against the tested Gram-positive bacteria. Meanwhile, none of these compounds were proved to be active against Candida albicans.


[Diagnostic delay in bronchopulmonary cancers at the USFR Befelatanana Pneumology, Antananarivo, Madagascar].
The time between clinical symptoms onset and the diagnosis of bronchial cancer should be as short as possible so that it can be managed early and effectively. In Madagascar, this diagnostic delay is unknown. Therefore this study aims to evaluated the diagnostic delay of bronchopulmonary cancers at the the USFR Befelatanana Pneumology, Antananarivo, Madagascar. We conducted a retrospective descriptive study of patients with bronchopulmonary cancers diagnosed at the USFR Befelatanana Pneumology over the period 1st January 2011 to 31st December 2015 (5 years). All patients hospitalized during the study period and receiving anatomopathologically-confirmed diagnosis of bronchopulmonary cancer were included in the study. During the study period we collected data from 43 medical records of patients with bronchopulmonary cancer confirmed histologically, reflecting a rate of 0.64% of hospitalized patients. Pre-hospital delay, hospital delay and total delay were 171.74 days, 13.97 days and 185.71 days respectively. The time between symptom onset and consultation with a doctor was less than three months in 30 cases (69.76%), between 3 and 6 months in 8 cases (18.60%). Pre-hospital delay was very long according to the international recommendation for delayed diagnosis of bronchopulmonary cancers. An effort should be made to improve the diagnostic delay.


Rodent retinal ganglion cell cultures.
Central neurons lose the ability for axonal regrowth during development and typically do not regenerate their axons following axotomy once they become mature unless given a growth-permissive environment, for example, a peripheral nerve graft. Retinal ganglion cells (RGCs) of the optic nerve represent a highly useful cell model for the study of neurotrophic factor responsiveness, although the presence of nonneuronal cells in the retina makes it difficult to interpret the direct effects of tested factors on RGCs. Cultures of purified RGCs thus represent an excellent tool for the study of optic nerve cell trophic responsiveness, in terms of both survival and axonal regeneration.


Synthesis, growth, structural, spectral, thermal, chemical etching, linear and nonlinear optical and mechanical studies of an organic single crystal 4-chloro 4-nitrostilbene (CONS): a potential NLO material.
4-Chloro 4-nitrostilbene (CONS) a new organic nonlinear optical material has been synthesized. Employing slow evaporation method, good optical quality single crystals (dimensions up to 6×2×3 mm(3)) have been grown using ethyl methyl ketone (EMK) as a solvent. The grown crystals have been subjected to various characterizations such as single crystal X-ray diffraction, powder XRD, Fourier Transform Infrared spectroscopy (FTIR), proton NMR, solid UV absorption, SHG studies. Single crystal X-ray diffraction reveals that the crystal system belongs to monoclinic with noncentrosymmetric space group P21. The UV-Vis absorption spectrum has been recorded and found that the cut off wavelength is 380 nm. Functional groups and the structure of the title compound have been confirmed by FTIR and (1)H NMR spectroscopic analyses respectively. Molecular mass of the CONS confirmed by the high resolution mass spectral analysis .The thermal behavior of the grown crystal has been studied by TG/DTA analysis and it shows the melting point is at 188.66 °C. Dislocations and growth pattern present in the grown crystal revealed by the etching study. The mechanical strength of the CONS crystal has been studied by Vicker's hardness measurement. The SHG efficiency of the grown crystal has been determined by Kurtz and Perry powder test which revealed that the CONS crystal (327 mV) has 15 times greater efficiency than that of KDP (21.7 mV).


High-throughput sequencing in mutation detection: A new generation of genotoxicity tests?
The advent of next generation sequencing (NGS) technology has provided the means to directly analyze the genetic material in primary cells or tissues of any species in a high throughput manner for mutagenic effects of potential genotoxic agents. In principle, direct, genome-wide sequencing of human primary cells and/or tissue biopsies would open up opportunities to identify individuals possibly exposed to mutagenic agents, thereby replacing current risk assessment procedures based on surrogate markers and extrapolations from animal studies. NGS-based tests can also precisely characterize the mutation spectra induced by genotoxic agents, improving our knowledge of their mechanism of action. Thus far, NGS has not been widely employed in genetic toxicology due to the difficulties in measuring low-abundant somatic mutations. Here, we review different strategies to employ NGS for the detection of somatic mutations in a cost-effective manner and discuss the potential applicability of these methods in testing the mutagenicity of genotoxic agents.


Cross talk between heat shock protein 10 and a heat shock factor identified from Marsupenaeus japonicus.
Heat shock factors (HSFs) and heat shock proteins (HSPs) are crucial regulators and effectors of the heat shock response (HSR). In this study, the full-length cDNA sequences of MjHSP10 and MjHSF1 were cloned by rapid amplification of cDNA ends (RACE). The deduced MjHSP10 and MjHSF1 amino acid (aa) sequences exhibited conserved structures and the functional features of HSP10 and HSF1, respectively. The tissue distributions and mRNA expression profiles of the two genes in response to heat stress were analyzed by quantitative real-time PCR (qRT-PCR). MjHSP10 and MjHSF1 were ubiquitously expressed in various tissues. Heat stress induced a significant increase in MjHSP10 expression that tend to positively correlate with temperature. Additionally, MjHSF1 transcription was up-regulated less than MjHSP10 transcription under heat stress. MjHSF1 expression in the hepatopancreas was up-regulated under only long-term (48 h) heat stress, and MjHSF1 transcription in the gill increased under only acute (34 °C) heat stress. MjHSF1 knockdown by RNA interference (RNAi) down-regulated MjHSP10 expression. Glutathione-S-transferase (GST) pull-down assays showed an interaction between MjHSP10 and the DNA-binding domain (DBD) of MjHSF1. This study provided new insights into cross talk between HSP10 and HSF1 in Marsupenaeus japonicus.


The perception of odor pleasantness is shared across cultures.
Humans share sensory systems with a common anatomical blueprint, but individual sensory experience nevertheless varies. In olfaction, it is not known to what degree sensory perception, particularly the perception of odor pleasantness, is founded on universal principles,1-5 dictated by culture,6-13 or merely a matter of personal taste.6,8-10,12,14 To address this, we asked 225 individuals from 9 diverse nonwestern cultures-hunter-gatherer to urban dwelling-to rank the monomolecular odorants from most to least pleasant. Contrary to expectations, culture explained only 6% of the variance in pleasantness rankings, whereas individual variability or personal taste explained 54%. Importantly, there was substantial global consistency, with molecular identity explaining 41% of the variance in odor pleasantness rankings. Critically, these universal rankings were predicted by the physicochemical properties of out-of-sample molecules and out-of-sample pleasantness ratings given by a tenth group of western urban participants. Taken together, this shows human olfactory perception is strongly constrained by universal principles.


Serological response to an adsorbed killed trivalent influenza vaccine (including A/New Jersey 8/76 antigen).
The serological evaluation of a trivalent vaccine (A/Victoria 3/75, A/New Jersey 8/76, B/Hong Kong 8/73) has been done by HI and NI tests on 77 paired sera representing all age groups. The percentage of seroconversion induced by the antigens A/Victoria 3/75, A/New Jersey 8/75 and B/Hong Kong 8/73 were 85.95 and 89.6 respectively and the percentage of protective antibodies (greater than 1:40) were 84.4, 72.7 and 80.5 respectively.


Robotic-assisted versus open simple prostatectomy: Results from a systematic review and meta-analysis of comparative studies.
To review safety and efficacy of robotic-assisted simple prostatectomy (RASP) compared to open simple prostatectomy (OP). A comprehensive literature search was performed to assess the differences in perioperative course and functional outcomes in patients with benign prostatic hyperplasia and surgical indication. The incidences of complications were pooled using the Cochran-Mantel-Haenszel Method and expressed as odds ratio (OR), 95% confidence interval (CI), and p-values. Perioperative course and functional outcomes were pooled using the inverse variance of the mean difference (MD), 95% CI, and p-values. Analyses were two-tailed and the significance was set at p<0.05. Eight studies were accepted. Meta-analysis showed significantly longer surgical time (MD, 43.72; 95% CI, 30.57-56.88; p<0.00001) with a significantly lower estimated blood loss (MD, -563.20; 95% CI, -739.95 to -386.46; p<0.00001) and shorter postoperative stay (MD, -2.85; 95% CI, -3.72 to -1.99; p<0.00001) in RASP. Catheterization time did not differ (MD, 0.65; 95% CI, -2.17 to 3.48; p=0.65). The risk of blood transfusion was significantly higher in OP (OR, 0.23; 95% CI, 0.17-0.33; p<0.00001). The risk of recatheterization (OR, 1.96; 95% CI, 0.32-11.93; p=0.47), postoperative urinary infections (OR, 0.89; 95% CI, 0.23-3.51; p=0.87) and 30-day readmission rate (OR, 0.96; 95% CI, 0.61-1.51; p=0.86) did not differ. At 3-month follow-up, functional outcomes were similar. RASP demonstrated a better perioperative outcome and equal early functional outcomes as compared to OP. These findings should be balanced against the longer operative time and higher cost of robotic surgery.


Immunopathogenesis of HBV Infection.
More than 95% of adult infected with HBV show acute self-limited infection and eventually eliminate the virus. In contrast, about 90% of people exposed to HBV in early childhood develop chronic infection. The specificity of the virus and the host's antiviral immune responses together determine the outcome of HBV infection. It is generally believed that viral genome variation, viral titers, and inhibition of viral components against the host immune system are associated with persistent infection and liver damage. The dysfunction of innate immune cells (NK cells, monocyte/macrophages, NKT cells, etc.) and adaptive immune cells (antigen-presenting cells, T cells, B cells) is a key factor leading to virus clearance failure and liver inflammation. In this chapter, we summarize these viral factors and host factors in acute and chronic hepatitis B and update recent understanding of the immune-tolerant phase and pathological mechanisms associated with age and vertical transmission. This will help us to understand more fully the mechanisms of chronic HBV infection and liver injury and to develop combined treatment strategies of direct antiviral drugs for HBV life cycle and immunomodulators.


Panel of potential lncRNA biomarkers can distinguish various types of liver malignant and benign tumors.
Liver cancers are among the deadliest malignancies due to a limited efficacy of early diagnostics, the lack of appropriate biomarkers and insufficient discrimination of different types of tumors by classic and molecular methods. In this study, we searched for novel long non-coding RNA (lncRNA) as well as validated several known candidates suitable as probable biomarkers for primary liver tumors of various etiology. We described a novel lncRNA HELIS (aka "HEalthy LIver Specific") and estimated its expression by RT-qPCR in 82 paired tissue samples from patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), combined HCC-CCA, pediatric hepatoblastoma (HBL) and non-malignant hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH). Additionally, we examined expression of cancer-associated lncRNAs HULC, MALAT1, UCA1, CYTOR, LINC01093 and H19, which were previously studied mainly in HCC. We demonstrated that down-regulation of HELIS strongly correlates with carcinogenesis; whereas in tumors with non-hepatocyte origin (HBL, CCA) or in a number of poorly differentiated HCC, this lncRNA is not expressed. We showed that recently discovered LINC01093 is dramatically down-regulated in all malignant liver cancers; while in benign tumors LINC01093 expression is just twice decreased in comparison to adjacent samples. Our study revealed that among all measured biomarkers only down-regulated HELIS and LINC01093, up-regulated CYTOR and dysregulated HULC are perspective for differential diagnostics of liver cancers; whereas others demonstrated discordant results and cannot be considered as potential universal biomarkers for this purpose.