Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling.
MicroRNAs (miRNAs) are noncoding RNAs with specific regulatory role in gene expression. Recent reports suggested their involvement in human malignancies. Currently, there is no information concerning miRNA expression and functions in squamous cell carcinoma (SCC) of tongue. In this study, we evaluated the expression patterns of 156 mature miRNAs in tongue SCC using Taqman-based microRNA assays. Of these 156 miRNAs, miR-133a and miR-133b were significantly reduced in tongue SCC cells in comparison with the paired normal epithelial cells. Tongue SCC cell lines transfected with miR-133a and miR-133b precursors displayed reduction in proliferation rate. In addition, the number of apoptotic cells was increased in response to the introduction of precursors. Computational target gene prediction suggested that both miR-133a and miR-133b are targeting transcript of pyruvate kinase type M2 (PKM2), a potential oncogene in solid cancers. In tongue SCC cell lines, PKM2 expression was reduced in response to miR-133a and miR-133b precursors transfection. Immunohistochemical staining results of tongue SCC tissues suggested that PKM2 was overexpressed in tongue SCC and was associated with the downregulation of miR-133a and miR-133b. Our results suggested that aberrant reduction of miR-133a and miR-133b was associated with the dysregulation of PKM2 in SCC of tongue.


Fibrosing alveolitis (pulmonary interstitial fibrosis) evoked by experiemntal inhalation of Gasoline vapours.
Rats exposed to an atmosphere contaminated with gasoline vapour for 6--12 weeks exhibit progressive focal interstitial fibrosis of the lung, which is associated with irregular alveolar collapse. It is suggested that this experimental model of diffuse fibrosing lung disease constitutes a useful tool for the study of the dynamics of pulmonary reactivity to atmospheric pollutants and which may facilitate an understanding of the pathogenesis of fibrosing alveolitis in man.


Synthesis of hydrophobic derivatives of the G/\C base for rosette nanotube self-assembly in apolar media.
Eleven self-complementary G/\C derivatives bearing hydrophobic moieties were synthesized and characterized. One representative derivative from this family was shown to self-assemble into rosette nanotubes in hexane and form Langmuir-Blodgett films at the air-water interface.


[Sarcomalike patterns in laryngeal carcinoma (pseudosarcoma, carcinosarcoma, spindle-cell-carcinoma, pleomorphic carcioma (author's transl)].
Report on 5 cases of so called carcinosarcomas of the larynx and hypopharynx and review of literature. These polypoid tumors have a small epidermoid carcinomatous part and a major part with sarcoma like appearance. The sarcomatoid tissue resembles to fibrosarcomas or some undifferentiated pleomorphic sarcoma. Observations of a gradual transition from the epithelial tumor cells to cells with a mesodermal appearance show that these tumors are varieties of squamous cell carcinomas (spindle cell or pleomorphic variety) and not "combination"--or "collision-tumors", "carcinosarcomas" or "seudosarcomas". These tumors appear in the larynx predominantly in man, at the same sites and in the same ageclasses as common squamous cell cancers and are not less malignant. The sarcomatoid tissue can arise at the beginning of the disease or at a later stage it can appear or disappear after operation or irradiation. The reason for this change of cellular structure is unknown.


Heterogeneity of the COVID-19 epidemic: what can we learn from it?
The goal of this article is to evaluate and explain the heterogeneity of the Coronavirus disease 2019 (COVID-19) epidemic in Australia, to offer advice for stopping the current outbreak and preparing for a suitable response to epidemics in the future. We conducted a review to analyze the epidemic and explain its variable manifestation across states in Australia. Most COVID-19 cases and deaths were in the states of Victoria and New South Wales due to differences in the governance of the epidemic and public health responses (quarantine and contact tracing) among states. Countries could learn from Australia's overall successful response not only through good governance, effective community participation, adequate public health, adequate health system capacity and multisectoral actions but also from the heterogeneity of the epidemic among states. A successful response to epidemics in countries with a decentralized administration requires multilevel governance with alignment and harmonization of the response.


Efficacy of amitraz (Taktic 12.5% EC) as a dip for the control of Boophilus microplus (Canestrini) (Acari: Ixodidae) on cattle.
Four groups of cattle infested with Boophilus microplus (Canestrini) were each dipped in a different concentration of amitraz diluted from a 12.5% EC formulation to determine the efficacy and performance of the product in an 11,400 l dipping vat. Except for the period when heifers were dipped, animals were restrained in stanchions placed individually inside 3.3 x 3.3 m2 stalls within an open-sided barn. The amitraz in the vat was stabilized with hydrated lime to maintain a pH of ca. 12. Analyses of vat samples showed that concentrations of amitraz in the vat were 7.6 to 13% lower than the targeted concentrations of 0.010, 0.015, 0.020, and 0.025% active ingredient (AI) for dilutions prepared according to instructions on the manufacturer's label. The large quantity of hydrated lime added to the vat (10 kg/1000 l) interfered with the HPLC analysis of vat samples. Therapeutic efficacy of each of the four observed concentrations (0.0088, 0.0131, 0.0174, and 0.0231% AI) of amitraz was excellent (> 99% control). However, the rapid detachment of all ticks from an animal within a few hours after treatment with amitraz, that has been frequently observed, was not pronounced in the present study. Only 47% of the B. microplus detached in the first 4 h post-treatment, and 84% detached within the first 24 h. All of the treatments, except the lowest concentration, provided protection of cattle against re-infestation by B. microplus larvae for 14 days post-treatment. Possibly as a result of the formation of a compact layer of lime and amitraz on the bottom after the vat was undisturbed for six weeks, intense agitation was required to re-suspend the active ingredient.


Exploration of Parascaris species in three different Equus populations in China.
The roundworms, Parascaris spp., are important nematode parasites of foals and were historically model organisms in the field of cell biology, leading to many important discoveries. According to karyotype, ascarids in Equus are commonly divided into Parascaris univalens (2n = 2) and Parascaris equorum (2n = 4). Here, we performed morphological identification, karyotyping and sequencing of roundworms from three different hosts (horses, zebras and donkeys). Phylogenetic analysis was performed to study the divergence of these ascarids based on cytochrome c oxidase subunit I (COI) and internal transcribed spacer (ITS) sequences. Karyotyping, performed on eggs recovered from worms of three different Equus hosts in China, showed two different karyotypes (2n = 2 in P. univalens collected from horses and zebras; 2n = 6 in Parascaris sp. collected from donkeys). There are some differences in the terminal part of the spicula between P. univalens (concave) and Parascaris sp. (rounded). Additionally, it was found that the egg's chitinous layer was significantly thicker in Parascaris sp. (> 5 μm) than P. univalens (< 5 μm) (F(2537) = 1967, P < 0.01). Phylogenetic trees showed that the sequences of Parascaris from Equus hosts were divided into two distinct lineages based on sequences of the COI and ITS. Comparing the differences in roundworms collected from three different Equus hosts, this study describes a Parascaris species (Parascaris sp.) with six chromosomes in donkeys. It is worth noting that the thickness of the chitinous layer in the Parascaris egg may serve as a diagnostic indicator to distinguish the two roundworms (P. univalens and Parascaris sp.). The Parascaris sp. with six chromosomes in donkeys in the present study may be a species of P. trivalens described in 1934, but the possibility that it is a new Parascaris species cannot be ruled out. Both karyotyping and molecular analysis are necessary to solve the taxonomic problems in Parascaris species.


Cytotoxicity of substituted alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates in L1210 lymphoid leukemia cells.
Two alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synthesis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP-amido transferase and IMP dehydrogenase. Other enzymatic activities which were suppressed by the drugs were DNA polymerase alpha, RNA polymerases, ribonucleoside reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside kinase and the pyrimidine pathway were not affected by the presence of drugs. The DNA molecule itself was not the target of the agents, i.e. no alkylation of nucleotide bases, intercalation between bases or cross-linking of DNA strands occurred. The agents did cause L1210 DNA fragmentation after 24 h incubation at 100 microM.


Natural killer cells in human colostrum.
The presence of natural killer cells in human colostrum was disclosed with the use of a fluorochrome-labeled monoclonal antibody HNK-1 (Leu-7) that recognizes cells with natural killer and killer activity. Approximately 0.5% of total colostral cells were stained with this reagent. These cells were separated by the fluorescence-activated cell sorter and examined for their morphology by electron microscopy and for their cytotoxic activity against 51Cr-labeled K562 target cells. Two morphological types of natural killer cells were observed in colostrum: the first was represented by large cells with numerous vacuoles but without dense cytoplasmic granules; the second type, which occurred with lower frequency, resembled the large granular lymphocytes associated with natural killer activity in peripheral blood. The HNK-1-positive cells from colostrum displayed low cytotoxic activity against K562 target cells. Incubation of HNK-1-positive cells from peripheral blood with cell-free colostrum resulted in a dose-dependent inhibition of the cytotoxic activity. The functional changes were accompanied by morphological alterations which included degranulation and the formation of numerous vacuoles. The variances in the cytotoxic activity of peripheral blood HNK-1-positive cells suspended in different dilutions of colostrum suggest that this fluid contains humoral factors which modify morphology and function depending on their concentrations.


Case-based object recognition for airborne fungi recognition.
Model-based object recognition is a well-known task in Computer Vision. Usually, one object that can be generalized by a model should be detected in an image based on this model. Biomedical applications have the special quality that one object can have a great variation in appearance. Therefore the appearance of this object cannot be generalized by one model. A set of cases of the appearance of this object (sometimes 50 cases or more) is necessary to detect this object in an image. The recognition method is rather case-based object recognition than model-based object recognition. Case-based object recognition is a challenging task. It puts special requirements to the similarity measure and needs a matching algorithm that can work fast in a large number of cases. It also needs a case acquisition procedure that can capture the great variation in appearance of an object and generalize these data into a case description. In this paper we describe the chosen case representation, the similarity measure and the matching as well as the case acquisition procedure. We evaluate our method based on a large enough set of digital images containing biological objects such as fungi spores. We can show that the similarity measure is superior to detect the objects in the images. The developed method for case acquisition and learning of generalized cases allows us to learn interactively a sufficient number of cases that are further stored into our case base. Finally, we give results on the performance of the system by calculating the recognition rate. These result show that we have developed a novel similarity measure for object detection in digital grey-level images and a novel procedure for case acquisition and learning that allows us to learn a sufficiently large enough case base and to generalize over a group of cases.


Bile acids cycle disruption in patients with nasopharyngeal carcinoma promotes the elevation of interleukin-10 secretion.
Unclear pathogenesis existed for nasopharyngeal carcinoma. to analyze the role of bile acids in the pathogenesis of nasopharyngeal carcinoma. 20 healthy volunteers and 20 patients with nasopharyngeal carcinoma were enrolled between January 1(st), 2013 and December 31(st), 2014. ESI-QTOF-MS analysis of serum was performed to find altered bile acids components. The biological function of changed bile acids was investigated using in vitro experiment. Compared with healthy volunteers, the level of DCA and GDCA exhibited higher abundance in patients with nasopharyngeal carcinoma (p<0.01). Furthermore, the biological function was investigated for the inhibition of DCA and GDCA towards the secretion of IL-10 by CD4+CD25- T cells. Both DCA and GDCA significantly inhibited the secretion of IL-10 by CD4+CD25- T cells. Furthermore, DCA+GDCA can show stronger inhibition towards the secretion of IL-10 than DCA and GDCA. The inhibition of IL-10 secretion by elevated DCA and GDCA components in nasopharyngeal carcinoma patients is the inducer for nasopharyngeal carcinoma.


Assessment of structurally related chemicals: toxicity and ecotoxicity of acrylic acid and acrylic acid alkyl esters (acrylates), methacrylic acid and methacrylic acid alkyl esters (methacrylates).
BUA compiled the available data on toxicity and ecotoxicity for several acrylic and methacrylic acid esters and their corresponding acids. A comparison of these data revealed a qualitative similarity in the toxicological and ecotoxicological properties of the compounds considered. The data indicate that methacrylates are less reactive than the corresponding acrylates.


Mediator, TATA-binding protein, and RNA polymerase II contribute to low histone occupancy at active gene promoters in yeast.
Transcription by RNA polymerase II (Pol II) in eukaryotes requires the Mediator complex, and often involves chromatin remodeling and histone eviction at active promoters. Here we address the role of Mediator in recruitment of the Swi/Snf chromatin remodeling complex and its role, along with components of the preinitiation complex (PIC), in histone eviction at inducible and constitutively active promoters in the budding yeast Saccharomyces cerevisiae. We show that recruitment of the Swi/Snf chromatin remodeling complex to the induced CHA1 promoter, as well as its association with several constitutively active promoters, depends on the Mediator complex but is independent of Mediator at the induced MET2 and MET6 genes. Although transcriptional activation and histone eviction at CHA1 depends on Swi/Snf, Swi/Snf recruitment is not sufficient for histone eviction at the induced CHA1 promoter. Loss of Swi/Snf activity does not affect histone occupancy of several constitutively active promoters; in contrast, higher histone occupancy is seen at these promoters in Mediator and PIC component mutants. We propose that an initial activator-dependent, nucleosome remodeling step allows PIC components to outcompete histones for occupancy of promoter sequences. We also observe reduced promoter association of Mediator and TATA-binding protein in a Pol II (rpb1-1) mutant, indicating mutually cooperative binding of these components of the transcription machinery and indicating that it is the PIC as a whole whose binding results in stable histone eviction.


How communication about risk and role affects women's decisions about birth after caesarean.
This study investigated how health care provider communication of risk information, and women's role in decision-making, influenced women's preferences for mode of birth after a previous caesarean birth. Women (N = 669) were randomised to one of eight conditions in a 2 (selectivity of risk information) × 2 (format of risk information) × 2 (role in decision making) experimental design. After exposure to a hypothetical decision scenario that varied information communicated by an obstetrician to a pregnant woman with a previous caesarean birth across the three factors, women were asked to decide their preferred hypothetical childbirth preference. Women provided with selective information (incomplete/biased toward repeat caesarean) and relative risk formats (ratio of incidence being compared e.g. 2.5 times higher), perceived lower risk for caesarean and were significantly more likely to prefer repeat caesarean birth than those provided with non-selective information (complete/unbiased) and absolute risk formats (incidence rate e.g. 0.01 per 100). Role in decision-making did not significantly influence childbirth preferences CONCLUSIONS: Modifiable aspects of healthcare provider communication may influence women's decision-making about childbirth preferences PRACTICE IMPLICATIONS: Optimised communication about risks of all options may have an impact on over-use of repeat CS.


Comparison of properties of mistletoe lectin I A-chain and ricin B-chain conjugate with native toxins.
Chimeric toxin protein was prepared from the mistletoe lectin I A-chain and ricin B-chain by using the disulfide exchange reaction. Ricin and chimeric protein were indistinguishable in binding to immobilized asialofetuin in ELISA. Chimeric protein was more toxic to Jurkat cells than native mistletoe lectin I, but not so effective as native ricin. In the presence of NH4Cl, which enhances the toxicity of some toxins and immunotoxins, but does not influence ricin toxicity, both ricin and chimeric toxin had equal cytotoxic activity. The possibility is discussed that the ricin B-chain protects the ricin A-chain (RTA) from degradation during delivering RTA from the cell surface to the place where RTA is translocated into the cytosol.


Potential of water quality wetlands to mitigate habitat losses from agricultural drainage modernization.
Given widespread biodiversity declines, a growing global human population, and demands to improve water quality, there is an immediate need to explore land management solutions that support multiple ecosystem services. Agricultural water quality wetlands designed to provide both water quality benefits and wetland and grassland habitat are an emerging restoration solution that may reverse habitat declines in intensive agricultural areas. Installation of water quality wetlands in the Upper Midwest, USA, when considered alongside the repair and modification of aging agricultural tile drainage infrastructure, is a likely scenario that may mitigate nutrient pollution exported from agricultural systems and improve crop yields. The capacity of water quality wetlands to provide habitat within the wetland pool and the surrounding grassland is not well-studied, particularly with respect to potential habitat changes resulting from drainage infrastructure upgrades. For the current study, we produced spatially explicit models of 37 catchments distributed throughout an important region for agriculture and biodiversity, the Des Moines Lobe of Iowa. Four scenarios were considered - with and without improved drainage and with and without water quality wetlands - to estimate the net potential habitat implications of these scenarios for amphibians, grassland birds, and wild bees. Model results indicate that drainage modification alone will likely result in moderate direct losses of suitable amphibian habitat and large declines in overall habitat quality. However, inclusion of water quality wetlands at the catchment scale may mitigate these amphibian habitat losses while also increasing grassland bird and pollinator habitat. The impacts of water quality wetlands and drainage modernization on waterfowl in the region require additional study.


Oral challenge with balsam of Peru.
A placebo-controlled, double-blind, oral challenge with balsam of Peru was carried out in 221 patients with various types of dermatitis. 210 patients completed the study, and 45 of them experienced a flare of their symptoms after challenge with balsam of Peru but not after placebo. 15 patients reacted to the placebo, and 5 reacted to both balsam and placebo. Specific reactivity to balsam of Peru was seen particularly in patients with positive patch tests to this compound and in some patch-test-negative patients with vesicular hand eczema, ano-genital and axillary eczema. Dietary restriction of the intake of balsams was followed by marked improvement or clearance of the dermatitis in approximately half of the patients who adhered to the diet for at least 1 month.


Association of the low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and major adverse cardiac and cerebrovascular events in patients with coronary heart disease undergoing percutaneous coronary intervention: a cohort study.
Although dyslipidemia increases the risk of coronary heart disease (CHD) and its adverse prognosis, the association between the ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) and major adverse cardiovascular and cerebrovascular events (MACCE) after percutaneous coronary intervention (PCI) in patients with CHD has not been adequately demonstrated. Therefore, the aim of this study was to assess the role of LDL-C/HDL-C in the risk of MACCE after PCI in patients with CHD. In this large cohort observational study, we enrolled 2226 patients with CHD treated with PCI. LDL-C/HDL-C was considered as an exposure variable and MACCE was considered as an outcome variable. Univariate and multivariate Logistic regression models and subgroup analyses were used to assess the relationship between LDL-C/HDL-C and the risk of MACCE. A total of 2226 patients (mean age: 60.02 years; 68.00% male) were included in the analysis, and 373 patients suffered MACC. Patients who developed MACCE had higher levels of LDL-C/HDL-C compared to patients who did not develop MACCE [(2.79 ± 1.15) vs (2.64 ± 1.09), p = 0.023]. Univariate Logistic regression analysis showed a correlation between LDL-C/HDL-C and the risk of MACCE (OR: 1.121, 95% CI: 1.019-1.233, p = 0.019). Multivariate Logistic regression analysis showed that higher levels of LDL-C/HDL-C remained strongly associated with a higher risk of MACCE after stepwise adjustment for confounding variables [Model 4: T3 vs T1, OR: 1.455, 95% CI: 1.095-1.933, p = 0.010; per unit increase, OR: 1.158, 95% CI: 1.047-1.281, p = 0.004]. Further subgroup analysis showed that the association between LDL-C/HDL-C and MACCE risk remained in the subgroup ≤60 years, male, without diabetes, and with hypertension (p < 0.05). Higher LDL-C/HDL-C was closely associated with a higher risk of MACCE after PCI in patients with CHD.


Structural and Chemical Evolutions of Li/Electrolyte Interfaces in Li-Metal Batteries: Tracing Compositional Changes of Electrolytes under Practical Conditions.
Despite the promises in high-energy-density batteries, Li-metal anodes (LMAs) have suffered from extensive electrolyte decomposition and unlimited volume expansion owing to thick, porous layer buildup during cycling. It mainly originates from a ceaseless reiteration of the formation and collapse of solid-electrolyte interphase (SEI). This study reveals the structural and chemical evolutions of the reacted Li layer after different cycles and investigates its detrimental effects on the cycling stability under practical conditions. Instead of the immediately deactivated top surface of the reacted Li layer, the chemical nature underneath the reacted Li layer can be an important indicator of the electrolyte compositional changes. It is found that cycling of LMAs with a lean electrolyte (≈3 g Ah-1 ) causes fast depletion of salt anions, leading to the dynamic evolution of the reacted Li layer structure and composition. Increasing the salt-solvent complex while reducing the non-solvating diluent retards the rate of depletion in a localized high-concentration electrolyte, thereby demonstrating prolonged cycling of Li||NMC622 cells without compromising the Li Coulombic efficiencies and high-voltage stability.


Epidemiology and antibiotic susceptibility profiles of obligate anaerobes in a hospital of central Italy during a one-year (2019) survey.
In this study, we report on the epidemiology and susceptibility profiles of anaerobic pathogens consecutively isolated from various clinical samples at an Italian hospital during a one-year survey. The collection included all non-duplicated consecutively collected anaerobic clinical isolates during 2019 in San Luca Hospital (Lucca, Italy). Antimicrobial susceptibility testing was performed using MICRONAUT-S Anaerobes MIC lyophilized plates (MERLIN Diagnostika, Germany) and interpreted using EUCAST criteria (11.0). A total of 169 Gram-negative and 213 Gram-positive were collected. The most frequent anaerobes were Bacteroides spp. (120, 31.4%) followed by Finegoldia magna (62, 16.2%). External ulcers were the most common source of isolates (39%), followed by blood (25.7%). In 230 patients (65%) polymicrobial aerobic/anaerobic isolates were cultured from the same external ulcer specimen. High resistance rates to clindamycin were overall detected, with the highest values among the genera Parabacteroides, Bacteroides, Prevotella, Gram-positive anaerobic cocci and Clostridium. High resistance rates were also observed to metronidazole among both Gram-positive and Gram-negative species, ranging between 10.8-50% and 13.8-46.2%, respectively. Our findings revealed that anaerobes susceptibility patterns have become less predictable due to an increase of resistance and suggest that periodic resistance surveillance should also be carried out for anaerobes in order to guide empirical therapy.


Preparation of a Klebsiella pneumoniae conjugate nanovaccine using glycol-engineered Escherichia coli.
Engineered strains of Escherichia coli have been used to produce bioconjugate vaccines using Protein Glycan Coupling Technology (PGCT). Nanovaccines have also entered the vaccine development arena with advances in nanotechnology and have been significantly developed, but chassis cells for conjugate nanovaccines have not been reported. To facilitate nanovaccine preparation, a generic recombinant protein (SpyCather4573) was used as the acceptor protein for O-linked glycosyltransferase PglL, and a glycol-engineered Escherichia coli strain with these two key components (SC4573 and PglL) integrated in its genome was developed in this study. The targeted glycoproteins with antigenic polysaccharides produced by our bacterial chassis can be spontaneously bound to proteinous nanocarriers with surface exposed SpyTag in vitro to form conjugate nanovaccines. To improve the yields of the targeted glycoprotein, a series of gene cluster deletion experiments was carried out, and the results showed that the deletion of the yfdGHI gene cluster increased the expression of glycoproteins. Using the updated system, to the best of our knowledge, we report for the first time the successful preparation of an effective Klebsiella pneumoniae O1 conjugate nanovaccine (KPO1-VLP), with antibody titers between 4 and 5 (Log10) after triple immunization and up to 100% protection against virulent strain challenge. Our results define a convenient and reliable framework for bacterial glycoprotein vaccine preparation that is flexible and versatile, and the genomic stability of the engineered chassis cells promises a wide range of applications for biosynthetic glycobiology research.


Association between IL-4 genotype and IL-4 production in the Japanese population.
We have identified that there are only two IL-4 gene haplotypes (I and II) in the Japanese population. There are significant differences among three genotypes (I/I, I/II and II/II) in the IL-4 producing proportion of peripheral Th cells using intracellular cytokine detection assay. These results make it likely that IL-4 genotype could influence the type of immune response.


Quantitative lineage tracing strategies to resolve multipotency in tissue-specific stem cells.
Lineage tracing has become the method of choice to study the fate and dynamics of stem cells (SCs) during development, homeostasis, and regeneration. However, transgenic and knock-in Cre drivers used to perform lineage tracing experiments are often dynamically, temporally, and heterogeneously expressed, leading to the initial labeling of different cell types and thereby complicating their interpretation. Here, we developed two methods: the first one based on statistical analysis of multicolor lineage tracing, allowing the definition of multipotency potential to be achieved with high confidence, and the second one based on lineage tracing at saturation to assess the fate of all SCs within a given lineage and the "flux" of cells between different lineages. Our analysis clearly shows that, whereas the prostate develops from multipotent SCs, only unipotent SCs mediate mammary gland (MG) development and adult tissue remodeling. These methods offer a rigorous framework to assess the lineage relationship and SC fate in different organs and tissues.


The influence of surgery on recurrence pattern of glioblastoma.
Glioblastoma recurs within 2 cm from the primary tumor's margins in 90-95% of cases. Natural history of recurrence is not well defined. The aim of this study was to verify if pattern of recurrence can be influenced by the extent of surgery. 131 patients with glioblastoma underwent tumor removal, followed by standard adjuvant radio-chemotherapy. Depending on the amount of apparently normal white matter measured around the tumor in the surgical specimen, the extent of surgery was classified into: "border resection" (BR, resection margins at the level of tumor border) or "extended resection" (ER, resection margins 1-2 cm far from tumor border). 88 patients had no residual tumor at post-operative MRI. Among these, 60 patients had a local recurrence (LR) - within 2 cm from the primary tumor's margins, 15 patients had a distant recurrence (DR), 13 patients had no recurrence. Survival curves were obtained through the Kaplan-Meier method. Dichotomous data were compared with the chi-square test. Patients who underwent ER presented a LR in 67% of cases. Patients who underwent BR presented a LR in 87.5% of cases (p=0.03). Survival for 60 patients with LR was 16 months vs 35 months for 15 patients with DR (p=0.06). PFS for patients with LR was 9 months vs 21 months for patients with DR (p=0.05). If tumor grows far from eloquent areas, ER may increase the probability to obtain a gross total resection, a greater number of patients with DR and, therefore, a longer survival.


Specificity of the links between workplace harassment and PTSD: primary results using court decisions, a pilot study in France.
France is one of the first countries to have passed specific legislation concerning "mental harassment" (In French the term used in the legislation is "harcèlement moral" referring to harassment or bullying leading to mental or psychological distress.) in the workplace. However, the definition of mental harassment at work remains fairly vague. It is, indeed, a complex issue, since no objective and precise consensual definition has been given so far. The objective of this study is to clarify the criteria that French judges consider as characteristic of mental harassment, and to check whether the specific links between mental harassment at work and PTSD pointed to in recent international studies have been taken into account. This study proposes the main lines for debate in countries that have not yet adopted legal clauses on mental harassment at work. Our study is based on a sample of 22 people who were legally recognised as having been mentally harassed at work; this sample is taken as representative of all court decisions passed on harassment and published as such on the French Ministry of Justice website. To establish whether they were considering a case of harassment, the judges based their decisions on the nature of the accusations. In all cases (22/22), the charges brought against the defendant had to do with offences against the employee's dignity. Five cases out of 22 dealt with an offence infringing their rights, 10 cases out of 22 related to the employee's future within the company being compromised, while half of the cases (11/22) concerned a deterioration in the person's health. In more than half of the cases, the judges also looked for other factors, such as repetition and duration of the period of harassment. Whenever the judges noted a deterioration in the victim's mental health, they also referred to medical certificates reporting anxio-depressive syndromes or psychological disorders without providing further detail. No PTSD-like symptomatology was mentioned among these cases, although several studies have shown that many victims of mental harassment at work have specific symptoms of PTSD. This study is the first study to be carried out on mental harassment at work and to refer to court decisions since the law was promulgated in France (2002). It appears that, in order to be recognised as a victim of mental harassment at work, numerous proofs of harassment or bullying need to be produced. It must have been repeated and have led to consequences in several domains. Several attestations and documents are required demonstrating clearly that harassment or bullying did indeed occur. Further to this, although to date judges have not considered PTSD to be an element contributing to the presumption of harassment, connections between bullying or harassment and clinical signs of PTSD have been attested by several studies that confirm that bullied victims can suffer from PTSD-like symptoms, although they do not necessarily match the strict DSM-IV criteria (absence of A1 criterion). It would seem advisable to request psychiatric examination in cases of harassment.


Local-Global Parcellation of the Human Cerebral Cortex from Intrinsic Functional Connectivity MRI.
A central goal in systems neuroscience is the parcellation of the cerebral cortex into discrete neurobiological "atoms". Resting-state functional magnetic resonance imaging (rs-fMRI) offers the possibility of in vivo human cortical parcellation. Almost all previous parcellations relied on 1 of 2 approaches. The local gradient approach detects abrupt transitions in functional connectivity patterns. These transitions potentially reflect cortical areal boundaries defined by histology or visuotopic fMRI. By contrast, the global similarity approach clusters similar functional connectivity patterns regardless of spatial proximity, resulting in parcels with homogeneous (similar) rs-fMRI signals. Here, we propose a gradient-weighted Markov Random Field (gwMRF) model integrating local gradient and global similarity approaches. Using task-fMRI and rs-fMRI across diverse acquisition protocols, we found gwMRF parcellations to be more homogeneous than 4 previously published parcellations. Furthermore, gwMRF parcellations agreed with the boundaries of certain cortical areas defined using histology and visuotopic fMRI. Some parcels captured subareal (somatotopic and visuotopic) features that likely reflect distinct computational units within known cortical areas. These results suggest that gwMRF parcellations reveal neurobiologically meaningful features of brain organization and are potentially useful for future applications requiring dimensionality reduction of voxel-wise fMRI data. Multiresolution parcellations generated from 1489 participants are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Schaefer2018_LocalGlobal).


Post-resuscitation management of asphyxiated neonates.
Inspite of major advances in monitoring technology and knowledge of fetal and perinatal medicine, perinatal asphyxia is one of the significant causes of mortality and long term morbidity. Data from National Neonatal Perinatal Database suggests that perinatal asphyxia contributes to almost 20% of neonatal deaths in India. "Failure to initiate or sustain respiration after birth" has been defined as criteria for the diagnosis of asphyxia by WHO. Perinatal asphyxia results in hypoxic injury to various organs including kidneys, lungs and liver but the most serious effects are seen on the central nervous system. Levene's classification is a useful clinical tool for grading the severity of hypoxic ischemic encephalopathy. Good supportive care is essential in the first 48 hours after asphyxia to prevent ongoing brain injury in the penumbra region. Strict monitoring and prompt correction is needed for common problems including temperature maintenance, blood sugars, blood pressure and oxygenation. Phenobarbitone is the drug of choice for the treatment of convulsions.


Repression of PUM1-mediated mRNA decay activates translesion synthesis after DNA damage.
Biological roles of Pumilio1 (PUM1) in ubiquitous cells remain unclear. Here we identify 48 degrading target mRNAs by combined analysis of transcriptome-wide mRNA stabilities and the binding of mRNAs. Further analysis revealed that cells respond to DNA damage by inhibiting PUM1-mediated mRNA decay to activate translesion synthesis (46/50).


Analysis of intracellular distribution and apoptosis involvement of the Ufd1l gene product by over-expression studies.
UFD1L is the human homologue of the yeast ubiquitin fusion degradation 1 (Ufd1) gene and maps on chromosome 22q11.2 in the typically deleted region (TDR) for DiGeorge/velocardiofacial syndromes (DGS/VCFS). In yeast, Ufd1 protein is involved in a degradation pathway for ubiquitin fused products (UFD pathway). Several studies have demonstrated that Ufd1 is a component of the Cdc48-Ufd1-Npl4 multiprotein complex which is active in the recognition of several polyubiquitin-tagged proteins and facilitates their presentation to the 26S proteasome for protein degradation or even more specific processing. The multiprotein complex Cdc48-Ufd-Npl4 is also active in mammalian cells. The biochemical role of UFD1L protein in human cells is unknown, even though the interaction between UFD1L and NPL4 proteins has been maintained. In order to clarify this issue, we examined the intracellular distribution of the protein in different mammalian cells and studied its involvement in the Fas and ceramide factors-mediated apoptotic pathways. We established that in mammalian cells, Ufd1l is localized around the nucleus and that it does not interfere with Fas-and ceramide-mediated apoptosis.


A study of bleeding time in 120 long-term aspirin trial patients.
The bleeding time was measured in 120 patients participating in a longterm randomised double-blind trial of aspirin in thromboembolic prophylaxis (UK-TIA aspirin Study). In 70 patients taking aspirin 300 mg or 1,200 mg daily for a mean duration of 35 months the bleeding time averaged 228 seconds. In comparison with 30 patients randomised to placebo and not taking aspirin whose bleeding time averaged 217 seconds, there was no significant difference. Stratification of bleeding time estimation by duration of treatment suggested no significant trend in either placebo or aspirin groups over several years. These results suggest that the longterm trials of aspirin should be looked at again from the point of view of efficacy of treatment by time from randomisation.


DOCA-salt hypertension does not require the ouabain-sensitive binding site of the α2 Na,K-ATPase.
We have shown that the ouabain-sensitive α2 Na,K-ATPase is required for adrenocorticotropic hormone (ACTH)-induced hypertension and gestational blood pressure regulation. It is therefore of interest to explore whether this binding site participates in the development of other forms of hypertension, such as deoxycorticosterone acetate (DOCA)-salt using mutant mice with altered sensitivity to ouabain. Wild-type (α1 ouabain-resistant, α2 ouabain-sensitive: α(R/R)α2(S/S)), α1-resistant, α2-resistant (α1(R/R)α2(R/R)) and α1-sensitive, α2-resistant (α1(S/S)α2(R/R)) mice were uninephrectomized and implanted with DOCA pellets. The animals were given either tap water or 1% NaCl, and blood pressure was measured before and after DOCA. DOCA-salt-treated α1(R/R)α2(R/R) mice developed hypertension to the same extent as α1(R/R)α2(S/S) mice (wild type), and the α1(S/S)α2(R/R) mice given DOCA-salt also showed no difference from the other two genotypes. The expression of the α1 isoform was not changed by DOCA-salt treatment in either α1(R/R)α2(S/S) or α1(R/R)α2(R/R) mice. However, the α2 subunit was expressed at substantially higher levels in the hearts of α1(R/R)α2(R/R) than α1(R/R)α2(S/S) mice, regardless of treatment. Plasma levels of ouabain did not change consistently, but those of marinobufagenin were modestly higher in DOCA-salt treated mice relatively to those without salt. The ouabain-binding site of either the α1 or α2 Na,K-ATPase subunit does not play an essential role in the development of DOCA-salt hypertension in this mouse model. These findings indicate that the underlying mechanisms of hypertension induced by DOCA-salt treatment are different from those of ACTH-induced hypertension.


Dystroglycan modulates the ability of insulin-like growth factor-1 to promote oligodendrocyte differentiation.
The adhesion receptor dystroglycan positively regulates terminal differentiation of oligodendrocytes, but the mechanism by which this occurs remains unclear. Using primary oligodendrocyte cultures, we identified and examined a connection between dystroglycan and the ability of insulin-like growth factor-1 (IGF-1) to promote oligodendrocyte differentiation. Consistent with previous reports, treatment with exogenous IGF-1 caused an increase in MBP protein that was preceded by activation of PI3K (AKT) and MAPK (ERK) signaling pathways. The extracellular matrix protein laminin was further shown to potentiate the effect of IGF-1 on oligodendrocyte differentiation. Depletion of the laminin receptor dystroglycan using siRNA, however, blocked the ability of IGF-1 to promote oligodendrocyte differentiation of cells grown on laminin, suggesting a role for dystroglycan in IGF-1-mediated differentiation. Indeed, loss of dystroglycan led to a reduction in the ability of IGF-1 to activate MAPK, but not PI3K, signaling pathways. Pharmacological inhibition of MAPK signaling also prevented IGF-1-induced increases in myelin basic protein (MBP), indicating that MAPK signaling was necessary to drive IGF-1-mediated enhancement of oligodendrocyte differentiation. Using immunoprecipitation, we found that dystroglycan, the adaptor protein Grb2, and insulin receptor substrate-1 (IRS-1), were associated in a protein complex. Taken together, our results suggest that the positive regulatory effect of laminin on oligodendrocyte differentiation may be attributed, at least in part, to dystroglycan's ability to promote IGF-1-induced differentiation.


The Relationship Between Epilepsy, Obstructive Sleep Apnea, and Treatment Outcome.
Both epilepsy and obstructive sleep apnea are common conditions and hence frequently coexist in a given patient. A complex bidirectional relationship exists between the 2 conditions where the presence of one affects the other. Treatment of obstructive sleep apnea with continuous positive airway pressure may improve seizure control in medically refractory epilepsy patients, leading to improved quality of life. Understanding of this complex relationship between epilepsy, sleep, and sleep disorders such as obstructive sleep apnea continues to evolve.


Propagation of hippocampal seizure activity arising from the hippocampus: a local cerebral blood flow study.
We studied the propagation of spike discharges and the changes in local cerebral blood flow (LCBF) by means of the electroencephalogram (EEG) and autoradiographs to elucidate the underlying mechanism and the propagation pathway in rats with limbic seizures. Seizures were induced by the unilateral microinjection of kainic acid (KA) into the dorsal hippocampus during which behavioral, EEG and LCBF changes were documented. Overall, the results indicate an initial spreading to the contralateral hippocampus from the ipsilateral hippocampus, followed by activation of the ipsilateral amygdala, other limbic structures, striatum and sensorimotor cortex. Finally, seizure activity spreads to the ipsilateral globus pallidus, substantia nigra, subthalamic nucleus, thalamus, septum and parietal cortex. The activation of the contralateral hippocampus in the KA model studied here occurs earlier than in the acute amygdaloid seizure model. Elucidation of the mechanisms underlying this difference in the propagation pathway will require the application in parallel of techniques examining these and other aspects of seizure activity.


Neurobrucellosis developing unilateral oculomotor nerve paralysis.
Brucellosis is a zoonotic infectious disease that is common around the world. Its clinical course demonstrates great diversity as it can affect all organs and systems. However, the central nervous system is rarely affected in the pediatric population. Neurobrucellosis is most frequently observed with meningitis and has numerous complications, including meningocephalitis, myelitis, cranial nerve paralyses, radiculopathy, and neuropathy. Neurobrucellosis affects the second, third, sixth, seventh, and eighth cranial nerves. Involvement of the oculomotor nerves is a very rare complication in neurobrucellosis although several adult cases have been reported. In this article, we present the case of a 9-year-old girl who developed unilateral nerve paralysis as a secondary complication of neurobrucellosis and recovered without sequel after treatment. This case is notable because it is a very rare, the first within the pediatric population. Our article emphasizes that neurobrucellosis should be considered among the distinguishing diagnoses in every case that is admitted for nerve paralysis in regions where Brucella infection is endemic.


RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell type.
The human terminal uridyl transferases TUT4 and TUT7 (TUT4/7) catalyze the additions of uridines at the 3' end of RNAs, including the precursors of the tumor suppressor miRNA let-7 upon recruitment by the oncoprotein LIN28A. As a consequence, let-7 family miRNAs are down-regulated. Disruption of this TUT4/7 activity inhibits tumorigenesis. Hence, targeting TUT4/7 could be a potential anticancer therapy. In this study, we investigate TUT4/7-mediated RNA regulation in two cancer cell lines by establishing catalytic knockout models. Upon TUT4/7 mutation, we observe a significant reduction in miRNA uridylation, which results in defects in cancer cell properties such as cell proliferation and migration. With the loss of TUT4/7-mediated miRNA uridylation, the uridylated miRNA variants are replaced by adenylated isomiRs. Changes in miRNA modification profiles are accompanied by deregulation of expression levels in specific cases. Unlike let-7s, most miRNAs do not depend on LIN28A for TUT4/7-mediated regulation. Additionally, we identify TUT4/7-regulated cell-type-specific miRNA clusters and deregulation in their corresponding mRNA targets. Expression levels of miR-200c-3p and miR-141-3p are regulated by TUT4/7 in a cancer cell-type-specific manner. Subsequently, BCL2, which is a well-established target of miR-200c is up-regulated. Therefore, TUT4/7 loss causes deregulation of miRNA-mRNA networks in a cell-type-specific manner. Understanding of the underlying biology of such cell-type-specific deregulation will be an important aspect of targeting TUT4/7 for potential cancer therapies.


The Diabetes-Cardiovascular Connection in Women: Understanding the Known Risks, Outcomes, and Implications for Care.
Cardiovascular disease (CVD) complications constitute about 50-70% of mortality in people with diabetes. However, there remains a persistently greater relative increase in CVD morbidity and mortality in women with diabetes than in their male counterparts. This review presents recent evidence for the risks, outcomes, and management implications for women with diabetes. Compared to men, women have higher BMI and more adverse cardiovascular risk profile at time of diabetes diagnosis with greater risk for coronary heart disease, stroke, vascular dementia, and heart failure. Pregnancy-specific risk factors of gestational diabetes and pre-eclampsia are associated with future type 2 diabetes (T2D) and CVD. Women with T2D may experience greater benefits than men from GLP-1 receptor agonists. Women with diabetes are at greater relative risk for CVD complications than men, with poorer outcomes, superimposed on preexisting gender disparities in social determinants of health, lower likelihood of being offered cardioprotective interventions, and enrollment in trials. Further research and the utilization of SGLT-2 inhibitors, GLP-1 receptor agonists, and other CVD prevention strategies will help reduce morbidity and mortality.


Pharmaceutical development and specification of stereoisomers.
The pharmaceutical development of chiral drugs requires the activities of many different research and development groups. Guidelines which help to coordinate the activities of these groups and assist in the successful development of compounds with either single or multiple chiral centers are outlined and discussed.


Directional selectivities of visual afferents to the pretectal neuropil in the fire salamander.
Single-unit recordings from visual afferents in the pretectal neuropil of Salamandra salamandra were performed to characterize the properties of direction specific units which are probably involved in the optokinetic reflex. It was shown that afferents from the contralateral eye were more sharply tuned than those from the ipsilateral eye. However, the majority of both were selective for temporonasal movements.


A comparison of the Antileukaemic Effects of Recombinant Human Tumour Necrosis Factor-alpha and its Muteins on Leukaemia L1210 and Leukaemia P388 in Mice.
We investigated the influence of recombinant human tumour necrosis factor alpha (TNF-alpha) and its derivatives termed muteins III, V, VI-in which the first 3 to 7 amino acids of native TNF-alpha have been replaced-on the survival time of mice inoculated with leukaemia L1210 or leukaemia P338. TNF-alpha prolonged the survival of mice with leukaemia L1210 but did not have any therapeutic activity in leukaemia P388-bearing mice. Muteins-treated mice with leukaemia P388 lived longer than animals receiving TNF-alpha, while those inoculated with leukaemia L1210 did not show any significant prolongation of life compared with the TNF-alpha treated group. The results presented in this report indicate that the antileukaemic activity of TNF-alpha is governed at least in part by the nature of the N-terminal amino acids.


[A patient with a painful swelling and a foot drop].
A 72-year old patient presented himself at the outpatient clinic with a painful swelling on the dorsum of the left foot and a foot drop. The diagnosis was a complete rupture of the tibialis anterior tendon.


Anal incontinence-sphincter ani repair: indications, techniques, outcome.
Fecal incontinence is a debilitating problem that has many different causes. There also are many treatments options, from behavioral modification to sphincteroplasty to artificial anal sphincter and colostomy. In a society with an aging population, fecal incontinence is an ever-increasing problem and will continue to grow. Treatment plans need to be individually tailored for each patient. The surgeon should be proficient in different types of procedures and match the procedure with the needs of the patient. Long-term follow-up of these patients must continue to help us better serve this patient population.


Cloning, sequence and characterization of a sunflower (Helianthus annuus L.) pathogen-induced gene showing sequence homology with auxin-induced genes from plants.
The establishment of a plant-pathogen interaction involves changes in gene expressions in both organisms. To isolate Helianthus annuus genes whose expression is induced during processes of resistance to Plasmopara halstedii, a comparison of the expression pattern of healthy sunflowers was made with sunflowers infected with 2 races of P. halstedii, either virulent or avirulent, using differential display of mRNA. A full-length cDNA, HaAC1, representing a sunflower gene whose expression is enhanced during early stages of the incompatible interaction, was isolated. Different timing of RNA accumulation is observed between compatible and incompatible combinations. Sequence analysis and database search revealed significant homology with auxin-induced genes from plants. The expression of this gene, is also induced after treatment with 2,4-dichlorophenoxyacetic acid (2,4-D), salicylic acid (SA) and wounding.


Nonlinear averaging of thermal experience predicts population growth rates in a thermally variable environment.
As thermal regimes change worldwide, projections of future population and species persistence often require estimates of how population growth rates depend on temperature. These projections rarely account for how temporal variation in temperature can systematically modify growth rates relative to projections based on constant temperatures. Here, we tested the hypothesis that time-averaged population growth rates in fluctuating thermal environments differ from growth rates in constant conditions as a consequence of Jensen's inequality, and that the thermal performance curves (TPCs) describing population growth in fluctuating environments can be predicted quantitatively based on TPCs generated in constant laboratory conditions. With experimental populations of the green alga Tetraselmis tetrahele, we show that nonlinear averaging techniques accurately predicted increased as well as decreased population growth rates in fluctuating thermal regimes relative to constant thermal regimes. We extrapolate from these results to project critical temperatures for population growth and persistence of 89 phytoplankton species in naturally variable thermal environments. These results advance our ability to predict population dynamics in the context of global change.


Neuroendocrine cells in the dental pulp in health and disease.
Neuroendocrine cells were identified in human dental pulp by immunohistochemical method using monoclonal antibodies. A population of neuroendocrine cells positively reacting to neuron-specific enolase, synaptophysin, chromogranin A, and stained with paraldehyde-fuchsin, was detected in the subodontoblastic layer of the pulp. Changes in their count, morphology, and function in caries and pulpitis concomitant with periodontitis were proven.


Incubation of ovine scrapie with environmental matrix results in biological and biochemical changes of PrP(Sc) over time.
Ovine scrapie can be transmitted via environmental reservoirs. A pool of ovine scrapie isolates were incubated on soil for one day or thirteen months and eluted prion was used to challenge tg338 mice transgenic for ovine PrP. After one-day incubation on soil, two PrP(Sc) phenotypes were present: G338 or Apl338ii. Thirteen months later some divergent PrP(Sc) phenotypes were seen: a mixture of Apl338ii with either G338 or P338, and a completely novel PrP(Sc) deposition, designated Cag338. The data show that prolonged ageing of scrapie prions within an environmental matrix may result in changes in the dominant PrP(Sc) biological/biochemical properties.


Structure and mechanism of a neuropeptide-activated channel in the ENaC/DEG superfamily.
Phe-Met-Arg-Phe-amide (FMRFamide)-activated sodium channels (FaNaCs) are a family of channels activated by the neuropeptide FMRFamide, and, to date, the underlying ligand gating mechanism remains unknown. Here we present the high-resolution cryo-electron microscopy structures of Aplysia californica FaNaC in both apo and FMRFamide-bound states. AcFaNaC forms a chalice-shaped trimer and possesses several notable features, including two FaNaC-specific insertion regions, a distinct finger domain and non-domain-swapped transmembrane helix 2 in the transmembrane domain (TMD). One FMRFamide binds to each subunit in a cleft located in the top-most region of the extracellular domain, with participation of residues from the neighboring subunit. Bound FMRFamide adopts an extended conformation. FMRFamide binds tightly to A. californica FaNaC in an N terminus-in manner, which causes collapse of the binding cleft and induces large local conformational rearrangements. Such conformational changes are propagated downward toward the TMD via the palm domain, possibly resulting in outward movement of the TMD and dilation of the ion conduction pore.


Effect of the Inclusion Nanocomplex Formed of Titanium Tetrafluoride and β-Cyclodextrin on Enamel Remineralization.
Titanium tetrafluoride (TiF4) is a topical agent used in the control of dental caries; however, it is highly acidic. To minimize this effect, cyclodextrins (CDs) are used. This study evaluated the in vitro potential of TiF4 and β-CD on remineralization. Forty bovine enamel blocks were selected by microhardness and randomly assigned to four groups (n = 10 per group): control (distilled and deionized water), 1% β-CD solution, 1% TiF4 solution, and TiF4: β-CD solution. The blocks were subjected to a pH cycling regimen for 8 days. After that, samples were evaluated by cross-sectional microhardness (CSMH), scanning electron microscopy (SEM), and energy dispersive spectrometry (EDS). Data were assessed for normality and analyzed using ANOVA and Tukey's tests (α = 0.05). Regarding CSMH, TiF4: β-CD was statistically superior to the control (P = 0.033), β-CD (P = 0.022), and TiF4 (P = 0.006). SEM photomicrography revealed the titanium dioxide coating on slabs treated with TiF4 and TiF4: β-CD. EDS assessment demonstrated the presence of titanium on the surface of slabs treated with TiF4 and TiF4: β-CD. The solution containing the inclusion nanocomplex formed of TiF4 and β-CD was able to reharden the enamel subsurface.


An audit of the results of a triplet metronomic chemotherapy regimen incorporating a tyrosine kinase inhibitor in recurrent/metastatic head and neck cancers patients.
Addition of erlotinib to metronomic chemotherapy (MCT) may lead to further improvement in progression-free survival (PFS) and overall survival in head and neck cancers. The aim of this study was to study the PFS with MCT + erlotinib combination in our setting. A single-arm prospective observational study conducted at Malabar Cancer Center. Patients warranting palliative chemotherapy for head and neck cancers, having adequate organ function, not-affording cetuximab and not willing for intravenous chemotherapy were included in this study. Oral methotrexate (15 mg/m(2)/week), oral celecoxib (200 mg twice daily), and erlotinib (150 mg once daily) were administered till the progression of the disease or till intolerable side-effects. Patients underwent toxicity (CTCAE version 4.02) and response (RECIST version 1.1) assessment every 30 days. Statistical analysis was performed using SPSS version 16 (IBM, New York, USA). Descriptive statistics and Kaplan-Meier analysis have been performed. A total of 15 patients received MCT. The median age of these patients was 65 years (range: 48-80). The Eastern Cooperative Oncology Group Performance Status was 0-1 in seven patients (46.7%), while it was 2 in eight patients (53.3%). The primary sites of tumor were predominantly oral cavity, 11 (73.4%). Prior to MCT, treatment with palliative radiation therapy was given in 11 patients and curative treatment in two patients. The best response post-MCT was complete remission in two patients, partial remission in seven patients, stable disease in four patients, and progressive disease in two patients. The median estimated PFS was 148 days (95% confidence interval 95.47-200.52 days). For a median follow-up of 181 days, there were only three deaths. Grade 3-4 toxicity was seen in six patients (40%). Dose reduction was required in four patients (26.7%). The addition of erlotinib to an MCT schedule of methotrexate and celecoxib resulted in a promising PFS and should be tested in future studies.


Using ethnographic film in tackling podoconiosis.
Ethiopia has one of the worst podoconiosis rates in the world, affecting >1.5 million patients. We present our ethnographic film 'Tigist, the story of a girl with podoconiosis' and its potential use in tackling podoconiosis. We conducted visual ethnography, consisting of video-recorded participant observations and interviews with seven patients, three healthcare workers and two podoconiosis experts. We acquired video recordings of social moments, the state of podoconiosis patients' bodies and minds, their emotions and the impact of poverty. Our film allows for an intensified understanding of patients' daily experiences with podoconiosis, potentially impacting care, awareness and medical teaching programs.


The role of water mass dynamics in controlling bacterial abundance and production in the middle Adriatic Sea.
Month-to-month fluctuations in the abundance of bacteria and heterotrophic nanoflagellates (HNF) and bacterial production, as well as various chemical (nutrients, oxygen) and physical (salinity, temperature) parameters were analysed at a station located in the open middle Adriatic Sea during one decade (1997-2006). Being influenced by both coastal waters and open Adriatic circulation in the surface layer, and by the deep Adriatic water masses in the deep layers (100 m), this station is quite suitable for detecting the environmental changes occurring in the open Adriatic Sea with respect to the circulation of its water masses and their long-term changes and anomalies. Multivariate methods were used to identify seasonal and inter-annual changes of the investigated parameters, associating observed changes to the changes in Adriatic water masses and circulation regimes. The analyses showed that bacterial abundance and production were controlled by different water mass dynamics during 1997-2001 compared to 2002-2006 period, particularly noticeable in different seasonal patterns of biological parameters. The interplay between North Adriatic Dense Water (NAdDW) and Levantine Intermediate Water (LIW) resulted in a change in the available nutrients (NAdDW is poor in orthophosphates), and as a consequence different bacterial abundance and production. A few periods were examined in detail, such as 2004, when LIW inflow was particularly strong and was accompanied by an increase of bacterial and HNF abundances, as well as of bacterial production.


Purification of membrane vesicles from Gram-positive bacteria using flow cytometry, after iodixanol density-gradient ultracentrifugation.
Membrane vesicles (MVs) play biologically important roles in Gram-positive bacteria, and purification is essential for their study. Although high-performance flow cytometry has the capability to quantify and isolate specific small particles, it has not been examined for MV isolation. In this study, we used high-performance flow cytometry to analyze MV from Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, prepared by iodixanol density-gradient ultracentrifugation. Analysis of the quality of MV samples before and after sorting showed that the flow cytometric sorting provided higher purity and uniformity compared to gradient isolation alone. The MV purification method using flow cytometry should prove useful for applications requiring a very high purity of MV samples such as proteomic, metagenomic or lipidomic studies.


A comparison of vertebral venous networks in adolescent idiopathic scoliosis patients and healthy controls.
Cadaveric studies have previously documented a typical pattern of venous drainage within vertebral bodies (VBs), comprised primarily of the basivertebral vein. These studies, however, are limited by the number of samples available. MRI is able to provide 3D images of soft tissue structures in the spine, including the basivertebral vein without the use of contrast in both healthy controls and subjects with abnormal anatomy such as adolescent idiopathic scoliosis (AIS). This study aimed to quantify the venous networks within VBs of 15 healthy adolescent controls and 15 AIS patients. Five transverse slices through the VBs were examined simultaneously and the observable vascular network traced. The length of the network on the left and right sides of the VB was calculated, and the spatial patterning assessed level-by-level within each subject. Significant differences were seen in the left/right distribution of vessels in both the control and AIS subjects, with both groups having greater length on the right side of all of their VBs. No difference was seen between AIS and control subjects in any region. Large individual variations in patterns were seen in both groups; however, the control group showed more consistent spatial patterning of the vascular networks across levels in comparison to the AIS group. The length of the basivertebral vein was seen to have a significant bias to the right hand side of the VB in both healthy and AIS adolescents. The spatial pattern of this vein showed large variations in branching both within and across individuals. No significant differences were seen between AIS and control subjects, suggesting both that this network is preserved in deformed AIS vertebrae, and that the vertebral venous system does not play a role in the etiology of AIS.


Response to 'The essential role of dermatology publications in enhancing professional diversity, equity and inclusion'.
Burgin et al. Br J Dermatol 2021; 185:473-4.


Synthesis of copper nanoclusters from Bacopa monnieri leaves for fluorescence sensing of dichlorvos.
In this work, a facile one-step green synthesis was developed for the fabrication of blue fluorescent copper nanocluster (Brahmi-CuNCs) from the extract of Bacopa monnieri (common name is Brahmi) via a microwave method. The as-prepared Brahmi-CuNCs emitted blue fluorescence at 452 nm when excited at 352 nm and showed a quantum yield of 31.32%. Brahmi-derived blue fluorescent CuNCs acted as a probe for fluorescence sensing of dichlorvos. Upon the addition of dichlorvos, the blue emission for Brahmi-CuNCs was gradually turned off, favouring establishment of a calibration graph in the range 0.5-100 μM with a detection limit of 0.23 μM. The as-synthesized Brahmi-CuNCs exhibited marked sensitivity and selectivity towards dichlorvos, favourable for assaying dichlorvos in various samples (cabbage, apple juice, and rice).


Laparoscopic management of paraduodenal hernias: mesh and mesh-less repairs. A report of four cases.
Paraduodenal hernias are the most common form of internal hernias. There are few reports in the literature, with the total number of reported cases being less than 500. We report four patients with paraduodenal hernias causing intestinal obstruction. All of the four patients with paraduodenal hernias presented with features of intestinal obstruction. A clinical diagnosis was not made in any of the cases, and computed tomography (CT) scanning was performed to confirm this. They were all successfully managed by a laparoscopic repair. The operating time was 55-72 mins. Postoperatively, three patients recovered uneventfully, while one patient had ileus for 3 days and, thereafter, recovered spontaneously. Hospital stay was in the range 2-6 days. There were no conversions. One patient had recurrent paraduodenal hernia, for which a laparoscopic mesh repair was successfully performed. The mechanism of the herniation is thought to be a defective rotation of the superior mesenteric vein during embryonic development. Paraduodenal hernias are not high on the list of differentials for bowel obstruction. Some form of surgery is mandatory for all cases. The inferior mesenteric vein has to be sacrificed in some cases to facilitate reduction of the hernia contents. A mesh repair is reserved for large defects and recurrent hernias. Laparoscopic repair has been infrequently reported in the literature. Based on our experience, the laparoscopic approach seems to be effective in the repair of paraduodenal hernias. It carries all of the benefits of minimal access surgery, while providing a sound repair.


The C1q Receptors: Focus on gC1qR/p33 (C1qBP, p32, HABP-1)1.
In the past several years, a number of C1q binding surface proteins or receptors have been described. This is not of course surprising considering the complexity of the C1q molecule and its ability to bind to a wide range of cellular and plasma proteins via both its collagen-like [cC1q] region and its heterotrimeric globular heads [gC1q] each of which in turn is capable of binding a specific ligand. However, while each of these "receptor" molecules undoubtedly plays a specific function within its restricted microenvironment, and therefore merits full attention, this review nonetheless, will singularly focus on the structure and function of gC1qR-a multi-functional and multi-compartmental protein, which plays an important role in inflammation, infection, and cancer. Although first identified as a receptor for C1q, gC1qR has been shown to bind to a plethora of proteins found in plasma, on the cell surface and on pathogenic microorganisms. The plasma proteins that bind to gC1qR are mostly blood coagulation proteins and include high molecular weight kininogen [HK], Factor XII [Hageman factor], fibrinogen, thrombin [FII], and multimeric vitronectin. This suggests that gC1qR can play an important role in modulating not only of fibrin formation, particularly at local sites of immune injury and/or inflammation, but by activating the kinin/kallikrein system, it is also able to generate, bradykinin, a powerful vasoactive peptide that is largely responsible for the swelling seen in angioedema. Another important function of gC1qR is in cancer, where it has been shown to play a role in tumor cell survival, growth and metastatic invasion by interacting with critical molecules in the tumor cell microenvironment including those of the complement system and kinin system. Finally, by virtue of its ability to interact with a growing list of pathogen-associated molecules, including bacterial and viral ligands, gC1qR is becoming recognized as an important pathogen recognition receptor [PRR]. Given the numerous roles it plays in a growing list of disease settings, gC1qR has now become a potential target for the development of monoclonal antibody-based and/or small molecule-based therapies.


Urinary 6-beta-OH-cortisol and paracetamol metabolites as a probe for assessing oxidation and conjugation of chemicals in humans.
The ratio between urinary 6-beta-OH-cortisol and 17-OH-corticosteroids was taken as an indirect estimate of monoxygenase activity in a population of controls and epileptic patients undergoing therapy with diphenylhydantoin and phenobarbital. Cortisol hydroxylation was increased in the group of epileptics with large inter-individual variations notwithstanding a similar dosage of inducers. The levels of some phase II conjugating enzymes were followed by administering paracetamol and measuring the urinary excretion of its main metabolites. Paracetamol glucuronate was increased by levels of cysteine and mercapturic derivatives of paracetamol did not vary, whereas sulfate derivatives were decreased in epileptic patients. Plasma N-acetyl-transferase activity did not vary in either group. Hydroxylated cortisol and paracetamol glucuronide excretion were not correlated in the same individuals, and no correlation was found between the ratio of 6-beta-OH-cortisol/17-OH-corticosteroids and the plasma levels of diphenylhydantoin or phenobarbital. Oxidation of cortisol and conjugation of paracetamol were controlled with different mechanisms, varied considerably between individuals and were not predictive of the pharmacokinetics of the inducers in treated patients.


Sino-bronchial reflex, asthma and sinusitis.
Sinusitis should be suspected in cases of chronic, difficult to control asthma or other pulmonary diseases. Appropriate measures to diagnose and treat sinus disease are listed, and an upright Waters roentgenogram may be all that is required for diagnosis. A true sino-bronchial reflex is proposed in these patients. Nasal receptors and reflexes are effective in the physiology of the nose, and in many cases, the diagnosis and treatment of rhinitis and sinusitis results in the improvement of various chronic pulmonary conditions.


Differences in survival based on the type of follow-up for the detection of hepatocellular carcinoma: an analysis of 547 patients.
The aim of this study was to identify any significant variables in the prognosis of 547 cases with hepatocellular carcinoma (HCC), and simultaneously confirm the survival among the different surveillance modalities for the initial detection of HCC in a closely followed-up group (regular periodic follow-up with monthly alpha-fetoprotein (AFP) and ultrasonography at least every 4 months), a not closely followed-up group (neither performed with AFP nor ultrasonography regularly) and an incidental group (incidentally discovered due to related symptoms). Five hundred and forty-seven consecutive patients with HCC diagnosed at the Internal Medicine Department of Saga Prefectural Hospital Koseikan from January 1989 to December 1998 were retrospectively analyzed. The 1-, 3- and 5-year survivals in all 547 cases were 69.7, 42.4 and 26.9%, respectively. The 1-, 3- and 5-year survivals in the cases found to have solitary HCC measuring 2 cm or less in diameter at the time of diagnosis were 97.3, 76.2 and 52.3%, respectively. Forty-seven point one percent of the closely followed-up group, which was the high-risk group were found to have solitary HCC measuring 2 cm or less in diameter (48 out of the 102 followed-up cases), while only 18.5 and 11.8% were found in the not closely followed-up group (46 out of 248 cases) and the incidental group (22 out of 186 cases), respectively. The 5-year survival in the closely followed-up, the not closely followed-up and the incidental groups were 42.9, 26.1 and 15.3%, respectively. The significant factors obtained in the closely followed-up group compared to those from the not closely followed-up group included AFP, tumor size, tumor number and portal thrombosis. These findings indicate the importance of a close follow-up for high-risk groups in order to identify HCC at an early stage, and thereby have a positive influence on survival.


Survey of Campylobacter species, VTEC O157 and Salmonella species in Swedish wildlife.
Samples collected from 791 wild animals (Canada geese, roe deer, hares, moose, wild boar and gulls) shot during hunting were examined for verocytotoxin-producing Escherichia coli (VTEC) O157, and thermophilic Campylobacter and Salmonella species. With the exception of one positive isolate from a wild boar, VTEC O157 was not isolated from any of the animals. Salmonella species were isolated only from the gulls, of which 4 per cent were estimated to be positive. Thermophilic Campylobacter species were commonly isolated from all the species except deer.


Increased incidence of abnormal foetuses in the offspring of cyclophosphamide-treated male mice.
The incidence of morphologically abnormal foetuses in the litters of cyclophosphamide (CP)-treated male mice was investigated and compared with control values. In two experiments (100 mg/kg) CP was shown to increase the incidence of grossly abnormal foetuses over that seen in the controls, although neither was statistically significant in isolation. When the probabilities from the two tests of significance were combined using the method of Fisher the result was significant (P = 0.02). These results suggest that an acute exposure to a mutagen in male mice can cause genetic damage that results in an increased incidence of phenotypically abnormal offspring. However, the large numbers of animals required and the variable control level of abnormalities, indicate that this dosing regimen is an inefficient method of studying the genetic mechanisms responsible for the effects seen.


Conserved sequences of prokaryotic proteomes and their compositional age.
A full repertoire of octapeptides which are present in at least 30 bacterial proteomes of total 131 currently available is computationally derived and filtered. An original search technique is used that, in terms of computational time and memory, is similar to the Suffix tree method. The presence of a given sequence in a large number of proteomes qualifies it as a conserved sequence. The larger the number of proteomes where it is found, the higher is the conservation. The concept of compositional age of the amino acid sequences ("compositional clock") is introduced for the first time. The compositional age is calculated on the basis of the consensus temporal order of appearance of amino acids in early evolution. The correlation between the compositional age and the sequence conservation is established.


Label-free and dual-mode biosensor for HPV DNA based on DNA/silver nanoclusters and G-quadruplex/hemin DNAzyme.
Specific and cost-effective methodologies for human papillomavirus (HPV) gene detection are significant for clinical diagnosis and cancer control. Herein, a label-free and fluorimetric/colorimetric dual-mode sensing strategy was developed for the quantitative determination of HPV DNA based on the integration of fluorescent DNA-silver nanoclusters (DNA/AgNCs) and G-quadruplex/hemin DNAzyme. The fluorimetric sensing strategy was based on the phenomena that the fluorescence enhancement of DNA/AgNCs obtained in proximity of guanine-rich DNA sequences and the photoinduced electron transfer (PET) effect between the electron donor (DNA/AgNCs) and electron receptor (G-quadruplex/hemin). The colorimetric sensing strategy was relied on the peroxidase-like activity of G-quadruplex/hemin DNAzyme. By integrating DNA/AgNCs and DNAzyme, this dual-mode strategy could produce two independent signals to improve the analytical diversity and accuracy. Under optimized conditions, the fluorimetry and colorimetry of the strategy displayed a linear range of 0.01-4 and 0.02-4 nM, with the low detection limit of 2.3 and 5.2 pM, respectively. Additionally, this dual-mode strategy has been successfully applied to HPV DNA analysis in different real samples with excellent results. Moreover, the sensing platform could be developed for different HPVs DNA assay by only adjusting the recognition sequence, which provided a universal strategy for various kinds of virus analysis.


Analysis of the role of CD4+ T-cells during murine cytomegalovirus infection in different strains of mice.
We examined the role of CD4+ T-cells in peritoneal exudate cells (PECs) during the course of acute murine cytomegalovirus (MCMV) infection in two strains of mice. Cell counts of PECs and cytofluorometric analysis showed that C57BL/6, a resistant strain, had more CD4+ T-cells than BALB/c, a susceptible strain, after intraperitoneal infection of 3 x 10(3) PFU of the Smith strain of MCMV, though both strains had an equivalent number of CD8+ T-cells. CD4+ T-cells of both strains expressed mRNA of IFN-gamma, IL-2, and IL-4 on days 5 and 7 after infection, with much higher expression of these cytokines in C57BL/6 than in BALB/c. At the same time point after infection, macrophages were shown to express mRNA of IL-1 alpha and TNF-alpha with higher expression of IL-1 alpha in C57BL/6 than in BALB/c. Production of nitric oxide, recently shown to be one of the antiviral effector mechanisms of macrophages, by macrophages of both strains was examined showing more production of nitric oxide on day 7 after infection in C57BL/6 than in BALB/c. From these findings, we suggest the possibility that CD4+ T-cells contribute to the protection against MCMV infection via the secretion of cytokines and the resultant activation of macrophages to produce nitric oxide.


The preclinical evaluation of the water vapour transmission rate through burn wound dressings.
The control of evaporative water loss, following burn injury, is of major importance to the overall condition of the patient, whether this control is by natural eschar or by a dressing. It is therefore important to preclinically determine the water vapour transmission rate of these dressings, firstly to make comparisons between different materials and secondly to screen prototype materials, under controlled conditions. A preclinical (in vitro) technique is described and the results are given for several commercially available dressings which encompass foam, film and hydrogel material categories.


Antimicrobial activity and phytochemical analyses of Polygonum aviculare L. (Polygonaceae), naturally growing in Egypt.
Polygonum aviculare (Polygonaceae) is an herb commonly distributed in Mediterranean coastal regions in Egypt and used in folkloric medicine. Organic and aqueous solvent extracts and fractions of P. aviculare were investigated for antimicrobial activities on several microorganisms including bacteria and fungi. Phytochemical constituents of air-dried powered plant parts were extracted using aqueous and organic solvents (acetone, ethanol, chloroform and water). Antimicrobial activity of the concentrated extracts was evaluated by determination of the diameter of inhibition zone against both Gram-negative and Gram-positive bacteria and fungi using paper disc diffusion method. Results of the phytochemical studies revealed the presence of tannins, saponins, flavonoids, alkaloids and sesquiterpenes and the extracts were active against both Gram-negative and Gram-positive bacteria. Chloroform extract gave very good and excellent antimicrobial activity against all tested bacteria and good activity against all tested fungi except Candida albicans. Structural spectroscopic analysis that was carried out on the active substances in the chloroform extract led to the identification of panicudine (6-hydroxy-11-deoxy-13 dehydrohetisane). Evaluation of the antimicrobial activity of panicudine indicated significant activity against all tested Gram-negative and Gram-positive organisms. Panicudine displayed considerable activity against the tested fungi with the exception of C. albicans. Antimicrobial activity of the extracts was unaffected after exposure to different heat treatments, but was reduced at alkaline pH. Studies of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of panicudine on the tested organisms showed that the lowest MIC and the MBC were demonstrated against Salmonella paratyphi, Bacillus subtilis and Salmonella typhi and the highest MIC and MBC were against Staphylococcus aureus.


Differential localization of dengue virus protease affects cell homeostasis and triggers to thrombocytopenia.
Thrombocytopenia is one of the symptoms of many virus infections which is the "hallmark" in the case of dengue virus. In this study, we show the differential localization of existing two forms of dengue virus protease, i.e., NS2BNS3 to the nucleus and NS3 to the nucleus and mitochondria. We also report a nuclear transcription factor, erythroid differentiation regulatory factor 1 (EDRF1), as the substrate for this protease. EDRF1 regulates the expression and activity of GATA1, which in turn controls spectrin synthesis. Both GATA1 and spectrins are required for platelet formation. On the other hand, we found that the mitochondrial activities will be damaged by NS3 localization which cleaves GrpEL1, a co-chaperone of mitochondrial Hsp70. Levels of both EDRF1 and GrpEL1 were found to deteriorate in dengue virus-infected clinical samples. Hence, we conclude that NS2BNS3-mediated EDRF1 cleavage and the NS3-led mitochondrial dysfunction account for thrombocytopenia.


Haplotype-Assisted Noninvasive Prenatal Diagnosis of Genetic Diseases by Massively Parallel Sequencing of Maternal Plasma Cell-Free DNA.
Early prenatal diagnosis of genetic diseases allows for timely intervention or prevention of the diseases in newborns. Conventional prenatal diagnosis of most genetic diseases relies on testing fetal DNA obtained by invasive procedures such as amniocentesis or chorionic villus sampling, which are associated with small risks of fetal loss. Maternal circulating blood contains cell-free DNA (cfDNA) from the fetal genome and can thus be used to noninvasively detect fetal genetic diseases such as chromosomal abnormalities, copy number variants, and single gene diseases. However, due to the presence of a high level of maternal cfDNA in the maternal blood stream, a relative haplotype dosage (RHDO) analysis is required to detect the mutant loci in the fetal genome when performing noninvasive prenatal diagnosis (NIPD) by massively parallel sequencing (MPS) of cfDNA. In this chapter, we describe a protocol utilizing the RHDO strategy for NIPD of any gene of interest associating with single gene diseases.


Recurrence and extension of lobar hemorrhage related to cerebral amyloid angiopathy: multivariate analysis of clinical risk factors.
Many recent studies have analyzed clinical risk factors for the recurrence and extension of intracerebral hemorrhage. However, they have not been investigated in patients with lobar hemorrhage related to cerebral amyloid angiopathy (CAA). We studied 40 surgically treated patients with lobar hemorrhage diagnosed histologically as being related to CAA. To determine clinical factors influencing the recurrence and hematoma size their clinical data (demographics, medical history, and radiographic and laboratory data) were examined retrospectively and subjected to multivariate analysis. Twelve patients (30%) had recurrent lobar hemorrhage. Twenty-one patients had a small hematoma and 19 had a large hematoma. Hypertension was the only significant clinical factor influencing the recurrence of CAA-related lobar hemorrhage. There was no significant clinical factor influencing the hematoma size of CAA-related lobar hemorrhage. The history of hypertension is associated with an increase in the recurrence of CAA-related lobar hemorrhage.


The electrical response of the human eye to patterned stimuli: clinical observations.
Following the first recording of electroretinographic responses in man to a barred pattern by Riggs and associates (1964) in normal and by Lawwill (1973, 1974) in clinical cases, the first striking observation of a complete loss of pattern electroretinogram (PERG) after injurious section of the optic nerve by Groneberg & Teping (1980) has led to the conclusion that the PERG originates from proximal retinal structures different from those responsible for the luminance electroretinogram (LERG). Typical changes of the PERG are seen during branch occlusion of the central retinal artery and vein. In ocular hypertension without visual field loss and glaucoma-related papillary changes the PERG is decreased at intraocular pressures above 26 mm Hg. In cases of primary glaucoma with regulated intraocular tension and without using miotics the amplitude of the PERG reflects the damage to the inner retinal layers. This favorably compares with the P100 latencies of the visual evoked cortical potential (VECP) which in primary glaucoma were partly within, partly outside the normal range. Other retinal diseases showing amplitude changes in the PERG are primary macular dystrophy, diabetic retinopathy, and the acute stage of optic neuritis. In all these cases the Ganzfeld LERG may be normal or nearly normal, whereas the PERG undergoes typical changes. On the contrary a highly preserved PERG can be recorded in cases of retinitis pigmentosa where the electrooculogram light rise and the LERG are already missing. In light of these findings the recording of PERG constitutes a new promising method of clinical electroretinography reflecting the activity of the hitherto omitted innermost retinal layers. It thereby contributes essentially to the location of disturbances within the visual system.


Clarity and caution in the natural history of low-grade dysplasia in ulcerative colitis.
A substantial body of evidence supports the safety of conservative endoscopic polypectomy for discrete, adenomatous-appearing colonic polyps in patients with ulcerative colitis (UC). Much less is known about the clinicopathologic factors of low-grade dysplastic lesions at risk for subsequent high-grade dysplasia or colorectal cancer. In this issue of the American Journal of Gastroenterology, Choi et al. examine the outcome of patients with low-grade dysplasia participating in a surveillance cohort at St Mark's Hospital, one of the oldest and largest programs of its kind. Long-term follow-up of many, well-phenotyped, low-grade dysplasia cases sheds new light, and raises new questions, on our UC surveillance practice.


Identification of Paracentrone in Fucoxanthin-Fed Mice and Anti-Inflammatory Effect against Lipopolysaccharide-Stimulated Macrophages and Adipocytes.
Fucoxanthin is converted to fucoxanthinol and amarouciaxanthin A in the mouse body. However, further metabolism such as cleavage products (i.e., apocarotenoids) remains unclear. The fucoxanthin-derived apocarotenoid in vivo is investigated and the anti-inflammatory effect of apocarotenoids with fucoxanthin partial structure such as allenic bond and epoxide residue against activated macrophages and adipocytes in vitro is evaluated. LC-MS analysis indicates the presence of paracentrone, a C31 -allenic-apocarotenoid, in white adipose tissue of diabetic/obese KK-Ay and normal C57BL/6J mice fed 0.2% fucoxanthin diet for 1 week. In lipopolysaccharide-activated RAW264.7 macrophages, paracentrone as well as C26 - and C28 -allenic-apocarotenoids suppresses the overexpression of inflammatory factors. Further, apo-10'-fucoxanthinal, a fucoxanthin-derived apocarotenoid which retained epoxide residue, exhibits a most potent anti-inflammatory activity through regulating mitogen-activated protein kinases and nuclear factor-κB inflammatory signal pathways. In contrast, β-apo-8'-carotenal without allenic bond and epoxide residue lacks suppressed inflammation. In 3T3-L1 adipocytes, paracentrone, and apo-10'-fucoxanthinal downregulate the mRNA expression of proinflammatory mediators and chemokines induced by co-culture with RAW264.7 cells. Dietary fucoxanthin accumulates as paracentrone as well as fucoxanthinol and amarouciaxanthin A in the mouse body. Allenic bond and epoxide residue of fucoxanthin-derived apocarotenoids have pivotal roles for anti-inflammatory action against activated macrophages and adipocytes.


Pushing Yourself to the Maximum: What Do Prehospital Interventions Do to the Heart Rates of the Prehospital Team Involved? A Case Report.
Little is known about the heart rate changes of prehospital clinicians when performing potentially "stressful" interventions. This case report demonstrates the heart rate changes of two prehospital clinicians when performing a resuscitative thoracotomy. It demonstrates the peak heart rates correlating to the main intervention performed. This highlights areas for future research including the effect heart rate has on optimal performance.


Efficient resonance assignment of proteins in MAS NMR by simultaneous intra- and inter-residue 3D correlation spectroscopy.
Resonance assignment is the first step in NMR structure determination. For magic angle spinning NMR, this is typically achieved with a set of heteronuclear correlation experiments (NCaCX, NCOCX, CONCa) that utilize SPECIFIC-CP (15)N-(13)C transfers. However, the SPECIFIC-CP transfer efficiency is often compromised by molecular dynamics and probe performance. Here we show that one-bond ZF-TEDOR (15)N-(13)C transfers provide simultaneous NCO and NCa correlations with at least as much sensitivity as SPECIFIC-CP for some non-crystalline samples. Furthermore, a 3D ZF-TEDOR-CC experiment provides heteronuclear sidechain correlations and robustness with respect to proton decoupling and radiofrequency power instabilities. We demonstrate transfer efficiencies and connectivities by application of 3D ZF-TEDOR-DARR to a model microcrystalline protein, GB1, and a less ideal system, GvpA in intact gas vesicles.


Identification of novel halophilic/halotolerant bacterial species producing compatible solutes.
Ectoine and hydroxyectoine are compatible solutes with enormous potential for use in the medical and cosmetic industries. Considering the excellent osmoprotective properties of these compatible solutes, we investigate the presence of four compatible solutes (ectoine, hydroxyectoine, proline, and glutamic acid) quantitatively by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in forty-five halophilic/halotolerant bacterial isolates. We determined ectoine production by Marinibacillus sp., Nesterenkonia xinjiangensis, Halobacillus sp., Bacillus patagoniensis, Virgibacillus picturae, Halomonas neptunia, Bacillus patagoniensis, Gracilibacillus sp., Thalassobacillus devorans, Microbacterium sp., Nesterenkonia sp., and Bacillus agaradhaerens, and this production was NaCl dependent. Additionally, the production of hydroxyectoine was observed in six bacterial isolates (Nesterenkonia xinjiangensis, Halobacillus sp., Halomonas neptunia, Thalassobacillus devorans, Nesterenkonia sp., and Bacillus agaradhaerens) which was NaCl and temperature dependent. The study identified new bacterial isolates producing ectoine or hydroxyectoine. While the ectoine production in many different Bacillus members and a few Nesterenkonia have been documented before, ectoine production by Bacillus patagoniensis and Nesterenkonia xinjiangensis has not been shown so far. Further, ectoine production by a member of the genus Thalassobacillus (Thalassobacillus devorans) was demonstrated experimentally for the first time. The findings reported in the study may serve as a basis for the large-scale production of ectoine and hydroxyectoine in the future.


An assessment of the potential role of routine radionuclide thyroid scanning in the differentiation between solid and cystic lesions in the solitary thyroid nodule.
The value of the conventional 99mTc-pertechnetate scan, to differentiate cystic from solid solitary or dominant non-functioning nodules in the thyroid was investigated in 104 patients. Although these nodules are thought to be non-functioning, a low level of radioactivity can be detected in some of the nodules. The assessment was based on the level of radioactivity in the nodules. The nodules with higher activity were considered to have a higher probability of being solid. This diagnosis was confirmed either by ultrasound, or by histological examination, or both, and sensitivity and specificity evaluated with ROC curve analysis which reached 81% sensitivity with a specificity of 44%. The method was more reliable for larger than for smaller nodules reaching a sensitivity of 81% with a specificity of 84%. The results indicate that 99mTc-pertechnetate scanning can provide a useful procedure to distinguish between cystic and solid lesions in the thyroid.


Differences in Parenting Behavior are Systematic Sources of the Non-shared Environment for Internalizing and Externalizing Problem Behavior.
Although there is evidence for non-shared environmental links between parenting and problem behavior, so far, age-, informant-, and parent-specific patterns for both internalizing and externalizing problem behaviors have not been examined within one study yet. Using the twin differences design, the present study aimed to test how maternal and paternal parenting systematically act as a source of non-shared environment for problem behavior across different age groups and informants. We examined 1327 monozygotic twin pairs and their parents drawn from three birth cohorts of the German TwinLife study. Our results revealed that particularly child-reported less positive and more negative parenting by both parents contribute significantly to the unique environmental variance of problem behavior, although we did not find a clear pattern across age groups. Our study underlines the necessity of controlling for genetic confounding to uncover the truly environmentally mediated (and thus environmentally influenceable) pathways between parenting and problem behavior. A practical implication could be that it may be useful to primarily consider the child's perspective and focus on maternal as well as paternal parenting in interventions that address parenting to reduce problem behavior.


Emergency surgery in an elective setting: a case report detailing incidental diagnosis of a de Garengeot hernia.
We present a case of acute appendicitis within an incarcerated femoral hernia. This is a rare complication of the phenomenon eponymously known as a 'De Garengeot Hernia', which describes a vermiform appendix in an incarcerated femoral hernia sac. Our case is somewhat unique in the manner by which the affected patient had presented. Attending hospital for an unrelated elective surgery, an incarcerated hernia was diagnosed at time of admission. Thorough assessment in advance of the procedure and decisive action led to a satisfactory outcome. This may be the first case in literature reporting a 'De Garengeot Hernia' presenting in such a fashion.