Two types of acetylcholine receptor channels in developing Xenopus muscle cells in culture: further kinetic analyses.
1. Further developmental changes in acetylcholine (ACh) receptor channel function were examined in Xenopus muscle cultures using the cell-attached patch-clamp technique. 2. Two types of acetylcholine (ACh) receptor channel events, low- and high-conductance channel events, were distinguished as reported earlier. Apparent open-time histograms for high-conductance channel events were well fitted by a single exponential but those for low-conductance channel events were sometimes fitted better by two exponentials. 3. In low-conductance channel events when the open-time histogram was well fitted by two exponentials, successive open times were correlated: an event with a long open time tended to be followed after a brief interval (less than 1 ms) by another long-duration event. A short-duration event was less frequently followed by an event within a short interval (1 ms) with a long-duration event. 4. Closed-time histograms for the interval between successive low-conductance channel events and between successive high-conductance channel events were both fitted by two exponentials. The fast time constant was 0.36 ms for the high-conductance channel event and 0.31 ms for the low-conductance channel event. There was an indication that a third and faster component was hidden in the first bin (0-200 microseconds) in the closed-time histogram of both types of channel events. 5. Defining a burst as successive openings separated by closures briefer than 1 ms, the number of gaps per burst was different for the two types of channel events. They were 0.16 for high- and 0.37 for low-conductance channel events. In both types of channels, neither the fast component in the closed-time histogram nor the number of gaps per burst changed with time in culture. 6. The apparent open time of both types of channels increased progressively as ACh concentration was increased, suggesting an increasing number of unresolved closures at higher concentrations. At 100 microM-ACh the apparent open time became shorter probably due to channel blockade by ACh molecules. Closed-time histograms were fitted by two exponentials. The time constant of the fast component remained similar to that at low concentration (0.2 microM) up to 20 microM, but the relative number of closures belonging to this component increased with ACh concentration. In contrast, the slow component shortened its time constant as ACh concentration increased and the relative frequency decreased. Again, there was an indication that another faster component existed in the closed-time histogram.(ABSTRACT TRUNCATED AT 400 WORDS)


The effect of pneumococcal conjugate vaccines on incidence and microbiology associated with complicated acute otitis media.
The objectives of this study were to investigate the incidence of complicated acute otitis media (cAOM) as well as the associated microbiology before and after introduction of the 7- and 13-valent pneumococcal conjugate vaccines (PCV-7 and -13), respectively. CAOM comprises "heavy" AOM (AOM demanding hospitalization), mastodismus (M) and acute mastoiditis (AM). A retrospective cohort study of the incidence and microbiology associated with cAOM during the non-PCV era, the PCV-7 and 13 eras, respectively. Clinical and microbiological data were prospectively registered in a local database. The incidences of cAOM as well as the distribution of various bacterial strains in the three eras were compared. A total of 246 cases of cAOM (125 in the pre-vaccine period (2001-2006), 50 in the PCV-7 period (2007-2010) and 71 in the PCV-13 period (2011-2015)) were identified. The incidence of hAOM decreased by 62% in the PCV7-era but increased to almost pre-vaccine levels in the PCV-13 era. In the M + AM group, a decrease by almost 21% in the PCV7-era was found compared to the pre vaccine era, whereas the decrease was only 12% in the PCV13-era. The three most common findings in both hAOM and M + AM were Streptococcus pneumonia (SP), group A streptococcus (GAS) and "no growth". In the hAOM group, SP decreased from 38% in the pre-vaccine era to 31% in the PCV7-era and further to 16% in the PCV13-era. GAS decreased from 17% in the pre-vaccine era to 0% in the PCV7-era and 16% in the PCV13-era. The percentage of "no growth" increased from 12% to 38% and 44%, respectively. In the M + AM group, SP decreased to 10% in the PCV13-era compared with 44% in the pre-vaccine era and 41% in the PCV7-era. An increase in GAS from 15% in the pre-vaccine era and PCV7-era to 30% in the PCV13-era was observed. The "no growth" percentage increased from 13% in the pre-vaccine era to 26% in the PCV7-era and 33% in the PCV13-era. Introduction of PCV7 and PCV13 has been associated with an overall reduction of cAOM in Central Region Denmark. Pneumococci were still one of the two most common bacteria species related to cAOM though a decrease in pneumococci positive cases was observed. We found an increase in M + AM induced by GAS and a relatively large increase in "no growth", which might be caused by a more aggressive pre-hospital approach to treatment with antibiotics. Consequently, it is not evident whether the reduction of incidences is caused by the vaccines or a more aggressive antimicrobial attitude to manage AOM. The shift to GAS from SP is worrisome, and therefore continuous surveillance of the microbiology associated with AOM is warranted.


Essential in vitro test before treatment of patients with intractable chronic lymphocytic leukemia.
About 23% of all chronic lymphocytic leukemic (CLL) patients have intractable CLL (ICLL) which is resistant to conventional therapy and has a poor prognosis. The ICLL patients complicate the determination of the efficacy of new therapeutic agents. An in vitro test is needed for the diagnosis of ICLL patients during the first examination.


Ciliated Foregut Cyst of Gallbladder: A First in Childhood and Review of Literature.
Ciliated foregut cyst (CFC) is a rare developmental anomaly. We report first case of CFC of gallbladder diagnosed in a 9-year-old child. CFCs are usually located above the diaphragm, commonly in a bronchus or oesophagus. A duplex gallbladder was originally suspected, but histology confirmed the CFC. gallbladder.


Characterization of Mn3 O4 -MnO2 nanocomposites biosynthesized by cell lysate of Haloferax alexandrinus GUSF-1.
Manganese oxide nanocomposites attract huge attention in various biotechnological fields due to their extensive catalytic properties. This study reports an easy, rapid, and cost-effective method of using the cell lysate of haloarchaeon, Haloferax alexandrinus GUSF-1 for the synthesis of manganese oxide nanoparticles. The reaction between the cell lysate and manganese sulfate resulted in the formation of a dark brown precipitate within 48 h at room temperature. The X-ray diffraction pattern showed the existence of Mn3 O4 and MnO2 phases consistent with the JCPDS card no. (01-075-1560 and 00-050-0866). The dark brown colloidal suspension of MnO3 -MnO2 in methanol showed maximum absorption between 220 and 260 nm. The EDX spectrum confirmed the presence of manganese and oxygen. The Transmission electron microscopy revealed the spherical morphology with an average particle size between 30 and 60 nm. The magnetic moment versus magnetic field (MH) curve, at room temperature (300 K) did not saturate even at a high magnetic field (±3T) indicating the paramagnetic nature of the prepared nanocomposite. The Atomic Emission Spectroscopic analysis showed a negligible amount of soluble manganese (0.03 ppm in 50 ppm) in the Mn3 O4 -MnO2 suspension suggesting the maximum stability of the material in the solvent over time. Interstingly, Mn3 O4 -MnO2 nanocomposites evidenced antimicrobial activity in the order of Pseudomonas aeruginosa > Salmonella typhi > Escherichia coli > Proteus vulgaris > Candida albicans > Staphylococcus aureus. Conclusively, this is the first report on the formation of Mn3 O4 -MnO2 nanocomposites using cell lysate of salt pan haloarcheon Haloferax alexandrinus GUSF-1 with antimicrobial potential.


Anti-neovascular therapy using novel peptides homing to angiogenic vessels.
Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculature-specific drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH- or ASSSYPLIHWRPWAR-peptide respectively. After the determination of the epitope sequences of these peptides, we modified liposomes with epitope penta-peptides. Liposome modified with APRPG-peptide showed high accumulation in murine tumor xenografts, and APRPG-modified liposome encapsulating adriamycin effectively suppressed experimental tumor growth. Finally, specific binding of APRPG-modified liposome to human umbilical endothelial cells, and that of PRP-containing peptide to angiogenic vessels in human tumors, i.e., islet cell tumor and glioblastoma, were demonstrated. The present study indicates the usefulness of APRPG-peptide as a tool for anti-neovascular therapy, a novel modality of cancer treatment.


Brain imaging in type 2 diabetes.
Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction and dementia. Brain imaging may provide important clues about underlying processes. This review focuses on the relationship between T2DM and brain abnormalities assessed with different imaging techniques: both structural and functional magnetic resonance imaging (MRI), including diffusion tensor imaging and magnetic resonance spectroscopy, as well as positron emission tomography and single-photon emission computed tomography. Compared to people without diabetes, people with T2DM show slightly more global brain atrophy, which increases gradually over time compared with normal aging. Moreover, vascular lesions are seen more often, particularly lacunar infarcts. The association between T2DM and white matter hyperintensities and microbleeds is less clear. T2DM has been related to diminished cerebral blood flow and cerebrovascular reactivity, particularly in more advanced disease. Diffusion tensor imaging is a promising technique with respect to subtle white matter involvement. Thus, brain imaging studies show that T2DM is associated with both degenerative and vascular brain damage, which develops slowly over the course of many years. The challenge for future studies will be to further unravel the etiology of brain damage in T2DM, and to identify subgroups of patients that will develop distinct progressive brain damage and cognitive decline.


GM 58/8: a monoclonal antibody that identifies a new lineage-specific determinant expressed by myeloid progenitors (CFU-GM) and their progeny.
A cytotoxic (IgM) monoclonal antibody (McAb) raised against human erythroleukaemia cell line HEL appears specific for the myelomonocytic lineage. Indirect immunofluorescence and fluorescence-activated cell sorter analyses of peripheral blood and bone marrow cells showed that this McAb (designated GM 58/8) reacts exclusively with more than 90% of the granulocytes, monocytes and myeloid precursors. The positive (fluorescent) fraction sorted from McAb-treated bone marrow buffy coat cells showed a marked enrichment of myeloid precursors, while nonmyeloid cells were recovered in the negative fraction. GM 58/8 specifically inhibited the growth of 90-100% of the committed myelomonocytic progenitors (CFU-GM) in five complement-mediated cytotoxicity experiments. GM 58/8 had virtually no effect on the erythroid progenitor (BFU-E and CFU-E) growth. Cell sorting experiments using this McAb resulted in recovery of 84% of CFU-GM among the fluorescent fractions. Comparisons with other anti-myelomonocytic McAbs reported so far suggest that GM 58/8 has more restricted reactivity and shows more efficient CFU-GM cytotoxicity. Patterns of reactivity with normal cells and established lines indicate that the antigenic determinant identified by GM 58/8 is different from that recognized by previously described anti-myelomonocytic McAbs. McAb GM 58/8 could be used to isolate or remove pure populations of progenitors and/or more differentiated cells of the myelomonocytic lineage for in vitro studies. This study also provides evidence that the HEL cell line, derived originally from an erythroleukaemia patient, expresses an antigenic determinant shared by the normal cells of myelomonocytic lineage.


Serum zinc concentration during childhood.
Serum zinc concentrations in subjects of different ages were estimated by neutron activation analysis to obtain reliable reference values for the diagnosis of primary or secondary zinc deficiency during childhood. In these healthy individuals a small age-dependent variation of the mean values was found. Serum zinc concentrations were lower in cord blood (mean value: 880 X 10(-9) g/ml) and in infant;s (mean value: 820 X 10(-9) g/ml) than in adults (mean value 1178 X 10(-9) g/ml). In comparison to these values, the serum zinc concentration in a patient with secondary zinc deficiency and 4 patients with acrodermatitis enteropathica was reduced to about 25% of normal.


Crystal Clear with Active Visualization: Understanding Medication Adherence Among Youth Living with HIV.
Adherence to antiretroviral therapy (ART) among youth remains low. We piloted an adapted active visualization device that demonstrates how ART works in the body. Youth living with HIV were randomized to: (1) standard care (n = 14) or the (2) adapted active visualization intervention (n = 14) and 71% of the sample (n = 19) were re-assessed on viral load, adherence behaviors, and illness perceptions 2.5 months later. Intervention youth had lower viral loads, reported less difficulty in adhering to ART, and more motivation and control over their HIV than standard care at follow-up. Active visualization may be an acceptable tool to address ART adherence among youth.


Tipping points in the arctic: eyeballing or statistical significance?
Arctic ecosystems have experienced and are projected to experience continued large increases in temperature and declines in sea ice cover. It has been hypothesized that small changes in ecosystem drivers can fundamentally alter ecosystem functioning, and that this might be particularly pronounced for Arctic ecosystems. We present a suite of simple statistical analyses to identify changes in the statistical properties of data, emphasizing that changes in the standard error should be considered in addition to changes in mean properties. The methods are exemplified using sea ice extent, and suggest that the loss rate of sea ice accelerated by factor of ~5 in 1996, as reported in other studies, but increases in random fluctuations, as an early warning signal, were observed already in 1990. We recommend to employ the proposed methods more systematically for analyzing tipping points to document effects of climate change in the Arctic.


The envelope protein of Usutu virus attenuates West Nile virus virulence in immunocompetent mice.
West Nile virus (WNV) and Usutu virus (USUV) are the two most widespread mosquito-borne flaviviruses in Europe causing severe neuroinvasive disease in humans. Here, following standardization of the murine model with wild type (wt) viruses, we engineered WNV and USUV genome by reverse genetics. A recombinant virus carrying the 5' UTR of WNV within the USUV genome backbone (r-USUV5'-UTR WNV) was rescued; when administered to mice this virus did not cause signs or disease as wt USUV suggesting that 5' UTR of a marked neurotropic parental WNV was not per se a virulence factor. Interestingly, a chimeric virus carrying the envelope (E) protein of USUV in the WNV genome backbone (r-WNVE-USUV) showed an attenuated profile in mice compared to wt WNV but significantly more virulent than wt USUV. Moreover, except when tested against serum samples originating from a live WNV infection, r-WNVE-USUV showed an identical antigenic profile to wt USUV confirming that E is also the major immunodominant protein of USUV.


Effects of selective cyclooxygenase enzyme inhibitors on lipopolysaccharide-induced dual thermoregulatory changes in rats.
The effects of selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors (valeryl salicylate and SC-58236, respectively) on Escherichia coli O111:B4 lipopolysaccharide (LPS)-induced dual thermoregulatory changes and serum tumor necrosis factor-alpha elevation were investigated in rats. LPS (50 microg/kg, intraperitoneal) produced an initial hypothermia that was then followed by fever. Serum tumor necrosis factor-alpha levels elevated at the initial phase of hypothermia. Valeryl salicylate injections (20, 40, and 80 mg/kg, subcutaneous [s.c.]) completely inhibited hypothermia without any effect on the elevated serum tumor necrosis factor-alpha levels and on the subsequent fever. On the other hand, SC-58236 injections (10, 20, and 40 mg/kg, s.c.) only partially abolished the hypothermia. SC-58236 had no effect on the initiation of fever, however completely inhibited the maintenance of fever. The serum tumor necrosis factor-alpha elevation was not reduced by SC-58236 treatment. The combination of valeryl salicylate and SC-58236 also failed to inhibit the initiation of fever. These findings suggest that cycloxygenase-1 may have a predominant role for the development of LPS-induced hypothermia, but cyclooxygenase-1 does not seem to be involved in the mediation of LPS-induced fever. Meanwhile, cyclooxgenase-2 may be critical for the late phase rather than the initiation of the fever response in rats.


Human pharmacology of 5-epi-sisomicin (Sch 22591) following intramuscular administration.
5-epi-sisomicin was given as a single intramuscular injection of 1 mg/kg to six healthy male adults. Serum peak concentrations averaged 3.07 mg/l, the mean elimination half life was 179 min and the mean 24 h urinary recovery was 85.3%. Local and systemic tolerance was good.


Evidence of a functional effect of transient transurethral catheterization on micturition in women.
The objective of this study is to evaluate the effect of transient catheterization on uroflow parameters. Consenting women (ages 18-90) provided an uninstrumented uroflow pre- and post-indicated in urodynamic procedures. Voided volume, Qmax, and Qave were recorded for both uninstrumented uroflows. Uroflow curves were classified as "normal" or "abnormal." Pre- and post-urodynamic uroflow data were compared. Thirty-five patients were included in the study. There was a statistically significant decrease in Qave from the pre- to the post-urodynamic uroflows from 14.71 to 10.55 ml/s (p = 0.012). Additionally, 28.6% of uroflow tracing patterns changed from "normal" to "abnormal," whereas only one (2.9%) changed from "abnormal" to "normal" (p = 0.031). This study showed a degradative effect of transient catheterization on uroflow parameters, suggesting that catheterization may cause more than simply a passive obstructive effect. Urethral stimulation due to catheterization may perturb detrusor urethral function, altering voiding and possibly filling performance.


Redo third ventriculostomy.
Endoscopic third ventriculostomy (ETV) is the treatment of choice for obstructive hydrocephalus. In some cases a reclosure of the ventriculostoma occurs. This could be caused by different reasons, such as operative technique, size of the stoma, scarring, or a persisting Liliequist membrane. The databases of the Neurosurgical Department of the Philipps University Marburg and the International Neuroscience Institute Hannover have been explored. The medical reports of patients who suffered from hydrocephalus and were treated with ETV between 1990 and 2010 were reviewed, with special consideration of a nonpatent ventriculostoma and a repeated ETV. Of 148 patients with ETV, we had 14 patients in whom the stoma was not patent. In 8 of those, we performed a successful second ventriculostomy. Five patients were treated with application of a ventriculoperitoneal shunt. One patient died of an acute obstructive hydrocephalus due to the closure of the ventriculostoma. The success rate of repeat ETV has been 87.5%. In cases of secondary closure of the stoma after ETV, an endoscopic reventriculostomy is recommended using the same operative approach and should be taken into consideration before the application of a cerebrospinal fluid diversion system.


Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS.
Amyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to ∼97% of ALS cases. Using a Drosophila model of ALS, we show that TDP-43 overexpression (OE) in motor neurons results in decreased expression of the Hsc70-4 chaperone at the neuromuscular junction (NMJ). Mechanistically, mutant TDP-43 sequesters hsc70-4 mRNA and impairs its translation. Expression of the Hsc70-4 ortholog, HSPA8, is also reduced in primary motor neurons and NMJs of mice expressing mutant TDP-43. Electrophysiology, imaging, and genetic interaction experiments reveal TDP-43-dependent defects in synaptic vesicle endocytosis. These deficits can be partially restored by OE of Hsc70-4, cysteine-string protein (Csp), or dynamin. This suggests that TDP-43 toxicity results in part from impaired activity of the synaptic CSP/Hsc70 chaperone complex impacting dynamin function. Finally, Hsc70-4/HSPA8 expression is also post-transcriptionally reduced in fly and human induced pluripotent stem cell (iPSC) C9orf72 models, suggesting a common disease pathomechanism.


Site-directed mutagenesis of potential protein-coding regions in expressible cloned cDNAs of cucumber mosaic viral satellites.
Site-directed mutagenesis was used to alter potential protein-coding regions (open reading frames or ORFs) within the cloned, expressible cDNAs of two satellites of cucumber mosaic virus (CMV), S-CARNA 5 and D-CARNA 5. RNA transcripts synthesized in vitro from the mutant and wild-type satellite cDNAs were tested for biological activity on tomato plants by coinfection with CMV RNAs 1, 2, and 3, and progeny CARNA 5s generated from such transcripts were isolated and sequenced. Two mutants of S-CARNA 5 were constructed in attempts to test whether the ORF (ORF IIB, beginning at nucleotide 135) responsible for synthesis in vitro of two small proteins (M. J. Avila-Rincon, C. W. Collmer, and J. M. Kaper (1986). Virology 152, 455-458) could be eliminated without loss of the satellite's biological activity. Biological tests with mutant transcripts that either lacked the AUG initiation codon or contained a premature translation termination codon were foiled by instability and/or reversion in the progeny. With progeny CARNA 5 of the former mutant, one of two altered nucleotides reverted, thus restoring the AUG but not the nucleotide immediately preceding it. In contrast, a mutation in the necrogenic D-CARNA 5 which altered the initiation codon of ORF I (nucleotides 11-94), whose predicted amino acid sequence is conserved in all necrogenic CMV satellites sequenced to date, was stable in biological testing and did not destroy necrogenicity. This was shown by nucleotide sequencing of the progeny CARNA 5 from necrotic test plants and by its direct comparison with wild-type D-CARNA 5 progeny in a tomato necrosis dilution assay. This experiment provides convincing evidence that a possible protein product of ORF I is not involved in the induction of tomato necrosis by D-CARNA 5.


Burkitt translocation (8;22)(q24;q11) in a patient with multiple myeloma.
The prevalence of chromosomal abnormalities in multiple myeloma (MM) has been difficult to detect by karyotyping primarily because of the low proliferative rate of malignant plasma cells. The reported incidences of abnormal karyotypes range from 24% to 63% in bone marrows obtained from MM patients, with the higher rates being seen in aggressive disease [1-8]. Detection of abnormal karyotypes in MM has been associated with a poor prognosis. We report a MM patient with an 8;22 Burkitt translocation, the first such reported case.


Tryptophan and 5-hydroxyindoles in different CNS regions following acute morphine.
Morphine induces naloxone-reversible increases of tryptophan and 5-hydroxyindoles in rat cerebral hemispheres, thalamus and cerebellum, but does not do so in striatum, hypothalamus, hippocampus and brain stem. Morphine also induces a rise in spinal cord 5-HIAA which is antagonized by naloxone, but there is no parallel change in tryptophan. Increases in brain 5-hydroxyindoles may be related to greater availability of tryptophan, but the elevation in spinal cord 5-HIAA appears to be unrelated to precursor availability.


High initial FSH dosage reduces the number of available cleavage-stage embryos in a GnRH-antagonist protocol: Real-world data of 8,772 IVF cycles from China.
To evaluate the relationship between the initial follicle stimulating hormone (FSH) dose and the number of available cleavage-stage embryos in in vitro fertilization (IVF) cycles.We included 8772 fresh IVF cycles using a GnRH antagonist protocol at the Genetic and Reproductive Institution of Chongqing, P. R. China, from January 2016 to June 2021.Univariate linear regression was used to evaluate the associations between the initial FSH dosage (≤ 150, 187.5-200, 225, 250, or 300 IU) with the number of available cleavage-stage embryos on day 3. A two-factor linear regression model was applied to calculate the threshold effect of the initial FSH dosage on the number of available cleavage-stage embryos based on a smoothing plot. The initial FSH dose was negatively correlated with the number of available cleavage-stage embryos, independent of female age, body mass index, infertility factors, duration of infertility, anti-Müllerian hormone and basal FSH levels, antral follicle count and the proportions of patients with poor ovarian response or polycystic ovarian syndrome. Using a two-factor linear regression model, we calculated the inflection point to be 200 IU of FSH. The relationship between the initial FSH dose and the number of available cleavage-stage embryos was nonlinear. The initial FSH dose was negatively associated with the number of available cleavage-stage embryos when the initial FSH dose was > 200 IU. Therefore, clinicians should try to avoid unnecessarily increasing the initial FSH dose.


Baked corn (Zea mays L.) and bean (Phaseolus vulgaris L.) snack consumption lowered serum lipids and differentiated liver gene expression in C57BL/6 mice fed a high-fat diet by inhibiting PPARγ and SREBF2.
The aim was to determine the effect of consuming a baked white corn/bean snack (70/30% blend) on improving diet-induced dyslipidemia and liver differential gene expression in mice fed a high-fat diet (HFD). C57BL/6 mice were randomized into six groups and different doses of the snack (0.5-2.0 g/d) supplemented to a basal HFD for 12 weeks. Unsupplemented HFD and a standard diet were used as positive and negative controls, respectively. Groups receiving HFD1.0, HFD1.5 and HFD2.0 showed attenuation in body weight gain (20%). Serum cholesterol and triglycerides were reduced (P<.05), 29% and 31%, respectively. Blood glucose was also reduced (P<.05) in all groups receiving the snack. Histological analysis showed a reduction in adipocyte diameters (P<.05) suggesting an attenuation of lipid accumulation. Snack consumption induced differential expression of 529 genes in the liver; RGS16 was the highest up-regulated molecule (+15-fold change). Increased expression of this gene could have improved glucose metabolism in HFD2.0. Ingenuity Pathway Analysis downstream analysis showed a predicted inhibition of target genes of peroxisome PPARγ and key regulators of lipogenic genes in the liver. The results suggest that consumption of a white corn/bean snack (70%/30% blend) attenuates weight gain, fat mass accumulation, adipocyte size and nonalcoholic fatty liver disease in HFD-fed mice by inhibiting PPARγ and SREBF2. The study proposes that this type of product might be beneficial by preventing dyslipidemia, obesity and hepatic steatosis.


Tandem mass tag (TMT) proteomic analysis of fetal lungs revealed differential expression of tight junction proteins in a rat model of congenital diaphragmatic hernia.
Congenital diaphragmatic hernia (CDH) is a common and often lethal birth defect characterized by congenital lung malformation, which severely affects neonate prognosis and mortality. This study aimed to investigate differences in protein expression in order to elucidate the mechanism of CDH-associated pulmonary hypoplasia during the early stage of lung development using tandem mass tag (TMT) quantitative proteomics. Nitrofen was administered orally to establish a rat CDH model, and pathological changes were evaluated through hematoxylin-eosin (H&E), PCNA, and Ki67 staining at the pseudoglandular stage. Fetal lungs were then collected, pooled before TMT labeling, and subjected to mass spectrometry. Immunohistochemistry (IHC), Western blotting, and Q-PCR were used to further validate the candidate proteins. A total of 79 differentially expressed proteins (DEPs) were identified when CDH and control lungs were compared, and further bioinformatics analysis showed that these proteins play important roles in tight-junctions, phospholipase D signaling, and the HIF-1 signaling pathway. Three differentially expressed proteins, Cldn3, Magi1, and Myh9 are involved in the tight-junction pathway (P < 0.05), and their differential expressions were confirmed by IHC, Western blotting, and Q-PCR. These findings indicate that alterations of tight-junction protein expression may play an important role in the pathogenesis of abnormal lung development in CDH. Further studies are warranted to verify the mechanism by which these tight-junction proteins influence the pathogenesis of CDH-associated pulmonary hypoplasia.


Rapid genotypic detection of rpoB and katG gene mutations in Mycobacterium tuberculosis clinical isolates from Northern India as determined by MAS-PCR.
There is a growing need to develop rapid laboratory research methods to counter the menace of drug resistant tuberculosis (MDR-TB) cases worldwide especially in developing countries. The present study was undertaken to investigate the type and frequency of rpoB and katG mutations in rifampicin (RIF) and isoniazid (INH) resistant strains respectively of Mycobacterium tuberculosis (MTB) circulating in Northern India and to explore the utility of multiplex-allele-specific (MAS)-PCR assay for detection of drug-resistant MTB isolates in low resource set up. Phenotypic and genotypic drug susceptibility testing (DST) was performed on 354 MTB isolates. Mutation in rpoB gene was found most frequently at codons 531, 526 and 516 (59.83%, 45.29% and 22.22%, respectively). Further, combinations of 2-3 point mutations were also observed in 19.66% of RIF-resistant MTB strains. The frequency of mutations in katG gene was found at codon 315 among 82.95% of the INH-resistant MTB isolates. MAS-PCR detected rpoB and katG mutations in phenotypically resistant isolates with sensitivities of 93% and 83% respectively. MAS-PCR assays can be used for rapid detection of drug-resistant TB strains in routine diagnostic practice, enabling early administration of appropriate treatment regimens to the affected patients.


Selection of reliable reference genes for qRT-PCR studies on cetacean fibroblast cultures exposed to OCs, PBDEs, and 17beta-estradiol.
Quantitative real-time PCR (qRT-PCR) represents an effective molecular technique for the detection of mRNA expression in biological samples. Its sensitivity allows the quantification of slight changes in the regulation of gene transcription but is strictly dependent upon the method followed during the normalization procedure. Relative quantification determines changes in the steady-state mRNA levels of genes across multiple samples and it is assessed by comparison with the levels of one or more internal control RNA. In this context, the choice of constitutively expressed control genes, whose transcription is not affected by the contaminants, appears to be fundamental for the reliability of this technique. During this study, fibroblast cell cultures originated from integumentum biopsies, sampled in the cetacean species Stenella coeruleoalba, have been exposed for 6h to increasing concentrations of different mixtures of compounds with endocrine disruptor capacities (EDCs): organochlorines (OCs), polybrominated diphenyl ethers (PBDEs), and 17beta-estradiol. Ten common housekeeping genes have been tested for the expression of their transcripts in exposed cell cultures using qRT-PCR assays and raw data were analyzed with the two Excel applets geNorm and NormFinder. The genes encoding for SDHA, GAPDH and YWHAZ appear to be the most reliable controls, respectively, for the OC, PBDE and 17beta-estradiol treatments. These results clearly show that the transcription of even widely diffused control genes can be regulated by different treatments and underlie the importance of a careful selection of the optimal housekeeping genes in toxicological studies.


Glycyrrhizin inactivates toll-like receptor (TLR) signaling pathway to reduce lipopolysaccharide-induced acute lung injury by inhibiting TLR2.
This study aimed to explore glycyrrhizin on acute lung injury (ALI) and how glycyrrhizin (GL) attenuated lipopolysaccharide (LPS)-induced ALI. Bioinformatics analysis was performed to screen the expressed genes in LPS-induced ALI mice. The enrichment of functions and signaling pathways of deregulated genes were conducted. Combined with DIGSEE and STICH, the target gene for further investigation was chosen. To verify target gene in mice, we performed experiment in vivo. Forty mice were randomized into NC, LPS, LPS + S, and LPS + GL group. Mice in the LPS + GL group received glycyrrhizin l mg and mice in LPS + S received saline. Then, HE and Masson staining detected pathological changes of lung tissues; enzyme-linked immunosorbent assay analyzed bronchoalveolar lavage fluid concentrations of MIP-2, mice growth-related oncogene homologue (KC), IL-4, IL-6, GM-CSF, IFN-γ, and IgM; western blot analysis determined the expression of toll-like receptor (TLR) signaling and NF-κB pathway-related proteins. Tlr2 which was not only upregulated but also closely related to glycyrrhizin. TLR2 was upregulated in following LPS induced in cells and TLR2 overexpression-activated TLR signaling pathway to promote ALI. After glycyrrhizin treatment, the expression of TLR2 was reduced. Furthermore, it was found out that the number of inflammatory cells, collagen deposition, MIP-2, KC, IL-4, IL-6, GM-CSF, and IFN-γ expression increased in ALI mice and glycyrrhizin mitigated it. Similarly, the expression of TLR signaling pathway and NF-κB pathway-related protein also increased. Glycyrrhizin functioned as a suppressor in TLR signaling pathway to reduce LPS-induced ALI by inhibiting TLR2.


Alcohol withdrawal: effects of clonidine treatment on sympathetic activity, the renin-aldosterone system, and clinical symptoms.
Twenty male alcoholics with alcohol withdrawal syndrome were randomized to receive either oral clonidine (3-600 micrograms, six hourly) or oral chlormethiazole (500-1000 mg, six hourly) for 4 days. All subjects were also given oral carbamazepine (200 mg, 12 hourly) throughout the study. Nine subjects given clonidine and eight given chlormethiazole completed the study. Clonidine was as effective as chlormethiazole in suppressing the symptoms and signs of alcohol withdrawal. However, plasma catecholamines, blood pressure, and pulse rate fell more rapidly and to a greater extent during clonidine than following chlormethiazole, findings which could have therapeutic implications. It is suggested that activation of brain noradrenergic neurons constitutes a common denominator in the pathophysiology of several withdrawal syndromes.


Effect of theophylline on myocardial adenylate cyclase activity.
Theophylline (0.001-10.0 mM) did not increase but rather decrased adenylate cyclase activity (AC) of guinea-pig auricles. Isoprenaline (1-100 microgram) and sodium fluoride (0.3-10.0 mM) stimulated AC in a concentration-dependent manner.


[Alkaloid constituents of Corydalis adunca].
To study the alkaloid component of Corydalis adunca Maxim. The constituents were isolated by chromatographic methods, their structures were elucidated by spectroscopic evidences. Three compounds were purified and their structures were identified, they were identified as dorydaline (I), dehydrocorydaline (II), dihydrosanguinarine (III). Compounds I , II are isolated from this plant for the first time.


Helicobacter pylori infection does not accelerate the age-related progression of arteriosclerosis: a 4-year follow-up study.
Helicobacter pylori (H. pylori) infection has been reported to correlate with the onset of cardiovascular diseases. However, the relationship between H. pylori infection and the progression of arteriosclerosis has not been fully investigated. The aim of this study was to clarify the possible role of H. pylori infection in the development of arteriosclerosis. Study subjects were 258 cases who attended their annual medical check-ups and were twice investigated by the parameters of arteriosclerosis at a 4-year interval. Arteriosclerotic parameters (systolic blood pressure [SBP]), ankle brachial index [ABI], and pulse wave velocity [PWV]) were measured non-invasively using an automatic device. H. pylori-infection status was determined by assaying serum anti-H. pylori IgG antibodies. The changes in the arteriosclerotic parameters during the 4 years were compared between H. pylori-seropositive and seronegative individuals. A total of 166 subjects (64.3%) were H. pylori-seropositive. After adjustment for gender, age, body mass index, and smoking and drinking habits, there were no differences in any of the arteriosclerotic parameters between the groups, not only at enrollment but after the 4 years, although the high-density lipoprotein cholesterol levels of the seropositive groups were significantly lower than those of seronegative groups. SBP and PWVs were significantly increased during 4 years in both the seropositive and seronegative groups. The percentage of changes in SBP and PWVs, which were calculated by ([values after 4 years--values at enrollment/values at enrollment] x 100), did not differ between the groups. H. pylori infection does not accelerate the age-related progression of arteriosclerosis in Japanese individuals.


The effects of diet composition and chronic obesity on muscle growth and function.
Diet-induced obesity (DIO) is associated with glucose intolerance, insulin resistance (IR), and an increase in intramyocellular lipids (IMCL), which may lead to disturbances in glucose and protein metabolism. To this matter, it has been speculated that chronic obesity and elevated IMCL may contribute to skeletal muscle loss and deficits in muscle function and growth capacity. Thus, we hypothesized that diets with elevated fat content would induce obesity and insulin resistance, leading to a decrease in muscle mass and an attenuated growth response to increased external loading in adult male mice. Male C57BL/6 mice (8 wk of age) were subjected to five different diets, namely, chow, low-dat-diet (LFD), high-fat-diet (HFD), sucrose, or Western diet, for 28 wk. At 25 wk, HFD and Western diets induced a 60.4% and 35.9% increase in body weight, respectively. Interestingly, HFD, but not Western or sucrose, induced glucose intolerance and insulin resistance. Measurement of isometric torque (ankle plantar flexor and ankle dorsiflexor muscles) revealed no effect of DIO on muscle function. At 28 wk of intervention, muscle area and protein synthesis were similar across all diet groups, despite insulin resistance and increased IMCL being observed in HFD and Western diet groups. In response to 30 days of functional overload, an attenuated growth response was observed in only the HFD group. Nevertheless, our results show that DIO alone is not sufficient to induce muscle atrophy and contractile dysfunction in adult male C57BL/6 mice. However, diet composition does have an impact on muscle growth in response to increased external loading.NEW & NOTEWORTHY The effects of diet-induced obesity on skeletal muscle mass are complex and dependent on diet composition and diet duration. The present study results show that chronic exposure to high levels of fatty acids does not affect muscle mass, contractile function, or protein synthesis in obese C57BL/6 mice compared with the consumption of chow. Obesity did result in a delay in load-induced growth; however, only a 45% HFD resulted in attenuated growth following 30 days of functional overload.


Multimerization of the Toxoplasma gondii MIC2 integrin-like A-domain is required for binding to heparin and human cells.
Toxoplasma gondii is an obligate intracellular parasite that causes toxoplasmosis in humans and animals. To invade host cells, T. gondii deploys the contents of its apically oriented secretory organelles that include the micronemes. Contained within the micronemes are proteins that possess adhesive motifs resembling those found in mammalian proteins. The micronemal protein MIC2 is a member of the thrombospondin-related anonymous protein (TRAP) family of adhesive proteins, which characteristically feature at least one integrin-like A-domain. Because of its strict conservation within the family, we sought to define the role of this domain by testing the adhesive properties of recombinant MIC2 A-domain fusion proteins. Since MIC2 is found as a multimeric species in parasite lysate, we also wanted to test whether recombinant MIC2 A-domain bound to its substrate in a multimeric state. In vitro assays of binding to several different potential receptors revealed that the MIC2 A-domain binds specifically to heparin, a ubiquitous sulfated proteoglycan found in the extracellular matrix (ECM). Additional studies demonstrated that this binding is not dependent on the MIDAS site, a well-conserved divalent cation-binding motif that the MIC2 A-domain shares with its mammalian counterparts. The recombinant MIC2 A-domain bound to heparin as a high molecular weight species, as did MIC2 from parasite lysate, indicating that the recombinant A-domain mimics the binding of native MIC2. Multimerization of MIC2 may increase the number of interactions with host cell receptors, thereby forming a multivalent adhesive junction during parasite entry.


Age-mediated gut microbiota dysbiosis promotes the loss of dendritic cells tolerance.
The old age-related loss of immune tolerance inflicts a person with a wide range of autoimmune and inflammatory diseases. Dendritic cells (DCs) are the sentinels of the immune system that maintain immune tolerance through cytokines and regulatory T-cells generation. Aging disturbs the microbial composition of the gut, causing immune system dysregulation. However, the vis-à-vis role of gut dysbiosis on DCs tolerance remains highly elusive. Consequently, we studied the influence of aging on gut dysbiosis and its impact on the loss of DC tolerance. We show that DCs generated from either the aged (DCOld ) or gut-dysbiotic young (DCDysbiotic ) but not young (DCYoung ) mice exhibited loss of tolerance, as evidenced by their failure to optimally induce the generation of Tregs and control the overactivation of CD4+ T cells. The mechanism deciphered for the loss of DCOld and DCDysbiotic tolerance was chiefly through the overactivation of NF-κB, impaired frequency of Tregs, upregulation in the level of pro-inflammatory molecules (IL-6, IL-1β, TNF-α, IL-12, IFN-γ), and decline in the anti-inflammatory moieties (IL-10, TGF-β, IL-4, IDO, arginase, NO, IRF-4, IRF-8, PDL1, BTLA4, ALDH2). Importantly, a significant decline in the frequency of the Lactobacillus genus was noticed in the gut. Replenishing the gut of old mice with the Lactobacillus plantarum reinvigorated the tolerogenic function of DCs through the rewiring of inflammatory and metabolic pathways. Thus, for the first time, we demonstrate the impact of age-related gut dysbiosis on the loss of DC tolerance. This finding may open avenues for therapeutic intervention for treating age-associated disorders with the Lactobacillus plantarum.


Loss of Serpin E2 alters antimicrobial gene expression by microglia but not astrocytes.
Microglia are the brain-resident immune cells responsible for surveilling and protecting the central nervous system. These cells can express a wide array of immune genes, and that expression can become highly dynamic in response to changes in the environment, such as traumatic injury or neurological disease. Though microglial immune responses are well studied, we still do not know many mechanisms and regulators underlying all the varied microglial responses. Serpin E2 is a serine protease inhibitor that acts on a wide variety of serine proteases, with particularly potent affinity for the blood clotting enzyme thrombin. In the brain, Serpin E2 is highly expressed by many cell types, especially glia, and loss of Serpin E2 leads to behavioral changes as well as deficits in synaptic plasticity. To determine whether Serpin E2 is important for maintaining homeostasis in glia, we performed RNA sequencing of microglia and astrocytes from Serpin E2-deficient mice in a healthy state or under immune activation due to lipopolysaccharide (LPS) injection. We found that microglia in Serpin E2-deficient mice had higher expression of antimicrobial genes, while astrocytes did not display any robust changes in transcription. Furthermore, the lack of Serpin E2 did not affect transcriptional responses to LPS in either microglia or astrocytes. Overall, we find that Serpin E2 is a regulator of antimicrobial genes in microglia.


Routine Screening Radiography for Retained Wire Following Arch Bar Removal Is Not Indicated.
To estimate the screening test value of routine radiography after arch bar wire removal by assessing the incidence of retained wires and the importance of their sequelae. This was a retrospective medical record review. Records of arch bar removal procedures were examined and divided into those screened with radiography after removal (screen group) and those that were not screened (comparison group). The incidence of retained wire was calculated for each group. Study variables included wire-related radiographic or clinical findings. Records of 546 mandible fractures were reviewed; 95 met the study criteria. Most exclusions were due to lack of arch bars, missing postoperative radiographs, or insufficient postoperative documentation. Of the 55 records in the screen group, 1 wire was detected (2%); of the 40 records in the comparison group, 1 wire was detected (3%). The total incidence of retained wire findings was not statistically different between the 2 groups and there were no adverse wire-related sequelae reported by any of the 95 patients. Because of the low incidence of retained wires and wire-related sequelae, routine imaging after wire removal is probably not an effective screening test for retained wire and should be limited to situations in which there is clinical suspicion of retained wire.


Distribution of extended-spectrum beta-lactamase genes using a commercial DNA micro-array system.
Extended-spectrum beta-lactamase (ESBL) genes are distributed worldwide and their epidemiology is complex. Using the Check-ESBL assay, the distribution of class A ESBL genes in clinical isolates of aerobic Gram-negative bacilli from three laboratories in the East of The Netherlands was determined. Four patient categories were distinguished: (i) patients admitted to an intensive care unit (ICU); (ii) non-ICU inpatients; (iii) outpatients admitted less than a year before collection of the isolate, (<1); (iv) outpatients admitted more than one-year prior to isolate collection or who had never been hospitalized (>1). From February 2009 until March 2010, out of 491 putative ESBL-positive isolates detected by the Vitek2 or Phoenix automated sensitivity testing systems, ESBL genes were detected in 247 (50.3%) by the Check-ESBL assay. Of these, 116 were from hospitalized patients (35 ICU, 81 non-ICU) and 131 were from outpatients (43 <1, 88 >1). In all, 274 ESBL genes were identified in these 247 isolates: 153 CTX-M-1 group (predominantly in E. coli and K. pneumoniae, 70.4% and 51.6% respectively), 67 CTX-M-9 group (predominantly in E. cloacae, 57.9%), 32 SHV, 14 TEM and 8 CTX-M-2 group. ESBL-producing E. cloacae were significantly more common in hospitalized patients than in outpatients, 20.7% and 3.8% respectively (P=0.001). CTX-M-9 group ESBLs were significantly more prevalent in ICU patients (P=0.003), whereas SHV ESBLs were more common in hospitalized patients than in outpatients (P<0.001). There was no significant difference in distribution of ESBL genes between the two outpatient groups.


Pd(CH3CN)2Cl2-catalyzed oxidative heterodimerization reaction of 2,3-allenamides and 1,2-allenyl ketones: an efficient synthesis of 4-(furan-3'-yl)-2(5H)-furanimines.
The Pd(II)-catalyzed oxidative heterodimerization reaction of 2,3-allenamides and 1,2-allenyl ketones was studied. It provides an efficient route for the synthesis of the polysubstituted 4-(furan-3'-yl)-2(5H)-furanimines, which are not readily available from the known methods. Due to the application of benzoquinone, the loadings of both the palladium catalyst and ketone have been greatly reduced for the oxidative heterodimerization of 2,3-allenamides and 1,2-allenyl ketones in acetic acid.


The effect of phenylthiocarbamide (PTC) on mouse brain development.
PTC--when dispensed during the whole fetal development--causes a disturbance of brain development in new born mice. This disturbance in manifested by a reduction of the cell number, a reduced protein content and a reduced activity of acetylcholinesterase in the brain.


Cognitive stimulation intervention for elders with mild cognitive impairment compared with normal aged subjects: preliminary results.
Cognitive training programs have been developed for Alzheimer's disease patients and the healthy elderly population. Collective cognitive stimulation programs have been shown to be efficient for subjects with memory complaint. The aim of this study was to evaluate the benefit of such cognitive programs in populations with Mild Cognitive Impairment (MCI). Twelve patients with MCI and twelve cognitively normal elders were administered a cognitive stimulation program. Cognitive performance (Logical Memory, Word paired associative learning task, Trail Making Test, verbal fluency test) were collected before and after the intervention. A gain score [(post-score - pre-score)/ pre-score] was calculated for each variable and compared between groups. The analysis revealed a larger intervention size effect in MCI than in normal elders' performances on the associative learning task (immediate recall: p<0.05, delayed recall: p<0.01). The intervention was more beneficial in improving associative memory abilities in MCI than in normal subjects. At the end of the intervention, the MCI group had lower results than the normal group only for the delayed recall of Logical Memory. Although further studies are needed for more details on the impact of cognitive stimulation programs on MCI patients, this intervention is effective in compensating associative memory difficulties of these patients. Among non-pharmacological interventions, cognitive stimulation therapy is a repeatable and inexpensive collective method that can easily be provided to various populations with the aim of slowing down the rate of decline in elderly persons with cognitive impairment.


The laminar source of efferent projections from the avian Wulst.
Following horseradish peroxidase injections into the pigeon tractus septomesencephalicus, the efferent outflow bundle of the avian Wulst, retrogradely labeled neurons within the Wulst were confined to the superficialmost layer, the hyperstriatum accessorium. These results suggest that the hyperstriatum accessorium is the sole source of Wulst efferent projections. In similarity to the laminar organization of mammalian striate cortex, this efferent layer is juxtaposed to the thalamorecipient layer of Wulst.


Is there a role for vindesine in the treatment of non-small cell lung cancer?
Vindesine is a semisynthetic derivative of vinblastine which has been evaluated in clinical studies since the late 1970's. The literature on vindesine in the treatment of non-small cell lung cancer has been reviewed and all aspects of vindesine treatment in this disease has been covered. It is concluded that vindesine as a single agent yields a response rate of 18% based on the treatment of 295 patients included in phase II trials (95% confidence limits 13%-22%). No difference was observed among the three major histologic types of non-small cell lung cancer. In phase III trials, the response rate and confidence limits are at a similar level. Combination chemotherapy including vindesine plus cisplatin ranks among the most active treatments in non-small cell lung cancer and is as active as etoposide plus cisplatin, both with respect to response rate and survival. It has not been documented that the addition of one or two other drugs to the combination of vindesine yields an increase in survival. When best supportive care was compared with a combination of vindesine plus cisplatin, the group with chemotherapy was attributed a survival advantage in all three studies published, and the difference was statistically significant in two of these three studies. Thus, vindesine has a well documented activity in non-small cell lung cancer and ranks among the most active single agents in this disease. Vindesine is also part of several active combination chemotherapies among which the combination of vindesine plus cisplatin is particularly interesting, because it has been repeatedly shown to prolong survival as compared to supportive care. Especially this latter point leads to the conclusion that there is a role for vindesine in the treatment of non-small cell lung cancer. However, the concept of chemotherapy in this disease remains investigational even though the advances seen in recent years clearly merit further studies.


Effects of sulfur dioxide or ammonium sulfate exposure, alone or combined, for 4 or 8 months on normal and elastase-impaired rats.
Normal and lung-impaired rats were compared after exposure to SO2 and/or (NH4)2SO4 for 4 or 8 months, or for 8 months plus 3 months recovery. Young adult male Sprague-Dawley rats were pretreated intratracheally with either physiologic saline (normal lungs) or porcine pancreatic elastase (impaired lungs). Rats from each pretreatment group were exposed to filtered air (control), to SO2 (1 ppm) or (NH4)2SO4 (0.5 mg/m3), or to combined SO2 + (NH4)2SO4 for 5 hr/day, 5 days/week. Morphologic, physiologic, and immunologic criteria were evaluated. At 4 months cellular immunologic responsiveness was not impaired, but physiologic changes were detected. Morphologic changes were apparent in all time periods. Elastase-induced changes included greater lung volumes, emphysema, and alveolar interstitial fibrosis. Pollutant effects included bronchiolar epithelial hyperplasia and changes in alveolar mean chord length (MCL). Relative to controls, bronchiolar epithelial hyperplasia and MCL increased in saline/pollutant groups, but decreased in elastase/pollutant rats at 4 months. The pretreatment/pollutant interaction was not observed at 8 months. Elastase effects persisted throughout the recovery period. Pollutant effects were more transitory, although alveolar septal fibrosis was greater in saline/(NH4)2SO4 rats at 8 months. Pulmonary function changes associated with elastase included increases in residual volume, functional residual capacity, and the residual volume/total lung capacity ratios. The alveolar plateau of single-breath washout (N2 slope) was significantly steeper in elastase-treated rats but less steep in animals exposed to SO2 or to (NH4)2SO4 than in those exposed to air only.


First case of a centropelvic recurrence after radical trachelectomy: literature review and implications for the preoperative selection of patients.
To report the first case of a centropelvic recurrence in a patient who underwent a radical trachelectomy (RT) for a stage IB1 cervical carcinoma. A 32-year-old woman presented with a stage IB1 adenocarcinoma that was treated by radical trachelectomy. The tumor measured 21 x 20 mm. Minimal lymphatic space involvement was observed close to the tumor associated with 30 negative nodes and free margins. The upper free margin measured only 5 mm. Twenty-six months after the surgical procedure, the patient became pregnant. Clinical examination and pap smears were normal 2 months prior. During the first trimester, ultrasonography depicted a suspicious lesion in the bladder. Abdomino-pelvic magnetic resonance imaging (MRI) demonstrated a suspicious 20-mm tumor in the bladder associated with suspicious common iliac nodes. Cystoscopy and biopsies were carried out which confirmed recurrent disease. The patient received external radiation therapy combined with concomitant chemotherapy. More data are required to establish what is the safety distance between the tumor and the uterine transection. A distance of 5 mm or less is likely to be too limited for radical trachelectomy to be accepted as treatment for cervical cancer.


Effect of Structural Design of Silver/Silver Chloride Electrodes on Stability and Response Time and the Implications for Improved Accuracy in pH Measurement.
The response time of thermal electrolytic Ag/AgCl reference electrodes is defined by the porous structure that limits the rate at which traces of any previous solution are diluted by any new solution environment. The electrode stabilisation time when transferred from one electrolyte to another has been shown to change when different structural designs to the conventional sphere of Ag/AgCl are used. Electrodes fabricated with cylindrical architectures of Ag/AgCl have shown improved stability and reach equilibrium faster than spherical electrodes. This work has positive implications for the accuracy and throughput of primary pH measurements made using the Harned cell.


The Endoscopic Reference Score shows modest accuracy to predict histologic remission in adult patients with eosinophilic esophagitis.
The relationship between the severity of endoscopic signs scored according to the Endoscopic Reference Score (EREFS) and histopathologic signs of eosinophilic esophagitis (EoE) has not been sufficiently explored. We aimed to determine if the EREFS system predicts histopathologic activity in EoE patients. We included 69 patients with EoE (age 35 [IQR 29-48] years; 80% male) who, between 2006 and 2014, underwent esophagogastroduodenoscopy (EGD) during which high-quality endoscopic images were taken and esophageal biopsy specimens were obtained. Per EGD, three or more depersonalized images were scored by an expert endoscopist, and histopathologic signs were scored by a pathologist with gastrointestinal expertise; both in a blinded fashion. The predictive values of endoscopic signs for disease activity (peak eosinophil count) were calculated. In addition, we measured the utility of the EREFS in the follow-up of 35 EoE patients. Individual endoscopic signs did not correspond to the peak eosinophil count or other histopathologic signs. Although the composite fibrotic signs score, inflammatory signs score, and total EREFS correlated weakly to moderately with the peak eosinophil count, none of these scores had both high positive and negative predictive values for histopathologic disease activity. In the follow-up of 35 patients, lower peak eosinophil counts were not associated with a decrease in endoscopic abnormalities. In adult patients with EoE, the EREFS system correlates with peak eosinophil counts, but their predictive value for disease activity is insufficient for clinical use. Therefore, biopsies remain indispensable for the assessment of disease activity.


Expanding roles for the Schwann cell: ensheathment, myelination, trophism and regeneration.
Schwann cells show remarkable versatility in undertaking a broad repertoire of functions. It is now clear that the well known functions of ensheathment and myelination are specifically regulated by contact with axons, that the Schwann cell is centrally involved in extracellular matrix production in the peripheral nerve trunk, and that the Schwann cell plays a critical role in promoting axonal regeneration in the peripheral nervous system. The Schwann cell's ability to promote regenerative efforts in many central neurons has led to an increasing interest in using Schwann cell autografts for central nervous system repair.


Glycomics reveal that ST6GAL1-mediated sialylation regulates uterine lumen closure during implantation.
Implantation failure is a major cause of prenatal mortality. The uterine lumen closure contributes to embryo adhesion to the uterus, but its underlying mechanisms are largely unknown. Our previous study has reported that endometrial fold extension can lead to uterine lumen closure in pigs. The objective of this study was to reveal molecular mechanisms of the uterine lumen closure by characterizing the molecular basis of the endometrial fold extension during implantation in pigs. Uterine and endometrium tissues during implantation were collected in pigs. MALDI-TOF MS was used to characterize the N-glycomic profiles. Histochemistry, siRNA transfection, Western blotting, lectin immumoprecipitation, mass spectrometry and assays of wounding healing and cell aggregation were performed to investigate the molecular basis. We observed that uterine luminal epithelium (LE) migrated collectively during endometrial fold extension. For the first time, we identified a large number of N-glycan compositions from endometrium during implantation using MALDI-TOF MS. Notably, the α2,6-linked sialic acid and ST6GAL1 were highly expressed in uterine LE when the endometrial folds extended greatly. Subsequently, the role of ST6GAL1-mediated 2,6-sialylation in collective epithelial migration was demonstrated. Finally, we found that ST6GAL1-mediated α2,6-sialylation of E-cadherin may participate in collective migration of uterine LE. The study reveals a mechanism of uterine lumen closure by identifying that ST6GAL1-mediated α2,6-sialylation of cell adhesion molecules contributes to endometrial fold extension through regulating collective migration of uterine LE.


5-Oxo-ETE analogs and the proliferation of cancer cells.
MDA-MB-231, MCF7, and SKOV3 cancer cells, but not HEK-293 cells, expressed mRNA for the leukocyte G protein-coupled 5-oxo-eicosatetraenoate (ETE) OXE receptor. 5-Oxo-ETE, 5-oxo-15-OH-ETE, and 5-HETE stimulated the cancer cell lines but not HEK-293 cells to mount pertussis toxin-sensitive proliferation responses. Their potencies in eliciting this response were similar to their known potencies in activating leukocytes and OXE receptor-transfected cells. However, high concentrations of 5-oxo-ETE and 5-oxo-15-OH-ETE, but not 5-HETE, arrested growth and caused apoptosis in all four cell lines; these responses were pertussis toxin-resistant. The same high concentrations of the oxo-ETEs but again not 5-HETE also activated peroxisome proliferator-activated receptor (PPAR)-gamma. Pharmacological studies indicated that this activation did not mediate their effects on proliferation. These results are the first to implicate the OXE receptor in malignant cell growth and to show that 5-oxo-ETEs activate cell death programs as well as PPARgamma independently of this receptor.


Hydroxy-corrole and its gallium(III) complex as new photosensitizer for photodynamic therapy against breast carcinoma.
Three mono-hydroxy corroles 1-3 and their gallium(III) complexes Ga1-3 were synthesized, and their photodynamic antitumour activities towards breast cancer cells were investigated. All corroles showed excellent cytotoxicity against the MDA-MB-231 and 4T1 cell lines upon light irradiation at 625 nm. Ga3 exhibited excellent phototoxicity and selectivity against MDA-MB-231 cells, with an IC50 of 0.06 ± 0.03 μM and a selective index value of 1338.83 (relative to human normal Huvec cells). The performance of Ga3 was even better than that of the clinical photodynamic therapy drug m-THPC. A preliminary mechanistic investigation revealed that corrole 3 and Ga3 were mainly located in the cytoplasm. Upon irradiation, they could generate intracellular reactive oxygen to destroy the mitochondrial membrane potential and arrest the cell cycle at the sub-G1 phase. Flow cytometry revealed that corrole 3 and Ga3 induced cancer cell apoptosis after photodynamic treatment. Corrole 3 and Ga3 displayed negligible cytotoxicity in the dark. These results suggest that corrole 3 and Ga3 are promising candidates for use in the photodynamic therapy of breast cancer.


Fish feeds supplemented with calcium-based buffering minerals decrease stomach acidity, increase the blood alkaline tide and cost more to digest.
Predatory fish in the wild consume whole prey including hard skeletal parts like shell and bone. Shell and bone are made up of the buffering minerals calcium carbonate (CaCO3) and calcium phosphate (Ca3(PO4)2). These minerals resist changes in pH, meaning they could have physiological consequences for gastric acidity, digestion and metabolism in fish. Using isocaloric diets supplemented with either CaCO3, Ca3(PO4)2 or CaCl2 as non-buffering control, we investigated the impacts of dietary buffering on the energetic cost of digestion (i.e. specific dynamic action or SDA), gastric pH, the postprandial blood alkalosis (the "alkaline tide") and growth in juvenile rainbow trout (Oncorhynchus mykiss). Increases in dietary buffering were significantly associated with increased stomach chyme pH, postprandial blood HCO3-, net base excretion, the total SDA and peak SDA but did not influence growth efficiency in a 21 day trial. This result shows that aspects of a meal that have no nutritional value can influence the physiological and energetic costs associated with digestion in fish, but that a reduction in the SDA will not always lead to improvements in growth efficiency. We discuss the broader implications of these findings for the gastrointestinal physiology of fishes, trade-offs in prey choice in the wild, anthropogenic warming and feed formulation in aquaculture.


Goal-directed therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a prospective observational study.
Cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in peritoneal carcinomatosis treatment causes significant hemodynamic, metabolic, and hematological alterations. Studies on the anesthetic intraoperative management are heterogeneous and scarce. There is a great heterogeneity in the anesthetic management of CRS and HIPEC. The aim of this study is to analyze perioperative hemodynamic goal-directed management and to evaluate the complications arisen until the seventh postoperative day. Prospective, observational study of all CRS and HIPEC patients from March 2014 to May 2017. Hemodynamic and clinical parameters were registered during surgery and the first 3 postoperative days. We correlated intraoperative data with the postoperative course until the seventh day. A total of 92 patients were included in the study (age 58.5 ± 10.9 years, 47% colorectal carcinoma, and 38% ovarian carcinoma). Peritoneal Carcinomatosis Index (PCI) (median and ranges) was 10 [0-39]. Cardiac Index (CI) 3.15 l/min-1/m-2 [1.79-5.60]) and Systolic Volume Variation (SVV) (10% [3%-17%]) remained within the values of normality in all surgery phases. A large difference was observed between the minimum and maximum ranges of fluid therapy administered (median 9.8 ml/kg/h [5.3-24.3]), showing a great interindividual variation in the fluids requirement. A direct relationship was observed between PCI and surgery duration, fluid therapy, and intraoperative transfusion percentage (p < 0.02). There is a great variability in the intraoperative fluid therapy needs of the patients. SVV monitoring makes it possible to adjust the fluid therapy needs in each surgery phase. The use of a hemodynamic goal-directed anesthetic protocol in CRS and HIPEC enables to individually adjust the fluid therapy, avoiding over-hydration and ensuring hemodynamic stability in all surgery phases.


Rapid biosynthesized AgNPs from Gelidiella acerosa aqueous extract mitigates quorum sensing mediated biofilm formation of Vibrio species-an in vitro and in vivo approach.
The present study explores the non-bactericidal anti-virulence efficacy of green synthesized silver nanoparticles (AgNPs) from Gelidiella acerosa against multi-drug resistant Vibrio spp. Spectral characterization of AgNPs was performed through UV-Visible, FT-IR, and energy-dispersive spectroscopic techniques followed by X-ray crystallography and zeta potential analysis. Further, the structural characterization was done by electron and atomic force microscopic techniques. AgNPs profoundly quelled the quorum sensing mediated violacein production in Chromobacterium violaceum and CV026. Characterized AgNPs at 100 μg mL-1 concentrations depicted a phenomenal anti-biofilm efficacy against Vibrio parahaemolyticus (71%) and Vibrio vulnificus (83%) biofilms, which was further confirmed through light, confocal, and scanning electron microscopic analyses. In vitro bioassays revealed the remarkable inhibitory values of AgNPs, by inhibiting the exopolysaccharide production, hydrophobicity, and motility. In vivo studies using Artemia franciscana larvae also confirmed the anti-infective proficiency, as the AgNPs effectively reduced the bacterial colonization and enhanced the survival rate of larvae up to 100% without any toxicity effect. Graphical abstract Rapid biosynthesized AgNPs from Gelidiella acerosa quench quorum sensing controlled virulence traits in vibrios.


Inappropriate ICD shocks do not induce pro-arrhythmic electrocardiographic changes in men.
Longer-term electrocardiographic effects of multiple inappropriate ICD shocks were investigated to study their hypothesized pro-arrhythmic potential. Thirteen male patients with ischemic cardiomyopathy who received ≥2 inappropriate shocks within 24 h and for whom 12-lead ECGs were available both before and within 72h after the inappropriate shocks were analyzed. Exclusion criteria included continuous ventricular pacing, underlying AF, events within 6 weeks after lead implantation and concomitant acute medical problems. A total of 149 inappropriate shocks (mean 11 ± 19) were received. There were no significant differences in any of the measured intervals or morphological indices, nor was there a correlation between the "before-after" differences and the number of shocks received. Non-significant changes showed Percentage of Loop Area increase and relative T-wave Residuum decrease while the opposite changes have previously been associated with arrhythmic risk. No potentially pro-arrhythmic electrocardiographic changes were found 19 h after multiple inappropriate shocks.


Exercise for fall prevention in community-dwelling people aged 60+: more effective in trials with higher fall rates in control groups.
Exercise is beneficial for fall prevention. Targeting interventions to people who fall more may lead to greater population impacts. As trials have used varying methods to assess participant risk level, prospectively-measured control group fall rates may provide a more accurate and poolable way to understand intervention effects in different subpopulations. We aimed to explore differences in effectiveness of fall prevention exercise according to prospectively-measured fall rate. Secondary analysis of a Cochrane review investigating exercise for fall prevention in peopled aged ≥60 years. Meta-analysis assessed the impact of exercise on fall rate. Studies were dichotomized according to the median control group fall rate (0.87, IQR 0.54-1.37 falls/person-year). Meta-regression explored the effects on falls in trials with higher and lower control group fall rates. Exercise reduced the rate of falls in trials with higher (rate ratio 0.68, 95% CI 0.61-0.76, 31 studies) and lower control group fall rates (rate ratio 0.88, 95% CI 0.79-0.97, 31 studies, P = 0.006 for difference in effects). Exercise prevents falls, moreso in trials with higher control group fall rates. As past falls strongly predict future falls, targeting interventions to those with more past falls may be more efficient than other falls risk screening methods.


A real-world, observational study of weekly exenatide added to basal insulin in patients with type 2 diabetes mellitus (NCT02895672).
This is a pre-post observational study from an endocrinology ambulatory care practice which assessed the effectiveness and safety following the addition of a glucagon-like peptide-1 (GLP-1) agonist, weekly exenatide (Bydureon), to basal insulin therapy in patients with type 2 diabetes mellitus (T2DM). Liraglutide plus basal insulin served as a comparison group. A data collection form was utilized to collect study-related information. The primary study outcome was change in HbA1c from baseline to 12 months after GLP-1 receptor agonist therapy was added to basal insulin therapy. Secondary outcomes were change in weight, percentage of patients achieving an HbA1c of <7% (53 mmol/mol) or ≤6.5% (48 mmol/mol) and changes in blood pressure and lipid parameters. Safety was assessed by a collection of reported adverse events. One-hundred and fifty patients met inclusion criteria (seventy-five per treatment arm). After 1 year of therapy, HbA1c decreased by 0.7% in the entire cohort (once-weekly exenatide: -0.7%; once-daily liraglutide: -0.8%; no significant between-group difference). More subjects in the weekly exenatide arm achieved an HbA1c < 7% (53 mmol/mol) (P = .03), but a comparable number achieved an HbA1c ≤ 6.5% (48 mmol/mol). Although significantly more patients achieved an HbA1c < 7% (53 mmol/mol) in the once-weekly exenatide arm, the baseline HbA1c was lower (7.9%) than the liraglutide arm (8.4%). No significant differences were observed between groups for other secondary outcomes. A similar number of subjects discontinued therapy, mainly due to gastrointestinal-ill effects, and hypoglycaemia incidence did not increase compared with the previous year. The addition of once-weekly exenatide to basal insulin was associated with appreciable reductions in HbA1c and weight without an increase in hypoglycaemia.


The pattern of gamma-glutamyl transpeptidase, alkaline phosphatase, serum glutamyl oxalate transaminase and serum glutamyl pyruvate transaminase in patients with disseminated non-seminomatous testicular tumors.
The serum enzyme activities of gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), serum glutamyl oxalate transaminase (sGOT) and serum glutamyl pyruvate transaminase (sGPT) were determined longitudinally in 51 patients with a disseminated non-seminomatous testicular tumor. Elevated levels of one or more enzymes before chemotherapy were observed in 13 patients, all with stage III disease. If, after two cycles of chemotherapy, the established tumor markers alpha-fetoprotein (AFP), human chorionic-gonadotropin (HCG) and/or lactate dehydrogenase (LDH) were normalized, the initially increased enzyme activities were declined to normal values as well. Peaking concentrations of one or more of the tumor markers during induction chemotherapy, probably due to tumor cell lysis, were found in 34 of 45 marker-positive patients (76%). In addition, increases of one or more of the investigated enzyme activities were also noticed in 20 patients. In 76% of these patients the highest point of the tumor marker concentration coincided well with that of the enzyme activities. Indications are given that the peak activities were probably not caused by liver damage. Enzyme elevations were also found in 3 out of 7 patients with progressive disease. The behaviour of the enzyme activities of GGT, AP, sGOT and sGPT in patients with a disseminated non-seminomatous testicular tumor coincided with the known tumor markers. It favors the hypothesis that these enzymes are synthesized in the tumor. The mortality amongst stage III patients with or without initially raised GGT levels differed significantly (P less than 0.02). Finally, it is concluded that in patients with a non-seminomatous testicular tumor, sGOT, sGPT, GGT and AP cannot be used to diagnose liver function.


Outcomes after implementing a heart failure diuretic pathway in an emergency department setting.
Among patients with acute decompensated heart failure (HF), national and international loop diuretic therapy recommendations may not be followed in the emergency department (ED). To examine if loop diuretic treatment and patient disposition from the ED differed after implementing a clinical pathway based on national HF guidelines. Using an observational, pre- and post-intervention design, after clinical pathway implementation, loop diuretic medications and clinical outcomes were retrieved from medical records. Analyses included Pearson's Chi-square or Fisher's exact test, 2-sample T-test or Wilcoxon rank sum test. Of 182 pre- and 122 post-intervention patients, mean (SD) patient age was 67.9 (13.4) years and 44.2% were Caucasian. There were no between-group differences in pre-ED visit loop diuretic prescription or dosages. More post-intervention ED patients received at least one dose of loop diuretic (94.3% vs. 81.9%, p = 0.010); however, the overall dose (mg) across groups was lower than the home dose and was not based on national guideline expectations. Doses from home to ED decreased less in the post-intervention group for patients who received doses at both time points and for all patients: p = 0.047 and p = 0.048, respectively. There was no between-group differences in short-stay unit (SSU) admissions, p = 0.33. Post-intervention patients were hospitalized from the ED (p = 0.050) and SSU (p = 0.005) less often than pre-intervention patients. Discharge to home from the ED or SSU increased in the post-intervention period; 16.4% vs. 4.9%, p = 0.009. Among ED patients treated for HF, diuretic dosing was non-optimized. New interventions are needed to enhance adherence to national guidelines.


High-dose methylprednisolone sodium succinate (pulse therapy) in the treatment of renal disease: plasma and urine concentrations.
Methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) concentrations in plasma and urine were monitored in renal transplant and glomerulonephritis patients who were given i.v. infusions of 0.5 g or 1 g of MPS. A marked individual variation of peak plasma levels of both MPS and MP was observed after the same dose and MPS disappeared from plasma more rapidly than MP. Their clearances from the circulation, however, did not appear to be significantly influenced by the peak plasma levels of the drug, creatinine clearance, administration of previous pulses of MPS or the urinary excretion of unconjugated MPS and MP. Even in patients with profoundly reduced renal function, no accumulation of the drug was apparent when repeated doses of MPS were administered at 48-h intervals.


Immunological non-inferiority and safety of a quadrivalent inactivated influenza vaccine versus two trivalent inactivated influenza vaccines in China: Results from two studies.
U1111-1174-4615 and U1111-1174-4698. NCT04210349 and NCT03430089.


Value of dobutamine echocardiography for the assessment of myocardial viability for revascularization.
Coronary artery disease accounts for a majority of heart failure cases in the western world. Many cardiologists believe that abnormal regional contractions in patients with coronary artery disease is equivalent to irreversibly damaged myocardium. Studies now challenge this long-held assumption. Data exist regarding the value of assessing myocardial viability in those patients with severe left ventricular dysfunction and coronary artery disease. This report discusses dobutamine echocardiography as a technique for assessing myocardial viability and for selecting patients for revascularization. (c)2001 by CHF, Inc.


Characterization of the folding pathway of recombinant human macrophage-colony stimulating-factor beta (rhM-CSF beta) by bis-cysteinyl modification and mass spectrometry.
Melarsen oxide [p-(4,6-diamino-1,3,5-triazin-2-yl)aminophenylarsonous acid (MEL)], which selectively bridges spatially neighboring bis-cysteinyl residues in (reduced) proteins, was used to trap folding intermediates chemically during 1) time-dependent renaturation of recombinant human macrophage colony-stimulating factor (rhM-CSF); by redox refolding in vitro; 2) reductive unfolding in the presence of the trapping reagent; and 3) denaturing unfolding reactions in urea and guanidinium hydrochloride. Characterization of intermediates from folding and unfolding reactions was performed by electrospray ionization mass spectometry (ESI-MS). In all folding and unfolding reactions a characteristic dimeric intermediate with two attached melarsen oxide (MEL) groups was observed, suggesting that these rhM-CSF beta species were important refolding intermediates. These intermediates presented a characteristic "charge structure" in ESI spectra with a most abundant 26+ charged molecular ion whereas the mature homodimeric rhM-CSF beta showed a most abundant 23+ molecular ion, indicating that the final product was more compact. The major locations of the two MEL groups were identified by mass spectrometric peptide mapping at cysteine residues C157 and C159 from each monomer. Cysteine residues C7 and C90 were minor modification sites. The mass spectrometric results from the in vitro folding reactions of rhM-CSF beta are in agreement with intrinsic tryptophan fluorescence measurements and are consistent with the folding pathway that starts with a fully reduced monomer (R), includes partially folded monomeric intermediates (M) and dimeric intermediates (D), and yields a final product with the native tertiary structure (N): 2R ==> 2M ==> D ==> N. Our results show that selective chemical trapping of bis-thiol groups of proteins with MEL permits study of folding pathways by mass spectrometric structure characterization of intermediates with otherwise transient conformations.


Miniaturized micromachined gas chromatography with universal and selective detectors for targeted volatile compounds analysis.
An effective analytical strategy for targeted analysis of volatile organic compounds which combines two orthogonal separation mechanisms and multiple tunable detection in a compact transportable analytical system is introduced. This strategy uses a commercially available micromachined gas chromatograph comprising a micromachined on-board thermal conductivity detector. The chromatograph capability is enhanced by incorporating a modified diode array detector and a radio frequency modulated ion mobility spectrometry microfabricated electromechanical system. The analytical platform offers powerful detection capabilities of individual compounds and various classes of volatile organic compounds with improved provisional confirmatory capability. The transportable micromachined gas chromatograph employs field replaceable conventional capillary columns for the separation of analytes. The use of a silicon micromachined sample introduction device affords fast injection to minimize band broadening with fast chromatographic separation rendered in the order of minutes. Advantaged synergy also includes leveraging the resolving power of gas chromatography to minimize charge exchange in the ionization chamber of the differential mobility spectrometer for improved detector performance. Performance of this scalable and transportable analytical system is demonstrated with relevant volatile compounds such as acetaldehyde, acetone, carbon disulfide, benzene, and ethyl butyrate having a day-to-day variability less than 5% and with a high degree of reliability.


[Measurement of blood chloroquine concentrations during neuromyopathies and toxic retinopathies (author's transl)].
Blood chloroquine concentrations were measured in 5 patients having complications related to this treatment. No significant differences were noted when compared to controls. Further studies are required however before drawing any definite conclusions. The persistence of fairly high residual levels, several months after stopping treatment, is evidence of chloroquine retention in these patients.


Separate brain potential characteristics in children with reading disability and attention deficit disorder: color and letter relevance effects.
This experiment was on event-related potential (ERP) indicants of the selective neural processing of black vs. white and letter vs. nonletter stimuli in boys (8-12 years of age) with and without a reading disability (RD) and/or attentional deficit disorder (ADD). Selective neural processing was measured by the increase or difference in ERP amplitude in response to stimuli that were relevant as compared to irrelevant to the color or letter attention task. The 52 children that participated in the study constituted four groups: 25 normal reading children (17 without ADD and 8 with ADD), and 27 RD children (11 without ADD and 16 with ADD). ERPs were recorded over the left and right occipital, central, and frontal regions. Selective neural processing due to stimulus relevance was reduced in boys with RD as compared to normal readers. This reduced selectivity was indicated by a predominantly symmetrical reduction in the magnitude of a positive difference potential over the central regions, between 300 and 360 msec, and then by a left greater than right hemisphere reduction in the magnitude of a positive difference potential over the occipital regions, at about 400 msec. Task relevance increased the within-subject and condition variability of this occipital positive component and this effect was greater for boys without than with RD, particularly over the left hemisphere. Selective neural processing due to stimulus relevance was greater in boys with ADD as compared to those without ADD. This was indicated by an increase in the magnitude of a positive difference potential between 320 and 400 msec over the central and frontal regions and a slow, late, negative difference potential between 600 and 800 msec over the central and occipital regions. These ADD effects tended to be greater over the right than left hemisphere. The unique polarity, scalp distribution, and time course of the effects of RD as compared to ADD on ERPs to relevant stimuli clearly indicated these two disorders, in part, involve different underlying brain deficits.


The 2021 KDIGO blood pressure target and the progression of chronic kidney disease: Findings from KNOW-CKD.
The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) recommends a target systolic BP of <120 mmHg as this target can provide cardiovascular benefits. However, it remains unclear whether implementing the new BP target could improve kidney outcomes. The association between the 2021 KDIGO BP target and CKD progression was examined and compared with the 2012 KDIGO BP target among 1724 participants included in the KoreaN Cohort Study for Outcomes in Patients With CKD. The main exposure was the BP status categorized according to the 2012 or 2021 KDIGO guideline: (1) controlled within the 2021 target, (2) controlled within the 2012 target only, and (3) above both targets. The primary outcome was a composite kidney outcome of ≥50% decline in the estimated glomerular filtration rate from baseline or the initiation of kidney replacement therapy during the follow-up period. Composite kidney outcomes occurred in 650 (37.7%) participants during the 8078 person-years of follow-up (median, 4.9 years). The incidence rates of this outcome were 55, 66.5, and 116.4 per 1000 person-years in BP controlled within the 2021 and 2012 KDIGO targets, and BP above both targets, respectively. In the multivariable cause-specific hazard model, hazard ratios for the composite outcome were 0.76 (95% confidence interval (CI), 0.60-0.95) for BP controlled within the 2021 target and 1.36 (95% CI, 1.13-1.64) for BP above both targets, compared with BP controlled within 2012 target only. The newly lowered BP target by the 2021 KDIGO guideline was associated with improved kidney outcome compared with BP target by the 2012 KDIGO guideline.


Field disease investigation-A differentiating and integrative approach to problems in animal populations.
The economically important diseases of agricultural animals are those that affect groups of animals to result in impaired productivity or mortality. Herd and flock disease result from complex interactions between inciting agents (or other etiologies), and factors such as management systems, nutrition, environment and other contributory causes. For these reasons herd and flock disease problems must be addressed, researched, and taught, in the areas where they occur-on the farm and in the field. For political and educational reasons this needs to be on farms throughout the state or region represented by a veterinary school. Like most studies, this type of study needs to have a multidisciplinary input but these inputs often involve disciplines that are different from those that address clinical disease in individual animals in the veterinary teaching hospital setting. Clinical departments in veterinary schools have not traditionally found funds to support this approach to agricultural animal disease. This talk will discuss the establishment of a conjoint program between the College of Veterinary Medicine and the College of Agriculture at Washington State University (Field Disease Investigation Unit) to address these requirements and its activities over the past 25 years.


What's the cut-point?: a systematic investigation of tau PET thresholding methods.
Tau positron emission tomography (PET) is increasing in popularity for biomarker characterization of Alzheimer's disease (AD), and recent frameworks rely on tau PET cut-points to stage individuals along the AD continuum. Given the lack of standardization in tau PET thresholding methods, this study sought to systematically canvass and characterize existing studies that have derived tau PET cut-points and then directly assess different methods of tau PET thresholding in terms of their concurrent validity. First, a literature search was conducted in PubMed to identify studies of AD and related clinical phenotypes that used the Flortaucipir (AV-1451) tau PET tracer to derive a binary cut-point for tau positivity. Of 540 articles screened and 47 full-texts reviewed, 23 cohort studies met inclusion criteria with a total of 6536 participants. Second, we derived and compared tau PET cut-points in a 2 × 2 × 2 design that systematically varied region (temporal meta-ROI and entorhinal cortex), analytic method (receiver operating characteristics and 2 standard deviations above comparison group), and criterion/comparison variable (amyloid-beta negative cognitively unimpaired or cognitively unimpaired only) using a sample of 453 older adults from the Alzheimer's Disease Neuroimaging Initiative. For the systematic review, notable variability in sample characteristics, preprocessing methods, region of interest, and analytic approach were observed, which were accompanied by discrepancy in proposed tau PET cut points. The empirical follow-up indicated the cut-point derived based on 2 standard deviations above a either comparison group in either ROI best differentiated tau positive and negative groups on cerebrospinal fluid phosphorylated tau, Mini-Mental State Examination score, and delayed memory performance. Given the impact of discrepant thresholds on tau positivity rates, biomarker staging, and eligibility for future clinical treatment trials, recommendations are offered to select cut-point derivations based on the unique goals and priorities of different studies.


L-carnitine and Zinc supplementation impedes intestinal damage in methotrexate-treated adjuvant-induced arthritis rats: Reinstating enterocyte proliferation and trace elements.
Methotrexate (MTX), a folic acid analogue, is used as a first-line treatment for rheumatoid arthritis (RA) since it has more therapeutic mechanisms than any other drug. Being an undeniable drug for the treatment of arthritis, even low-dose MTX provokes intestinal toxicity as a primary adverse effect and does not revive an anti-inflammatory element. Thus, our study aims to elucidate the anti-arthritic and prophylactic activity of supplements L-carnitine (L) and zinc (Z) against MTX-mediated intestinal damage in arthritis rats. The rats were assessed for arthritic parameters such as body weight, paw volume, x-ray scan, and serum trace elements level. To analyze the toxic effects of MTX in the rats, intestine pH, mucosal weight, digestive enzymes, myeloperoxidase, histopathological, and immunohistochemical analysis were performed. Our study demonstrated that the arthritic parameters have shown that MTX has an ameliorative effect on arthritic rats. Besides, our findings showed that low-dose MTX (2.5 mg/kg b.w.) given once a week for two weeks during arthritis treatment had toxic effects in the rat's intestine, as evidenced by changes in intestine pH and mucosal weight, decreased digestive enzymes, increased MPO, and degenerative changes in histopathological analysis. Concurrent therapy of LZ with MTX, on the other hand, restored the modifications in these parameters. MTX in combination with LZ effectively manages arthritis than monotherapy and significantly prevents MTX-induced intestinal damage in arthritis rats. Thus, LZ could be used as an improved therapeutic and safety for MTX-instigated intestinal damage during arthritis treatments. Therefore, our combination of L-carnitine and zinc with MTX would be promising prophylactic activity for arthritis patients.


Dynamic radionuclide phlebography. A clinical study in patients after total hip replacement.
Dynamic radionuclide phlebography was performed in 50 consecutive patients after total hip replacement to evaluate the diagnostic value of the method compared to contrast phlebography. The investigation was limited to the diagnosis of iliofemoral thrombi. A special injection technique was developed and flow curves, mean transit time and distribution of flow were recorded with a scintillation camera interfaced to a digital computer. Three principally different types of flow curves were observed. Mean transit time was of value in differentiating particle flow in the superficial veins from passage through the deep veins. Out of 15 legs with thrombi in the iliofemoral region, the distribution of flow was significantly changed in 12. Deep vein thrombosis in the lower leg did not influence mean transit time or distribution of flow in the iliofemora region. Extensive collateral flow was rare. Ninety per cent of the thrombi were asymptomatic. The method compares favorably with the 125 I fibrinogen method and cuff impedance phlebography, in diagnosing iliofemoral thrombi after total hip replacement.


Two-Stage Exchange Using a Total Femur Spacer in the Management of Periprosthetic Joint Infection - Spacer Complications and Implant Survivorships.
Chronic periprosthetic joint infection after revision hip and knee arthroplasties can lead to subsequent massive femoral bone loss. In these cases, resection of the residual femur and placement of an antibiotic total femoral spacer can be an option to salvage the limb. This is a single-center retrospective analysis of 32 patients (median age 67 years; range 15-93; 18 women) who underwent placement of a total femur spacer for chronic periprosthetic joint infection with massive femoral bone loss between 2010 and 2019 as part of a planned two-stage exchange. The median follow-up period amounted to 46 months (range, 1-149). Implant and limb survival were analyzed using Kaplan-Meier survival estimates. Potential risk factors for failure were analyzed. There were 34% (11 of 32) of patients having a spacer-associated complication, and 25% underwent revision for this reason. After the first stage, 92% were considered infection-free. There were 84% of patients who underwent second-stage reimplantation of a total femoral arthroplasty using a modular megaprosthetic implant. Infection-free implant survival was 85% after 2 years and 53% after 5 years. There were 44% of patients who underwent amputation after a median time of 40 months (range, 2-110). Most commonly, coagulase-negative staphylococci were cultured at first-stage surgery, while polymicrobial growth was most common at reinfection. Total femur spacers can lead to infection control in over 90% of cases with a reasonable complication rate for the spacer itself. However, the reinfection and subsequent amputation rate after second-stage megaprosthetic total femoral arthroplasty is around 50%.


Effects of growth conditions on the ion composition of Bifidobacterium bifidum subsp. pennsylvanicum.
The cation content of Bifidobacterium bifidum subsp. pennsylvanicum was markedly influenced by the washing procedure of the cells, by the growth phase and the temperature, and by the composition of the culture medium. Optimal retention of cations was achieved by washing with 0.25 M MgCl2 at 20C. The intracellular Na+ concentration rose during growth in normal medium to a constant value in the stationary phase, the K+ concentration rose in the exponential phase, but fell in the stationary phase. Cells from 29-C cultures contained more Na+ and less K+ in the stationary phase than did cells from 37-C cultures, but the total cation content was the same at 29 and 37C. Intracellular Na+ and K+ concentrations were dependent on the concentrations in the medium and on its osmolarity. The intracellular Na+/K+ ratio varied from 0.04 to 2.3. The concentrations of Na+,K+ and phosphate in the medium hardly affected growth. Mg2+-deficiency of the medium markedly decreased the concentration of Mg2+ within the cell; its concentration in the cell sap was greatly affected, but the amount of sedimentable, bound Mg2+ only slightly. The content of K+ within the cell decreased in Mg2+-deficient medium, but the concentration of Na+ did not. Omission of Tween 80 as well as its substitution by Tween 20 caused a decrease of intracellular K+. Cells from Tween 40 and Tween 60 cultures additionally contained markedly less Na+.