Repeated and patterned stimulation of cutaneous reflex pathways amplifies spinal cord excitability.
Priming with patterned stimulation of antagonist muscle afferents induces modulation of spinal cord excitability as evidenced by changes in group Ia reciprocal inhibition. When assessed transiently with a condition-test pulse paradigm, stimulating cutaneous afferents innervating the foot reduces Ia presynaptic inhibition and facilitates soleus Hoffmann (H)-reflex amplitudes. Modulatory effects (i.e., priming) of longer lasting sensory stimulation of cutaneous afferents innervating the foot have yet to be examined. As a first step, we examined how priming with 20 min of patterned and alternating stimulation between the left and right foot affects spinal cord excitability. During priming, stimulus trains (550 ms; consisting of twenty-eight 1-ms pulses at 51 Hz, 1.2 times the radiating threshold) were applied simultaneously to the sural and plantar nerves of the ankle. Stimulation to the left and right ankle was out of phase by 500 ms. We evoked soleus H-reflexes and muscle compound action potentials (M waves) before and following priming stimulation to provide a proxy measure of spinal cord excitability. H-reflex and M-wave recruitment curves were recorded at rest, during brief (<2 min) arm cycling, and with sural conditioning [train of five 1-ms pulses at 2 times the radiating threshold (RT) with a condition-test interval (C-T) = 80 ms]. Data indicate an increase in H-reflex excitability following priming via patterned sensory stimulation. Transient sural conditioning was less effective following priming, indicating that the increased excitability of the H-reflex is partially attributable to reductions in group Ia presynaptic inhibition. Sensory stimulation to cutaneous afferents, which enhances spinal cord excitability, may prove useful in both rehabilitation and performance settings.NEW & NOTEWORTHY Priming via patterned stimulation of the nervous system induces neuroplasticity. Yet, accessing previously known cutaneous reflex pathways to alter muscle reflex excitability has not yet been examined. Here, we show that sensory stimulation of the cutaneous afferents that innervate the foot sole can amplify spinal cord excitability, which, in this case, is attributed to reductions in presynaptic inhibition.


Association of AQP8 in women with PCOS.
Aquaporin 8 (AQP8) has been identified as a novel gene participating in female reproductive physiology. The present study was designed to determine whether an association exists between AQP8 and polycystic ovary syndrome (PCOS). This study recruited 192 women with PCOS and 191 controls. High-resolution melting and sequencing were employed to investigate the genotypes of six single-nucleotide polymorphisms within AQP8 (rs7198838, rs1076973, rs1076974, rs2287797, rs2287798 and rs2287796). A significant difference was found in rs2287798 between PCOS cases and controls (P=0.0007). Possible associations between AQP8 genotypes and three different phenotypes of this syndrome were investigated. The results support the earlier evidence for a possible role of AQP8 in the pathogenesis of PCOS. Further studies are still needed to elucidate its functional role. Aquaporin 8 (AQP8) has been identified as a novel gene participating in female reproductive physiology. The present study was designed to determine whether there is an association between AQP8 and polycystic ovary syndrome (PCOS). This study recruited 192 women with PCOS and 191 controls. High-resolution melting and sequencing were employed to investigate the genotypes of six single-nucleotide polymorphisms within AQP8 (rs7198838, rs1076973, rs1076974, rs2287797, rs2287798 and rs2287796). We observed a significant difference in allele frequency of rs2287798 between PCOS cases and controls (P=0.0007). The possible association between AQP8 genotypes and three different phenotypes of this syndrome in this locus were investigated. Our results support the earlier evidence for a possible role of AQP8 in the pathogenesis of PCOS. Further studies are still needed to elucidate its functional role.


GluN2B Subunit Labeling with Fluorescent Probes and High-Resolution Live Imaging.
Laser Scanning Confocal Microscopy (LSCM) imaging using an appropriate fluorescent probe enables the visualization of a molecular target with high resolution, and represents a method of choice for studying expression, subcellular location, and trafficking of receptors in living cells. The chemical, physical, and pharmacological properties of the probe remain essential. Here, we describe (1) the preparation of a specific probe for NMDAR GluN2B receptor by conjugation of fluorescein to an ifenprodil-based ligand, (2) an in vitro functional assay by calcium imaging for GluN2B binding and inhibition evaluation of the probe, and (3) the labeling and confocal imaging of GluN2B in DS-red labeled living cortical neurons.


Anti-oxidative Responses on Hepatic Tissue of Zebrafish (Danio rerio) in a Short Duration of Sub-lethal Concentrations of Cadmium Exposure.
The aim of the present study was to identify whether the responses of oxidative stress in zebrafish liver are similar to those in mammalians upon low doses of Cd2+ exposure in short durations. Fish were exposed to 1.78 μM Cd2+ (treatment) and 0.0 μM Cd2+ (control) for 0, 1, 3, and 6 h. The reactive oxygen species (ROS) and lipid peroxidation (LPO) of hepatic tissues significantly increased after 3 and 6 h of Cd2+ exposure, respectively. Antioxidants glutathione peroxidase (gpx1a), superoxide dismutase (sod), and catalase (cat) were up regulated after 1-3 h, and metallothionein isoforms (smtB and mt2) increased after 3-6 h of Cd2+ exposure. The caspase-3 and p53 mRNA expressions significantly increased threefolds after 1 h of Cd2+ exposure. Results confirmed that oxidative stress in the hepatic tissue was induced by Cd2+ within 3 h. However, anti-oxidative functions immediately up regulated, causing cell apoptosis levels to decrease after 6 h of Cd2+ exposure.


Fatal esorubicin-induced cardiomyopathy: report of a case and review of the literature.
A case of fatal dilated cardiomyopathy induced by esorubicin (ESO) at a total dose of 740 mg/m2, given in 27 doses over 650 days, is reported. The sudden onset, rapid clinical deterioration, and fatal outcome are detailed. The outcome was not predicted by serial rest ejection fractions or clinical signs. The data from animal studies, phase 1 and phase 2 clinical testing, are reviewed, demonstrating the almost complete absence of reports of ESO-induced cardiotoxicity. Studies reviewing ejection fractions and myocardial biopsy scores show that ESO can be cardiotoxic and may produce fatal dilated cardiomyopathy.


Prenatal fetal sex diagnosis by detecting amelogenin gene in maternal plasma.
To provide a new, reliable noninvasive method for fetal sex determination. Fetal sex was detected in 32 early pregnant women by identifying the amelogenin gene in maternal plasma using nested PCR analysis. First, the 122/128 bp of X-Y homologous region containing 6 bp deletions in the intron 3 of amelogenin gene in X chromosome was amplified, and then the nested PCR was carried out, whose 3' end of the upstream primer is just located in the deletion region. The fetus was male or female, depending on whether it had the 89-bp nested PCR product or not. The 89 bp of nested PCR product was detected in 19 plasma samples obtained from pregnant women, deducing they bear the male fetus and the remaining pregnant women bear female. When compared with the birth outcome, two samples were pseudo-positive. The coincidence was 93.8%. This method had high sensitivity that even trace amount of target fetal DNA (10 pg) could be detected. This conventional nested PCR analysis of amelogenin gene promises to be a reliable method for noninvasive fetal sex determination at early pregnancy using maternal plasma DNA.


Proteomics analysis to investigate the potential mechanism of theacrine against UV-induced skin photodamage.
This study aimed to explore the underlying mechanism of theacrine treatment of UV-induced skin photodamage. Tandem Mass Tag (TMT) relative quantitative proteomics analysis was used to characterize the proteins and pathways associated with the ability of theacrine to combat photodamage in mouse skin by modeling UV irradiation of the backs of ICR mice. Apoptosis-related proteins and signaling pathways play a key role in the ability of theacrine to protect against skin photodamage, according to proteomic and bioinformatics analysis; molecular docking and Western blotting further revealed that theacrine was associated with apoptosis-related proteins (p53, Bcl-2, Bax, caspase-3, and cleaved-caspase-3) with strong binding affinity, which can significantly reduce skin cell apoptosis induced by UV exposure. The findings revealed that theacrine can reduce UVB-induced epidermal damage by controlling the apoptosis signaling pathway, implying that theacrine could be a useful anti-UVB damage agent.


Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence.
By comparison with ovarian carcinomas, borderline ovarian tumours are characterised clinically by superior overall survival, even in women with peritoneal spread. In this Review, we aimed to clarify the histological and clinical factors potentially defining a high-risk group in whom disease is likely to evolve to invasive disease. Invasive peritoneal implants (in serous borderline ovarian tumours) and residual disease after surgery were the two factors clearly identified. Other factors are controversial owing to increased risk of invasive recurrence: micropapillary patterns in serous borderline ovarian tumour, intraepithelial carcinoma in mucinous lesions, stromal microinvasion in serous lesions, and use of cystectomy in mucinous borderline ovarian tumours. The pathologist has a pivotal role in assessment of the borderline nature of ovarian tumours and in identification of high-risk criteria, most of which are histological. But, reproducibility of the histological interpretation of some of these potential criteria--eg, classification of peritoneal implants (particularly in desmoplastic subtype), stromal microinvasion, micropapillary patterns, and intraepithelial carcinoma in mucinous borderline ovarian tumours--remains unclear, and should be investigated.


Evaluation of total oxidant and antioxidant status in localized and generalized vitiligo.
Vitiligo is an acquired depigmentation disorder, and oxidative stress is suggested to have a major role in its aetiopathogenesis. To assess whether oxidative stress has a greater role in generalized than in localized vitiligo. We assessed 31 patients with active vitiligo (17 localized, 14 generalized) and 38 healthy controls. Serum total oxidant status (TOS), total antioxidant status (TAS) and oxidative stress index (OSI) were determined. Patients with vitiligo had significantly lower TAS and higher TOS and OSI values than controls. Both localized and generalized vitiligo were associated with lower TAS and higher TOS and OSI values, compared with controls, and all three did not differ with vitiligo type. A systemic oxidative stress exists in patients with vitiligo. These results indicate that the global antioxidant capacity of patients might have been exhausted through a defence mechanism against oxidative processes. The imbalance in TOS/TAS status may have an important role in the aetiopathogenesis of vitiligo, regardless of the clinical variant of the disease.


The Action of the Hexokinase Inhibitor 2-deoxy-d-glucose on Cryptosporidium parvum and the Discovery of Activities against the Parasite Hexokinase from Marketed Drugs.
Cryptosporidium parvum is one of the major species causing mild to severe cryptosporidiosis in humans and animals. We have previously observed that 2-deoxy-d-glucose (2DG) could inhibit both the enzyme activity of C. parvum hexokinase (CpHK) and the parasite growth in vitro. However, the action and fate of 2DG in C. parvum was not fully investigated. In the present study, we showed that, although 2DG could be phosphorylated by CpHK to form 2DG-6-phosphate (2DG6P), the anti-cryptosporidial activity of 2DG was mainly attributed to the action of 2DG on CpHK, rather than the action of 2DG or 2DG6P on the downstream enzyme glucose-6-phosphate isomerase (CpGPI) nor 2DG6P on CpHK. These observations further supported the hypothesis that CpHK could serve as a drug target in the parasite. We also screened 1,200 small molecules consisting of marketed drugs against CpHK, from which four drugs were identified as CpHK inhibitors with micromolar level of anti-cryptospordial activities at concentrations nontoxic to the host cells (i.e. hexachlorphene, thimerosal, alexidine dihydrochloride, and ebselen with EC50 = 0.53, 1.77, 8.1 and 165 μM, respectively). The anti-CpHK activity of the four existing drugs provided us new reagents for studying the enzyme properties of the parasite hexokinase.


CRISPR/Cas13d targeting GZMA in PARs pathway regulates the function of osteoclasts in chronic apical periodontitis.
Chronic apical periodontitis is a prevalent oral disease characterized by bone loss, and its underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of the serine protease GZMA in osteoclasts during chronic apical periodontitis. To address this, we employed crRNA/Cas13d to inhibit GZMA expression and examined its impact on osteoclast behavior. Our findings revealed that GZMA plays a significant role in promoting osteoclast cell proliferation while inhibiting cell apoptosis. Additionally, the inhibition of GZMA led to a notable increase in miR-25-3p expression, which, in turn, downregulated the expression of TGF-β. Consequently, the reduction in TGF-β expression led to a decrease in PAR1 expression within the PARs pathway. These results suggest that GZMA might serve as a promising therapeutic target for the treatment of chronic apical periodontitis. Furthermore, our study highlights the potential of targeting GZMA using crRNA/Cas13d as a valuable approach for future therapeutic interventions.


Heavy metal concentrations in diploid and triploid oysters (Crassostrea gigas) from three farms on the north-central coast of Sinaloa, Mexico.
The concentrations of Cu, Cd, Pb, Zn, and Hg in diploid and triploid oysters from three farms (Guasave, Ahome, and Navolato) on the north-central coast of Sinaloa, Mexico, were assessed based on samples recovered during a single culture cycle 2013-2014. Metal burdens were more strongly correlated (p < 0.05) with the location of the farm than with either the ploidy or the interaction of both variables. The metal concentration ranking for oysters of both ploidies from the three farms was Zn > Cu > Cd > Pb > Hg. For all three farms, the mean concentrations of Cd and Pb in Crassostrea gigas were high, ranging from 2.52 to 7.98 μg/g wet weight for Cd and from 0.91 to 2.83 μg/g wet weight for Pb. Diploid and triploid oysters from the Guasave farm contained high levels of Cu (76.41 and 68.97 μg/g wet weight, respectively). Cu, Cd, and Zn were highly correlated (p < 0.05), and their concentrations may be influenced by agrochemical inputs. The mean levels of Cu for the Guasave farm and of Cd and Pb for all three farms exceeded permissible limits and represented a threat to human health during the sampling period (July 2014 to July 2014).


Pitfalls in using the ring finger test alone for the diagnosis of carpal tunnel syndrome.
Latency differences (>0.5 ms) of median and ulnar sensory action potentials (mSAP and uSAP) at the wrist evoked by ring finger stimulation are considered a sensitive and specific test for diagnosis of carpal tunnel syndrome (CTS). In this study, we aimed to assess the practical usefulness of the ring finger test (RFT) in routine electromyography (EMG) examinations. We investigated 2 series of patients: in the first prospective series we considered 300 hands affected by only mild CTS; in the second series we examined retrospectively the EMG charts of 961 hands affected only by CTS but not selected for severity or duration of symptoms. In the first series we found pathological RFT scores in 87% of cases, and pathological RFT or mSAP latency results in 92%. In the second series, pathological RFT scores were found only in 55% of cases, while in 20% where mSAP failed, a volume conducted uSAP had been erroneously interpreted as arising from the median nerve. RFT sensitivity tested in routine EMG examinations of unselected hands affected by CTS drops considerably. Fingers innervated by one only nerve, such as the index and the little fingers, must also be investigated to increase the diagnostic value of RFT.


A randomized, double-blind, placebo-controlled trial of transfer factor as adjuvant therapy for malignant melanoma.
One hundred and sixty-eight evaluable patients participated in a randomized, double-blind study of transfer factor (TF) versus placebo as surgical adjuvant therapy of Stage I and Stage II malignant melanoma. Eighty-five patients received TF prepared from the leukocytes of healthy volunteer donors; eighty-three participants received placebo. Therapy was initiated within 90 days of resection of all evident tumor and continued until 2 years of disease-free survival or the occurrence of unresectable dissemination of melanoma. Known prognostic variables were similarly distributed in the treatment and control groups, documenting the randomization efficacy. Three endpoints were analyzed: disease-free interval, time to Stage III metastasis, and survival. After a median follow-up period of 24.75 months, there was a trend in favor of the placebo group with regard to all three endpoints and this was significant (P less than or equal to 0.05) for time to Stage III metastasis. These findings indicate that TF is not effective as surgical adjuvant therapy of malignant melanoma.


2,3-Dihydroxypyridine-loaded cellulose: a new macromolecular chelator for metal enrichment prior to their determination by atomic absorption spectrometry.
New macromolecular chelators have been synthesized, by loading 2,3-dihydroxypyridine (DHP) on cellulose via linkers -NH-CH(2)-CH(2)-NH-SO(2)-C(6)H(4)-N=N- and -SO(2)-C(6)H(4)-N=N-, and characterized by elemental analysis, TGA, IR, and CPMAS (13)C NMR spectra. The cellulose with DHP anchored by the shorter linker had better sorption capacity (between 69.7 and 431.1 micromol g(-1)) for Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Pb(II), and Fe(III)) than the other (51.9-378.1 micromol g(-1)); the former was therefore studied in detail as a solid extractant for these metal ions. The optimum pH ranges for quantitative sorption (recovery 97.6-99.8%) on this matrix were: 7.0-9.0, 6.0-9.0, 3.0-8.0, 6.0-8.0, 6.0-9.0, 6.0-7.0, and 2.0-6.0 respectively. Desorption was quantitative with 0.5 mol L(-1) HCl and 0.5 mol L(-1) HNO(3) (for Pb). Simultaneous sorption (at pH 7.0) of all metal ions other than Fe(III) was possible if their total concentration did not exceed the sorption capacity (lowest value). The recovery of seven metal ions from their mixture at pH 6.0 was nearly quantitative when the concentration level of each metal ion was 0.2 microg mL(-1). The optimum flow rate of metal ion solutions for quantitative sorption of metal onto a column packed with DHP-modified cellulose was 2-7 mL min(-1), whereas for desorption the optimum flow rate for the acid solution was 2-4 mL min(-1). The time needed to reach 50% of the total loading capacity ( t(1/2)) was <5 min for all the metal ions except Ni and Pb. The limit of detection (blank+3 s) was from 0.70 to 4.75 microg L(-1) and the limit of quantification (blank+10 s) was between 0.79 and 4.86 microg L(-1). The tolerance limits for NaCl, NaBr, NaI, NaNO(3), Na(2)SO(4), Na(3)PO(4,) humic acid, EDTA, Ca(II), and Mg(II) for sorption of all metal ions are reported. The column packed with DHP-anchored cellulose can be reused at least 20 times for enrichment of metal ions in water sample. It has been used to enrich all the metal ions in pharmaceutical and water samples before their determination by flame AAS. RSD for these determinations was between 1.1 and 6.9%.


Morphine use in hospitalized children in the United States: a descriptive analysis of data from pediatric hospitalizations in 2008.
Morphine is among the top 10 medications given to children in the inpatient setting. It is not labeled for any pediatric indication, making it one of the drugs most widely used off-label in pediatrics. The aims of this study were to describe the epidemiology of morphine use in pediatric inpatients in the United States and to describe the characteristics of patients and hospitals in hospitalizations with morphine use. Deidentified data from the Premier Perspective Database (2008) were analyzed. Morphine use was defined as any morphine administration during the hospital stay and estimated by patient age in years, sex, race, and type of insurance; and hospital bedsize, teaching status, setting (urban or rural), and geographic location. Proportions (95% CI) were calculated for the entire population and for individual strata. The estimate was applied to national data to calculate the number of pediatric hospitalizations with morphine use in the United States in 2008. Logistic mixed-effects modeling was used to calculate the probability of morphine use by hospital after controlling for hospital and patient effects. The database contained records from 877,201 pediatric hospitalizations and 423 hospitals in the United States. Morphine was administered in 54,613 of pediatric hospitalizations (6.2%). Use was higher in boys than girls (6.4% and 6.1%, respectively) and in blacks compared with whites or other racial groups (7.5%, 6.7%, and 5.0%). Use increased from 1.6% in children aged <2 years to 27.4% in those aged 12 to 17 years. Based on these data, morphine may have been administered in 476,205 pediatric hospitalizations in the United States in 2008. The 2 diagnoses most frequently associated with morphine use were appendicitis (14.4%) and fracture (11.1%). On logistic mixed-effects modeling for patients with appendicitis and for patients with fractures, there was hospital variation in morphine use after controlling for variables in the model. Based on the data from this analysis, morphine was used in hospitalized children in all age groups, despite the lack of pediatric labeling. Common conditions such as appendicitis and fracture were leading diagnoses associated with morphine use.


Impact of orthologous gene replacement on the circuitry governing pilus gene transcription in streptococci.
The evolutionary history of several genes of the bacterial pathogen Streptococcus pyogenes strongly suggests an origin in another species, acquired via replacement of the counterpart gene (ortholog) following a recombination event. An example of orthologous gene replacement is provided by the nra/rofA locus, which encodes a key regulator of pilus gene transcription. Of biological importance is the previous finding that the presence of the nra- and rofA-lineage alleles, which are approximately 35% divergent, correlates strongly with genetic markers for streptococcal infection at different tissue sites in the human host (skin, throat). In this report, the impact of orthologous gene replacement targeting the nra/rofA locus is experimentally addressed. Replacement of the native nra-lineage allele with a rofA-lineage allele, plus their respective upstream regions, preserved the polarity of Nra effects on pilus gene transcription (i.e., activation) in the skin strain Alab49. Increased pilus gene transcription in the rofA chimera correlated with a higher rate of bacterial growth at the skin. The transcriptional regulator MsmR, which represses nra and pilus gene transcription in the Alab49 parent strain, has a slight activating effect on pilus gene expression in the rofA chimera construct. Data show that exchange of orthologous forms of a regulatory gene is stable and robust, and pathogenicity is preserved. Yet, new phenotypes may also be introduced by altering the circuitry within a complex transcriptional regulatory network. It is proposed that orthologous gene replacement via interspecies exchange is an important mechanism in the evolution of highly recombining bacteria such as S. pyogenes.


Densitometer type and impact on risk assessment for osteoporosis.
Studies have shown a high correlation between measurements of bone mineral density (BMD) obtained on differentdual-energy X-ray absorptiometry machines. Challenger osteodensitometers (Diagnostic Medical System [DMS],Montpellier, France) are becoming widely used but little is known about their clinical performance. The aim of this study was to compare BMD measurements and the resulting patient classification based on T-scores obtained on a DMS Challenger device to those obtained on Hologic 4500A (Bedford, MA) device. Fifty-three volunteers were studied. The BMD of the spine and of the hip were simultaneously measured on both densitometers. BMD values obtained on the Challenger were significantly higher than those obtained with the Hologic QDR4500 (p<0.001). The correlations coefficients between the Hologic QDR4500 and the DMS Challenger measured BMDs were r=0.70 at the femoral neck, r=0.70 at the trochanter, and r=0.83 at the spine (p<0.001). Among the 35 postmenopausal women, there was discordance in the WHO T-score-based classification in 28 subjects (80%) at the spine, 18 subjects (52%) at the femoral neck, and 14 subjects (42%) at the trochanter. The intermachine agreement was low: The kappa score was -0.10 at the spine, 0.2 at the femoral neck, and 0.3 at the trochanter. In conclusion, this study cautions against the use of non established densitometers that leads to underdiagnosis of patients and, subsequently, to inappropriate treatment strategies.


Regulated translocation of neutral sphingomyelinase-2 to the plasma membrane drives insulin resistance in steatotic hepatocytes.
Obesity-associated diabetes is linked to the accumulation of ceramide in various organs, including the liver. The exact mechanisms by which ceramide contributes to diabetic pathology are unclear, but one proposed scenario is that ceramide accumulation may inhibit insulin signaling pathways. It is unknown however whether the excess ceramide is generated proximal to the insulin receptor, that is, at the plasma membrane (PM), where it could affect the insulin signaling pathway directly, or the onset of insulin resistance is due to ceramide-induced mitochondrial dysfunction and/or lipotoxicity. Using hepatic cell lines and primary cultures, gain- and loss- of function approach, and state-of-the art lipid imaging, this study shows that PM-associated neutral sphingomyelinase 2 (nSMase2) regulates ceramide homeostasis in fat-loaded hepatocytes and drives the onset of insulin resistance. Our results provide evidence of a regulated translocation of nSMase2 to the PM which leads to local generation of ceramide and insulin resistance in cells treated with palmitic acid (PAL), a type of fat commonly found in diabetogenic diets. Oleic acid, which also causes accumulation of lipid droplets, does not induce nSMase2 translocation and insulin resistance. Experiments using the acyl-biotin exchange method to quantify protein palmitoylation show that cellular PAL abundance regulates the rate of nSMase2 palmitoylation. Furthermore, while inhibition of nSMase2 with GW4869 prevents PAL-induced insulin resistance, the overexpression of wild type nSMase2 but not palmitoylation-defective mutant protein potentiates the suppressive effect of PAL on insulin signaling. Overall, this study identifies nSMase2 as a novel component of the mechanism of insulin resistance onset in fat-loaded hepatocytes, that is, cell-autonomous and driven by PAL.


Deep sequencing of non-ribosomal peptide synthetases and polyketide synthases from the microbiomes of Australian marine sponges.
The biosynthesis of non-ribosomal peptide and polyketide natural products is facilitated by multimodular enzymes that contain domains responsible for the sequential condensation of amino and carboxylic subunits. These conserved domains provide molecular targets for the discovery of natural products from microbial metagenomes. This study demonstrates the application of tag-encoded FLX amplicon pyrosequencing (TEFAP) targeting non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) genes as a method for determining the identity and diversity of natural product biosynthesis genes. To validate this approach, we assessed the diversity of NRPS and PKS genes within the microbiomes of six Australian marine sponge species using both TEFAP and metagenomic whole-genome shotgun sequencing approaches. The TEFAP approach identified 100 novel ketosynthase (KS) domain sequences and 400 novel condensation domain sequences within the microbiomes of the six sponges. The diversity of KS domains within the microbiome of a single sponge species Scopalina sp. exceeded that of any previously surveyed marine sponge. Furthermore, this study represented the first to target the condensation domain from NRPS biosynthesis and resulted in the identification of a novel condensation domain lineage. This study highlights the untapped potential of Australian marine sponges for the isolation of novel bioactive natural products. Furthermore, this study demonstrates that TEFAP approaches can be applied to functional genes, involved in natural product biosynthesis, as a tool to aid natural product discovery. It is envisaged that this approach will be used across multiple environments, offering an insight into the biological processes that influence the production of secondary metabolites.


Isolation and Characterization of Chemopreventive Agent from Sphaeranthus amaranthoides Burm F.
To investigate the in vitro cytotoxic effect and to isolate and characterize a chemopreventive secondary metabolite from Sphaeranthus amaranthoides Burm F (sivakaranthai). In vitro cytotoxic effect was carried out by 3 (4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Different concentrations of the extracts were tested on three different cell lines namely A549, HT29, and MCF7. The chloroform extract was subjected to column chromatography, and the isolated compound was characterized by various spectral methods and by single crystal X-ray crystallography. The concentration that cause 50% growth inhibition value of chloroform extract was found to be 0.9 and 19 μg/mL against MCF7 and A549 cell lines, respectively. Chloroform extract was subjected to column chromatography for the isolation of phytoconstituent. The structure of the isolated compound was identified by spectroscopic techniques such as infrared, nuclear magnetic resonance, XRD, and mass spectroscopy. On comparison of complete spectral detail of the compound, the proposed structure was identified as chrysosplenol D (a flavonoid). Chrysosplenol D was isolated for the first time from this plant. The chloroform extract had higher cytotoxic effect, and the isolated chrysosplenol D may be responsible for the anti-proliferative effect of the plant. The plant Sphaeranthus amaranthoides Burm F was extracted with solvents of increasing polarity. The chloroform extract was found to have cell inhibition towards MCF 7 and HT 29 cell lines. This was subjected to fractionation. Chrysosplenol D was isolated from the chloroform extract.


Calcium transient and sodium-calcium exchange current in human versus rabbit sinoatrial node pacemaker cells.
There is an ongoing debate on the mechanism underlying the pacemaker activity of sinoatrial node (SAN) cells, focusing on the relative importance of the "membrane clock" and the "Ca(2+) clock" in the generation of the small net membrane current that depolarizes the cell towards the action potential threshold. Specifically, the debate centers around the question whether the membrane clock-driven hyperpolarization-activated current, I f , which is also known as the "funny current" or "pacemaker current," or the Ca(2+) clock-driven sodium-calcium exchange current, I NaCa, is the main contributor to diastolic depolarization. In our contribution to this journal's "Special Issue on Cardiac Electrophysiology," we present a numerical reconstruction of I f and I NaCa in isolated rabbit and human SAN pacemaker cells based on experimental data on action potentials, I f , and intracellular calcium concentration ([Ca(2+)] i ) that we have acquired from these cells. The human SAN pacemaker cells have a smaller I f , a weaker [Ca(2+)] i transient, and a smaller I NaCa than the rabbit cells. However, when compared to the diastolic net membrane current, I NaCa is of similar size in human and rabbit SAN pacemaker cells, whereas I f is smaller in human than in rabbit cells.


[Imatinib-induced DRESS].
Imatinib (Glivec) is a tyrosine kinase inhibitor used to treat certain cases of leukaemia. We report a case of a drug-induced reaction with eosinophilia and systemic symptoms (DRESS) caused by imatinib. A 77-year-old woman with a chronic myeloid leukaemia was treated with imatinib and allopurinol. Nineteen days after the start of treatment, the patient presented fever with a generalized polymorphous rash associated with oral erosions, facial oedema, diffuse lymphadenopathy and blood hypereosinophilia. Histological analysis of skin biopsy specimens suggested a drug-induced reaction. The outcome was favourable two weeks after discontinuation of treatment. Three months later, imatinib was reintroduced because of progression of the patient's chronic myeloid leukaemia, and recurrence of the skin rash and fever was observed within 12 hours. Allopurinol was stopped definitively because of its more frequent imputability. Imatinib was reintroduced after considering the benefit-risk ratio and in full knowledge of the existence of cutaneous reactions to imatinib, despite there being only one recent report of DRESS following treatment with imatinib. According to the causality criteria of Bégaud et al. regarding imatinib, inherent causality of the drug in our patient was initially possible (I2) and appeared likely (I3) after the rechallenge test. This case clearly illustrates that imatinib is a potential cause of DRESS.


Localization of proteinase expression in the developing rabbit brain.
In developing rabbit brain we studied expression of metalloproteinases (MMP) 1 and 3 by in situ hybridization and MMP2 and tissue and urokinase-type plasminogen activators (tPA and uPA) by immunohistochemistry. All are detected in developing cell populations. Mature olfactory bulb neurons express MMP1 and MMP3. uPA is expressed by glial cells during myelination and by mature cortical neurons. MMP2 is expressed by mature subpial and perivascular astrocytes.


Comparison of API 50 CH strips to whole-chromosomal DNA probes for identification of Lactobacillus species.
The API 50 CH identification system was evaluated for the identification of 97 strains of commensal lactobacilli. This system agreed with the species-level identifications for none of the 7 reference strains and only 4 of 90 vaginal isolates identified using whole-chromosomal DNA probes.


Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down syndrome.
Virtually all adults with Down syndrome (DS) have neuropathological manifestations of Dementia in Alzheimer's disease (DAD) but not all develop clinical psychopathology. The effect of allelic variants of Apolipoprotein (APOE) gene in development and progression of DAD and mortality in persons with DS is examined. Recruited participants with DS underwent two to 14 sequential assessments over a follow up period of 6 years on average and their APOE genotype determined. Dementia status was confirmed as recommended by the Working Group for the Establishment of Criteria for the Diagnosis of Dementia in Individuals with Intellectual Disability. APOE genotype results were available for 252 individuals. Participants with APOE epsilon 4 allele had significantly higher risk of developing DAD (HR = 1.8, 95% CI: 1.12-2.79), had an earlier onset of DAD (55.0 vs 57.0 years; p = 0.0027) and a more rapid progression to death compared with participants with epsilon 3 allele (4.2 years vs. 5.4 years, respectively, p = 0.048). In non-demented persons with DS, epsilon 4 allele was associated with earlier death by 17 years (mean survival age, 55.7 vs. 72.7 years; HR = 5.9, 95% CI: 1.7-21.3). This study highlights the relationship of APOE genotype to morbidity and mortality in persons with DS which has important clinical implications. We recommend screening for APOE genotype in persons with DS to identify those at risk of DAD and premature death. Further research is required to investigate the underlying reasons for the early mortality in non-demented DS persons with an epsilon 4 allele.


A prediction model on incident chronic kidney disease among individuals with type 2 diabetes in the United States.
Early identification of incident chronic kidney disease (CKD) in individuals with diabetes may help improve patients' clinical outcomes. This study aimed to develop a prediction equation for incident CKD among people with type 2 diabetes (T2D). A time-varying Cox model was applied to data from the ACCORD trial to predict the risk of incident CKD. A list of candidate variables was chosen based on literature reviews and experts' consultations, including demographic characteristics, vitals, laboratory results, medical history, drug use and health care utilization. Model performance was evaluated. Decomposition analysis was conducted, and external validation was performed. In total, 6006 patients with diabetes free of CKD were included, with a median follow-up of 3 years and 2257 events. The risk model included age at T2D diagnosed, smoking status, body mass index, high-density lipoprotein, very-low-density lipoprotein, alanine aminotransferase, estimated glomerular filtration rate, urine albumin-creatinine ratio, hypoglycaemia, retinopathy, congestive heart failure, coronary heart disease history, antihyperlipidaemic drug use, antihypertensive drug use and hospitalization. The urine albumin-creatinine ratio, estimated glomerular filtration rate and congestive heart failure were the top three factors that contributed most to the incident CKD prediction. The model showed acceptable discrimination [C-statistic: 0.772 (95% CI 0.767-0.805)] and calibration [Brier Score: 0.0504 (95% CI 0.0477-0.0531)] in the Harmony Outcomes Trial. Incident CKD prediction among individuals with T2D was developed and validated for use in decision support of CKD prevention.


Basal cell carcinoma and lifestyle characteristics.
A number of lifestyle factors are important in the etiology of basal cell carcinoma. Previous studies have investigated smoking, alcohol, diet, and sun exposure as possible contributing factors. No previous studies have investigated case-controlled lifestyle influences in basal cell carcinomas referred for Mohs micrographic surgery. Cases were obtained from Mohs-referred basal cell carcinoma patients. Matched controls were selected from a busy dermatology clinic. The only criteria for selection of controls was never having had cancer previously. Cases and controls were surveyed regarding lifestyle characteristics. Forty-six age, sex, and skintype-matched controls were compared. Sun exposure, alcohol, and smoking were not significant factors. Dietary fat, fiber, and the vitamins A, C, and beta carotene, as well as selenium showed important, but not significant differences. Caffeine consumption was higher in the cancer group. Our findings agree with previously published studies in regard to antioxidant consumption as a protective factor for basal cell carcinoma. Caffeine consumption was higher in the cancer patients.


Increasing ERK phosphorylation by inhibition of p38 activity protects against cadmium-induced apoptotic cell death through ERK/Drp1/p38 signaling axis in spermatocyte-derived GC-2spd cells.
Many studies report that cadmium chloride (CdCl2)-induces oxidative stress is associated with male reproductive damage in the testes. CdCl2 also induces mitochondrial fission by increasing dynamin-related protein 1 (Drp1) expression as well as the mitochondria-dependent apoptosis pathway by extracellular signal-regulated kinase (ERK) activation. However, it remains unclear whether mechanisms linked to the mitochondrial damage signal via CdCl2-induced mitogen-activated protein kinases (MAPK) cause damage to spermatocytes. In this study, increased intracellular and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) depolarization, and mitochondrial fragmentation and swelling were observed at 5 μM of CdCl2 exposure, resulting in increased apoptotic cell death. Moreover, CdCl2-induced cell death is closely associated with the ERK/Drp1/p38 signaling axis. Interestingly, SB203580, a p38 inhibitor, effectively prevented CdCl2-induced apoptotic cell death by reducing ∆Ψm depolarization and intracellular and mitochondrial ROS levels. Knockdown of Drp1 expression diminished CdCl2-induced mitochondrial deformation and ROS generation and protected GC-2spd cells from apoptotic cell death. In addition, electron microscopy showed that p38 inhibition reduced CdCl2-induced mitochondrial interior damage more effectively than N-acetyl-L-cysteine (NAC), an ROS scavenger; ERK inhibition; or Drp1 knockdown. Therefore, these results demonstrate that inhibition of p38 activity prevents CdCl2-induced apoptotic GC-2spd cell death by reducing depolarization of mitochondrial membrane potential and mitochondrial ROS levels via ERK phosphorylation in a signal pathway different from the CdCl2-induced ERK/Drp1/p38 axis and suggest a therapeutic strategy for CdCl2-induced male infertility.


Polymorphisms of the DNA methyltransferase 1 associated with reduced risks of Helicobacter pylori infection and increased risks of gastric atrophy.
DNA methyltransferase-1(DNMT1) is an important enzyme in determining genomic methylation patterns in mammalian cells. We investigated the associations between SNPs in the DNMT1 gene and risks of developing H. pylori seropositivity, gastric atrophy and gastric cancer in the Chinese population. The study consisted of 447 patients with gastric cancer; 111 patients with gastric atrophy; and 961 healthy controls. Five SNPs, rs10420321, rs16999593, rs8101866, rs8111085 and rs2288349 of the DNMT1 gene were genotyped. Anti-H.pylori IgG was detected by ELISA. Gastric atrophy was screened by the level of serum pepsinogen Ι and II and then confirmed by endoscopy and histopatholgical examinations. The age- and sex-adjusted OR of H. pylori seropositivity was 0.67 (95%CI: 0.51-0.87) for rs8111085 TC/CC genotypes, significantly lower than the TT genotype in healthy controls. The adjusted OR of H.pylori seropositivity was 0.68 (95%CI: 0.52-0.89) for rs10420321 AG/GG genotypes. In addition, patients carrying rs2228349 AA genotype have a significantly increased risk for H.pylori seropositivity (OR=1.67; 95%CI: 1.02-2.75). Further haplotype analyses also showed that the ATTTG and ATCTA are significantly associated with increased risks in H.pylori infection compared to the GTCCG haplotype (OR=1.38, 95%CI: 1.08-1.77; OR=1.40, 95% CI: 1.09-1.80). The adjusted ORs of gastric atrophy were 1.66 (95%CI: 1.06-2.61) for rs10420321 GG genotype, and 1.67 (95%CI 1.06-2.63, P=0.03) for rs8111085 CC genotype, but no association was found between SNPs in the DNMT1 gene and risk of developing gastric cancer. Individuals with rs10420321 GG and rs8111085 CC genotype of the DNMT1 gene were associated with reduced risks for H.pylori infection. On the other hand, higher risks of gastric atrophy were found in the carriers with these two genotypes compared to other genotypes. Our results suggested that SNPs of DNMT1 could be used as genotypic markers for predicting genetic susceptibilities to H.pylori infection and risks in gastric atrophy.


Identification of component-based approach for prediction of joint chemical mixture toxicity risk assessment with respect to human health: A critical review.
Toxicity risk assessment of chemical mixture possesses huge challenges due to limited evidence on toxicity of compounds, the infinite number of chemical combinations makes the problem even more difficult. Normally, prediction of joint mixture toxicity depends on toxicological data of constituent compounds, although lack of information on dose-response of chemical mixture raises serious concerns on human health. Component-based approaches mainly use dose-addition or response-addition method to assess mixture toxicity risk exposure. Several models based on theoretical concepts of concentration/dose addition and independent/response action were also developed but these models do not address chemical interactions in mixture, and were mostly used to assess ecological risk exposure with limited or no information on human health risk assessment. This paper reviews available models to predict joint toxicity of chemical mixtures, and most applicable one to address human health risk exposure was identified. United States Environmental Protection Agency (US EPA) weight-of-evidence hazard index (HI) based approach seems to be most appropriate to predict joint toxicity of chemical mixtures, and applicability of model is explained using emerging contaminants as an example. The review also identified challenges in implementing the interaction-based EPA approach and highlighted the need for necessary future research actions.


[Healthy and pathologically changed laryngeal epithelium in a model. 1].
This model attempts to consummate the biological processes of laryngeal epithel on a biophysical basis with the end of prediction optimally therapeutic methods.


Elbow arthroscopy.
Decreased surgical morbidity and rapid recovery time associated with arthroscopic surgery of the elbow justify its preference over more extensive open incisions in selected cases. Not all elbow conditions can be treated arthroscopically, however, and open incisions are still preferred in more extensive problems such as displaced fractures and olecranon impingement syndromes.


Fluoroquinolone (Lomefloxacin) International Surveillance Trial: a report of 30 months of monitoring in vitro activity.
The antimicrobial activity and spectrum of lomefloxacin were assessed by standardized disk diffusion methods in 36 countries. More than 500,000 facultative organisms were tested during the first 30 months of a 3-year monitoring interval. Lomefloxacin demonstrated inhibition (zones greater than or equal to 19 mm) of greater than 90% of Enterobacteriaceae, greater than 99% of Moraxella (Branhamella) catarrhalis, greater than 98% of Haemophilus spp., and 91% of Staphylococcus aureus strains. Pseudomonas spp., especially Pseudomonas aeruginosa (18% resistance), were considered moderately susceptible, as were most strains of streptococci and enterococci. Some variation of national/regional fluoroquinolone resistance rates was observed, using lomefloxacin as an index or indicator drug, with the highest numbers of resistant strains being isolated in France. However, these data demonstrated a wide spectrum of lomefloxacin activity in all nations monitored.


Utilization path of bulk industrial solid waste: A review on the multi-directional resource utilization path of phosphogypsum.
Phosphogypsum is one of the hottest issues in the field of environmental solid waste treatment, with complex and changeable composition. Meanwhile, phosphogypsum contains a large number of impurities, thus leading to the low resource utilization rate, and it can only be stockpiled in large quantities. Phosphogypsum occupies a lot of land and poses a serious pollution threat to the ecological environment. This paper mainly summarizes the existing pretreatment and resource utilization technology of phosphogypsum. The pretreatment mainly includes dry method and wet method. The resource utilization technology mainly includes building materials, chemical raw materials, agriculture, environmental functional materials, filling materials, carbon sequestration and rare and precious extraction. Although there are many aspects of resource utilization of phosphogypsum, the existing technology is far from being able to consume a large amount of accumulated and generated phosphogypsum. Through the analysis, the comparison and mechanism analysis of the existing multifaceted and multi-level resource treatment technologies of phosphogypsum, the four promising resource utilization directions of phosphogypsum are put forward, mainly including prefabricated building materials, eco-friendly materials and soil materials, and new green functional materials and chemical fillers. Moreover, this paper summarizes the research basis of multi field and all-round treatment and disposal of phosphogypsum, which reduces repeated researches and development, as well as the treatment cost of phosphogypsum. This paper could provide a feasible research direction for the resource treatment technology of phosphogypsum in the future, so as to improve the consumption of phosphogypsum and reduce environmental risks.


The many faces of scleroderma.
Scleroderma autoantibodies are associated with very specific demographic, clinical, organ system, and survival features. The use of scleroderma autoantibodies may be very helpful in determining the prognosis, as well as monitoring and treatment of scleroderma patients. There are many faces of scleroderma that seem to be closely associated with scleroderma autoantibodies. These antibodies should be used in performing clinical trials and in doing genetic and basic research. Hopefully, these scleroderma antibodies will lead to a better understanding of the pathogenesis of scleroderma.


Health care reform and change in public-private mix of financing: a Korean case.
The objective of this paper is to examine the changes in the Korean health care system invoked by the reform (in the latter part of 2000) in regard to the separation of drug prescription and dispensation, especially from the point of view of the public-private financing mix. It seeks particularly to estimate and analyse the relative financing mix in terms of both modes of production and types of medical provider. The data used to estimate health care expenditure financed by out-of-pocket expenditure by were sourced from the National Health and Nutritional Survey (conducted by interviewing representatives of households) and the General Household Survey (a household diary survey). National Health Insurance data, etc. were used to estimate health expenditure financed by public sources. This study concentrates on the short-run empirical links between the reform and the public-private mix in finance. The reform increased remarkably the public share in total health expenditure. This public share increase has been prominent particularly in the case of expenditure on drugs since the reform has absorbed much of the previously uncovered drugs into the National Health Insurance coverage. However, a higher public share in medical goods than in out-patient care would raise an issue in terms of prioritization of benefit packages. The five-fold increase in the public share of expenditure at pharmacies reflects not only the fact that drugs previously not covered by NHI are covered now but also the fact that prescribed drugs are currently purchased mainly at pharmacies, as opposed to in doctors' clinics, as a result of the reform.


A possible screening test for inherited p53-related defects based on the apoptotic response of peripheral blood lymphocytes to DNA damage.
The cellular response, in terms of cell cycle arrest(s) and apoptosis, to radiation-induced DNA damage was studied. Experiments were performed on both mitogen-stimulated and resting peripheral blood lymphocytes (PBLs) from normal and cancer-prone (C-P) individuals. The C-P individuals comprised three patients carrying germline p53 mutations and three members of two families apparently without such mutations, but with an inherited defect which results in p53 deregulation as shown by high levels of stabilised p53 protein in normal tissues. Interestingly, mitogen-stimulated PBL, from both normal and C-P individuals failed to demonstrate a G1 arrest after gamma radiation. However, a clear difference was seen in the apoptotic response to DNA damage, of PBL from normal and C-P individuals; PBLs from C-P individuals with inherited p53-related defects had a reduced apoptotic response (P = 0.0003). There was a wide margin of separation, with no overlap between the two groups, supporting the possibility of using this altered apoptotic response as a screening test. This simple and rapid procedure could be used to identify those individuals in a C-P family who carry germline p53-related defects. The method appears to detect both individuals with p53 mutations and those apparently without mutations but with other p53-related defects.


A randomized controlled trial on preweaning morbidity, growth and mortality in Holstein heifers fed a lacteal-derived colostrum replacer or pooled maternal colostrum.
The objective of this randomized controlled trial was to determine the effect of feeding a commercial lacteal-derived colostrum replacer (CR) or pooled maternal colostrum (MC) on preweaning morbidity, growth and mortality in Holstein heifer calves. A total of 568 calves were randomly assigned to be fed either 3.8 L of pooled MC or two doses (200 g IgG) of a CR. Calves were monitored daily for preweaning morbidity until weaning at 60 d old. Birth and weaning weights were measured to estimate growth rates. Calves fed CR were significantly less likely to be affected with a diarrhea event (OR = 0.58; 95% CI, 0.38 to 0.88; P value = 0.011) and had a higher rate of daily weight gain (0.051 kg/day; 95% CI, 0.03 to 0.08; P value <0.001) compared to calves fed pooled MC. Use of lacteal-derived colostrum replacer was not significantly associated with respiratory disease (OR = 1.01; 95% CI 0.67 to 1.51; P value = 0.974 ), omphalitis (OR = 0.93; 95% CI 0.06 to 14.86; P value = 0.956), or mortality (HR = 0.71; 95% CI 0.27 to 1.92; P value = 0.505) in the study calves. The lacteal-derived CR fed at the study dose was a viable colostrum alternative in the event of poor quality pooled MC for the prevention of preweaning diarrhea and resulted in higher growth rates in comparison to calves fed pooled MC in the study herd.


CDKF;1 and CDKD protein kinases regulate phosphorylation of serine residues in the C-terminal domain of Arabidopsis RNA polymerase II.
Phosphorylation of conserved Y₁S₂P₃T₄S₅P₆S₇ repeats in the C-terminal domain of largest subunit of RNA polymerase II (RNAPII CTD) plays a central role in the regulation of transcription and cotranscriptional RNA processing. Here, we show that Ser phosphorylation of Arabidopsis thaliana RNAPII CTD is governed by CYCLIN-DEPENDENT KINASE F;1 (CDKF;1), a unique plant-specific CTD S₇-kinase. CDKF;1 is required for in vivo activation of functionally redundant CYCLIN-DEPENDENT KINASE Ds (CDKDs), which are major CTD S₅-kinases that also phosphorylate in vitro the S₂ and S₇ CTD residues. Inactivation of CDKF;1 causes extreme dwarfism and sterility. Inhibition of CTD S₇-phosphorylation in germinating cdkf;1 seedlings is accompanied by 3'-polyadenylation defects of pre-microRNAs and transcripts encoding key regulators of small RNA biogenesis pathways. The cdkf;1 mutation also decreases the levels of both precursor and mature small RNAs without causing global downregulation of the protein-coding transcriptome and enhances the removal of introns that carry pre-microRNA stem-loops. A triple cdkd knockout mutant is not viable, but a combination of null and weak cdkd;3 alleles in a triple cdkd123* mutant permits semidwarf growth. Germinating cdkd123* seedlings show reduced CTD S₅-phosphorylation, accumulation of uncapped precursor microRNAs, and a parallel decrease in mature microRNA. During later development of cdkd123* seedlings, however, S₇-phosphorylation and unprocessed small RNA levels decline similarly as in the cdkf;1 mutant. Taken together, cotranscriptional processing and stability of a set of small RNAs and transcripts involved in their biogenesis are sensitive to changes in the phosphorylation of RNAPII CTD by CDKF;1 and CDKDs.


Perception of teaching competencies by medical educators.
The purpose of this study was to determine the effect of an introductory educational planning workshop on perception of teaching competencies by medical educators. A questionnaire containing twenty-seven teaching competencies (TC) was administered before and after the workshop. The twenty-five participants, from four different countries, were asked to rate each TC regarding its importance for teachers and whether they possessed them or needed further training. The results showed that this workshop created more awareness regarding the importance of these TCs and also created a need for further training for specific TCs in order to put educational principles into practice.


Microbiological quality indicators in waters of dairy farms: detection of pathogens by PCR in real time.
When contaminated water is used to wash the udders of dairy cattle and milking utensils, raw milk may become contaminated with pathogens. Washing with high quality water is essential to reduce the microbial contamination of milk. Furthermore, the wastewater generated in dairy herds also contains high populations of pathogens, antibiotics and nutrients that more often are thrown into the water bodies without any treatment. In this work, both supply water and wastewater from 20 dairy farms from Antioquia, Colombia was monitored for 10months to determine the presence of pathogenic microorganisms. Both Cryptosporidium and Fasciola were determined by the Polymerase Chain Reaction (PCR) technique in real time. The results showed that the supply water used for drinking and activities involving the herd, has high populations of Fasciola hepatica and Cryptosporidium parvum, with percentages of about 53.7% and 64.75% respectively. Additionally high populations of Pseudomonas aeruginosa, Shigella, Salmonella, total coliforms and Escherichia coli were found in both types of water, with values around 9.4×10(7), 2.1×10(7), 1.8×10(7), 1.9×10(10) and 1.5×10(10) UFC/100 ml respectively for the wastewater and 3.1×10(4), 1.9×10(4), 7.3×10(3), 1.2×10(5) and 6.2×10(3) UFC/100 ml for the supply water.


A European survey of bowel preparation in colorectal surgery.
Meta-analysis has shown that mechanical bowel preparation (MBP) does not improve outcomes in colonic surgery; however, there is uncertainty regarding MBP use in laparoscopic and rectal surgery and the addition of oral antibiotic regimens. The aim of this study was to assess current use of bowel preparation among European surgeons. An online survey was circulated to members of the European Society of Coloproctology. Chi-squared analysis was used to compare subgroups. A total of 426 surgeons responded to the survey. MBP is routinely prescribed by 29.6% of respondents prior to colonic surgery and in 77.0% prior to rectal surgery. In the cohort performing > 30% of colorectal operations laparoscopically (n = 294), routine use of MBP in colonic surgery was significantly lower (19.7% vs 51.5%, P < 0.01). Less than 10% prescribe oral antibiotic bowel preparation whereas 96% prescribe perioperative intravenous antibiotics. Among the majority of respondents to this survey, MBP is used routinely for rectal operations. For colonic surgery, laparoscopic surgeons have a significantly lower use of MBP. Use of oral antibiotic bowel preparation remains uncommon.


Problems of persons with HIV/AIDS hospitalized for Pneumocystis carinii pneumonia.
The authors of this prospective study describe the problems of persons living with HIV/AIDS hospitalized for Pneumocystis carinii pneumonia (PCP) (N = 90) and examine how the problems change over time. Data were obtained from four sources and were classified into major problem categories. The largest mean number of problems were reported in the category of PCP. Specific psychosocial problems were more likely to be reported in the patient and nurse interviews than in the chart and intershift report. The study findings validate the physical symptoms addressed in the published care plans and guidelines for caring for patients with PCP. The study identified the limitation of using the patient record as the only data source in determining nursing care needs and emphasized the importance of the patients perspective.


Precise determination of the Alternaria mycotoxins alternariol and alternariol monomethyl ether in cereal, fruit and vegetable products using stable isotope dilution assays.
Cereal, fruit and vegetable products were analyzed for contamination with the Alternaria mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) using stable isotope dilution assays (SIDAs). Both toxins were practically not detected in cereals and cereal products: AOH-one out of 13 samples at a content of 4.1 μg/kg; AME-two out of 13 samples at contents ranging between 0.2 and 0.6 μg/kg. However, if cereals for animal nutrition were analyzed, much higher values were found: AOH-five out of six samples (13-250 μg/kg); AME-six out of six samples (3-100 μg/kg). This finding may pose a potential problem concerning animal health. AOH and AME were frequently detected in vegetable products: AOH-5 out of 10 samples (2.6-25 μg/kg); AME-6 out of 10 samples (0.1-5 μg/kg). Tomato products were affected, especially. The highest content of AOH (25 μg/kg) and AME (5 μg/kg) were found in triple concentrated tomato paste. Special wines like "Trockenbeerenauslese" or "Spätlese" (affected by noble rot in the vineyard) contained AOH (4/6 samples; 1.2-4.9 μg/kg) and AME (4/6 samples; 0.1-0.3 μg/kg), but the values did not exceed the values of both toxins that were found generally in wines.


The accreditation process of an Australian health fund's dental centre.
Accreditation by a recognised national quality control organisation is the ultimate accolade for any service provider. This paper describes the processes and procedures that were undertaken by an Australian Health Fund's dental centres for accreditation by the Australian Council on Healthcare Standards.


Anti-asthmatic property and possible mode of activity of an ethanol leaf extract of Polyscias fruticosa.
Polyscias fruticosa (L.) Harms (Araliaceae) is used as a traditional remedy for asthma in Ghana. The objective of this study is to establish the anti-asthmatic property and a possible mode of activity of an ethanol leaf extract of P. fruticosa (PFE). The time (min) for pre-convulsive dyspnea, and time for recovery, after sensitization with 150 μg OVA and induction of bronchospasm with 1% acetylcholine or histamine in normal, and 100, 250, and 500 mg/kg PFE-treated Dunkin Hartley guinea pigs, were recorded. Atropine (0.1 mg), mepyramine (0.1 mg), and PFE (1 mg) effect on a contractile response of 2.0 × 10(-2) μg/ml acetylcholine and 5.8 × 10(-2) μg/ml histamine on the isolated guinea pig ileum was investigated. Cytological and histological studies were conducted using guinea pig peritoneal mast cells and mesenteric cells, respectively, to establish PFE effect on compound 48/80-induced mast cell degranulation. PFE (100-500 mg/kg) prolonged the onset of pre-convulsive dyspnea by 76.1-180.2% (p ≤ 0.01-0.001), and decreased recovery time by 71.9-78.5% (p ≤ 0.01-0.001). It also enhanced percentage protection against histamine-induced bronchospasm by 15.8-80.1-fold (p ≤ 0.05-0.01), and decreased percentage recovery time 2.5-3.3-fold (p ≤ 0.05-0.01). PFE significantly inhibited (60.4 ± 8.3%) contractile responses of histamine and produced significant inhibition (56-79%: p ≤ 0.001) of mast cell degranulation. PFE has anti-asthmatic, antihistaminic, and mast cell stabilization effect making it useful in traditional asthma management.


Hydrogen Peroxide Stress Induced in the Marine Cyanobacterium Synechococcus aeruginosus and Phormidium valdarianum.
Biochemical markers against hydrogen peroxide-induced oxidative stress were developed in marine cyanobacteria under standard laboratory conditions. To find out the ability to cope with different concentrations of hydrogen peroxide, two species of marine cyanobacteria including unicellular and filamentous forms were exposed for shorter duration. Synechococcus aeruginosus and Phormidium valderianum tolerated hydrogen peroxide by showing the highest growth of Superoxide dismutase in Synechococcus aeruginosus and Phormidium valderianum, catalase in Synechococcus aeruginosus, peroxidase in Synechococcus aeruginosus and Phormidium valderianum, Glutathione S-transferase in Synechococcus aeruginosus and Phormidium valderianum which were identified as biochemical markers of oxidative stress against H2O2 in marine cyanobacteria. Synechococcus aeruginosus showed new isoforms for Superoxide dismutase, catalase, peroxidase, Glutathione peroxidase, and Glutathione S-transferase and Phormidium valderianum for Superoxide dismutase, peroxidase, and Glutathione S-transferase. Synechococcus aeruginosus is suggested as the indicator species for biochemical markers against hydrogen peroxide in marine cyanobacteria. Peroxidase is suggested as biochemical enzyme marker. The present investigated on these new isoenzymes were identified as biochemical markers for oxidative stress.


Acute acalculous cholecystitis (AAC) in the pediatric population associated with Epstein-Barr Virus (EBV) infection. Case report and review of the literature.
Epstein Barr Virus (EBV) is a ubiquitous herpes virus that persists lifelong in normal humans by colonizing memory B cells. Infection during childhood is usually asymptomatic. Isolated gallbladder wall thickening or hydrops have been reported in patients with EBV infectious mononucleosis. However, acute acalculous cholecystitis is an atypical clinical presentation of primary EBV infection. We present a teenager with acute cholecystitis associated with EBV acute infection. Acute acalculous cholecystitis accounts for 2-15% of all cases of acute cholecystitis. Few cases of acute cholecystitis have been reported during the course of primary EBV infection. A 15-year-old female who came to the JDCH ER complaining of 3 days history of mild diffuse abdominal pain associated with two episodes of emesis. She also reports headache as well as a mild cough and low grade subjective fever. Blood test results showed mild leukocytosis with significant elevation in the lymphocytes (59%), High alkaline phosphatase (221 U/I), AST (191 U/I), ALT(221 U/I) and bilirubin (Total 1.8 and direct 1.5). Abdominal US showed a contracted gallbladder with wall thickness and pericholecystic fluid. During hospital stay number 2-3 laboratory work up show a trending up in the bilirubin levels. MRCP was ordered and no abdnormalities were found. At this point Hospital stay number 3 EBV acute infection was suspected. Serum serological studies were subsequently diagnostic for this viral disease. Management was conservative and the patient was discharged asymptomatic on hospital day number six.


[Mechanism of the inhibitory effect of BCG vaccine on specific antitumor immunity in Syrian hamsters].
The duration of inhibiting influence of BCG vaccine on specific antitumour immunity and possibility of SV40-induced resistance restoration in Syrian hamsters after the vaccination was studied. Antitumor immunity in animals immunized with SV40 virus and then inoculated with BCG was demonstrated to be abrogated one year after the vaccination. Reinoculation of the subjected to combined immunization animals with SV40 virus induced specific antitumour resistance in them again. The data presented may be interpreted as an argument favouring the cell-mediated nature of the phenomenon described.


Dysphania ambrosioides (L.) Mosyakin and Clemants: bridging traditional knowledge, photochemistry, preclinical investigations, and toxicological validation for health benefits.
Dysphania ambrosioides L. (Chenopodiaceae) is a Moroccan medicinal plant known locally as "M'Khinza." It is widely used in traditional medicine to treat numerous ailments, such as diabetes, digestive disorders, fever, fertility problems, immune disorders, hypertension, bronchitis, respiratory conditions, pharyngitis, cough, and flu. As part of this review, comprehensive preclinical investigations, including in vitro, in vivo, and in silico studies, were conducted to better understand the mechanisms of action of D. ambrosioides. Additionally, the phytochemical profile of the plant was examined, highlighting the presence of certain bioactive secondary metabolites. The information was gathered from electronic data sources such as Web of Science, PubMed, Science Direct, Scopus, Springer Link, and Google Scholars. Numerous studies have mentioned the pharmacological properties of D. ambrosioides, including its antioxidant, anti-inflammatory, antiparasitic, antiviral, antibacterial, and antifungal activities. Furthermore, research has also suggested its potential as an anticancer, antidiabetic, and vasorelaxant agent. Phytochemical characterization of D. ambrosioides has revealed the presence of over 96 major bioactive compounds, including terpenoids, polyphenols, flavonoids, alkaloids, and fatty acids. As for the toxicity of this plant, it is dose-dependent. Furthermore, more in-depth pharmacological studies are needed to establish the mechanisms of action of this plant more accurately before considering clinical trials. In conclusion, this review highlights the traditional use of D. ambrosioides in Moroccan medicine and emphasizes its potential pharmacological properties. However, to fully harness its therapeutic potential, further research, both in terms of chemistry and pharmacology, is necessary. These future studies could help identify new active compounds and provide a better understanding of the mechanisms of action of this plant, thus opening new prospects for its pharmaceutical application.


Initial Experience With Extraperitoneal Laparoscopic Radical Cystectomy With Pelvic Organ-Preserving and Orthotopic Neobladder Techniques for Bladder Cancer in Female Patients.
To present the extraperitoneal laparoscopic radical cystectomy (ELRC) technique, and initial outcomes of organ-preserving and orthotopic neobladder (ONB) techniques for bladder cancer in selected females. Data including patient characteristics, operative time, blood loss, transfusion rate, length of hospital stay, and pathologic outcomes, as well as 30- and 90-day complications were collected between April 2018 and May 2021 from females who underwent ONB after ELRC. Regular follow-up focused on patients' oncological and functional outcomes, and postoperative sexual function status was assessed using the Female Sexual Function Index (FSFI). Eleven females with a mean age of 53 years who underwent ELRC with pelvic organ-preservation and ONB were analyzed retrospectively. All procedures were completed successfully. The mean operative time was 264.82 ± 33.81 min, and the average intraoperative blood loss was 128 ± 18.19 mL. All patients had negative pathological margins and no lymph node metastases. The average hospital stay was 10.72 days. The single J ureteral stent and catheter were usually removed 3-4 weeks after the procedure. The FIFS assessment of postoperative sexual function showed that the patients were relatively satisfied. ELRC with pelvic organ preservation and ONB technology was a safe and feasible surgical strategy for the selected female patients. Preserving organs and vascular nerve bundles seemed to be safe in oncological and produced encouraging functional results. Further rigorous prospective studies with more patients and long-term follow-up data are needed to assess the oncologic and functional results.


Cyclooxygenases in cancer: chemoprevention and sensitization to conventional therapies.
We have focused on cyclooxygenase, the key enzyme in prostaglandin synthesis, from our basic knowledge regarding the enzyme, to its clinical application in the field of oncology. We will present evidence that this enzyme is intimately associated with carcinogenesis, invasion, metastasis, and the response of tumors to current therapeutic modalities in a variety of human malignancies. We will also discuss the applications of cyclooxygenase inhibitors to chemoprevention and to the sensitization of tumors to conventional anti-cancer therapies.


Value Proposition of Untapped Wet Wastes: Carboxylic Acid Production through Anaerobic Digestion.
Although traditional anaerobic digestion (AD) process to produce methane-rich biogas from wet waste is deep-rooted, high carbon footprint and its low value as compared with other renewable sources demand advanced strategies to avoid its production. An emerging conversion pathway to arrest methanogenesis for producing value-added fuels and chemicals instead of biogas is sought as a sustainable alternative. This research provides a comprehensive analysis on current technology development, process challenges, applications, and economics for producing high-value short-chain carboxylic acids from AD of wet wastes. We show that (1) the theoretical energy yields of acids equal or exceed biogas, and (2) the cost of these acids is competitive with those produced from chemical markets, making this economically viable for mass production. With global abundance of wet waste feedstocks, this process of short-chain acid production provides a promising alternative to conventional biogas production technology, while achieving waste management and carbon mitigation goals.


An electron microscope study of quantitative relationships between axon and Schwann cell sheath in myelinated fibres of peripheral nerves.
The quantitative relationships between the cross-sectional area of the Schwann cell sheath (myelin included) and that of its related axon were studied by electron microscopy in the nerve fibres of the spinal roots of lizard (Lacerta muralis). In both ventral and dorsal roots the cross-sectional area of the Schwann cell sheath (myelin included) was found to be directly proportional to that of its related axon (correlation coefficients between 0.88 and 0.92). The ratio between the cross-sectional area of the Schwann cell sheath (myelin included) and that of its related axon tends to diminish as the cross-sectional area of the latter increases. Thus, under normal conditions, in myelinated fibres of the spinal roots of the lizard a quantitative balance exists between the nerve tissue and its associated glial tissue. This result agrees with those previously obtained in the spinal ganglia of the lizard, gecko, cat and rabbit. Some of the mechanisms probably involved in the control of the quantitative balance between nerve tissue and its associated glial tissue in peripheral nerves are presented and discussed.


Incorporation of bleeding as an element of the composite end point in clinical trials of antithrombotic therapies in patients with non-ST-segment elevation acute coronary syndrome: validity, pitfalls, and future approaches.
With the large number of antithrombotic therapies available and under investigation for the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS), practice guidelines now stress the importance of selecting an antithrombotic strategy according to the efficacy and safety profiles of the chosen agent. Contemporary trials have incorporated bleeding along with ischemic end points into a composite end point commonly referred to as net clinical benefit, which allows for simultaneous evaluation of the differences between benefit and harm for an investigational antithrombotic therapy. However, incorporating major bleeding into a composite end point that includes ischemic events is not warranted and is associated with many pitfalls. In this article, we discuss the validity of combining efficacy and safety end points to form a net clinical benefit composite end point with the traditional time-to-event analysis for trials evaluating antithrombotic therapies for NSTE ACS. We describe alternative statistical approaches for concurrent assessment of the safety and efficacy of antithrombotic therapies used to treat patients with NSTE ACS.


The initial presentation of depression in family practice and psychiatric outpatients.
Most reports characterizing the initial presentation of depression are based on patients seen in psychiatric settings. It is not clear whether the difficulty in identifying depression in medical clinic outpatients is due to physician unfamiliarity with the diagnostic criteria or because the psychiatric syndrome is not the same in early, mild cases that present with somatic symptoms. In this study, depressed patients choosing the medical clinic for care presented the same somatic symptoms as nondepressed medical patients. In comparison to depressed patients who presented to the psychiatric clinic, depressed medical patients' chief complaints were more somatic, obscure, and less psychologically focused. Depressed psychiatric patients had more symptoms on a medical review of systems checklist than did medical patients with an equivalent level of depression. When DSM-III criteria were applied, depressed patients from each clinic tended to fulfill the major and minor criteria in a similar pattern. However, the prevalence of depression in the medical setting was much lower and milder than was that presenting to the psychiatry clinic. Once present at a diagnosable stage, however, the syndrome appeared to be the same in both patient groups.


Cooperativity between platelet-activating factor and collagen in aggregation of bovine platelets III.
In cooperative aggregation of bovine platelets induced by simultaneous addition of PAF and collagen at subthreshold concentrations the following observations were made. (i) Formation of phosphatidic acid and arachidonic acid metabolites, which characterize PAF and collagen alone-induced aggregation, respectively, was observed very obviously. (ii) A thromboxane antagonist did not completely block the cooperative aggregation. The extent of residual aggregation activity was dependent on concentration of collagen used in the simultaneous administration with PAF. These results suggest that both signal transduction pathways activated by PAF and collagen alone at high concentrations are attained by simultaneous addition of both agonists at subthreshold concentrations through unknown mechanisms.


[Axonal neuropathy and chronic Codobromyl poisoning].
We report a 56 year-old woman with a severe axonal neuropathy due to a chronic intoxication by a cough soothing (Codobromyl). Symptoms of codeine and alcohol intoxication were present. The problems of self medication are considered.


Easy axis anisotropy creating high contrast magnetic zones on magnetic tunnel junctions based molecular spintronics devices (MTJMSD).
Magnetic tunnel junction-based molecular spintronics device (MTJMSD) may enable novel magnetic metamaterials by chemically bonding magnetic molecules and ferromagnets (FM) with a vast range of magnetic anisotropy. MTJMSD have experimentally shown intriguing microscopic phenomenon such as the development of highly contrasting magnetic phases on a ferromagnetic electrode at room temperature. This paper focuses on Monte Carlo Simulations (MCS) on MTJMSD to understand the potential mechanism and explore fundamental knowledge about the impact of magnetic anisotropy. The selection of MCS is based on our prior study showing the potential of MCS in explaining experimental results (Tyagi et al. in Nanotechnology 26:305602, 2015). In this paper, MCS is carried out on the 3D Heisenberg model of cross-junction-shaped MTJMSDs. Our research represents the experimentally studied cross-junction-shaped MTJMSD where paramagnetic molecules are covalently bonded between two FM electrodes along the exposed side edges of the magnetic tunnel junction (MTJ). We have studied atomistic MTJMSDs properties by simulating a wide range of easy-axis anisotropy for the case of experimentally observed predominant molecule-induced strong antiferromagnetic coupling. Our study focused on understanding the effect of anisotropy of the FM electrodes on the overall MTJMSDs at various temperatures. This study shows that the multiple domains of opposite spins start to appear on an FM electrode as the easy-axis anisotropy increases. Interestingly, MCS results resembled the experimentally observed highly contrasted magnetic zones on the ferromagnetic electrodes of MTJMSD. The magnetic phases with starkly different spins were observed around the molecular junction on the FM electrode with high anisotropy.


Metacarpophalangeal hyperextension in thumb basal joint osteoarthritis: Radiological study and implications for treatment.
We report a series of 95 consecutive patients operated on for total trapeziometacarpal joint replacement, screening for radiological characteristics to differentiating patients with and without preoperative MCP hyperextension. Loss of thumb column length and metacarpal head circularity on lateral view were quantified. Statistically, a combination of reduced length and circular metacarpal head was a determining factor for MCP hyperextension. We therefore believe it is essential to restore thumb column length in surgery for trapeziometacarpal osteoarthritis and to avoid trapeziectomy in patients with a circular head on lateral view. LEVEL OF EVIDENCE: III; prospective cohort study.


Characterization of 5-fluorouracil loaded liposomes prepared by reverse-phase evaporation or freezing-thawing extrusion methods: study of drug release.
Entrapment of the anti-tumoral drug 5-fluorouracil (5-FU) in unilamellar liposomes prepared by freeze-thawing extrusion technique (FATVET) and the reverse-phase evaporation method (REV) from natural (bovine brain) sphingomyelin (SM) and synthetic distearoylphosphatidylcholine (DSPC) phospholipids was studied. Reverse-phase evaporation vesicles obtained from DSPC sized through polycarbonate membranes of 0.2 micron pore size were found to entrap roughly double amounts of drug than did extruded liposomes (0.1 micron pore size); however, s-REV in these preparations were more heterogenous in vesicle size than FATVET. The rate of in vitro drug release from the liposomes was found to be dependent of the bilayer composition and the method used to prepare the vesicles. The permeability coefficient P obtained was approx. 10(-11) m/s. The results suggest that 5-FU release is kinetically controlled by an interfacial process seemingly dependent on the surface activity of the drug. Also, the physical state of the bilayer determines the retention capacity of the vesicles. Thus, liposomes consisting of distearoylphosphatidylcholine whose acyl chains were in a gel state at the working temperature (37 degrees C) retained 70% of encapsulated 5-FU after 1 h, whereas liposomes composed of natural bovine brain sphingomyelin retained only 15% over the same period.


Nonsecretory and Light Chain Escape in Patients With Multiple Myeloma.
Multiple myeloma (MM) is characterized by the secretion of monoclonal protein by malignant plasma cells in the vast majority of cases. We identified and analyzed patterns of disease relapse and progression associated with disappearance of the paraprotein ("nonsecretory [NS] escape"), or conversion from production of intact Ig molecule to its associated light chain ("LC escape"). We retrospectively reviewed medical records and a database of 791 consecutive patients with symptomatic MM. Twenty-eight (3.5%) patients had disease evolution associated with either NS (n = 13) or LC (n = 15) escape. The event occurred at a median of 37 months (range, 3-156 months) after the diagnosis of MM, and after a median of 3 chemotherapy regimens (range, 1-8 regimens). Presence of extramedullary disease at progression was detected in 8 (29%) patients. Sensitivity to chemotherapy before and after escape was present in 21 (75%) and 14 (50%) patients, respectively. After a median follow-up of 55 months, 19 (68%) patients died, and progressive MM was the cause of death in 18 patients. The median overall survival after escape was 20 months (95% confidence interval, 9-25 months), and no significant difference was found between the NS and LC groups (P = .44). The median overall survival after diagnosis of MM was worse in patients with NS/LC escape than in those without escape (52 vs. 94 months; P = .018). Our study describes the largest series of NS and LC escape in MM to date. The development of this phenomenon is associated with more aggressive clinical features, frequent resistance to chemotherapy, and worse clinical outcome.


Robot-assisted radical cystectomy vs open radical cystectomy in patients with bladder cancer: a systematic review and meta-analysis of randomized controlled trials.
Even though there isn't enough clinical evidence to demonstrate that robot-assisted radical cystectomy (RARC) is preferable to open radical cystectomy (ORC), RARC has become a widely used alternative. We performed the present study of RARC vs ORC with a focus on oncologic, pathological, perioperative, and complication-related outcomes and health-related quality of life (QOL). We conducted a literature review up to August 2022. The search included PubMed, EMBASE and Cochrane controlled trials register databases. We classified the studies according to version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). The data was assessed by Review Manager 5.4.0. 8 RCTs comparing 1024 patients were analyzed in our study. RARC was related to lower estimated blood loss (weighted mean difference (WMD): -328.2; 95% CI -463.49--192.92; p < 0.00001), lower blood transfusion rates (OR: 0.45; 95% CI 0.32 - 0.65; p < 0.0001) but longer operation time (WMD: 84.21; 95% CI 46.20 -121.72; p < 0.0001). And we found no significant difference in terms of positive surgical margins (P = 0.97), lymph node yield (P = 0.30) and length of stay (P = 0.99). Moreover, no significant difference was found between the two groups in terms of survival outcomes, pathological outcomes, postoperative complication outcomes and health-related QOL. Based on the present evidence, we demonstrated that RARC and ORC have similar cancer control results. RARC is related to less blood loss and lower transfusion rate. We found no difference in postoperative complications and health-related QOL between robotic and open approaches. RARC procedures could be used as an alternate treatment for bladder cancer patients. Additional RCTs with long-term follow-up are needed to validate this observation.


Neural basis of social status hierarchy across species.
Social status hierarchy is a ubiquitous principle of social organization across the animal kingdom. Recent findings in social neuroscience reveal distinct neural networks associated with the recognition and experience of social hierarchy in humans, as well as modulation of these networks by personality and culture. Additionally, allelic variation in the serotonin transporter gene is associated with prevalence of social hierarchy across species and cultures, suggesting the importance of the study of genetic factors underlying social hierarchy. Future studies are needed to determine how genetic and environmental factors shape neural systems involved in the production and maintenance of social hierarchy across ontogeny and phylogeny.


Preclinical toxicity studies with two thymopoietin-like peptides.
Differentiation of T-lymphocytes is regulated by thymopoietin, a 49 amino acid polypeptide chain. The site of immunological activity is in the 32-36 (Arg-Lys-Asp-Val-Tyr) fragment. This pentapeptide can be reduced to a tetrapeptide (RGH-0206: Arg-Lys-Asp-Val) and further to a tripeptide (RGH-0205: Arg-Lys-Asp) which still retains immunological activity. To prepare Phase I and II clinical trials preclinical toxicity studies were duly performed. Mice, rats and dogs tolerated a single 1000 mg/kg dose i.v. without any symptom. In a 14-day i.v. test on Lati:Han:WISTAR rats daily doses of 10,25, 62.5, 150, 400 and 1000 mg/kg of either test compound were tolerated without symptom or damage. In a 28-day i.v. toxicity test on Wobe:BEAGLE dogs given daily doses of 6, 20 and 60 mg/kg of either test compound, no adverse reaction occurred. The low toxicity of both RGH-0205 and RGH-0206 are probably attributable to their short half-life, as half-life of the pentapeptide fraction is less than 30 sec in humans. It was concluded that the planned clinical dose of 1 mg/kg i.v. was safe for both peptides for short-term administration.


Radiotherapy for primary thyroid cancer as a risk factor for second primary cancers.
Although radiation is considered a risk factor for thyroid cancer, the potential relationship between radiation therapy and the risk of second primary cancer among patients with first primary thyroid cancer has not been evaluated. We identified 26,639 patients with first primary thyroid cancer in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2000. Information on radiation therapy as well as second primary cancers was recorded in SEER. The proportional hazards model was utilized to estimate adjusted risk ratios (RRs) and their 95% confidence intervals (CIs) to assess the potential association between radiation therapy for thyroid cancer and the risk of second primary cancers. With 270,674.33 person-years of follow-up, 1,896 (7.1%) of the 26,639 patients with first primary thyroid cancer developed second primary cancers. Among the second primaries, 35 occurred in the thyroid. No obvious association was observed between radiation therapy and the overall risk of second primary cancer after ten years of follow-up (RR=1.07, 95% CI=0.88-1.30). However, an increased risk was seen for several cancers, including upper digestive system cancers (RR=1.66, 95% CI=1.07-2.57) and myeloid malignancies (RR=3.26, 95% CI=1.39-7.67). Radiation therapy was associated with reduced second cancer risks for thyroid cancer (RR=0.18, 95% CI=0.04-0.76). Beam radiation might be important to the digestive system, radioactive implants might be associated with the male genital system, radioisotopes might have an effect on myeloid malignancies, and combined beam radiation with radioactive implants or radioisotopes might be related to the increased risk of respiratory system cancers. This study suggests that radiation therapy for patients with first primary thyroid cancer might be associated with an increased risk of developing a second primary cancer in the upper digestive system and second primary myeloid malignancies. Radiation therapy for adult patients with thyroid cancer might be associated with a reduced risk of second primary thyroid cancer.


Proposed three-dimensional model of the orbit and relevance to orbital fracture repair.
To describe the relationship of the orbital rim and depth in Far Eastern skulls by anatomical study, using morphometry to yield an octagonal three-dimensional model of the orbit. Forty-one orbits of 21 Far Eastern skulls from the Department of Anatomy of St George's, University of London were included in this study. A morphometric study was conducted, measuring between eight reproducible orbital rim landmarks to yield perimeters, and from these landmarks to the optic canal to yield orbital depth. Orbital height and width were also recorded. Results were statistically analysed to look for evidence of gender variation or laterality before comparison with those from other ethnicities. The authors then present a method for three-dimensional description of the orbit. 67 % of orbits were male. Orbital height and width were significantly greater in males (34.6 ± 2.0 and 39.4 ± 1.7, vs. 32.5 ± 2.3 and 37.2 ± 2.4 mm). Orbital perimeter tended towards being larger in males (126.3 vs. 122.2 mm, p = 0.05), as was the angle between medial and lateral walls (50.1° ± 2.0°, vs. 47.9° ± 3.0°). This study has proposed a new method for describing the orbit using three-dimensional measurements, yielding clinically useful morphometric data. These results and model have applications in surgical navigation of the orbit, repair of fractures, and prediction of post-traumatic or surgical enophthalmos.


Medication safety.
Patient safety is a state of mind, not a technology. The technologies used in the medical setting represent tools that must be properly designed, used well, and assessed on an on-going basis. Moreover, in all settings, building a culture of safety is pivotal for improving safety, and many nontechnologic approaches, such as medication reconciliation and teaching patients about their medications, are also essential. This article addresses the topic of medication safety and examines specific strategies being used to decrease the incidence of medication errors across various clinical settings.


Concentration of glycerol required for optimal survival and in vitro fertilizing capacity of frozen sperm is dependent on cryopreservation medium.
Sperm survival and in vitro fertilizing capacity were examined following cryopreservation with three concentrations of glycerol (0, 2, and 7.5%) and four cryopreservation media. Post-thaw motility and motility index increased with increasing concentrations of glycerol. Post-thaw velocity, linearity, percentage of zona-free hamster oocytes penetrated, and penetrations per oocyte were greater following freezing with 2 or 7.5% glycerol than with 0% glycerol. A significant interaction between media and glycerol was observed for motility, velocity, linearity, motility index, and percentage of oocytes penetrated. These results suggest that the concentration of glycerol required for optimal survival and in vitro fertilizing capacity of human sperm following cryopreservation is dependent on the type of medium used for freezing.


Production of soluble recombinant proteins with Kell, Duffy and Lutheran blood group antigen activity, and their use in screening human sera for Kell, Duffy and Lutheran antibodies.
The aim of this study was to show that soluble recombinant (sr) proteins can mimic blood group antigens and be used to screen human sera for blood-group-specific antibodies. The blood of all pregnant women and pretransfusion patients should be screened for blood-group-specific antibodies to identify and monitor pregnancies at risk of haemolytic disease of the foetus and newborn (HDFN), and to prevent haemolytic transfusion reactions. Current antibody screening and identification methods use human red blood cell panels, which can complicate antibody identification if more than one antibody specificity is present. COS-7 cells were transfected to produce sr forms of the extracellular domains of the red blood cell membrane proteins that express Kell, Duffy or Lutheran blood group antigens. These sr proteins were used to screen for and identify anti-Kell, anti-Duffy or anti-Lutheran blood-group-specific allo-antibodies in human sera by haemagglutination inhibition and in solid-phase enzyme-linked immunosorbent assays (ELISAs). There is a positive correlation (correlation coefficient 0.605, P value 0.002) between antibody titre by standard indirect antiglobulin test (IAT) and signal intensity in the ELISA test. This work shows that sr proteins can mimic blood group antigens and react with human allogeneic antibodies, and that such proteins could be used to develop solid-phase, high-throughput blood group antibody screening and identification platforms.


Distribution of 90Sr in coastal seawater, sediments and organisms off two atomic power stations in Korea.
We have measured 90Sr activities in the marine environment (seawater, sediments and organisms) off the two Korean atomic power stations at Gori and Weolseong. The marine sampling sites were chosen in the vicinity of the power stations to investigate the dispersion of any local 90Sr sources. The 90Sr activities in seawater ranged from 1.3 to 1.9 mBq/l (mean: 1.4, n = 16) and 0.9 to 1.5 mBq/l (mean: 1.3, n = 29) at the Gori and Weolseong sites, respectively. These activities are comparable with those reported for the remote open ocean, suggesting that the 90Sr at these sites originated primarily from global fallout, which occurred during the 1960s, rather than from any local sources. The 90Sr activities in marine sediments ranged from 116 to 1,277 mBq/kg (mean: 565, n = 12) and from 304 to 1,799 mBq/kg (mean 933, n = 6) at the Gori and Weolseong sites, respectively. The horizontal distribution of 90Sr in surface sediments appears to be affected by grain size as well as local sedimentation rate. The enrichment of 90Sr in fish (5.5 +/- 2.6 mBq/kg, n = 5) and shellfish (7.1 +/- 1.2 mBq/kg, n = 2) was much lower than that in seaweed (57 +/- 33 mBq/kg, n = 5).


Transcranial deep-tissue phototherapy for Alzheimer's disease using low-dose X-ray-activated long-afterglow scintillators.
Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Here, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillator (ScNPs@RB/Ab) for efficient deep-brain phototherapy. We demonstrate that the as-synthesized ScNPs@RB/Ab is capable of converting X-rays into visible light to activate the photosensitizers of rose bengal (RB) for Aβ oxygenation through the scalp and skull. We show that the ScNPs@RB/Ab persistently emitting visible luminescence can substantially minimize the risk of excessive X-ray exposure dosage. Importantly, peptide KLVFFAED-functionalized ScNPs@RB/Ab shows a blood-brain barrier permeability. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects. Our study paves a new pathway to develop high-efficiency transcranial AD phototherapy. STATEMENT OF SIGNIFICANCE: Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Herein, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillators (ScNPs@RB/Ab) for efficient deep-brain phototherapy. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects.