In vitro sequence-dependent interaction between nedaplatin and paclitaxel in human cancer cell lines.
To define the most effective combination schedule of paclitaxel and nedaplatin, a new platinum derivative, we investigated the in vitro interaction between these drugs in AZ-521 and NUGC-4 gastric adenocarcinoma and KSE-1 esophageal squamous carcinoma cell lines. Cytotoxic activity was determined by the WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism using a quantitative method based on the median-effect principle of Chou and Talalay. Cell-cycle perturbation and apoptosis were evaluated by means of flow cytometry. Upon 24-h sequential exposure, the sequence paclitaxel followed by nedaplatin induced greater than additive effects in all of the cell lines, with synergistic interactions in NUGC-4 and KSE-1 cells. By contrast, antagonistic effects were observed with the reverse sequence. Simultaneous treatment resulted in either a synergistic or antagonistic effect, depending on the cell line. Therefore, the sequence paclitaxel followed by nedaplatin appears most active, at least in these three cell lines. Flow cytometric analyses at IC50 indicated that paclitaxel induced G2/M arrest with subsequent induction of apoptosis (56%) in the sub-G1 phase. When paclitaxel preceded nedaplatin, apoptosis was most prominent (70%) with pronounced G2/M arrest. By contrast, the reverse sequence yielded only 28% induction of apoptotic cells, with almost identical cell-cycle distribution patterns to those observed with nedaplatin alone, indicating that the activity of paclitaxel is abolished by pretreatment with nedaplatin. Our findings suggest that the interaction of nedaplatin and paclitaxel is highly schedule dependent and that the sequential administration of paclitaxel followed by nedaplatin should be thus incorporated into the design of a clinical trial.


Hydration free energies of amino acids: why side chain analog data are not enough.
Using molecular dynamics based free energy simulations, we computed relative solvation free energies for pairs of N-acetyl-methylamide amino acids (Ala-Ser, Val-Thr, Phe-Tyr, Val-Ala, Thr-Ser, Phe-Ala, and Tyr-Ser) and compared the results with the relative solvation free energies of the corresponding pairs of side chain analogs. We observed differences in (relative) solvent affinity DeltaDeltaDeltaA between amino acids and side chain analogs of up to 66% or, in absolute numbers, 4.9 kcal/mol (Ala-Ser). To rationalize these findings, we estimated separately contributions from what we refer to as solvent exclusion and self-solvation. While the former accounts for the reduction in solute-solvent interactions as one part of the solute occludes other parts of the solute, the latter turned out to be the determining contribution for small polar amino acids and could be shown to arise from interactions between the polar backbone and the polar functional group of the respective side chain in the gas phase. Consequently, the solvent affinity of small polar amino acids depends strongly on the backbone conformation. Our results indicate that the still widely used group additivity-solvent exclusion assumption to estimate solvation free energies for large(r) molecules (such as peptides and proteins) from model compound data (such as side chain analogs) is insufficient. To illustrate practical consequences, we compare the explicit solvent results with those of implicit solvent models. While approaches based on the generalized Born model give results in (mostly) good agreement with explicit solvent, approaches relying (primarily) on the group additivity-solvent exclusion assumption fail to reproduce DeltaDeltaDeltaA. Finally, we briefly discuss the implications of our results for hydrophobicity scales.


Response of furniture factory workers to work-related airborne allergens.
The aim of this work was to determine the reactivity of furniture factory workers to microbial allergens associated with wood dust. Allergological examinations by skin and precipitin tests were performed in 48 workers employed in a factory producing furniture from fibreboards and chipboards, and in 32 healthy urban dwellers not exposed to organic dusts (referents). The skin test was performed by the intradermal method with the saline extracts of the cultures of 3 microbial species (Rahnella sp., Arthrobacter globiformis, Aspergillus fumigatus) associated with wood dust. Skin reactions were recorded after 20 minutes, 8 hours and 24 hours and graded 1-4, depending on the diameter of the reaction. The agar-gel test for the presence of precipitins in serum was performed with the extracts of 15 microbial isolates. The furniture factory workers showed a high skin response to the extracts of environmental microbes. The frequency of early grade 2 reactions (diameter 10 mm) to the extract of Rahnella sp. was 64.6% among furniture workers, being significantly higher (p < 0.001) compared to reference group (18.7%). High frequencies of grade 2 reactions in furniture workers were also found with the extracts of A. globiformis and A. fumigatus (52.1% and 62.5%, respectively). The frequencies of grade 2 delayed (after 8 h) and late (after 24 h) reactions to Rahnella sp. in furniture workers were non-specifically high (97.9%/93.7%) while the response rates to A. globiformis and A. fumigatus were much lower (10.4%/25.0%, and 4.2%/37.5%, respectively). In agar-gel test for detection of precipitins, in most cases very low percentages of positive reactions (0-2.1%) were noted in furniture factory workers. The only exception was a high percentage of positive reactions (27.1%) to the antigen of Pseudomonas maltophilia, which was significantly greater in furniture workers compared to the reference group (p < 0.01). The obtained results suggest that early allergic reactions to microorganisms associated with wood dust are common among workers of furniture industry, which may increase a potential risk of work-related disease in this occupational group.


Safety-Related Postmarketing Modifications of Drugs for Hematological Malignancies.
The prevalence of safety-related postmarketing label modifications of medications for hematological malignancies is unknown. We identified 35 new drugs indicated for hematological malignancies approved by the US Food and Drug Administration between January 1999 and December 2014. Characteristics of supporting trials and safety-related label modifications from approval to December 2017 were collected from drug labels. Regulatory review and approval pathways were also collected. New drug approvals were supported by trials with a median of 167 patients (interquartile range 115-316). All drugs were approved based on surrogate endpoints. Twenty-seven drug approvals (77%) were not supported by randomized controlled trials. All drugs received orphan drug designation, and most were granted fast track designation, priority review, and accelerated approval (83, 74, and 60%, respectively). A total of 28 drugs (80%) had postmarketing safety-related label modifications. Additions to black box warnings, contraindications, warnings and precautions, and common adverse reactions were identified in 31, 11, 77, and 46% of drugs, respectively. Five drugs (14%) were permanently or temporarily withdrawn from the US market. Drugs for hematological malignancies are often approved based on limited evidence through expedited regulatory pathways with incomplete safety profiles. Hematologists should be vigilant for unrecognized side effects when prescribing newly approved drugs.


Community mental health care: clients' perceptions of services and an evaluation of a voluntary agency support scheme.
A questionnaire assessment of mental health and of perceptions of formal care was conducted with a sample of clients before they received a voluntary agency mental health intervention in addition to normal community psychiatric and social services. The assessment was repeated three months later. A matched control group who received only the normal services were also assessed twice over a period of three months. Both groups improved significantly on the mental health measure over the three months and there was little difference between the treatment and control group. Clients in the voluntary agency group were less satisfied with community psychiatric services and may have chosen the voluntary agency as an alternative source of help. Women in both groups showed less improvement in measured mental health than men. Community Psychiatric Nurses (CPNs) were seen more frequently than social workers, psychologists and psychiatrists. Contacts with CPNs and social workers were rate most favourably.


Marijuana use and high school dropout: the influence of unobservables.
In this study, we reconsider the relationship between heavy and persistent marijuana use and high school dropout status. Using a unique prospective panel study of over 4500 7th grade students from South Dakota who are followed through high school, we developed propensity score weights to adjust for baseline differences found to exist before marijuana initiation occurs for most students (7th grade). We then used weighted logistic regression that incorporates these propensity score weights to examine the extent to which time-varying factors, including substance use, also influence the likelihood of dropping out of school. We found a positive association between marijuana use and dropping out (OR=5.6, RR=3.8), over half of which was explained by prior differences in observational characteristics and behaviors. The remaining association (OR=2.4, RR=1.7) became statistically insignificant when measures of cigarette smoking were included in the analysis. Because cigarette smoking is unlikely to seriously impair cognition, we interpret this result as evidence that the association between marijuana use and high school dropout is unlikely to be due to its adverse effects on cognition. We then explored which constructs drive this result, determining that they are time-varying parental and peer influences.


Risk assessment of substances that are both genotoxic and carcinogenic report of an International Conference organized by EFSA and WHO with support of ILSI Europe.
The European Food Safety Authority (EFSA) and the World Health Organization (WHO), with the support of the International Life Sciences Institute, European Branch (ILSI Europe), organized an international conference on 16-18 November 2005 to discuss how regulatory and advisory bodies evaluate the potential risks of the presence in food of substances that are both genotoxic and carcinogenic. The objectives of the conference were to discuss the possible approaches for risk assessment of such substances, how the approaches may be interpreted and whether they meet the needs of risk managers. ALARA (as low as reasonably achievable) provides advice based solely on hazard identification and does not take into account either potency or human exposure. The use of quantitative low-dose extrapolation of dose-response data from an animal bioassay raises numerous scientific uncertainties related to the selection of mathematical models and extrapolation down to levels of human exposure. There was consensus that the margin of exposure (MOE) was the preferred approach because it is based on the available animal dose-response data, without extrapolation, and on human exposures. The MOE can be used for prioritisation of risk management actions but the conference recognised that it is difficult to interpret it in terms of health risk.


Intracranial and intraspinal dissemination from pineal yolk sac tumor treated by PVB therapy--case report.
A 15-year-old male was admitted because of diplopia and persistent headache. Postcontrast computed tomography (CT) revealed a homogeneously enhanced large mass, 3 x 4 cm in size, in the pineal region and moderate obstructive hydrocephalus. A right ventriculoperitoneal shunt was installed. At that time, the serum alpha-fetoprotein (AFP) level increased to 23,036 ng/ml, but the level of serum beta-subunit of human chorionic gonadotropin was less than 0.2 ng/ml. These data indicated the tumor to be a pure yolk sac tumor. Following cisplatin-vinblastine-bleomycin (PVB) therapy and whole-brain irradiation (50 Gy), the tumor disappeared on CT, although the AFP level did not return to normal. Eight months after the completion of initial therapy, he had lumbago. Spinal magnetic resonance imaging revealed a metastatic mass at the L5-S2 levels, which was subtotally removed and histologically diagnosed as yolk sac tumor. Postoperative local irradiation (30 Gy) was performed. Seven months after the operation, spinal dissemination at the Th7 level occurred and, 1 month later, intracranial dissemination in the left cerebellopontine angle was detected. He died 25 months after the first admission. PVB therapy did not prevent spinal dissemination in this case.


Evaluating laboratory diagnostic tests and translational research.
In laboratory medicine, the evaluation of an assay is reasonably straightforward and allows broad applicable standards to be established. In contrast, the evaluation of a test is more complex and inherently less susceptible to standardization. The term "test" refers to the use of an assay in the context of a particular disease, in a particular population, and for a particular purpose. Therefore, the true evaluation is to demonstrate its effectiveness in helping a clinician achieve a correct diagnosis or improve patient clinical outcomes. The debate on the current weak framework used for evaluating laboratory tests has been stimulated by recent technological developments, in particular "omics" tests. Currently, consensus has been achieved concerning the proposal to use a model based on at least four steps to be investigated. These are analytical and clinical validity, clinical usefulness and, finally, any ethical, social and legal implications, including economic implications. As the pace of technological advancements in laboratory medicine accelerates, it is time to discuss the role of laboratory testing, and the related role of clinical laboratories. In particular, we should consider whether they should evolve as focused factories of numbers and results, or as knowledge services with an emphasis on improving appropriateness in test requesting, and the interpretation and utilization of laboratory information.


Caloric Restriction and Its Effect on Blood Pressure, Heart Rate Variability and Arterial Stiffness and Dilatation: A Review of the Evidence.
Essential hypertension, fast heart rate, low heart rate variability, sympathetic nervous system dominance over parasympathetic, arterial stiffness, endothelial dysfunction and poor flow-mediated arterial dilatation are all associated with cardiovascular mortality and morbidity. This review of randomised controlled trials and other studies demonstrates that caloric restriction (CR) is capable of significantly improving all these parameters, normalising blood pressure (BP) and allowing patients to discontinue antihypertensive medication, while never becoming hypotensive. CR appears to be effective regardless of age, gender, ethnicity, weight, body mass index (BMI) or a diagnosis of metabolic syndrome or type 2 diabetes, but the greatest benefit is usually observed in the sickest subjects and BP may continue to improve during the refeeding period. Exercise enhances the effects of CR only in hypertensive subjects. There is as yet no consensus on the mechanism of effect of CR and it may be multifactorial. Several studies have suggested that improvement in BP is related to improvement in insulin sensitivity, as well as increased nitric oxide production through improved endothelial function. In addition, CR is known to induce SIRT1, a nutrient sensor, which is linked to a number of beneficial effects in the body.


Pathogenesis of SIV encephalitis. Selection and replication of neurovirulent SIV.
To investigate the viral and host factors that contribute to neurological disease, nine macaques were intravenously co-inoculated with SIV/DeltaB670, a primary isolate of SIV consisting of at least 21 different genotypes, and SIV/17E-Fr, a neurovirulent recombinant clone. CD4+ cell counts and antigenemia were measured throughout infection. The SIV env V1 region was amplified from brain and peripheral blood mononuclear cell DNA to compare the genotypes present in brain and blood. Seven of the 9 macaques (78%) developed typical SIV-associated neurological lesions classified as severe (4 macaques), moderate (2 macaques), or mild (1 macaque) with a mean time to euthanasia of 7 months. Macaques with severe neurological lesions progressed more rapidly, with a mean time to euthanasia of 3-6 months. SIV/17E-Fr was detected in brain homogenates from all four macaques with severe encephalitis, and in three of the four, SIV/17E-Fr was the only genotype identified in the central nervous system. Macaques with less severe or no neurological lesions usually had one of various genotypes of SIV/DeltaB670 in brain. A variety of genotypes of SIV/DeltaB670 and SIV/17E-Fr were detected in peripheral blood mononuclear cells throughout infection. Macaques with severe neurological lesions had the most precipitous declines in CD4+ cell counts, the highest levels of antigenemia, and the greatest expression of viral RNA and protein in the central nervous system. Macaca nemestrina were more likely to develop severe neurological lesions than M. mulatta or M. fascicularis (P = 0.048). This study demonstrated that neurovirulent strains within the virus swarm can selectively enter and become established in the central nervous system and that the neurological lesions that develop are correlated with the development of host immunosuppression. The species differences in severity of neurological lesions seen in this study suggest that host factors are also important in determining the outcome of lentiviral infection.


Molecular evolution of growth hormone and insulin-like growth factor 1 receptors in long-lived, small-bodied mammals.
Mammals typically display a robust positive relationship between lifespan and body size. Two groups that deviate markedly from this pattern are bats and African mole-rats, with members of both groups being extremely long-lived given their body size, with the maximum documented lifespan for many species exceeding 20 years. A recent genomics study of the exceptionally long-lived Brandt's bat, Myotis brandtii (41 years), suggested that its longevity and small body size may be at least partly attributed to key amino acid substitutions in the transmembrane domains of the receptors of growth hormone (GH) and insulin-like growth factor 1 (IGF1). However, whereas elevated longevity is likely to be common across all 19 bat families, the reported amino acid substitutions were only observed in two closely related bat families. To test the hypothesis that an altered GH/IGF1 axis relates to the longevity of African mole-rats and bats, we compared and analysed the homologous coding gene sequences in genomic and transcriptomic data from 26 bat species, five mole-rats and 38 outgroup species. Phylogenetic analyses of both genes recovered the majority of nodes in the currently accepted species tree with high support. Compared to other clades, such as primates and carnivores, the bats and rodents had longer branch lengths. The single 24 amino acid transmembrane domain of IGF1R was found to be more conserved across mammals compared to that of GHR. Within bats, considerable variation in the transmembrane domain of GHR was found, including a previously unreported deletion in Emballonuridae. The transmembrane domains of rodents were found to be more conserved, with mole-rats lacking uniquely conserved amino acid substitutions. Molecular evolutionary analyses showed that both genes were under purifying selection in bats and mole-rats. Our findings suggest that while the previously documented mutations may confer some additional lifespan to Myotis bats, other, as yet unknown, genetic differences are likely to account for the long lifespans observed in many bat and mole-rat species.


Differences in relative hippocampus volume and number of hippocampus neurons among five corvid species.
The relative size of the avian hippocampus (Hp) has been shown to be related to spatial memory and food storing in two avian families, the parids and corvids. Basil et al. [Brain Behav Evol 1996;47:156-164] examined North American food-storing birds in the corvid family and found that Clark's nutcrackers had a larger relative Hp than pinyon jays and Western scrub jays. These results correlated with the nutcracker's better performance on most spatial memory tasks and their strong reliance on stored food in the wild. However, Pravosudov and de Kort [Brain Behav Evol 2006;67:1-9] raised questions about the methodology used in the 1996 study, specifically the use of paraffin as an embedding material and recalculation for shrinkage. Therefore, we measured relative Hp volume using gelatin as the embedding material in four North American species of food-storing corvids (Clark's nutcrackers, pinyon jays, Western scrub jays and blue jays) and one Eurasian corvid that stores little to no food (azure-winged magpies). Although there was a significant overall effect of species on relative Hp volume among the five species, subsequent tests found only one pairwise difference, blue jays having a larger Hp than the azure-winged magpies. We also examined the relative size of the septum in the five species. Although Shiflett et al. [J Neurobiol 2002;51:215-222] found a difference in relative septum volume amongst three species of parids that correlated with storing food, we did not find significant differences amongst the five species in relative septum. Finally, we calculated the number of neurons in the Hp relative to body mass in the five species and found statistically significant differences, some of which are in accord with the adaptive specialization hypothesis and some are not.


Evidence for transcellular osmotic water flow in rat proximal tubules.
To determine the predominant pathway for transepithelial osmotic water flow, the transepithelial osmotic water permeability [Pf(TE)] and the apparent dimensions of paracellular pores and slits were determined in rat proximal convoluted tubules microperfused in vivo. To measure Pf(TE), tubules were perfused with a hyposmotic, cyanide-containing solution. Pf(TE), calculated from the observed volume flux in response to the measured log mean osmotic gradient, was 0.12-0.15 cm/s, assuming sigmaNaCl equal to 1.0-0.7, respectively. The dimensions of the paracellular pathways were determined using measured sucrose and mannitol permeabilities (nonelectrolytes confined to the extracellular space). These were 0.43 and 0.87 X 10(-5) cm/s, respectively. By using the ratio of these permeabilities, their respective free solution diffusion coefficients and molecular radii, and the Renkin equation, the radius of the nonelectrolyte-permeable pores and the total pore area/cm2 surface area/channel length were calculated to be 1.4 nm and 3.56 cm-1, respectively. Similar calculations for slits yielded a slit half-width of 0.8 nm and a total slit area/cm2 surface area/channel length of 3.16 cm-1. The osmotic water permeability of these nonelectrolyte-permeable pathways was calculated by Poiseuille's law to be 0.0018 cm/s (pores) or 0.0014 cm/s (slits), at most 2% of Pf(TE). We conclude that the nonelectrolyte-permeable pathway in the tight junctions is not the major route of transepithelial osmotic water flow in the rat proximal tubule.


Potential novel therapeutic strategies in cystic fibrosis: antimicrobial and anti-biofilm activity of natural and designed α-helical peptides against Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.
Treatment of cystic fibrosis-associated lung infections is hampered by the presence of multi-drug resistant pathogens, many of which are also strong biofilm producers. Antimicrobial peptides, essential components of innate immunity in humans and animals, exhibit relevant in vitro antimicrobial activity although they tend not to select for resistant strains. Three α-helical antimicrobial peptides, BMAP-27 and BMAP-28 of bovine origin, and the artificial P19(9/B) peptide were tested, comparatively to Tobramycin, for their in vitro antibacterial and anti-biofilm activity against 15 Staphylococcus aureus, 25 Pseudomonas aeruginosa, and 27 Stenotrophomonas maltophilia strains from cystic fibrosis patients. All assays were carried out in physical-chemical experimental conditions simulating a cystic fibrosis lung. All peptides showed a potent and rapid bactericidal activity against most P. aeruginosa, S. maltophilia and S. aureus strains tested, at levels generally higher than those exhibited by Tobramycin and significantly reduced biofilm formation of all the bacterial species tested, although less effectively than Tobramycin did. On the contrary, the viability-reducing activity of antimicrobial peptides against preformed P. aeruginosa biofilms was comparable to and, in some cases, higher than that showed by Tobramycin. The activity shown by α-helical peptides against planktonic and biofilm cells makes them promising "lead compounds" for future development of novel drugs for therapeutic treatment of cystic fibrosis lung disease.


[Effects of Nourishing yin clearing heat ([Chinese characters: see text]) Chinese herbal medicine on vascular endothelial growth factor the epiphyseal cartilage of growth retardation].
To observe the effects of Nourishing yin clearing heat ([Chinese characters: see text]) Chinese herbal medicine on vascular endothelial growth factor (VEGF) in growth retardation induced by Decamethasone and observe its mechanisms. Thirty one-month-old New Zealand white rabbits were randomly divided into normal group, dexamethasone-treated group and Nourishing yin clearing heat ([Chinese characters: see text]) Chinese herbal medicine-treated group. The rabbits in dexamethasone group and Nourishing yin clearing heat ([Chinese characters: see text]) Chinese herbal medicine-treated group received dexamethasone (5 mg/kg x d). The rabbits were sacrificed at the 6th and 12th week after administration, and then rabbit tibia articular was removed. (1) Using TUNEL stain to detect apoptotic index. (2) Using immunohistochemical stain to detect the positive index of the expression of vascular endothelial growth factor (VEGF) in the epiphyseal cartilage of growth. (3) Using fluorescent quantitative PCR to detect the expression intensity of VEGF mRNA in each group. At the 6th and 12th week after administration, there were significant difference in apoptotic index and cell proliferation index between dexamethasone group and normal group (P<0.01, dexamethasone group more than normal group). Immunohistochemical stain and fluorescent quantitative PCR indicated that the expression of VEGF and VEGF mRNA in dexamethasone group was significantly decreased as compared with that in normal group (P<0.01), and also obviously lower than Chinese herbal medicine-treated group (P<0.01). VEGF has 2. an important role during the growth retardation induced by Dexamethasone. Nourishing yin clearing heat ([Chinese characters: see text]) Chinese herbal medicine can reduce the growth retardation induced by Dexamethasone through increasing the VEGF expression in growth plate chondrocytes and then increase angiogenesis.


Stable expression of rice dwarf virus Pns10 suppresses the post-transcriptional gene silencing in transgenic Nicotiana benthamiana plants.
RNA silencing is a conserved mechanism that defends against viral infection and retrotransposon activity for protection of the genome. Segment 10 (S10) of Rice dwarf virus (RDV) encodes Pns10 protein, a viral suppressor of RNAi that suppresses the host RNA silencing machinery. In this study, we obtained stable transgenic RDV-S10 Nicotiana benthamiana plants expressing Pns10. Suppression of post-transcriptional gene silencing (PTGS) by Pns10 supported the conclusion that this protein exhibited the RNA silencing suppressor activity. In particular, the transgenic plants stably expressing a viral suppressor of RNAi (VSR) provide a model system for investigating the mechanism of RNA silencing.<br /> RNA silencing; VSR; Rice dwarf virus; Pns10; transgenic plant.


Percutaneous endoscopic gastrostomy (PEG) site infections: a clinical and microbiological study from university teaching hospital, India.
Percutaneous endoscopic gastrostomy (PEG) is used to provide enteral access in patients who are unable to swallow. Infection of the stoma is an important complication and there is little data from India on this problem, which can be used to inform infection prevention and prophylactic strategies. The objective was to assess the prevalence and the role of contributory factors in PEG site infections. A total of 173 patients underwent PEG insertion from January 2011 to May 2012. Clinical and microbiological data were collected for culture-positive cases. Insertion was performed using a standard sterile pull-through technique. Infections were defined as two of: peristomal erythema, induration, and purulent discharge. A total of 54 PEG infections occurred in 43 patients (28.85%). Seventy-seven organisms were isolated. Pseudomonas aeruginosa was the most common (n=29) followed by coliforms (n=21) and meticillin resistant Staphylococcus aureus (MRSA) (n=6). Thirty-one (72%) received amoxicillin-clavulanic acid as prophylaxis and 12 (28%) were receiving concomitant antibiotics for their underlying conditions. The occurrence of PEG site infections was statistically independent of the administered prophylactic antibiotics (p=0.3). This study has demonstrated the importance of PEG sites as a cause of healthcare associated infections. Educating patients on wound care practices would play a significant role in prevention of PEG site infections.


Explorations in statistics: hypothesis tests and P values.
Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This second installment of Explorations in Statistics delves into test statistics and P values, two concepts fundamental to the test of a scientific null hypothesis. The essence of a test statistic is that it compares what we observe in the experiment to what we expect to see if the null hypothesis is true. The P value associated with the magnitude of that test statistic answers this question: if the null hypothesis is true, what proportion of possible values of the test statistic are at least as extreme as the one I got? Although statisticians continue to stress the limitations of hypothesis tests, there are two realities we must acknowledge: hypothesis tests are ingrained within science, and the simple test of a null hypothesis can be useful. As a result, it behooves us to explore the notions of hypothesis tests, test statistics, and P values.


Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway.
Aloe-emodin (AE), a natural, biologically active compound from the rhizome of Rheum palmatum, has been shown to induce apoptosis in several cancer cell lines in vitro. However, its molecular mechanism of action in the apoptosis induction of human nasopharyngeal carcinoma (NPC) cells has not been explored. This study shows that AE induced G(2)/M phase arrest by increasing levels of cyclin B1 bound to Cdc2, and also caused an increase in apoptosis of NPC cells, which was characterized by morphological changes, nuclear condensation, DNA fragmentation, caspase-3 activation, cleavage of poly (ADP-ribose) polymerase (PARP) and increased sub-G(1) population. Treatment of NPC cells with AE also resulted in a decrease in Bcl-X(L) and an increase in Bax expression. Ectopic expression of Bcl-X(L) but not Bcl-2 or small interfering RNA (siRNA)-mediated attenuation of Bax suppressed AE-induced apoptotic cell death. AE-induced loss of mitochondrial membrane potential (MMP) and increase in cellular Ca(++) content, reactive oxygen species (ROS) and apoptotic cell death were suppressed by the treatment of cyclosporin A (CsA) or caspase-8 inhibitor Z-IETD-FMK. Co-treatment with caspase-9 inhibitor Z-LEHD-FMK could inhibit AE-induced cell death and the activation of caspase-3 and -9. In addition, suppression of caspase-8 with the specific inhibitor Z-IETD-FMK inhibited AE-induced the activation of Bax, the cleavage of Bid, the translocation of tBid to the mitochondria and the release of cytochrome c, apoptosis-inducing factor (AIF) and Endo G from the mitochondria and subsequent apoptosis. Taken together, these results indicate that the caspase-8-mediated activation of the mitochondrial death pathway plays a critical role in AE-induced apoptosis of NPC cells.


Ions from Solution to the Gas Phase: A Molecular Dynamics Simulation of the Structural Evolution of Substance P during Desolvation of Charged Nanodroplets Generated by Electrospray Ionization.
Molecular dynamics (MD) simulations are used to model changes in the conformational preferences of a model peptide during the transition from a hydrated environment (charged nanodroplet generated by electrospray ionization) to the solvent-free peptide ion. The charged droplet consists of ∼2400 water molecules, 22 hydronium ions, and 10 chloride and contains a single Substance P (SP) [SP + 3H]3+ ion (SP3+; amino acid sequence RPKPQQFFGLM-NH2). Initially, droplet shrinkage involves a combination of solvent evaporation and ejection of excess charge, primarily hydronium ions. Further droplet shrinkage leads to a series of fission events, which includes the loss of some Cl- ions. SP3+ ions adapt to the smaller size droplet through small conformational changes that result in coiling of the hydrophobic C-terminus of the peptide on or near the droplet surface, intramolecular interactions involving the hydrophilic N-terminus of the peptide, and water-mediated interactions between the SP3+ ion and H3O+ and Cl- ions. Calculated collision cross sections (CCS) for SP3+ ions at various stages of desolvation are consistent with the results obtained from cryogenic ion mobility-mass spectrometry (cryo-IM-MS) measurements. Specifically, early in the decay of the charged droplet SP3+ ions favor an extended conformation, whereas a compact conformer is favored during the final stages of dehydration.


Properties of Multidrug-Resistant Mutants Derived from Heterologous Expression Chassis Strain Streptomyces albidoflavus J1074.
Streptomyces albidoflavus J1074 is a popular platform to discover novel natural products via the expression of heterologous biosynthetic gene clusters (BGCs). There is keen interest in improving the ability of this platform to overexpress BGCs and, consequently, enable the purification of specialized metabolites. Mutations within gene rpoB for the β-subunit of RNA polymerase are known to increase rifampicin resistance and augment the metabolic capabilities of streptomycetes. Yet, the effects of rpoB mutations on J1074 remained unstudied, and we decided to address this issue. A target collection of strains that we studied carried spontaneous rpoB mutations introduced in the background of the other drug resistance mutations. The antibiotic resistance spectra, growth, and specialized metabolism of the resulting mutants were interrogated using a set of microbiological and analytical approaches. We isolated 14 different rpoB mutants showing various degrees of rifampicin resistance; one of them (S433W) was isolated for the first time in actinomycetes. The rpoB mutations had a major effect on antibiotic production by J1074, as evident from bioassays and LC-MS data. Our data support the idea that rpoB mutations are useful tools to enhance the ability of J1074 to produce specialized metabolites.


Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts.
Diabetes alters cardiac substrate metabolism. The cardiac phenotype in insulin-resistant states has not been comprehensively characterized. The goal of these studies was to determine whether the hearts of leptin-deficient 8-week-old ob/ob mice were able to modulate cardiac substrate utilization in response to insulin or to changes in fatty acid delivery. Ob/ob mice were insulin resistant and glucose intolerant. Insulin signal transduction and insulin-stimulated glucose uptake were markedly impaired in ob/ob cardiomyocytes. Insulin-stimulated rates of glycolysis and glucose oxidation were 1.5- and 1.8-fold higher in wild-type hearts, respectively, versus ob/ob, and glucose metabolism in ob/ob hearts was unresponsive to insulin. Increasing concentrations of palmitate from 0.4 mmol/l (low) to 1.2 mmol/l (high) led to a decline in glucose oxidation in wild-type hearts, whereas glucose oxidation remained depressed and did not change in ob/ob mouse hearts. In contrast, fatty acid utilization in ob/ob hearts was 1.5- to 2-fold greater in the absence or presence of 1 nmol/l insulin and rose with increasing palmitate concentrations. Moreover, the ability of insulin to reduce palmitate oxidation rates was blunted in the hearts of ob/ob mice. Under low-palmitate and insulin-free conditions, cardiac performance was significantly greater in wild-type hearts. However, in the presence of high palmitate and 1 nmol/l insulin, cardiac performance in ob/ob mouse hearts was relatively preserved, whereas function in wild-type mouse hearts declined substantially. Under all perfusion conditions, myocardial oxygen consumption was higher in ob/ob hearts, ranging from 30% higher in low-palmitate conditions to greater than twofold higher under high-palmitate conditions. These data indicate that although the hearts of glucose-intolerant ob/ob mice are capable of maintaining their function under conditions of increased fatty acid supply and hyperinsulinemia, they are insulin-resistant, metabolically inefficient, and unable to modulate substrate utilization in response to changes in insulin and fatty acid supply.


45th annual meeting of the Italian Cancer Society. Bergamo, 9-12 November 2003.
The 45th Annual Meeting of the Italian Cancer Society (SIC), held at the Centro Congressi Giovanni XXIII in Bergamo, Italy on 9-12 November, 2003, attracted almost 400 participants. The Scientific Committee chaired by R Giavazzi (Mario Negri Institute, Bergamo) and the board of the Italian Cancer Society produced a packed and varied program. Plenary sessions with keynote speakers (24 lectures) were combined with oral proffered papers (20 selected presentations), providing a platform from laboratory science to clinical interventions. Two hundred and sixty-one abstracts were submitted to the conference and presented in poster and poster discussion sessions, providing a stimulating ground for discussion and a network of interactive collaboration among young investigators. The venue of Bergamo offered exceptional hospitality with social events in the beautiful old town and at the Modern Art Museum. We hope that the following report gives an idea of the event and will encourage the reader to attend the 46th meeting of the SIC, 24-26 October, 2004 in Pisa.


Porcine circovirus type 2 (PCV2)-infection and re-inoculation with homologous or heterologous strains: virological, serological, pathological and clinical effects in growing pigs.
Long-term PCV2 infection and/or concurrent infection with genotypes PCV2a and PCV2b may play a role in the development of clinical porcine circovirus-associated disease (PCVAD). To evaluate this premise, 24 11-week-old specific pathogen-free (SPF) pigs were randomly assigned to 1 of 4 treatments: negative controls, a single inoculation with PCV2a, single inoculation followed by re-inoculation with a homologous PCV2a strain, or repeated inoculations with heterologous strains (PCV2a, PCV2b). Pigs were evaluated for clinical signs daily through 140 days post inoculation (dpi). Serum samples were collected every other day from dpi 0 through 14 and weekly thereafter. PCV2-inoculated pigs were viremic by dpi 2 and 13 of 18 pigs remained viremic at 140 dpi. No statistical differences in the onset, level, or duration of PCV2 viremia were detected among treatment groups. Anti-PCV2 antibodies were detected between 14 and 28 dpi and were present through 140 dpi without statistical differences in antibody response among treatment groups. In the current study, pigs had extended viremia combined with detectable tissue PCV2 antigen levels despite the presence of high levels of anti-PCV2 antibody; however, no clinical disease was observed.


Loss of one Tgfbr2 allele in fibroblasts promotes metastasis in MMTV: polyoma middle T transgenic and transplant mouse models of mammary tumor progression.
Accumulation of fibroblasts is a phenomenon that significantly correlates with formation of aggressive cancers. While studies have shown that the TGF-β signaling pathway is an important regulator of fibroblast activation, the functional contribution of TGF-β signaling in fibroblasts during multi-step tumor progression remains largely unclear. In previous studies, we used a sub-renal capsule transplantation model to demonstrate that homozygous knockout of the Tgfbr2 gene (Tgbr2(FspKO)) enhanced mammary tumor growth and metastasis. Here, we show for the first time a significant role for loss of one Tgfbr2 allele during multi-step mammary tumor progression. Heterozygous deletion of Tgfbr2 in stromal cells in MMTV-PyVmT transgenic mice (PyVmT/Tgfbr2(hetFspKO) mice) resulted in earlier tumor formation and increased stromal cell accumulation. In contrast to previous studies of Tgbr2(FspKO) fibroblasts, Tgfbr2(hetFspKO) fibroblasts did not significantly increase tumor growth, but enhanced lung metastasis in PyVmT transgenic mice and in co-transplantation studies with PyVmT mammary carcinoma cells. Furthermore, Tgfbr2(hetFspKO) fibroblasts enhanced mammary carcinoma cell invasiveness associated with expression of inflammatory cytokines including CXCL12 and CCL2. Analyses of Tgbr2(FspKO) and Tgfbr2(hetFspKO) fibroblasts revealed differences in the expression of factors associated with metastatic spread, indicating potential differences in the mechanism of action between homozygous and heterozygous deletion of Tgfbr2 in stromal cells. In summary, these studies demonstrate for the first time that loss of one Tgfbr2 allele in fibroblasts enhances mammary metastases in a multi-step model of tumor progression, and demonstrate the importance of clarifying the functional contribution of genetic alterations in stromal cells in breast cancer progression.


Phase plane analysis of uniform and non-uniform propagation of activity in a model of squid giant axon.
Mathematical modeling of propagation in the squid giant axon using the Hodgkin-Huxley partial differential equation for propagation in a cable-like cell allowed us to study the effect of reduction in maximal sodium conductance in a short segment of the "axon membrane". The phase plane (V,V) display of the action potentials calculated in segments ahead of the gNa+ depressed site exhibited peculiar inflections in their ascending portion which are absent in the control situation. These inflections (upward or downward) varied with the distance from the depressed segments. The voltage of the first inflection point of the phase trajectories was an exponential function of this distance. This voltage is in close agreement with threshold voltage at points within a distance of 1.4 mm from the depressed segments. The model reproduces, qualitatively, the experimental behaviour of the squid axon topically exposed to TTX.


Medical management of first trimester miscarriage: a quality improvement initiative.
Medical management of first trimester pregnancy loss is a safe option that is well tolerated and affords women more autonomy in relation to their care. Recent trials provide robust evidence that mifepristone pretreatment is the optimal approach for women with missed miscarriage who desire medical management. Following a change in medical management of first trimester miscarriage in our unit, we conducted a retrospective audit over a 3-month period of all women who had elected medical management as their primary treatment option. We compared the results with a previous audit that had been undertaken prior to the change in practice. The implementation of mifepristone resulted in an increased effectiveness of primary medical treatment for first trimester miscarriage from 53.8% to 85.2% (p=<0.001). The results of our study support the introduction of mifepristone into routine clinical practice for medical management of first trimester pregnancy loss across all maternity units.


Plasma membrane intrinsic proteins from maize cluster in two sequence subgroups with differential aquaporin activity.
The transport of water through membranes is regulated in part by aquaporins or water channel proteins. These proteins are members of the larger family of major intrinsic proteins (MIPs). Plant aquaporins are categorized as either tonoplast intrinsic proteins (TIPs) or plasma membrane intrinsic proteins (PIPs). Sequence analysis shows that PIPs form several subclasses. We report on the characterization of three maize (Zea mays) PIPs belonging to the PIP1 and PIP2 subfamilies (ZmPIP1a, ZmPIP1b, and ZmPIP2a). The ZmPIP2a clone has normal aquaporin activity in Xenopus laevis oocytes. ZmPIP1a and ZmPIP1b have no activity, and a review of the literature shows that most PIP1 proteins identified in other plants have no or very low activity in oocytes. Arabidopsis PIP1 proteins are the only exception. Control experiments show that this lack of activity of maize PIP1 proteins is not caused by their failure to arrive at the plasma membrane of the oocytes. ZmPIP1b also does not appear to facilitate the transport of any of the small solutes tried (glycerol, choline, ethanol, urea, and amino acids). These results are discussed in relationship to the function and regulation of the PIP family of aquaporins.


Towards the Prediction of Rearrest during Out-of-Hospital Cardiac Arrest.
A secondary arrest is frequent in patients that recover spontaneous circulation after an out-of-hospital cardiac arrest (OHCA). Rearrest events are associated to worse patient outcomes, but little is known on the heart dynamics that lead to rearrest. The prediction of rearrest could help improve OHCA patient outcomes. The aim of this study was to develop a machine learning model to predict rearrest. A random forest classifier based on 21 heart rate variability (HRV) and electrocardiogram (ECG) features was designed. An analysis interval of 2 min after recovery of spontaneous circulation was used to compute the features. The model was trained and tested using a repeated cross-validation procedure, on a cohort of 162 OHCA patients (55 with rearrest). The median (interquartile range) sensitivity (rearrest) and specificity (no-rearrest) of the model were 67.3% (9.1%) and 67.3% (10.3%), respectively, with median areas under the receiver operating characteristics and the precision-recall curves of 0.69 and 0.53, respectively. This is the first machine learning model to predict rearrest, and would provide clinically valuable information to the clinician in an automated way.


A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication.
Cell-cell communication involves a large number of molecular signals that function as words of a complex language whose grammar remains mostly unknown. Here, we describe an integrative approach involving (1) protein-level measurement of multiple communication signals coupled to output responses in receiving cells and (2) mathematical modeling to uncover input-output relationships and interactions between signals. Using human dendritic cell (DC)-T helper (Th) cell communication as a model, we measured 36 DC-derived signals and 17 Th cytokines broadly covering Th diversity in 428 observations. We developed a data-driven, computationally validated model capturing 56 already described and 290 potentially novel mechanisms of Th cell specification. By predicting context-dependent behaviors, we demonstrate a new function for IL-12p70 as an inducer of Th17 in an IL-1 signaling context. This work provides a unique resource to decipher the complex combinatorial rules governing DC-Th cell communication and guide their manipulation for vaccine design and immunotherapies.


[Adequate life style of the handicapped patient].
Eventually, the continuous medical care is decisive for the answer to the question, whether our medical progress will constitute an increment in quality of life or an increased burden for the individual and society. Essential is advanced analysis with respect to the changes of the social role of the elderly. Most helpful is a warm-hearted family bond.


G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment.
Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unknown. To address such mechanisms, we subjected transformed cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag scheme, and assayed a range of cellular functions. The results indicated a specific circadian clock-dependent increase in cell proliferation. Transcriptome analysis revealed up-regulation of G1/S phase transition genes (myelocytomatosis oncogene cellular homolog [Myc], cyclin D1/3, chromatin licensing and DNA replication factor 1 [Cdt1]), concomitant with increased phosphorylation of the retinoblastoma (RB) protein by cyclin-dependent kinase (CDK) 4/6 and increased G1-S progression. Phospho-RB (Ser807/811) was found to oscillate in a circadian fashion and exhibit phase-shifted rhythms in circadian desynchronized cells. Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day-specific manner. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the use of treatment timed to endogenous circadian rhythms.


Genomic insights into syntrophy: the paradigm for anaerobic metabolic cooperation.
Syntrophy is a tightly coupled mutualistic interaction between hydrogen-/formate-producing and hydrogen-/formate-using microorganisms that occurs throughout the microbial world. Syntrophy is essential for global carbon cycling, waste decomposition, and biofuel production. Reverse electron transfer, e.g., the input of energy to drive critical redox reactions, is a defining feature of syntrophy. Genomic analyses indicate multiple systems for reverse electron transfer, including ion-translocating ferredoxin:NAD(+) oxidoreductase and hydrogenases, two types of electron transfer flavoprotein:quinone oxidoreductases, and other quinone reactive complexes. Confurcating hydrogenases that couple the favorable production of hydrogen from reduced ferredoxin with the unfavorable production of hydrogen from NADH are present in almost all syntrophic metabolizers, implicating their critical role in syntrophy. Transcriptomic analysis shows upregulation of many genes without assigned functions in the syntrophic lifestyle. High-throughput technologies provide insight into the mechanisms used to establish and maintain syntrophic consortia and conserve energy from reactions that operate close to thermodynamic equilibrium.


Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism.
The thyroid hormone, T 3, regulates cell growth, differentiation and development through binding to the nuclear thyroid hormone receptor (THR), a member of the steroid/TR superfamily of ligand-dependent transcriptional factors. T 3 modulates lipid metabolism in liver, although the detailed molecular mechanisms are unclear at present. Here, by a microarray analysis, we identified a novel chromosome 19 open reading frame 80 (C19orf80) which was activated by T 3. T 3 stimulation led to upregulation of both mRNA and protein levels of C19orf80. Immunofluorescence analysis revealed a vesicle-like pattern of C19orf80 around lipid droplets or within the lysosome-associated compartment in cells. Furthermore, T 3 treatment as well as C19orf80 overexpression specifically activated the autophagic response and lipid metabolism, as observed from lipidated LC3 (LC3-II) and levels of oxygen consumption rate, respectively. Reciprocally, knockdown of C19orf80 obstructed T 3-activated autophagy and lipolysis. Moreover, treatment with autolysosome maturation inhibitors, ammonium chloride and chloroquine, not only suppressed the T 3-activated autophagic process but also lipid metabolism. Our results collectively suggested that T 3 regulates lipid metabolism through a C19orf80-activated autophagic process.


Breastfeeding practices among Syrian refugees in Turkey.
We evaluated (a) opinion of Syrian and Turkish healthcare workers (HCWs), and perceptions and attitudes of Syrian refugee mothers, pregnant women, fathers and grandmothers on age-appropriate breastfeeding, (b) the effect of cultural characteristics, migration and pandemics on Syrian's infant nutrition, and (c) the suggestions of HCWs and Syrian family members to improve breastfeeding practices in the Syrian refugee society in a qualitative study. The qualitative study consisting of structured focus group discussions (FGDs) was held in four provinces in Turkey where Syrian refugees live intensely in September and October 2020. Seven different types of online FGDs were held with Turkish HCWs working in maternity hospitals, Syrian HCWs working in Refugee Health Centers (RHCs), Syrian pregnant women, mothers, fathers, and grandmothers. In total, we carried out 46 FGDs with 335 individuals. Thematic analysis of the transcripts in a deductive-inductive fashion was carried out with MAXQDA 11. Most Syrian HCWs did not get any training on breastfeeding counseling. The short duration of breastfeeding in Syrian refugees was seen to be related to the cultural characteristics, and migration. Some cultural characteristics can be summarized as "believing that breastfeeding harms mother's health", "adolescent marriages", "wanting to have as many children as possible", "giving anise to infants and not breastfeeding at night", "prelacteal feeding", "believing that milk is not enough", "over controlling mother-child interaction by grandmothers, which limits the interaction", "short pregnancy intervals", and "not using modern family planning techniques". We found out that migration increased the tendency for adolescent pregnancies, deepened the poverty, and decreased family social support. We did not observe any change in breastfeeding practices during pandemics. Breastfeeding counseling programs should be designed in consideration of cultural characteristics of Syrian HCWs and family members. Continuing health education programs for family members with socially appropriate interventions to prevent adolescent marriages are important.


Oligomeric State of β-Coronavirus Non-Structural Protein 10 Stimulators Studied by Small Angle X-ray Scattering.
The β-coronavirus family, encompassing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Severe Acute Respiratory Syndrome Coronavirus (SARS), and Middle East Respiratory Syndrome Coronavirus (MERS), has triggered pandemics within the last two decades. With the possibility of future pandemics, studying the coronavirus family members is necessary to improve knowledge and treatment. These viruses possess 16 non-structural proteins, many of which play crucial roles in viral replication and in other vital functions. One such vital protein is non-structural protein 10 (nsp10), acting as a pivotal stimulator of nsp14 and nsp16, thereby influencing RNA proofreading and viral RNA cap formation. Studying nsp10 of pathogenic coronaviruses is central to unraveling its multifunctional roles. Our study involves the biochemical and biophysical characterisation of full-length nsp10 from MERS, SARS and SARS-CoV-2. To elucidate their oligomeric state, we employed a combination of Multi-detection Size exclusion chromatography (Multi-detection SEC) with multi-angle static light scattering (MALS) and small angle X-ray scattering (SAXS) techniques. Our findings reveal that full-length nsp10s primarily exist as monomers in solution, while truncated versions tend to oligomerise. SAXS experiments reveal a globular shape for nsp10, a trait conserved in all three coronaviruses, although MERS nsp10, diverges most from SARS and SARS-CoV-2 nsp10s. In summary, unbound nsp10 proteins from SARS, MERS, and SARS-CoV-2 exhibit a globular and predominantly monomeric state in solution.


Chronic Intermittent Hypoxia Induces the Long-Term Facilitation of Genioglossus Corticomotor Activity.
Obstructive sleep apnea (OSA) is characterized by the repetitive collapse of the upper airway and chronic intermittent hypoxia (CIH) during sleep. It has been reported that CIH can increase the EMG activity of genioglossus in rats, which may be related to the neuromuscular compensation of OSA patients. This study aimed to explore whether CIH could induce the long-term facilitation (LTF) of genioglossus corticomotor activity. 16 rats were divided into the air group (n=8) and the CIH group (n=8). The CIH group was exposed to hypoxia for 4 weeks; the air group was subjected to air under identical experimental conditions in parallel. Transcranial magnetic stimulation (TMS) was applied every ten minutes and lasted for 1 h/day on the 1st, 3rd, 7th, 14th, 21st, and 28th days of air/CIH exposure. Genioglossus EMG was also recorded at the same time. Compared with the air group, the CIH group showed decreased TMS latency from 10 to 60 minutes on the 7th, 14th, 21st, and 28th days. The increased TMS amplitude lasting for 60 minutes was only observed on the 21st day. Genioglossus EMG activity increased only on the 28th day of CIH. We concluded that CIH could induce LTF of genioglossus corticomotor activity in rats.


UVB maintenance phototherapy in psoriasis.
Twenty-six patients with generalized stable plaque-type psoriasis were treated three to five times weekly with midwave fluorescent ultraviolet radiation (UVB) combined with either tar or lubricants. After clearing, patients received maintenance treatment with lubricant and UVB for a minimum of four weekly exposures, which were subsequently decreased in frequency. A shielded control site was observed. During maintenance treatments no prolongation in remissions with UVB maintenance could be demonstrated.


What Motivates People to Start a Graduate Entry Nursing Programme: An Interpretive Multi-Centred Case Study.
While graduate entry nursing programmes are well established in the United Kingdom and the United States of America (USA), they are relatively new to New Zealand and Australia. These programmes have been developed to meet the demands of the health workforce and provide graduates an alternative pathway to becoming a RN. Nursing is viewed as an attractive career option for this growing market of graduate entry students. This study explored the motivations underpinning students choosing a graduate entry MNSc degree over a traditional undergraduate nursing programme. A qualitative, longitudinal single case study design, informed by Yin was used. The first phase of the study is reported here. All students commencing a MNSc degree at the beginning of 2020 across four education providers (3 in New Zealand & 1 in Australia) were eligible to take part in the study. Ten students agreed to take part and undertake an interview. Braun and Clarke's approach to thematic analysis was used to analyse the interview data. Three key themes of motivation were identified from the data: the attraction of nursing; the clarity nursing offers in terms of career progression; and the design of the intensive programme. The motivations to choose a MNSc degree were deeply considered, multifaceted, and influenced by nursing role models. Students wanting to engage with a graduate entry MNSc programme did so through a reflective process of assessing their current career status and future career values. Participants in this study believed nursing would provide a secure and sustainable career path, potentially creating new horizons or possibilities beyond their previous work and life experiences. Having insight into what motivates individuals to enrol in such programmes may assist both education providers and the health sector with RN graduate recruitment and graduate entry programme enrolment.


[Origin of motion in the human ureter: mechanics, energetics and kinetics of the myosin molecular motors].
Ureteral peristalsis is the result of coordinated mechanical motor performance of longitudinal and circular smooth muscle layer of the ureter wall. The main aim of this study was to characterize in smooth muscle of proximal segments of human ureter, the mechanical properties at level of muscle tissue and at level of myosin molecular motors. Ureteral samples were collected from 15 patients, who underwent nephrectomy for renal cancer. Smooth muscle strips longitudinally and circularly oriented from proximal segments of human ureter were used for the in vitro experiments. Mechanical indices including the maximum unloaded shortening velocity (Vmax), and the maximum isometric tension (P0) normalized per cross-sectional area, were determined in vitro determined in electrically evoked contractions of longitudinal and circular smooth muscle strips. Myosin cross-bridge (CB) number per mm2 (Ψ) the elementary force per single CB (Ψ) and kinetic parameters were calculated in muscle strips, using Huxley's equations adapted to nonsarcomeric muscles. Longitudinal smooth muscle strips exhibited a significantly (p<0.05) faster Vmax (63%) and a higher P0 (40%), if compared to circular strips. Moreover, longitudinal muscle strips showed a significantly higher unitary force (Ψ) per CB. However, no significant differences were observed in CB number, the attachment (f1) and the detachment (g2) rate constants between longitudinal and circular muscle strips. The main result obtained in the present work documents that the mechanical, energetic and unitary forces per CB of longitudinal layer of proximal ureter are better compared to the circular one; these preliminary findings suggested, unlike intestinal smooth muscle, a major role of longitudinal smooth muscle layer in the ureter peristalsis.


HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency.
Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B*5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B*5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population. Objective. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity. We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010. Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens-Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (-)]. Among patients without HLA-B58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol. In this study, the incidence of allopurinol-induced SCARs was considerably high in CRI patients with HLA-B58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.


Improving the timeliness of procedures in a pediatric endoscopy suite.
Pediatric endoscopic procedures are essential in the evaluation and treatment of gastrointestinal diseases in children. Although pediatric endoscopists are greatly interested in increasing efficiency and through-put in pediatric endoscopy units, there is scarcely any literature on this critical process. The goal of this study was to improve the timeliness of pediatric endoscopy procedures at Children's Hospital at Montefiore. In June 2010, a pediatric endoscopy quality improvement initiative was formed at Children's Hospital at Montefiore. We identified patient-, equipment-, and physician-related causes for case delays. Pareto charts, cause and effect diagrams, process flow mapping, and statistical process control charts were used for analysis. From June 2010 to December 2012, we were able to significantly decrease the first case endoscopy delay from an average of 17 to 10 minutes (P < .001), second case delay from 39 to 25 minutes (P = .01), third case delay from 61 to 45 minutes (P = .05), and fourth case delay from 79 to 51 minutes (P = .05). Total delay time decreased from 196 to 131 minutes, resulting in a reduction of 65 minutes (P = .02). From June 2010 to August 2011 (preintervention period), an average of 36% of first endoscopy cases started within 5 minutes, 51% within 10 minutes, and 61% within 15 minutes of the scheduled time. From September 2011 to December 2012 (postintervention period), the percentage of cases starting within 5 minutes, 10 minutes, and 15 minutes increased to 47% (P = .07), 61% (P = .04), and 79% (P = .01), respectively. Applying quality improvement methods and tools helped improve pediatric endoscopy timeliness and significantly decreased total delays.


The influence of natural diet composition, food intake level, and body size on ingesta passage in primates.
An important component of digestive physiology involves ingesta mean retention time (MRT), which describes the time available for digestion. At least three different variables have been proposed to influence MRT in herbivorous mammals: body mass, diet type, and food intake (dry matter intake, DMI). To investigate which of these parameters influences MRT in primates, we collated data for 19 species from trials where both MRT and DMI were measured in captivity, and acquired data on the composition of the natural diet from the literature. We ran comparative tests using both raw species values and phylogenetically independent contrasts. MRT was not significantly associated with body mass, but there was a significant correlation between MRT and relative DMI (rDMI, g/kg(0.75)/d). MRT was also significantly correlated with diet type indices. Thus, both rDMI and diet type were better predictors of MRT than body mass. The rDMI-MRT relationship suggests that primate digestive differentiation occurs along a continuum between an "efficiency" (low intake, long MRT, high fiber digestibility) and an "intake" (high intake, short MRT, low fiber digestibility) strategy. Whereas simple-stomached (hindgut fermenting) species can be found along the whole continuum, foregut fermenters appear limited to the "efficiency" approach.


Insulin priming effect on estradiol-induced breast cancer metabolism and growth.
Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes.


Transamination of aminoalkylphosphonic acids with alpha ketoglutarate.
Dialyzed homogenates prepared from Escherichia coli, Tetrahymena pyriformis, sea anemone (Anthopleura elegantissima), and mouse liver were tested for ability to transaminate 17 aminoalkylphosphonic acids with alpha-ketoglutarate. 2-Aminoethylphosphonic acid (2-AEP), which occurs naturally in Tetrahymena and anemone, was transaminated by these latter organisms more than any of the substances tested, but not by preparations from liver or E. coli. 3-Aminopropylphosphonic acid was transaminated by all preparations, but much less by Tetrahymena or anemone than was 2-AEP. 2-Amino-3-phosphonopropionic acid was transaminated by all preparations. 2-Amino-4-phosphonobutyric acid was transaminated by three of the preparations, but not by liver. Of the other 13 substances tested, the following gave positive results: DL-1,2-diaminoethylphosphonic acid with E. coli, DL-1,2-diaminoethylphosphonic and aminomethylphosphonic acids with Tetrahymena, DL-1-aminopropylphosphonic acid with anemone, and DL-1-aminoethylphosphonic and DL-1-aminobutylphosphonic acids with liver. The significance of these transaminations is discussed.


Repression of c-myc gene expression by the thiol and disulfide forms of the cytoprotector amifostine.
The clinically approved cytoprotector amifostine, designated WR-2721, [S-2-(3-aminopropylamino)ethylphosphorothioic acid], protects against both radiation and drug-induced mutagenesis in animal systems. These effects extend over a wide concentration range making amifostine a strong candidate for evaluation as a possible cancer chemopreventive agent. To better identify and develop potential intermediate biomarkers for chemoprevention at the molecular level we applied the technique of differential display RT-PCR to assess the effects of both the thiol (SH), i.e. WR1065 and the disulfide (SS), i.e. WR-33278, metabolites of amifostine on gene expression in CHO-AA8 cells. Cells were exposed to either 40 microM or 4 mM of each agent for 30 min, and subsequent changes in gene expression were identified and contrasted to that found in corresponding untreated control cells. One band that showed a differential response was sequenced and was found to have 78% homology with a segment of the human pHL-1 cDNA clone contained in GenBank. This clone contains a COX III mitochondrial DNA insert and two exons of human c-myc. Northern blot analyses were performed by using the cloned human c-myc exon 1 probe to confirm whether c-myc gene expression was affected. Repression of c-myc expression was observed under all of the conditions evaluated. An exposure of cells to 40 microM of the disulfide form of amifostine was the most effective in repressing c-myc, i.e. 27% of control level. A concentration of 4 mM of the disulfide form reduced gene expression to 45% of the control level, while the thiol form was less effective, with 4 mM and 40 microM concentrations reducing c-myc gene expression to 65% and 46% of control levels, respectively.


The CART gene and human obesity: mutational analysis and population genetics.
The cocaine- and amphetamine-regulated transcript (CART) peptide is a recently characterized neuropeptide implicated in the control of appetite. We hypothesized that genetic variation in CART may contribute to human obesity. The entire coding region of CART was determined by nucleotide sequencing in 91 unrelated subjects with severe early-onset obesity. A novel amino acid change, Ser66Thr, was found in 2 probands and in 0 of 100 control subjects but did not cosegregate with obesity in family studies. Two common polymorphisms were found in the 3'-untranslated region (A1475G and deltaA1457). An effect of these polymorphisms on body composition and intermediate phenotypes related to obesity was examined in a large Caucasian population in the U.K. Neither polymorphism showed any significant relationship with obesity; however, men heterozygous for the A1475G variant had significantly lower waist-to-hip ratio (WHR), fasting plasma insulin, and fasting triglycerides. Regression analysis indicated that the effects on insulin and triglycerides were likely to be secondary to the effects on WHR. Thus, we have conducted the first systematic study of the CART gene in human obesity, and although no clear association with obesity was found, the data suggest that genetic variation in the CART locus might influence fat distribution and variables related to syndrome X.


Genomic identification and characterization of the elite strains Bradyrhizobium yuanmingense BR 3267 and Bradyrhizobium pachyrhizi BR 3262 recommended for cowpea inoculation in Brazil.
The leguminous inoculation with nodule-inducing bacteria that perform biological nitrogen fixation is a good example of an "eco-friendly agricultural practice". Bradyrhizobium strains BR 3267 and BR 3262 are recommended for cowpea (Vigna unguiculata) inoculation in Brazil and showed remarkable responses; nevertheless neither strain was characterized at species level, which is our goal in the present work using a polyphasic approach. The strains presented the typical phenotype of Bradyrhizobium with a slow growth and a white colony on yeast extract-mannitol medium. Strain BR 3267 was more versatile in its use of carbon sources compared to BR 3262. The fatty acid composition of BR 3267 was similar to the type strain of Bradyrhizobium yuanmingense; while BR 3262 was similar to Bradyrhizobium elkanii and Bradyrhizobium pachyrhizi. Phylogenetic analyses based on 16S rRNA and three housekeeping genes placed both strains within the genus Bradyrhizobium: strain BR 3267 was closest to B. yuanmingense and BR 3262 to B. pachyrhizi. Genome average nucleotide identity and DNA-DNA reassociation confirmed the genomic identification of B. yuanmingense BR 3267 and B. pachyrhizi BR 3262. The nodC and nifH gene analyses showed that strains BR 3267 and BR 3262 hold divergent symbiotic genes. In summary, the results indicate that cowpea can establish effective symbiosis with divergent bradyrhizobia isolated from Brazilian soils.


Comparing risk-adjustment methods for provider profiling.
Risk-adjustment and provider profiling have become common terms as the medical profession attempts to measure quality and assess value in health care. One of the areas of care most thoroughly developed in this regard is quality assessment for coronary artery bypass grafting (CABG). Because in-hospital mortality following CABG has been studied extensively, risk-adjustment mechanisms are already being used in this area for provider profiling. This study compares eight different risk-adjustment methods as applied to a CABG surgery population of 28 providers. Five of the methods use an external risk-adjustment algorithm developed in an independent population, while the other three rely on an internally developed logistic model. The purposes of this study are to: (i) create a common metric by which to display the results of these various risk-adjustment methodologies with regard to dichotomous outcomes such as in-hospital mortality, and (ii) to compare how these risk-adjustment methods quantify the 'outlier' standing of providers. Section 2 describes the data, the external and internal risk-adjustment algorithms, and eight approaches to provider profiling. Section 3 then demonstrates the results of applying these methods on a data set specifically collected for quality improvement.


Effect of sodium nitrite on toxin production by Clostridium botulinum in bacon.
Pork bellies were formulated to 0, 30, 60, 120, 170, or 340 mug of nitrite per g of meat and inoculated with Clostridium botulinum via pickle or after processing and slicing. Processed bacon was stored at 7 or 27 C and assayed for nitrite, nitrate, and botulinal toxin at different intervals. Nitrite levels declined during processing and storage. The rate of decrease was more rapid at 27 than at 7 C. Although not added to the system, nitrate was detected in samples during processing and storage at 7 and 27 C. The amount of nitrate found was related to formulated nitrite levels. No toxin was found in samples incubated at 7 C throughout the 84-day test period. At 27 C, via pickle, inoculated samples with low inoculum (210 C. botulinum per g before processing and 52 per g after processing) became toxic if formulated with 120 mug of nitrite per g of meat or less. Toxin was not detected in bacon formulated with 170 or 340 mug of nitrite per g of meat under these same conditions. Toxin was detected at all formulated nitrite levels in bacon inoculated via the pickle with 19,000 C. botulinum per g (4,300 per g after processing) and in samples inoculated after slicing. However, increased levels of formulated nitrite decreased the probability of botulinal toxin formation in bacon inoculated by both methods.


Protein expression changes during human triple negative breast cancer cell line progression to lymph node metastasis in a xenografted model in nude mice.
Triple negative breast cancers (TNBC) lacking hormone receptors and HER-2 amplification are very aggressive tumors. Since relevant differences between primary tumors and metastases could arise during tumor progression as evidenced by phenotypic discordances reported for hormonal receptors or HER-2 expression, in this analysis we studied changes that occurred in our TNBC model IIB-BR-G throughout the development of IIB-BR-G-MTS6 metastasis to the lymph nodes (LN) in nude mice, using an antibody-based protein array to characterize their expression profile. We also analyzed their growth kinetics, migration, invasiveness and cytoskeleton structure in vitro and in vivo. In vitro IIB-BR-G-MTS6 cells grew slower but showed higher anchorage independent growth. In vivo IIB-BR-G-MTS6 tumors grew significantly faster and showed a 100% incidence of LN metastasis after s.c. inoculation, although no metastasis was observed for IIB-BR-G. CCL3, IL1β, CXCL1, CSF2, CSF3, IGFBP1, IL1α, IL6, IL8, CCL20, PLAUR, PlGF and VEGF were strongly upregulated in IIB-BR-G-MTS6 while CCL4, ICAM3, CXCL12, TNFRSF18, FIGF were the most downregulated proteins in the metastatic cell line. IIB-BR-G-MTS6 protein expression profile could reflect a higher NFκB activation in these cells. In vitro, IIB-BR-G displayed higher migration but IIB-BR-G-MTS6 had more elevated matrigel invasion ability. In agreement with that observation, IIB-BR-G-MTS6 had an upregulated expression of MMP1, MMP9, MMP13, PLAUR and HGF. IIB-BR-G-MTS6 tumors presented also higher local lymphatic invasion than IIB-BR-G but similar lymphatic vessel densities. VEGFC and VEGFA/B expression were higher both in vitro and in vivo for IIB-BR-G-MTS6. IIB-BR-G-MTS6 expressed more vimentin than IB-BR-G cells, which was mainly localized in the cellular extremities and both cell lines are E-cadherin negative. Our results suggest that IIB-BR-G-MTS6 cells have acquired a pronounced epithelial-to-mesenchymal transition phenotype. Protein expression changes observed between primary tumor-derived IIB-BR-G and metastatic IIB-BR-G-MTS6 TNBC cells suggest potential targets involved in the control of metastasis.


Impact of a timed-release FSH treatment from 2 to 6 months of age in bulls I: Endocrine and testicular development of beef bulls.
In prepubertal males, FSH facilitates Sertoli cell proliferation and testis maturation. The study aimed to determine the effect of an exogenous FSH treatment on hormone secretion and testis development in Angus bulls. Bulls (n = 22) weaned at 53 ± 3.8 days of age were randomized into two treatment groups based on age and pedigree. Beginning at Day 59, bulls were injected im every 3.5 days with either 30 mg FSH (Folltropin-V; NIH-FSH-P1 units) in a 2% hyaluronan solution (FSH-HA, n = 11) or saline (control, n = 11) until Day 167.5. Blood samples to assess FSH, activin A, and testosterone were collected prior to each treatment. To determine how FSH profiles surrounding treatment were affected, three intensive blood sampling periods, each encompassing two treatment administrations, began at Day 66, 108, and 157, and blood was collected at 0, 6, 12, 18, 24, 36, 60, and 84 h respective to time of treatment. Scrotal circumference (SC) and BW were measured monthly. Bulls were castrated at Day 170 to measure testis size, seminiferous tubule diameter, and the number of Sertoli and germ cells per tubule cross-section. During intensive FSH sampling, FSH-HA bulls experienced an increase (P < 0.05) in FSH over control bulls for at least 18 h post-injection in all instances. In blood collected every 3.5 days, FSH concentrations in FSH-HA bulls were increased (P < 0.05) over initial Day 59 concentration from Day 97.5-167.5. FSH concentrations did not differ between treatments from Day 59-90.5, but were greater (P < 0.05) in FSH-HA from Day 94-167.5. Concentrations of activin A assessed for Day 59, 83.5, 94, 129, and 167.5 were greater (P < 0.05) in FSH-HA than control bulls on Day 83.5 and 94. The treatments did not differ (P > 0.1) in testosterone, BW, SC, testis size, tubule diameter, or number of germ cells per tubule. However, the number of Sertoli cells per tubule was greater in FSH-HA than control bulls (45.2 ± 1.4 vs. 41.6 ± 0.9 cells, P < 0.05). In summary, FSH-HA treatment every 3.5 days from Day 59-167.5 maintained elevated FSH for a minimum of 18 h post-injection, likely attributable to the addition of HA. We propose the exogenous FSH-HA treatment initiates a positive feedback loop that includes an increased density of Sertoli cells per tubule cross-section, which is related to increased activin A concentrations on Day 83.5 and 94. Furthermore, this activin A increase preceded an increase in endogenous FSH from Day 94-167.5 in FSH-HA bulls.


Direct-to-patient disclosure of results of mismatch repair screening for Lynch syndrome via electronic personal health record: a feasibility study.
The adoption of universal mismatch repair screening of colorectal and endometrial cancers has the potential to improve detection of Lynch syndrome, as well as to improve health outcomes among cancer patients and their family members. Electronic patient health records represent an innovative, resource-efficient route of delivering results directly to patients that could be enhanced by multimedia interventions to improve critical downstream outcomes. The current study examines the feasibility and acceptability of this approach. Patients hospitalized for resection of colorectal or endometrial cancer were recruited to receive their mismatch repair result via institutional electronic patient health record. Baseline and follow-up assessments were conducted. In all, 74% (49/66) of eligible patients consented, and 81% (29/36) of participants who had a result posted to their electronic patient health record completed follow-up, surpassing feasibility thresholds, with 14% (5/36) receiving an abnormal result. Ratings of the study approach surpassed the acceptability threshold--97% had a mean score of ≥ 4 on a 7-point scale--and were high, regardless of whether the results were normal or abnormal. Ineligibility was more common among non-white patients (P = 0.009) and patients ≥ 65 of age (P = 0.035) due to either low Internet use or access to the Internet. Electronic patient health record-based result disclosure for mismatch repair screening is feasible to study and is acceptable to patients, but minority and elderly patients may experience greater barriers to participation.Genet Med 16 11, 854-861.


Antioxidant health effects of aged garlic extract.
Oxidative modification of DNA, proteins and lipids by reactive oxygen species (ROS) plays a role in aging and disease, including cardiovascular, neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic that are aged over a prolonged period to produce aged garlic extract (AGE) contain antioxidant phytochemicals that prevent oxidant damage. These include unique water-soluble organosulfur compounds, lipid-soluble organosulfur components and flavonoids, notably allixin and selenium. Long-term extraction of garlic (up to 20 mo) ages the extract, creating antioxidant properties by modifying unstable molecules with antioxidant activity, such as allicin, and increasing stable and highly bioavailable water-soluble organosulfur compounds, such as S-allylcysteine and S-allylmercaptocysteine. AGE exerts antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and increasing glutathione in the cells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusion damage and inhibiting oxidative modification of LDL, thus protecting endothelial cells from the injury by the oxidized molecules, which contributes to atherosclerosis. AGE inhibits the activation of the oxidant-induced transcription factor, nuclear factor (NF)-kappa B, which has clinical significance in human immunodeficiency virus gene expression and atherogenesis. AGE protects DNA against free radical--mediated damage and mutations, inhibits multistep carcinogenesis and defends against ionizing radiation and UV-induced damage, including protection against some forms of UV-induced immunosuppression. AGE may have a role in protecting against loss of brain function in aging and possess other antiaging effects, as suggested by its ability to increase cognitive functions, memory and longevity in a senescence-accelerated mouse model. AGE has been shown to protect against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy and against liver toxicity caused by carbon tetrachloride (an industrial chemical) and acetaminophen, an analgesic. Substantial experimental evidence shows the ability of AGE to protect against oxidant-induced disease, acute damage from aging, radiation and chemical exposure, and long-term toxic damage. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE, i.e., reducing the risk of cardiovascular disease, stroke, cancer and aging, including the oxidant-mediated brain cell damage that is implicated in Alzheimer's disease.


[The psychophysiological aspects of treating obesity with Izolipan].
20 patients with obesity were examined. Their weight was increased as compared with ideal values by 30-140%. The patients were characterized by anxious or depressive disturbances (Spilberger's and Beck tests) and alterations of alimentary behaviour in form of prevalence of emotional and external alimentary behaviour (EMAB and EAB, respectively). The study of cognitive negative variations (CNV) revealed the decrease of late wave's area, which correlated reversely with levels of anxiety, depression and EMAB expression. The Isolipan administration (15 mg, 2 times/daily during 3 months) together with hypocaloric diet resulted in average weight loss equal to 12.3 kg in the whole group. These changes correlated well with normalization of both alimentary behaviour (in the form of decrease of EMAB and EAB indices) and emotional state, and increase of decreased late CNV with disappearance of pathological psycho-physiological correlations between CNV and emotional state.


Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease.
Mutations in protein kinase C substrate 80K-H (PRKCSH), encoding for the protein hepatocystin, cause autosomal dominant polycystic liver disease (PCLD), which is clinically characterized by the presence of multiple liver cysts. PCLD has been documented in families from Europe (Netherlands, Belgium, Finland) as well as from the United States. In this article, we report results from extensive mutational analysis of the PRKCSH gene in a group of 14 PCLD families and 65 singleton cases of Dutch and Finnish descent with multiple simple liver cysts. We identified PRKCSH mutations in 12 families and in 3 sporadic cases. In 8 of 10 Finnish families we detected the 1437+2delTG splice-site mutation. In Dutch families, we found 2 other mutations that affect correct splicing of PRKCSH: 292+1 G>C (2 families) and 1338-2 A>G (1 family). In another Dutch family, we detected a novel deletion (374-375delAG) in exon 6, predicting an abnormal shortened protein. Investigation of the carrier haplotypes identified a common founder chromosome in unrelated individuals in each of the 3 identified splice-site mutations. In 2 Finnish families with dominantly inherited PCLD, and in 62 of 65 sporadic cases with multiple simple liver cysts, we failed to demonstrate any PRKCSH mutation. This corroborates the notion that autosomal dominant PCLD is genetically heterogeneous. In conclusion, we propose that, on the basis of our results, genetic screening for PRKCSH gene mutations should be limited to patients either with a positive family history for PCLD or who have severe polycystic liver disease.


Changing activities of galactose-metabolizing enzymes during perfusion of suckling-rat liver.
The specific activities of the galactose-metabolizing enzymes, galactokinase (EC 184.108.40.206), galactose-1-phosphate uridyltransferase (EC 126.96.36.199), and UDPgalactose 4-epimerase (EC 22.214.171.124), in suckling-rat livers perfused for 90 min with 1 and 4 mM galactose fluctuate significantly with a different pattern of change for each enzyme. Perfusion for 30 min with galactose resulted in a significant increase of transferase specific activity followed by a precipitous decline to about one-fifth of the activity in unperfused liver at 90 min. The increase in transferase activity was also observed when D-glucose was perfused but not when L-glucose, D-fructose, D-xylose, or D-ribose was added to the perfusate. No such changes in transferase activity were observed when adult-rat liver was perfused with galactose. Epimerase activity in the suckling-rat liver was relatively low, and the changes in its activity correlated best with the uptake rate of galactose. The perfused suckling-rat liver may provide a model system for examination of factors that modulate the specific activity of galactose-metabolizing enzymes and effect the metabolism of galactose.


Growth restriction in pregnancies of opioid-dependent mothers.
Intrauterine growth restriction (IUGR) can lead to significant intellectual and behavioural problems in later life. IUGR represents a frequent feature of pregnancies of opioid-dependent mothers (ODMs), the causes of which are largely unknown. The objective of this study was to determine the independent risk factors for IUGR in ODMs. We performed a retrospective study analysing maternal and neonatal parameters from pregnancies of ODM maintained on methadone (n=215). These were compared to smoking non-ODM and non-smoking non-ODM control groups matched for maternal age, gestational age at delivery, infant birth date and sex. Logistic regression analysis was performed on all parameters with the outcome of IUGR. Fifty-seven infants (27%) of ODMs showed IUGR. Compared to non-smoking non-ODMs, the risk of IUGR in non-smoking ODMs was almost four times higher (relative risk 3.48, 95% CI 1.70 to 7.14). Growth restriction was independent of the last maternal methadone dose and the cumulative methadone dose during pregnancy. In addition, whereas nicotine and female sex impacted on IUGR in non-ODMs (nicotine: OR 3.45, 95% CI 1.82 to 6.67; sex: OR 2.37, 95% CI 1.25 to 4.50), these parameters had no influence on IUGR in ODMs. Maternal body mass index (BMI) was identified as the only independent risk factor for IUGR in infants of ODMs (OR 1.15, 95% CI 1.03 to 1.28). IUGR in pregnancies of ODM is related to maternal BMI rather than to opiate dosing, nicotine use or infant sex. BMI may itself be an indirect marker of several other genetic, nutritional and/or social determinants of IUGR.


Medication Adherence With Polypill in Cardiovascular Disease and High-Risk Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Involving 7364 Participants.
Considering the worldwide mortality and morbidity of cardiovascular diseases (CVDs), the necessity of using multiple pills due to the chronicity of this condition, and the importance of medication adherence in these patients, we conducted this systematic review and meta-analysis to assess the polypill effect on adherence in patients with established CVD and at high risk. To accomplish this review, we searched various databases to access grey literature and several electronic databases to find randomized controlled trials (RCTs) assessing polypills compared to individual pills from January 2000 to October 2022. The outcomes were primarily medication adherence, secondarily systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C) serum level, and serious adverse events (SAEs). Ultimately, 2820 studies were detected and narrowed to 8 RCTs based on the eligibility criteria. In this study, involving 7364 patients, there was a significant improvement in medication adherence in the polypill group compared to the individual pills group (Risk Ratio [RR] = 1.29; [95%CI: 1.10; 1.50]). Out of secondary outcomes, SBP was significantly decreased (Mean Difference [MD] = -1.72 mmHg; [95%CI: -2.40; 1.03]), but LDL-C serum level (MD = -0.65 mg/dl; [95%CI: -4.47; 3.16]) and SAE (RR = 1.08; [95%CI: f0.98; 1.20]) did not have a notable difference in polypill compared to individual pills.


Determining staffing requirements for blood donor clinics: the Canadian Blood Services experience.
Canadian Blood Services runs approximately 16,000 donor clinics annually. While there were more than 220 different clinic configurations used in 2011 and 2012, 67% of all clinic configurations followed one of 51 standard models. As part of operational planning for current and future configurations it was necessary for Canadian Blood Services to calculate staffing requirements for standard clinic models. In this article we present a method that incorporates both cost control and impact on donor experience. We calculate staffing requirements to minimize costs, but adjust using queuing theory to ensure donor wait time metrics are met. The method can be applied in a wide variety of situations. Although developed for a particular study, the methods described in this article can be applied in a wide variety of situations. A case study in which the model is used to review existing staffing arrangements at Canadian Blood Services is presented. The staffing model can be used to balance the requirements of minimizing staffing costs with that of ensuring that donors do not suffer unnecessary delays. Moreover, in an example application, savings of 3.4% were identified through the modeling process.


Hyperbaric oxygen as an adjuvant for athletes.
There has recently been a resurgence in interest in hyperbaric oxygen (HBO) treatment in sports therapy, especially in Japan. Oxygen naturally plays a crucial role in recovery from injury and physiological fatigue. By performing HBO treatment, more oxygen is dissolved in the plasma of the pulmonary vein via the alveolar, increasing the oxygen reaching the peripheral tissues. HBO treatment is therefore expected to improve recovery from injury and fatigue. HBO treatment has been reported to reduce post-injury swelling in animals, and in humans; swelling was also mitigated, but to a lesser extent. Positive results have also been reported regarding tissue remodelling after injury, with injuries involving bones, muscles and ligaments showing improved recovery. Furthermore, HBO treatment has effectively increased recovery from fatigue. This was clearly seen at the Nagano Winter Olympics, where sports players experiencing fatigue were successfully treated, enabling the players to continue performing in the games. Despite its potential, HBO treatment does have its risks. Increasing oxygen levels in tissues poses a risk to DNA through oxidative damage, which can lead to pathological changes in the CNS and the lungs. Regarding the operating of HBO systems, safer administration should be advised. Further research into HBO treatment is required if this therapy is to become more widespread. It should become possible to tailor treatment to an individual's condition in order to use HBO treatment efficiently.