A smooth covariate rank transformation for use in regression models with a sigmoid dose-response function.
We consider how to represent sigmoid-type regression relationships in a practical and parsimonious way. A pure sigmoid relationship has an asymptote at both ends of the range of a continuous covariate. Curves with a single asymptote are also important in practice. Many smoothers, such as fractional polynomials and restricted cubic regression splines, cannot accurately represent doubly asymptotic curves. Such smoothers may struggle even with singly asymptotic curves. Our approach to modeling sigmoid relationships involves applying a preliminary scaled rank transformation to compress the tails of the observed distribution of a continuous covariate. We include a step that provides a smooth approximation to the empirical cumulative distribution function of the covariate via the scaled ranks. The procedure defines the approximate cumulative distribution transformation of the covariate. To fit the substantive model, we apply fractional polynomial regression to the outcome with the smoothed, scaled ranks as the covariate. When the resulting fractional polynomial function is monotone, we have a sigmoid function. We demonstrate several practical applications of the approximate cumulative distribution transformation while also illustrating its ability to model some unusual functional forms. We describe a command, acd, that implements it.


Aliphatic C-H bond activation initiated by a (mu-eta2:eta2-peroxo)dicopper(II) complex in comparison with cumylperoxyl radical.
A (mu-eta(2):eta(2)-peroxo)dicopper(II) complex, [Cu(2)(H-L)(O(2))](2+) (1-O(2)), supported by the dinucleating ligand 1,3-bis[bis(6-methyl-2-pyridylmethyl)aminomethyl]benzene (H-L) is capable of initiating C-H bond activation of a variety of external aliphatic substrates (SH(n)): 10-methyl-9,10-dihydroacridine (AcrH(2)), 1,4-cyclohexadiene (1,4-CHD), 9,10-dihydroanthracene (9,10-DHA), fluorene, tetralin, toluene, and tetrahydrofuran (THF), which have C-H bond dissociation energies (BDEs) ranging from approximately 75 kcal mol(-1) for 1,4-CHD to approximately 92 kcal mol(-1) for THF. Oxidation of SH(n) afforded a variety of oxidation products, such as dehydrogenation products (SH((n-2))), hydroxylated and further-oxidized products (SH((n-1))OH and SH((n-2))=O), dimers formed by coupling between substrates (H((n-1))S-SH((n-1))) and between substrate and H-L (H-L-SH((n-1))). Kinetic studies of the oxidation of the substrates initiated by 1-O(2) in acetone at -70 degrees C revealed that there is a linear correlation between the logarithms of the rate constants for oxidation of the C-H bonds of the substrates and their BDEs, except for THF. The combination of this correlation and the relatively large deuterium kinetic isotope effects (KIEs), k(2)(H)/k(2)(D) (13 for 9,10-DHA, approximately > 29 for toluene, and approximately 34 for THF at -70 degrees C and approximately 9 for AcrH(2) at -94 degrees C) indicates that H-atom transfer (HAT) from SH(n) (SD(n)) is the rate-determining step. Kinetic studies of the oxidation of SH(n) by cumylperoxyl radical showed a correlation similar to that observed for 1-O(2), indicating that the reactivity of 1-O(2) is similar to that of cumylperoxyl radical. Thus, 1-O(2) is capable of initiating a wide range of oxidation reactions, including oxidation of aliphatic C-H bonds having BDEs from approximately 75 to approximately 92 kcal mol(-1), hydroxylation of the m-xylyl linker of H-L, and epoxidation of styrene (Matsumoto, T.; et al. J. Am. Chem. Soc. 2006, 128, 3874).


[Electron-microscopic and biochemical characteristics of pterygia (author's transl)].
Histologically, pterygium is characterized, apart from the presence of typical collagen fibers, by the appearance of fibres which take up elastic stain but differ from normal elastic tissue, as was confirmed by electron-microscopic investigations. Thus, "elastoid degeneration" of collagen is characterized by the loss of the characteristic periodic fibril structure and by the appearance of coiled and knotty fibres. Collagen types in pterygium were identified biochemically for the first time. The main bulk of collagenous tissue consists of 80-90% Type I collagen, while only 10-20% Type III collagen was detected. Type IV collagen (basal membrane collagen) was present in low amounts. Digestion with elastase resulted in 20% solubilization of pterygium, while bacterial collagenase digested up to 40% of the tissue dry weight.


Severe Acute Respiratory Syndrome Coronavirus-2 Inactivation Activity of the Polyphenol-Rich Tea Leaf Extract with Concentrated Theaflavins and Other Virucidal Catechins.
Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is producing a large number of infections and deaths globally, the development of supportive and auxiliary treatments is attracting increasing attention. Here, we evaluated SARS-CoV-2-inactivation activity of the polyphenol-rich tea leaf extract TY-1 containing concentrated theaflavins and other virucidal catechins. The TY-1 was mixed with SARS-CoV-2 solution, and its virucidal activity was evaluated. To evaluate the inhibition activity of TY-1 in SARS-CoV-2 infection, TY-1 was co-added with SARS-CoV-2 into cell culture media. After 1 h of incubation, the cell culture medium was replaced, and the cells were further incubated in the absence of TY-1. The viral titers were then evaluated. To evaluate the impacts of TY-1 on viral proteins and genome, TY-1-treated SARS-CoV-2 structural proteins and viral RNA were analyzed using western blotting and real-time RT-PCR, respectively. TY-1 showed time- and concentration-dependent virucidal activity. TY-1 inhibited SARS-CoV-2 infection of cells. The results of western blotting and real-time RT-PCR suggested that TY-1 induced structural change in the S2 subunit of the S protein and viral genome destruction, respectively. Our findings provided basic insights in vitro into the possible value of TY-1 as a virucidal agent, which could enhance the current SARS-CoV-2 control measures.


Lycopene and Metabolic Syndrome: A Systematic Review of the Literature.
Cardiometabolic risk factors increase the likelihood of cardiovascular disease development by 2-fold. Lycopene, a potent lipophilic antioxidant, may be able to mediate oxidative stress, a mechanism underpinning metabolic syndrome (MetS) and its risk factors. This is, to our knowledge, the first systematic review of the literature with the purpose of investigating the relation between circulating lycopene or dietary intake of lycopene and MetS as well as its risk factors. The review was conducted using PubMed and EBSCOhost databases with the search terms "lycopene" and "metabolic syndrome." Inclusion criteria included human studies published in English in a scholarly, peer-reviewed journal and evaluation of lycopene in relation to ≥3 of the 5 MetS risk factors as defined by the National Cholesterol Education Program's Adult Treatment Panel III (ATP III) report. The process identified 11 studies, including 8 cross-sectional and 3 intervention studies. Cross-sectional studies were grouped into 3 categories, with several studies falling into >1 category, based on results reporting associations of lycopene with the prevalence and outcomes of MetS (5 studies), presence of ATP III risk factors (4 studies), and variables mediating lycopene's influence on MetS risk (3 studies). All studies in each category reported significant protective associations. Of the 3 intervention studies, all reported significant protective effects from a lycopene-rich beverage, despite varying doses and durations of intake. Although a protective relation between lycopene and MetS was generally supported, different MetS components appeared to be influenced by lycopene rather than demonstrating consistent improvement in a single component. Thus, additional research is needed to elucidate the mechanistic effects of lycopene on MetS, as well as to determine evidence-based recommendations concerning dose-durational effects of lycopene and MetS risk reduction. In conclusion, the evidence of lycopene's benefit exists such that lycopene status or lycopene consumption may be associated with favorable alterations to the components of MetS.


Macrophage-derived apoptotic bodies impair the osteogenic ability of osteoblasts in periodontitis.
Periodontitis is induced by the imbalance between osteoblast and osteoclast activity, which leads to periodontal tissue destruction. Macrophages play a vital role in periodontitis. However, the hypoxic periodontal environment will also induce macrophage apoptosis within a short time. Apoptotic bodies (ABs) are the major products generated from apoptotic cells, but whether macrophage-derived ABs play a regulatory role as their mother cells in periodontitis remains unknown. In the present study, we aimed to investigate the effects of ABs on osteoblasts. ABs derived from hypoxia-induced macrophages were co-cultured with osteoblasts and the impact of ABs on osteoblast differentiation in vitro was assessed. In vivo, periodontitis model was established and macrophages-derived ABs were injected into the gingival sulcus. The effects of ABs on periodontal bone resorption were determined. The results showed that ABs significantly inhibit osteoblast differentiation and promoted alveolar bone resorption in periodontitis. MicroRNA (miRNAs) array analysis was performed and revealed that miR-483-5p is the key miRNA in ABs. Dual luciferase reporter assays were performed and confirmed that miR-483-5p targeted Col1A1 mRNA and attenuated its expression. Macrophage-derived ABs inhibit osteoblast differentiation via the transfer of miR-483-5p, which downregulates Col1A1 expression and finally suppresses osteogenic activity.


On the performance of chain codes for quantization of line drawings.
A class of quantization schemes is presented which generalizes various existing chain coding methods. For the general case, simple expressions are derived for the probabilities of the directional elements from which we can determine the number of curve points and the length of the quantized curve. These results allow for the comparison of performance of the various encoding schemes.


The origins, pathways and terminations of neurons with VIP-like immunoreactivity in the guinea-pig small intestine.
We have analyzed changes in the distributions of terminals with vasoactive intestinal polypeptide (VIP)-like immunoreactivity, and accumulations in severed processes, that occur after lesions of intrinsic and extrinsic nerve pathways of the guinea-pig small intestine. The observations indicate that enteric vasoactive intestinal polypeptide immunoreactive neurons have the following projections. Nerve cell bodies in the myenteric plexus provide varicose processes to the underlying circular muscle; the majority of these pathways, if they extend at all in the anal or oral directions, do so for distances of less than 1 mm. Nerve cell bodies of the myenteric plexus also project anally to provide terminals to other myenteric ganglia. The lengths of the majority of these projections are between 2 and 10 mm, with an average length of about 6 mm. Processes of myenteric neurons also run anally in the myenteric plexus and then penetrate the circular muscle to provide varicose processes in the submucous ganglia at distances of up to 15 mm, the average length being 9-12 mm. In addition, there is an intestinofugal projection of myenteric neurons whose processes end around nerve cell bodies of the coeliac ganglia. A similar projection from the colon supplies the inferior mesenteric ganglia. The nerve cell bodies in submucous ganglia give rise to a subepithelial network of fibres in the mucosa and also supply terminals to submucous arterioles. It is concluded that vasoactive intestinal polypeptide is contained in neurons of a number of intrinsic nerve pathways, influencing motility, blood flow and mucosal transport. The myenteric neurons that project to prevertebral sympathetic ganglia may be involved in intestino-intestinal reflexes.


Core body temperature in obesity.
A lower core body temperature set point has been suggested to be a factor that could potentially predispose humans to develop obesity. We tested the hypothesis that obese individuals have lower core temperatures than those in normal-weight individuals. In study 1, nonobese [body mass index (BMI; in kg/m(2)) <30] and obese (BMI ≥30) adults swallowed wireless core temperature-sensing capsules, and we measured core temperatures continuously for 24 h. In study 2, normal-weight (BMI of 18-25) and obese subjects swallowed temperature-sensing capsules to measure core temperatures continuously for ≥48 h and kept activity logs. We constructed daily, 24-h core temperature profiles for analysis. Mean (±SE) daily core body temperature did not differ significantly between the 35 nonobese and 46 obese subjects (36.92 ± 0.03°C compared with 36.89 ± 0.03°C; P = 0.44). Core temperature 24-h profiles did not differ significantly between 11 normal-weight and 19 obese subjects (P = 0.274). Women had a mean core body temperature ≈0.23°C greater than that of men (36.99 ± 0.03°C compared with 36.76 ± 0.03°C; P < 0.0001). Obesity is not generally associated with a reduced core body temperature. It may be necessary to study individuals with function-altering mutations in core temperature-regulating genes to determine whether differences in the core body temperature set point affect the regulation of human body weight. These trials were registered at clinicaltrials.gov as NCT00428987 and NCT00266500.


Mechanisms of thrombin-induced modifications of human platelet cytoskeleton.
Thrombin treated with phenylmethanesulphonyl fluoride, like active enzyme, promotes modifications to human platelet cytoskeleton. The removal of active thrombin by hirudin partially reverses this process. Chymotrypsin-treated platelets do not modify their cytoskeleton after thrombin stimulus, but are still able to increase their adhesiveness to collagen. It is concluded that thrombin influences the cytoskeleton and adhesion by non-enzymic mechanisms which may be mediated by different modulators.


[Maternal risk factors associated to stillbirth in a public hospital at West of Mexico].
Mortality rates in preterm births and stillbirth are high. To identify maternal risk factors relating to stillbirth in preterm infants. We conducted a cross-sectional, analytic study of 1,022 newborns between 20 and 36 weeks of gestation, from September 2004 to August 2005. Stillbirth was defined as fetal death prior to expulsion or extraction from the mother. Data was collected prospectively by directly interviewing the pregnant women and from the medical chart. The dependent variable was stillbirth and the independent ones were the maternal risk factors. Associations were evaluated by logistic regression. RESULTS. One thousand and twenty-four (1,024) preterm births were detected in a total of 14,882 births (6.9%/year). One hundred and fifty-two (152) were stillborn and 870 were live births. The fetal mortality rate was 10.3 per 1,000 live births. The least common maternal factors associated to stillbirth included: urinary tract infection (22/152, 14% vs. 224/869, 26%, p = 0.020), PMR > 24 h (18/152, 12% vs. 172/869, 20%, p = 0.020) and cesarean delivery (24/138, 17% vs. 344/719, 48%, p < 0.001). The crude odd risk ratios for stillbirth included spontaneous preterm delivery (OR 4.38, CI95% 2.70-7.17) and deficient prenatal care (OR 2.64, CI95% 1.83-3.82). By multivariate analysis, stillbirth predictors included: spontaneous preterm delivery (OR 4.00, CI 95% 2.61-6.61) and deficient prenatal care (OR 2.54, CI 95% 1.78-3.62). Deficient prenatal care was the only statistically significant and clinically coherent variable predicting stillbirth.


RNA splice site utilization by simian immunodeficiency viruses derived from sooty mangabey monkeys.
Alternative splicing of the full-length, primary transcript into numerous subgenomic mRNAs is one way that lentiviral gene expression is regulated. Because the behaviors of different viral isolates might reflect in part differences in splicing, we Investigated the patterns of splice site utilization by simian immunodeficiency viruses (SIVs)-originally isolated from sooty mangabey monkeys (Cercocebus atys) We used reverse transcription-polymerase chain reaction (RT-PCR), molecular cloning, and DNA sequencing approaches to characterize SIVdeltaB670, a pathogenic and neurovirulent isolate, and SIVsmmH4, a related molecular clone. The majority of randomly selected SIVdeltaB670 and SIVsmmH4 partial cDNAs contained tat, rev, nef, and long terminal repeat (LTR) intron splice donor and acceptor sites positioned as expected based on the proviral sequence of SIVsmmH4. Nearly all (87%) of the partial cDNAs analyzed contained a spliced LTR intron. A greater number of partial cDNAs derived from SIVdeltaB670-infected cells contained putative alternatively spliced introns In comparison to SIVsmmH4, including two previously undocumented splice junctions involving the LTR intron splice donor. These data provide the first comprehensive analysis of splice site utilization by an isolate of SIV in comparison to a related molecular clone and the first characterization of SIVsmm splice site utilization.


Effaced Enigmata.
Severe head injury or brain injury presents clinical neuroscientists with a unique challenge. Based on an objective assessment of cognitive and neurological function, it is sometimes hard to recognize our patients as members of our moral community (actually or potentially) but we treat them as if that were is the case, and, therefore, as if they need rescuing. Thus their existences as enigmata-beings who may or may not reveal themselves to us through social and personal function realized in conversations and relationships-are in doubt. However, the objective mode of assessing individuals and their mental functions needs to be bracketed here, as we reconnect with them and offer them our help in the restorative journey that they need to take. The journey has many tortuous paths comprising it, not the least of which is the existential question of whether the damaged human being with whom we are engaged actually can be restored to a meaningful life. A negative answer to that question can bring the whole process to an abrupt end. Neuroscience cannot answer some of these questions, as they are ethical. Is this a life worth living and are our commitments going to go the distance that must be traversed here. Therefore, this is an area where ethics take priority over neuroscience, and it is on our ethical response that everything else hinges. Understanding the light this throws on the nature of a human being takes us to the heart of the value of every human being and the nexus of mutuality that is the moral community.


Castrati singers--all for fame.
The phenomenon of castration is very closely associated with the baroque era. In a period that placed emphasis on pure sensual pleasure, castrati singers, with their angelic voices, were a perverted outcome of this ambition. It was the intention that these castrato voices with their supernatural sound would mesmerize audiences. At that time, it could be said that within certain society circles, an addiction to these voices existed. Equally, they were oblivious to the spiritual side of the lives of the castrati. Farinelli, Caffarelli, and Senesino, three of the most famous castrati, were the first musical superstars of the 18th century. Their voices moved decadent audiences to tears and standing ovations. The price for this fame was, however, high. The aim of this review is to provide an overview of castrati singers, especially in the baroque era, their sexuality and the effects of castration on their physical development. A literature search of relevant databases, books, and articles in journals was performed and compared with current data concerning androgen suppression and endocrine aspects of male sexual dysfunction. The effects of castration on physical development were notoriously erratic. Much depended on the timing of the operation: boys pruned before the age of 10 or so very often grew up with feminine features; smooth, hairless bodies, incipient breasts, infantile penis, and often a complete lack of sex drive. The peak success of the castrati ended with the end of the 18th century. The last castrato was Alessandro Moreschi, a solo singer in the choir of the Sistine Chapel of the Vatican. Following the ban on castration, Pope Pius X sent him into retirement in 1912, thus putting an end to a very impressive part of the history of music.


Pallidal neuronal discharge in Parkinson's disease following intraputamenal fetal mesencephalic allograft.
Human intrastriatal fetal allografts survive over long periods of time in the brains of Parkinson's disease (PD) patients and integrate into host circuitry. However, some grafted patients with a prior history of levodopa-induced dyskinesias have developed off-medication dyskinesias and dystonias following allografting whose mechanism remains poorly understood. The authors present single-unit discharge characteristics in the external and internal globus pallidus (GPe and GPi) in an awake patient with PD undergoing microelectrode-guided surgery for pallidal deep brain stimulation, 10 years following bilateral intraputamenal fetal mesencephalic allografting in an NIH-funded protocol. Pallidal single-unit activity at 'rest' and during active movement was evaluated and compared with data sets from 13 PD patients in the 'off-medication' state and from one non-dyskinetic PD patient in the 'on-medication' state. Analysis of firing rate, bursting discharge and oscillatory activity showed that the graft corrected some, but not all, of the abnormalities associated with the off-medication state. Additionally, in the transplanted patient, voluntary hand movement produced a marked reduction in pallidal discharge rate at multiple GPi recording sites, which was not observed during active movement in other patients. These findings are consistent with a persistent effect of transplanted dopamine cells on basal ganglia outflow and suggest a mechanism for the graft-induced dystonic phenotype.


Use of multiparameter flow cytometry to determine the effects of monoterpenoids and phenylpropanoids on membrane polarity and permeability in staphylococci and enterococci.
Monoterpenoids and phenylpropanoids are major components of many plant essential oils and are relatively simple, low-molecular-weight compounds with antimicrobial activity. This study used multiparameter flow cytometry to examine changes in membrane polarity and permeability in Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis following exposure to the monoterpenoids carvacrol, 1,8-cineole and terpinen-4-ol and the phenylpropanoids eugenol and cinnamaldehyde. Melaleuca alternifolia (tea tree) essential oil was also investigated. The fluorescent dyes DiOC(2)(3) (3,3'-diethyloxacarbocyanine oxide) and TO-PRO(®)-3 were used to assess membrane potential and permeability, respectively, following treatment with the minimum inhibitory concentration (MIC) of each test compound for 5 min and 30 min. Four subpopulations of cells were identified based on polarity and permeability. Eugenol treatment resulted in the greatest depolarisation and permeabilisation at 5 min, followed by carvacrol. Cinnamaldehyde, whilst having the lowest MICs (0.006-0.1%, v/v), did not induce changes in polarity or permeability at the MIC, and substantially higher concentrations were required to induce significant effects. At 30 min, treatment with all six compounds resulted in significant depolarisation (60.9-99.3% of cells), whereas fewer compounds (ranging from two to five per organism) resulted in significant permeabilisation. The extent of permeabilisation was always less than depolarisation, with overall means for all treatments of 46.1% and 89.4% of cells permeabilised and depolarised, respectively, at 30 min. These data demonstrate that several monoterpenoids and phenylpropanoids as well as tea tree oil alter membrane properties by decreasing polarity and increasing permeability in a time- and concentration-dependent manner.


Nurses' views of interprofessional education and collaboration: a comparative study of recent graduates from three universities.
Today interprofessional education (IPE) is spread throughout the world. In Sweden only one of the existing nursing programs has an IPE curriculum on several levels during the training. The aim of this study was to examine how nurses who recently graduated from universities with IPE or non-IPE curricula perceive the importance of different educational goals and whether they found themselves prepared for their profession, and especially for collaboration with other professions. Three universities with different commitments to IPE were studied. We used a survey with eight different targets: communication skills, cooperation with other professions, problem-solving capability, self-directed learning skills, whether their education has prepared them to work professionally, to perform research, to take care of acutely ill patients, to work preventively and working as a nurse. The participants were asked whether their undergraduate education had prepared them for these targets and whether they perceived that the targets were important goals for their education. A main result in this study was that nurses who had recently graduated from the IPE university perceived to a greater extent that their undergraduate training had prepared them to work together with other professions in comparison with nursing students from non-IPE universities.


Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors.
Hematopoiesis is tightly controlled by transcription regulatory networks, but how and when specific transcription factors control lineage commitment are still largely unknown. Within the hematopoietic stem cell (Lin(-)Sca-1(+)c-Kit(+)) compartment these lineage-specific transcription factors are expressed at low levels but are up-regulated with the process of lineage specification. CCAAT/enhancer binding protein α (C/EBPα) represents one of these factors and is involved in myeloid development and indispensable for formation of granulocytes. To track the cellular fate of stem and progenitor cells, which express C/EBPα, we developed a mouse model expressing Cre recombinase from the Cebpa promoter and a conditional EYFP allele. We show that Cebpa/EYFP(+) cells represent a significant subset of multipotent hematopoietic progenitors, which predominantly give rise to myeloid cells in steady-state hematopoiesis. C/EBPα induced a strong myeloid gene expression signature and down-regulated E2A-induced regulators of early lymphoid development. In addition, Cebpa/EYFP(+) cells compose a fraction of early thymic progenitors with robust myeloid potential. However, Cebpa/EYFP(+) multipotent hematopoietic progenitors and early thymic progenitors retained the ability to develop into erythroid and T-lymphoid lineages, respectively. These findings support an instructive but argue against a lineage-restrictive role of C/EBPα in multipotent hematopoietic and thymic progenitors.


Cocaine detection by a mid-infrared waveguide integrated with a microfluidic chip.
A germanium (Ge) strip waveguide on a silicon (Si) substrate is integrated with a microfluidic chip to detect cocaine in tetrachloroethylene (PCE) solutions. In the evanescent field of the waveguide, cocaine absorbs the light near 5.8 μm, which is emitted from a quantum cascade laser. This device is ideal for (bio-)chemical sensing applications.


Transcription of the rat skeletal muscle hexokinase II gene is increased by acute exercise.
A single bout of acute exercise increases hexokinase (HK) II mRNA and enzyme activity [R. M. O'Doherty, D. P. Bracy, H. Osawa, D. H. Wasserman, and D. K. Granner. Am. J. Physiol. 266 (Endocrinol. Metab. 29): E171-E178, 1994]. The present study addresses the mechanism of the increase in HK II mRNA. Male rats undertook a single bout of treadmill exercise and were then killed immediately or after a predetermined recovery period. The gastrocnemius/plantaris muscle complex, composed of mixed fiber types, was excised; the nuclei were isolated; and HK I, HK II, beta-actin, and alpha-tubulin gene transcription rates were measured. Genomic DNA and plasmid DNA were used as positive and negative controls, respectively. Immediately after the cessation of 30, 45, or 90 min of exercise, HK II gene transcription rates were 1.3 +/- 0.3-,2.9 +/- 0.3-, and 4.0 +/- 0.6-fold, respectively, above those of sedentary controls. The increases after 45 and 90 min of exercise were statistically significant (P < 0.01). One hour after the cessation of 30 min of exercise, HK II gene transcription was significantly increased (1.40 +/- 0.03-fold; P < 0.05). At all time points, transcription of the HK I, beta-actin, and alpha-tubulin genes was unchanged. We conclude that the exercise-induced increase in HK II gene transcription appears to play a major role in the increase of HK II mRNA and activity.


Central tolerance to myogenic cell transplants does not include muscle neoantigens.
Duchenne muscular dystrophy is a fatal genetic disease caused by lack of dystrophin. Myogenic cell transplantation (MT), a potential therapy for Duchenne muscular dystrophy, can restore dystrophin expression in muscles. Because allogeneic MT is highly resistant to peripheral tolerance, we proposed to induce central tolerance. However, given its immunogenicity, we asked whether central tolerance to donor major histocompatibility complex would allow long-term expression of dystrophin, a tissue-specific neoantigen in dystrophic recipients. Central tolerance was induced in C57BL/10J mdx (dystrophic) mice by allogeneic bone marrow transplantation (BMT) after conditioning with either lethal total body irradiation (TBI) or an established nonmyeloablative protocol (anti-CD154, anti-CD8 mAbs, and low-dose TBI). Recipients subsequently received donor-strain MT or skin grafts. Long-term hematopoietic chimeras generated using either lethal TBI or the nonmyeloablative regimen were tolerant to donor skin grafts and both primary and secondary donor MT (>90 days). Myogenic cell transplantation survival was decreased when chimerism was transient, which was most common with nonmyeloablative conditioning and fully rather than haplo-mismatched donors. Interestingly, regardless of conditioning, MT was associated with localized muscle infiltration with Foxp3CD4, CD25CD4, and PerforinCD8 cells, whereas skin grafts lacked infiltration. Central tolerance achieved using regimens that eliminate nearly all endogenous peripheral lymphocytes (i.e., lethal irradiation) or a nonmyeloablative protocol that depleted peripheral CD8 cells, results in lymphocytic infiltration in muscles that received MT but not in skin allografts. This suggests that muscle-specific infiltration may result from lack of negative selection for peripheral neoantigens in the thymus after BMT and that tolerance after MT may rely on peripheral regulatory mechanisms.


Update on rare epithelial ovarian cancers: based on the Rare Ovarian Tumors Young Investigator Conference.
There has been significant progress in the understanding of the pathology and molecular biology of rare ovarian cancers, which has helped both diagnosis and treatment. This paper provides an update on recent advances in the knowledge and treatment of rare ovarian cancers and identifies gaps that need to be addressed by further clinical research. The topics covered include: low-grade serous, mucinous, and clear cell carcinomas of the ovary. Given the molecular heterogeneity and the histopathological rarity of these ovarian cancers, the importance of designing adequately powered trials or finding statistically innovative ways to approach the treatment of these rare tumors has been emphasized. This paper is based on the Rare Ovarian Tumors Conference for Young Investigators which was presented in Tokyo 2015 prior to the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG).


Rate of degradation of [alpha]- and [beta]-oligodeoxynucleotides in Xenopus oocytes. Implications for anti-messenger strategies.
End-labelled oligodeoxynucleotides were injected into Xenopus laevis oocytes and their degradation products were analysed by high-performance ion-exchange liquid chromatography after various times of incubation. The oligonucleotides were synthesised with either the natural [beta] anomers or the synthetic [alpha] anomers of deoxynucleotide units. Oligo-[beta] deoxynucleotides are short-lived inside oocytes (half-life approximately equal to 10 min). Covalent attachment of an intercalating agent to the 3'-phosphate and of a methylthiophosphate group at the 5'-end protects oligodeoxynucleotides against 3'- and 5'-exonucleases, respectively. The half-life of such substituted oligodeoxynucleotides is increased to 40 minutes. Oligo-[alpha]-deoxynucleotides are quite resistant to both endo and exonucleases inside Xenopus oocytes. After 8 hours only 40% of a 16-mer oligo-[alpha]-deoxynucleotide were hydrolysed. The rapid degradation of oligo-[beta]-deoxynucleotides suggests that efficient inhibition of translation in Xenopus oocytes involves an RNase H-induced hydrolysis of mRNAs hybridized to oligo-[beta]-deoxynucleotides.


A targeted approach to vaccine hesitancy.
This short communication makes the case for targeted vaccine research when attempting to counter hesitancy, especially amongst vulnerable or rarefied patient groups. Far from disincentivizing vaccination, the freedom to research and publicize the limitations of these technologies for certain groups and personalizing dosing, pacing, adjuvants, and time-sensitive alternatives in response is essential for optimizing health outcomes while neutralizing the vaccine research landscape itself. Vaccine evangelism only arouses suspicion when it is not tempered by rigorous research into differential vaccine benefit-risk in this way. That said, the long-standing politicization of vaccination-a topic vulnerable to misinterpretation and media sensationalism-along with the commercial incentives associated with universal adoption makes more comparative and critical research difficult to fund and promote in practice. Likewise, a prescriptive approach to vaccination does little to address the issues of vaccine inequality that contribute to both hesitancy and conspiracy globally and will likely prove financially prohibitive in certain markets. These obstacles are not insurmountable, however, provided that comparative research is centrally subsidized, regulations ensure that vaccine development trials explore differentiated outcomes, especially amongst high-risk or rare groups, and findings are used to prioritize global vaccine allocation to those that stand to benefit most from them.


AGNES at vibrated gold microwire electrode for the direct quantification of free copper concentrations.
The free metal ion concentration and the dynamic features of the metal species are recognized as key to predict metal bioavailability and toxicity to aquatic organisms. Quantification of the former is, however, still challenging. In this paper, it is shown for the first time that the concentration of free copper (Cu(2+)) can be quantified by applying AGNES (Absence of Gradients and Nernstian equilibrium stripping) at a solid gold electrode. It was found that: i) the amount of deposited Cu follows a Nernstian relationship with the applied deposition potential, and ii) the stripping signal is linearly related with the free metal ion concentration. The performance of AGNES at the vibrating gold microwire electrode (VGME) was assessed for two labile systems: Cu-malonic acid and Cu-iminodiacetic acid at ionic strength 0.01 M and a range of pH values from 4.0 to 6.0. The free Cu concentrations and conditional stability constants obtained by AGNES were in good agreement with stripping scanned voltammetry and thermodynamic theoretical predictions obtained by Visual MinteQ. This work highlights the suitability of gold electrodes for the quantification of free metal ion concentrations by AGNES. It also strongly suggests that other solid electrodes may be well appropriate for such task. This new application of AGNES is a first step towards a range of applications for a number of metals in speciation, toxicological and environmental studies for the direct determination of the key parameter that is the free metal ion concentration.


Pain, quality of life, and spinal accessory nerve status after neck dissection.
To assess quality of life (QOL) in patients with head and neck cancer who underwent neck dissection and to compare QOL scores for patients in whom the spinal accessory nerve (CN XI) was resected or preserved. SETTING AND DESIGN AND OUTCOMES MEASURES: Three hundred ninety-seven patients who had undergone treatment for head and neck cancer completed the University of Michigan Head and Neck Quality of Life (HNQOL) instrument, the Medical Outcomes Study SF-12 General Health Survey, and questions on "pain despite pain medications" and headaches. Of the 397 patients, 222 had no neck dissection, 46 had neck dissections resecting CN XI, and 129 had dissection sparing CN XI. Of the latter group, 68 patients had dissections sparing level V and 61 dissections included level V. Age, sex, primary site distribution, and T stage were not different between the groups. Patients who had neck dissections sparing CN XI had better scores on the HNQOL pain domain (P = .002), had less shoulder or neck pain (P = .003), and took pain medications less frequently (P = .0004) compared with patients who had neck dissections sacrificing CN XI. When CN XI was preserved, patients who had no level V dissection had better pain domain scores (P = .03) and eating domain scores (P = .007) on the HNQOL, had less shoulder or neck pain (P = .006), and had less physical problems (P = .03) than patients who had level V dissected. On multivariate analysis, pain-related QOL scores after neck dissection were significantly better (P < .01) if patients had dissections with preservation of CN XI and if level V was not dissected. Neck dissections sparing CN XI are associated with better pain scores on the HNQOL, less shoulder and neck pain, and less need for medications. When CN XI is spared, not dissecting level V of the neck is associated with better HNQOL pain scores, less shoulder or neck pain, and fewer physical problems.


The role of dietary polyphenols in the moderation of the inflammatory response in early stage colorectal cancer.
Current focus in colorectal cancer (CRC) management is on reducing overall mortality by increasing the number of early-stage cancers diagnosed and treated with curative intent. Despite the success of screening programs in down-staging CRC, interval cancer rates are substantial and other strategies are desirable. Sporadic CRC is largely associated with lifestyle factors including diet. Polyphenols are phytochemicals ingested as part of a normal diet, which are abundant in plant foods including fruits/berries and vegetables. These may exert their anti-carcinogenic effects via the modulation of inflammatory pathways. Key signal transduction pathways are fundamental to the association of inflammation and disease progression including those mediated by NF-κB and STAT, PI3K and COX. Our aim was to examine the evidence for the effect of dietary polyphenols intake on tumor and host inflammatory responses to determine if polyphenols may be effective as part of a dietary intervention. There is good epidemiological evidence of a reduction in CRC risk from case-control and cohort studies assessing polyphenol intake. It would be premature to suggest a major public health intervention to promote their consumption; however, dietary change is safe and feasible, emphasizing the need for further investigation of polyphenols and CRC risk.


Biological activity of 3-methoxy-catecholamines.
The methoxy analogs of epinephrine, norepinephrine, and dopamine manifest some activity on smooth muscle and blood pressure. Metanephrine is as potent as epinephrine on rabbit aortic strips. The same compounds demonstrate a lesser potency on rabbit duodenum preparation, while 3-methoxy-dopamine produces a slight contraction of the duodenum. Both metanephrine and 3-methoxy-dopamine have 15 to 25 percent of the pressor activity of the original nonmethylated catecholamines. Normetanephrine is 1/600 as active as norepinephrine on the blood pressure of the cat.


Detection of natural autoantibodies in the serum of anti-HIV-positive individuals.
Twenty-six sera containing anti-HIV antibodies from individuals with AIDS, AIDS-related complex, lymphadenopathy syndrome, or from seropositive individuals without clinical symptoms, were tested for the presence of natural autoantibodies (NAb) to actin, DNA, tubulin, thyroglobulin, albumin, myosin and TNP-BSA. Sera from 22 seronegative individuals at high risk for HIV infection were also examined. NAb titres to all these antigens were found to be elevated in both groups as compared to the titres in pooled normal human sera. The most prevalent NAb were those of the IgG class directed against TNP found in high titre in seropositive individuals. On the basis of the above results, sera from 50 anti-HIV-positive and 67 anti-HIV-negative individuals were tested for IgG antibody activity against a panel of protein antigens with different degrees of TNP substitution. The greater the TNP substitution, the higher the titres of IgG antibodies detected in anti-HIV-positive sera. Antibody titres in seronegative individuals at high risk for HIV infection were independent of the degree of TNP substitution. In almost all cases, the highest titres of IgG anti-TNP antibodies were found in anti-HIV-positive sera from individuals with clinical manifestations.


Analysis of risk factors for recurrence in infertile endometrial cancer patients after in vitro fertilization treatment.
To investigate the oncologic outcomes of patients with early-stage endometrioid endometrial cancer (EEC) treated with in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) following fertility-sparing treatment (FST). A total of 62 patients who underwent IVF/ICSI treatment in a single fertility center between June 2010 and December 2021 after conservative treatment for early-stage EEC were assigned to a recurrence group and a non-recurrence group. Their clinical characteristics and disease outcomes were retrospectively evaluated. The 62 women with complete remission (CR) after FST for EEC underwent 103 IVF cycles, resulting in 41 fresh embryo transfers (ETs) and 70 frozen-thawed transfers; 27 (43.55%) achieved clinical pregnancies, and 20 (32.26%) gave birth to a total of 23 live neonates. Additionally, nine patients had live births from natural pregnancies after IVF failure, bringing the cumulative live birth rate to 46.77% (29/62). After a median follow-up period of 53.88 months (range 20.2-127.5 months), 17 patients (27.42%) experienced recurrence within 2.8 to 57.9 months after the first controlled ovarian stimulation (COS). The probability of relapse at 1, 2, and 3 years after the initiation of COS was 14.52% (9/62), 21% (13/62), and 25.81% (16/62), respectively. Factors such as the time to CR, the time to IVF, the frequency of COS, maintenance treatment before IVF, and histology type were not found to significantly affect recurrence (p = 0.079, 0.182, 0.093, 0.267, and 0.41, respectively). Live births (hazard ratio (HR): 0.28, 95% CI: 0.082-0.962, p = 0.043) and the protocol of letrozole plus gonadotropin-releasing hormone (GnRH) antagonist/agonist used during IVF (HR: 0.1, 95% CI: 0.011-0.882, p = 0.038) were identified as independent favorable factors for recurrence. Live birth was associated with decreased recurrence of EEC. Reducing estrogen levels during COS may serve to mitigate the risk of endometrial cancer recurrence.


Thermal stability and kinetic constants for 129 variants of a family 1 glycoside hydrolase reveal that enzyme activity and stability can be separately designed.
Accurate modeling of enzyme activity and stability is an important goal of the protein engineering community. However, studies seeking to evaluate current progress are limited by small data sets of quantitative kinetic constants and thermal stability measurements. Here, we report quantitative measurements of soluble protein expression in E. coli, thermal stability, and Michaelis-Menten constants (kcat, KM, and kcat/KM) for 129 designed mutants of a glycoside hydrolase. Statistical analyses reveal that functional Tm is independent of kcat, KM, and kcat/KM in this system, illustrating that an individual mutation can modulate these functional parameters independently. In addition, this data set is used to evaluate computational predictions of protein stability using the established Rosetta and FoldX algorithms. Predictions for both are found to correlate only weakly with experimental measurements, suggesting improvements are needed in the underlying algorithms.


The role of assembly parameters on polyplex poly(beta-amino ester) nanoparticle transfections.
Intracellular delivery of nucleic acids to mammalian cells using polyplex nanoparticles (NPs) remains a challenge both in vitro and in vivo, with transfections often suffering from variable efficacy. To improve reproducibility and efficacy of transfections in vitro using a next-generation polyplex transfection material poly(beta-amino ester)s (PBAEs), the influence of multiple variables in the preparation of these NPs on their transfection efficacy was explored. The results indicate that even though PBAE/pDNA polyplex NPs are formed by the self-assembly of polyelectrolytes, their transfection is not affected by the manner in which the components are mixed, facilitating self-assembly in a single step, but timing for self-assembly of 5-20 min is optimal. In addition, even though the biomaterials are biodegradable in water, their efficacy is not affected by up to eight freeze-thaw cycles of the polymer. It was found that there is a greater stability of nucleic acid-complexed polymer as a polyplex nanoparticle compared with free polymer. Finally, by exploring multiple buffer systems, it was identified that utilization of divalent cation magnesium or calcium acetate buffers at pH 5.0 is optimal for transfection using these polymeric materials, boosting transfection several folds compared with monovalent cations. Together, these results can improve the reproducibility and efficacy of PBAE and similar polyplex nanoparticle transfections and improve the robustness of using these biomaterials for bioengineering and biotechnology applications.


The Metabolic Score for Insulin Resistance (METS-IR) as a Predictor of Incident Ischemic Heart Disease: A Longitudinal Study among Korean without Diabetes.
The metabolic score for insulin resistance (METS-IR) is a novel noninsulin-based marker for assessing the risk of insulin resistance and cardiometabolic risk. However, whether METS-IR is associated with incident ischemic heart disease (IHD) risk is not well known. Therefore, we aimed to investigate the longitudinal effect of METS-IR on incident IHD risk in a large cohort of Korean adults without diabetes. Data were assessed from 17,943 participants without diabetes from the Health Risk Assessment Study (HERAS) and Korea Health Insurance Review and Assessment (HIRA) data. The participants were divided into four groups according to METS-IR index quartiles: (ln ((2 × fasting plasma glucose) + triglyceride) × body mass index)/(ln (HDL-cholesterol)). We prospectively assessed hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD using multivariate Cox proportional hazard regression models over a 50-month period. During the follow-up period, 332 participants (1.9%) developed IHD. HRs of IHD for METS-IR quartiles 1-4 were 1.00, were 1.62 (95% CI 1.04-2.53), 1.87 (95% CI 1.20-2.91), and 2.11 (95% CI 1.35-3.30), respectively, after adjusting for potential confounding variables. A higher METS-IR precedes future IHD among Koreans without diabetes. Moreover, compared with metabolic syndrome, METS-IR had a better predictive value for IHD.


Transcostal high-intensity-focused ultrasound: ex vivo adaptive focusing feasibility study.
Ex vivo experiments have been conducted through excised pork rib with bone, cartilage, muscle and skin. The aberrating effect of the ribcage has been experimentally evaluated. Adaptive ultrasonic focusing through ribs has been studied at low power. Without any correction, the pressure fields in the focal plane were both affected by inhomogeneous attenuation and phase distortion and three main effects were observed: a mean 2 mm shift of the main lobe, a mean 1.25 mm spreading of the half width of the main lobe and up to 20 dB increase of the secondary lobe level. Thanks to time-reversal focusing, a 5 dB decrease in the secondary lobes was obtained and the ratio between the energy deposited at the target location and the total amount of energy emitted by the therapeutic array was six times higher than that without correction. Time-reversal minimizes the heating of the ribs by automatically sonicating between the ribs, as demonstrated by temperature measurements using thermocouples placed at different locations on the ribcage. It is also discussed how this aberration correction process could be achieved non-invasively for clinical application.


[Tuberculous pneumonia in children].
Tuberculosis (TB) is one of the most common infectious diseases worldwide. Data from WHO show that one third of the world population is estimated to be infected with Mycobacterium Tuberculosis (TM). TB remains an important problem for adults and children in Lithuania as number of new diagnosed children's TB cases vary between 16.7-21.8 per 100 000 population. The aim of this article is to present the TB pneumonia in childhood: peculiarities of clinical forms, symptoms, diagnostics, treatment and results. The diagnosis of TB in children more often is made on epidemiological data, supposed by clinical symptoms, tuberculin skin test and chest radiography results, rather than bacteriological data. Clinical symptoms of TB pneumonia are mostly similar to atypical pneumonia, caused by Mycoplasma pneumoniae and Chlamydia pneumoniae. We discussed similarities and differences between atypical and TB pneumonia, based on 10-year data of our patient ill with atypical and TB pneumonia, (123 - 63.7%) and (69 - 36.3%) respectively. Chemotherapy of TB is directed towards the eradication of TM. The main principle of TB chemotherapy is regular, directly controlled and long-term usage of several antituberculous drugs. The child, ill with TB, is totally cured, when he has no clinical symptoms or laboratory findings specific for TB and is able to return to his normal social life. Two clinical cases of children ill with TB pneumonia are discussed as well. We hope that this article and two clinical cases would remind pediatricians and family doctors to be aware of still possible TB in childhood.


CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways.
The molecular mechanisms mediating cylindromatosis (CYLD) tumor suppressor function appear to be manifold. Here, we demonstrate that, in contrast to the increased levels of phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CYLD was decreased in a majority of the melanoma cell lines and tissues examined. Exogenous expression of CYLD but not its catalytically deficient mutant markedly inhibited melanoma cell proliferation and migration in vitro and subcutaneous tumor growth in vivo. In addition, the melanoma cells expressing exogenous CYLD were unable to form pulmonary tumor nodules following tail-vein injection. At the molecular level, CYLD decreased β1-integrin and inhibited pJNK induction by tumor necrosis factor-α or cell attachment to collagen IV. Moreover, CYLD induced an array of other molecular changes associated with modulation of the "malignant" phenotype, including a decreased expression of cyclin D1, N-cadherin, and nuclear Bcl3, and an increased expression of p53 and E-cadherin. Most interestingly, coexpression of the constitutively active MKK7 or c-Jun mutants with CYLD prevented the above molecular changes, and fully restored melanoma growth and metastatic potential in vivo. Our findings demonstrate that the JNK/activator protein 1 signaling pathway underlies the melanoma growth and metastasis that are associated with CYLD loss of function. Thus, restoration of CYLD and inhibition of JNK and β1-integrin function represent potential therapeutic strategies for treatment of malignant melanoma.


NGO facilitation of a government community-based maternal and neonatal health programme in rural India: improvements in equity.
Socio-economic disparities in health have been well documented around the world. This study examines whether NGO facilitation of the government's community-based health programme improved the equity of maternal and newborn health in rural Uttar Pradesh, India. A quasi-experimental study design included one intervention district and one comparison district of rural Uttar Pradesh. A household survey conducted between January and June 2003 established baseline rates of programme coverage, maternal and newborn care practices, and health care utilization during 2001-02. An endline household survey was conducted after 30 months of programme implementation between January and March 2006 to measure the same indicators during 2004-05. The changes in the indicators from baseline to endline in the intervention and comparison districts were calculated by socio-economic quintiles, and concentration indices were constructed to measure the equity of programme indicators. The equity of programme coverage and antenatal and newborn care practices improved from baseline to endline in the intervention district while showing little change in the comparison district. Equity in health care utilization for mothers and newborns also showed some improvements in the intervention district, but notable socio-economic differentials remained, with the poor demonstrating less ability to access health services. NGO facilitation of government programmes is a feasible strategy to improve equity of maternal and neonatal health programmes. Improvements in equity were most pronounced for household practices, and inequities were still apparent in health care utilization. Furthermore, overall programme coverage remained low, limiting the ability to address equity. Programmes need to identify and address barriers to universal coverage and care utilization, particularly in the poorest segments of the population.


A neural basis for melanocortin-4 receptor-regulated appetite.
Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.


Sequence clusters in human immunodeficiency virus type 1 reverse transcriptase are associated with subsequent virological response to antiretroviral therapy.
Many amino acid (aa) sites in reverse transcriptase (RT) have been implicated in resistance to nucleoside (NRTI) and nonnucleoside antiretrovirals. Interactions between these in response to combination therapy remain poorly understood. In a trial (ACTG 241) of zidovudine/didanosine (ddI) versus zidovudine/ddI/nevirapine in nucleoside-experienced patients, baseline sequence data from the RT coding region was analyzed from 55 individuals. Sequences were clustered by use of a parsimony method and the virological responses (ratio of baseline viral load to viral load after of therapy) for each cluster were analyzed at week 8 and week 48. Both clusters and genotype at aa 215 were significantly associated with virological response at both time points, whereas viral load showed a stronger association with sequence clusters. Sequence clusters identified one group of patients who never developed high-level resistance to NRTIs despite prior nucleoside exposure and poor suppression of viral replication.


The problem of medical officer recruitment in agricultural industry.
All developing countries have difficulty in persuading doctors to opt for service in rural areas. This problem is shared by the agricultural industries. Two factors play a major role in this: isolation and the lack of a career structure. Isolation is an unavoidable accompaniment to rural practice. It can be considered as isolation from amenities, social isolation and professional isolation. The doctor in the rural area is often deprived of all urban amenities e.g. suitable shopping facilities, entertainment, cultural amenities and suitable leisure pursuits. Most of all, perhaps, he has major difficulties in educating his children. The maintenance of friendships and family connections is made difficult. There is a lack of suitable social intercourse for himself and his wife, a lack which very often leads to his wife's unhappiness and his own resignation. Professional isolation is serious and reflects adversely after a time on his professional ability. It may be that he only sees a colleague at long intervals and there is no stimulus towards keeping up to date professionally, and no opportunity to talk out professional and ethical problems. In many agricultural industries there is no career structure and therefore no scope for the good, ambitious doctor. This is particularly true of small, single-ownership plantations. It is clear that there is nothing to attract a good doctor to a place where he may remain at the same status for the rest of his professional career. It is suggested that only by the creation of a service structure within agricultural industries, which will create opportunities and within which means can be found to alleviate the effects of isolation, can a solution be found to the recruitment problem.


Reactions of aqueous chlorine and chlorine dioxide with model food compounds.
Chlorine and chlorine dioxide (ClO2), common disinfecting and bleaching chemicals used in the food industry, are potent oxidizing and chlorinating agents. Unfortunately, little is known about the nature of the reactions of chlorine with organic food constituents. This presentation reviews published information concerning the reactions of chlorine gas (Cl2[g]), aqueous chlorine, and ClO2 with model food compounds, the fate of chlorine during the chlorination of specific food products, and the potential toxicity of the reaction products. Fatty acids and their methyl esters react with chlorine with the degree of incorporation corresponding to their degree of unsaturation. Aqueous chlorine oxidizes and chlorinates lipids and amino acids much more readily than ClO2. Several amino acids are highly susceptible to oxidation and chlorination by chlorine compounds. Reactions of chlorine and ClO2 with several food products, including flour and shrimp, have also been characterized. In one model system, 99% of Cl2(g) either reacted with components of flour or was consumed by oxidation/chlorination reactions. The lipids extracted from the chlorinated flour contained significant amounts of chlorine. Exposure of shrimp to hypochlorous acid (HOCl) solution resulted in significant incorporation of chlorine into the edible portion. Although significant quantities of chlorine can be incorporated into specific model compounds and food products, the health risks associated with exposure to chlorinated organic products are unknown. Preliminary studies using the Ames Salmonella/microsome mutagenicity assay indicate that the reaction products from mixtures of aqueous chlorine and various lipids or tryptophan are nonmutagenic. Nevertheless, additional studies are warranted, so that the toxicological significance of these reaction products can be understood more fully.


Vesicles containing Chlamydia trachomatis serovar L2 remain above pH 6 within HEC-1B cells.
Chlamydia trachomatis serovar L2 is an obligate intracellular bacterium which is internalized in target epithelial cells by endocytosis and resides within a membrane-bound vesicle. Over the next several hours following entry, individual serovar L2-containing vesicles fuse with one another to form a single membrane-bound vesicle (or inclusion) within which the microcolony develops. The experiments reported here directly examined the pH of vesicles containing chlamydiae. The pH was determined by measuring emission ratios of the fluorescent, pH-sensitive probe SNAFL (5-[and 6-]-carboxyseminaphthofluorescein-1, succinimidyl ester) conjugated to chlamydiae. The pH remained above 6.0 at 2, 4, and 12 h after infection, while the pH of vesicles contained heat-killed organisms fell 5.3. In the presence of amines, which raise the pH of acidic compartments, C. trachomatis inclusion formation was unaffected. Inactivation of Na+,K+ -ATPases, the ion pumps responsible for maintaining a pH above 6 within early endocytic vesicles, inhibited the growth of C. trachomatis within epithelial cells. Preventing vesicular acidification by inhibiting the vacuolar proton ATPase did not affect chlamydial growth. Thus, chlamydiae do not reside within highly acidic vesicles and avoid the pathway leading to lysosomes.


Transfusion-transmitted malaria masquerading as sickle cell crisis with multisystem organ failure.
Fever accompanying vaso-occlusive crisis is a common presentation in patients with sickle cell disease (SCD) and carries a broad differential diagnosis. Here, we report a case of transfusion-transmitted malaria in a patient with SCD presenting with acute vaso-occlusive crisis and rapidly decompensating to multisystem organ failure (MSOF). An 18-year-old African American male with SCD was admitted after multiple days of fever and severe generalized body pain. He received monthly blood transfusions as stroke prophylaxis. A source of infection was not readily identified, but treatment was initiated with continuous intravenous fluids and empiric antibiotics. The patient developed acute renal failure, acute hypoxic respiratory failure, and shock. He underwent red blood cell (RBC) exchange transfusion followed by therapeutic plasma exchange and continuous veno-venous hemodialysis. A manual peripheral blood smear revealed intraerythrocytic inclusions suggestive of Plasmodium, and molecular studies confirmed Plasmodium falciparum infection. Intravenous artesunate was given daily for 1 week. A look-back investigation involving two hospitals, multiple blood suppliers, and state and federal public health departments identified the source of malaria as a unit of RBCs transfused 2 weeks prior to admission. Clinical suspicion for transfusion-related adverse events, including hemolytic transfusion reactions and transfusion-transmitted infections, should be high in typically and atypically immunocompromised patient populations (like SCD), especially those on chronic transfusion protocols. Manual blood smear review aids in the evaluation of patients with SCD presenting with severe vaso-occlusive crisis and MSOF and can alert clinicians to the need for initiating aggressive therapy like RBC exchange and artesunate therapy.


Preliminary Results: The Impact of Smartphone Use and Short-Wavelength Light during the Evening on Circadian Rhythm, Sleep and Alertness.
Smartphone usage strongly increased in the last decade, especially before bedtime. There is growing evidence that short-wavelength light affects hormonal secretion, thermoregulation, sleep and alertness. Whether blue light filters can attenuate these negative effects is still not clear. Therefore, here, we present preliminary data of 14 male participants (21.93 ± 2.17 years), who spent three nights in the sleep laboratory, reading 90 min either on a smartphone (1) with or (2) without a blue light filter, or (3) on printed material before bedtime. Subjective sleepiness was decreased during reading on a smartphone, but no effects were present on evening objective alertness in a GO/NOGO task. Cortisol was elevated in the morning after reading on the smartphone without a filter, which resulted in a reduced cortisol awakening response. Evening melatonin and nightly vasodilation (i.e., distal-proximal skin temperature gradient) were increased after reading on printed material. Early slow wave sleep/activity and objective alertness in the morning were only reduced after reading without a filter. These results indicate that short-wavelength light affects not only circadian rhythm and evening sleepiness but causes further effects on sleep physiology and alertness in the morning. Using a blue light filter in the evening partially reduces these negative effects.


Usefulness of real-time three-dimensional echocardiography to identify right ventricular dysfunction in patients with congenital heart disease.
Because right ventricular (RV) dysfunction predicts a poor outcome in patients with congenital heart disease (CHD), regular monitoring of RV function is indicated. To date, cardiac magnetic resonance (CMR) imaging has been the reference method. A more practical, more accessible, and accurate tool would be preferred. We defined normality regarding RV systolic function using healthy controls and tested the ability of real-time 3-dimensional echocardiographic (RT3DE) findings to identify patients with CHD with RV dysfunction. The cutoff values for the RV volumes and ejection fraction (EF) were derived from the CMR imaging findings from 41 healthy controls (mean age 27 +/- 8 years, 56% men). In 100 patients with varying CHDs (mean age 27 +/- 11 years, 65% men), both RT3DE data sets (iE33) and short-axis CMR imaging (1.5 T) were obtained within 2 hours. The RT3DE and CMR RV volumes and EF were calculated using commercially available software. Receiver operating characteristic curves were created to obtain the sensitivity and specificity of the RT3DE data to identify RV dysfunction. Applying the cutoff values derived from the healthy controls using the CMR data of patients with CHD, we identified 23 patients with an enlarged indexed end-diastolic volume, 29 patients with an enlarged indexed end-systolic volume, and 21 patients with an impaired RVEF. The best cutoff values predicting RV dysfunction using the RT3DE findings were identified (indexed end-diastolic volume >105 ml/m(2), indexed end-systolic volume >54 ml/m(2), and EF <43%). The RT3DE findings revealed 23 patients with impaired RVEF, with 95% sensitivity, 89% specificity, and a negative predictive value of 99%. In conclusion, real-time 3-dimensional echocardiography is a very sensitive tool to identify RV dysfunction in patients with CHD and could be applied clinically to rule out RV dysfunction or to indicate additional quantitative analysis of RV function.


New concept in diagnostic endometrial cytology: diagnostic criteria based on composition and architecture of large tissue fragments in smears.
Routine endometrial cytology was used instead of curettage as the first step in a morphological investigation of the endometrium in patients with postmenopausal bleeding. Premenopausal women with symptoms or signs indicative of premalignant or malignant disease were also studied using this method. Patients with alarming cytological findings were further investigated with curettage. Diagnostic criteria for endometrial cytology have not been fully established: new diagnostic criteria were used in this study, which were based on the composition and architecture of larger tissue fragments in the smears. The new criteria were especially useful for tackling diagnostic problems caused by variation in nuclear size. Two thousand six hundred and twenty five cytological investigations were conducted over three years (January 1981 to January 1984). Adequate material for diagnosis was found in 2520 specimens (96%). Diagnosis based on the cytology was negative--that is, not indicative of malignant or premalignant disease in 2378 cases (94%). Follow up studies in 1984 showed no false negative results. Adenocarcinoma of the endometrium was diagnosed in 31 cases, carcinoma or carcinoma in situ of the cervix in 11 cases, and carcinoma of the ovary in four cases, all confirmed by histological investigation. Of 20 cases reported as suspected carcinoma, 12 of these were verified. The cytological diagnosis of adenomatous hyperplasia showed a low sensibility: only ten of 50 histologically controlled cases could be verified after curettage.


Cutting Edge: Biomarkers for Chronic Spontaneous Urticaria.
Chronic spontaneous urticaria (CSU) is defined by the appearance of wheals and a variable presence of angioedema which persists for at least 6 weeks. It represents the most common subtype of chronic urticaria and is gaining importance in civil society because of its association with impaired quality of life. Moreover, CSU has a growing impact on national health systems representing a great burden due to its variable rate of response to the approved therapies. In this scenario, the identification of clinical and molecular biomarkers is of pivotal importance. Some groups are trying to detect molecules which would be able to help clinicians in reaching a proper diagnosis; additionally, the opportunity to describe disease severity which leads to cluster patients in different groups could fill the gap in the numerous unmet clinical needs. Several biomarkers are currently being studied with the purpose to predict the response to a defined therapy; unfortunately, none of them are ready to be translated from bench to bedside.


Association between serrated epithelial changes and colorectal dysplasia in inflammatory bowel disease.
Serrated epithelial change (SEC) is a histologic finding in longstanding colitis that may be associated with dysplasia. Our primary aim was to determine the incidence of dysplasia and colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients with SEC. Secondary aims were to determine the rate of location concordance between SEC and dysplasia/CRC and to identify other risk factors associated with dysplasia in IBD patients with SEC. A retrospective, descriptive, observational study was performed by searching the Pathology Data System at a single tertiary referral center for a histologic finding of "serrated epithelial change." The patient's first pathology specimen with SEC was designated the index SEC. All subsequent pathology reports were evaluated for the occurrence and location of dysplasia or CRC. Univariable and multivariable logistic regression were performed to identify predictors of dysplasia. There were 187 patients with confirmed IBD and 1 or more histologic findings of SEC without prior dysplasia. Mean IBD duration was 16 years, and median follow-up time was 28 months. The rate of high-grade dysplasia or CRC was 17 per 1000 patient-years. Thirty-nine of 187 patients (21%) had synchronous or metachronous dysplasia or CRC. Location concordance was 68%. Multivariable analysis found SEC on follow-up examinations, older age at IBD diagnosis, male gender, and a first-degree relative with CRC were associated with dysplasia in IBD patients with SEC. This uncontrolled study describes a high frequency of dysplasia in patients with a histologic finding of SEC. SEC seen on successive endoscopic examinations further increased the risk of dysplasia. Further controlled studies are needed to determine if SEC is a precancerous lesion in IBD patients and if SEC can be endoscopically identified.


Serum Potassium Disorders Predict Subsequent Kidney Injury: A Retrospective Observational Cohort Study of Hospitalized Patients.
Electrolyte disorders are common findings in kidney diseases and might represent a useful biomarker preceding kidney injury. Serum potassium [K+] imbalance is still poorly investigated for association with acute kidney injury (AKI), and most evidence came from intensive care units. The aim of our study was to comprehensively investigate this association in a large, unselected cohort of hospitalized patients. We performed a retrospective observational cohort study on the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 1, 2010 and December 31, 2014, with inclusion of adult patients with at least 2 [K+] and 3 serum creatinine measurements who did not develop AKI during an initial 10-day window. The outcome of interest was in-hospital AKI. The exposures of interest were [K+] fluctuations and hypo (HoK) and hyperkalemia (HerK). [K+] variability was evaluated using the coefficient of variation. Cox proportional hazards regression models were used to obtain hazard ratios and 95% confidence intervals of the association between the exposures of interest and development of AKI. About 21,830 hospital admissions from 18,836 patients were included in our study. During a median follow-up of 5 (interquartile range [IQR] 7) days, AKI was observed in 555 hospital admissions (2.9%); median time for AKI development was 5 (IQR 7) days. Higher [K+] variability was independently associated with increased risk of AKI with a statistically significant linear trend across groups (p value = 0.012). A significantly higher incidence of AKI was documented in patients with HerK compared with normokalemia. No statistically significant difference was observed between HoK and HerK (p value = 0.92). [K+] abnormalities including fluctuations even within the normal range are associated with development of AKI.


Is menarche occuring earlier among Lebanese girls?
Early menarche is associated with increased risks for several diseases such as cardiovascular diseases and breast cancer. This analysis aimed at generating evidence on a historical trend towards younger age at menarche among Lebanese girls. A secondary analysis was conducted on data consolidated from three serial cross-sectional national surveys of women in Lebanon (2007, 2009 and 2012). A total of 6150 women were included in order to study the association between date of birth intervals and age at menarche. The mean age at menarche was 13.06 years, with a peak of the distribution at age 12. Women born before 1950 had a significantly higher mean age at menarche (13.21) compared to those born in 1970 and thereafter (12.95). A stratified analysis showed that women living outside the metropolitan Greater Beirut (GB) area were characterized by an older mean age at menarche (13.11) in all date of birth intervals compared to those in GB (12.89). However, age at menarche declined more significantly over the last two decades among women outside GB, compared to those living in GB. Epidemiological figures emerging from this study confirm that trends in Lebanon are in line with a global pattern of decreasing age at menarche. Urban-rural differences suggest that higher caloric content of diet and consequent early overweight, more evident in urban areas, are likely determinants of younger menarche. Evidence from this study calls for an urgent implementation of comprehensive multisectoral obesity prevention in children in Lebanon.


Safety and immunogenicity of rSh28GST antigen in humans: phase 1 randomized clinical study of a vaccine candidate against urinary schistosomiasis.
Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity. Volunteers randomly received 100 µg rSh28GST together with aluminium hydroxide (Alum) as adjuvant (n = 8), or Alum alone as a comparator (n = 8), twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8) received two doses of 300 µg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production. Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST. rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that clinical trials with rSh28GST could be continued in humans as a potential vaccine candidate against urinary schistosomiasis.


Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets.
Palliative chemotherapy is the mainstay of treatment of advanced gastric carcinoma (GC). Monoclonal antibodies including trastuzumab, ramucirumab, and pembrolizumab have been shown to provide additional benefits. However, the clinical outcomes are often unpredictable and they can vary widely among patients. Currently, no biomarker is available for predicting treatment response in the individual patient except human epidermal growth factor receptor 2 (HER2) amplification and programmed death-ligand 1 (PD-L1) expression for effectiveness of trastuzumab and pembrolizumab, respectively. Multi-platform molecular analysis of cancer, including GC, may help identify predictive biomarkers to guide selection of therapeutic agents. Molecular classification of GC by The Cancer Genome Atlas Research Network and the Asian Cancer Research Group is expected to identify therapeutic targets and predictive biomarkers. Complementary to molecular characterization of GC is molecular profiling by expression analysis and genomic sequencing of tumor DNA. Initial analysis of patients with gastroesophageal carcinoma demonstrates that the ratio of progression-free survival (PFS) on molecular profile (MP)-based treatment to PFS on treatment prior to molecular profiling exceeds 1.3, suggesting the potential value of MP in guiding selection of individualized therapy. Future strategies aiming to integrate molecular classification and profiling of tumors with therapeutic agents for achieving the goal of personalized treatment of GC are indicated.


[Positional changes of the magistral blood flow of the left kidney in men with varicocele and infertility].
This paper proves the correlation between characteristics of blood flow rate in the renal veins and resistance indices of the renal arteries. As a result of polypositional assessment of venous blood flow, it was found that the violations of magistral venous blood flow in the left kidney can affect the formation and progression of varicocele, and the severity of disorders of spermatogenesis. The necessity of assessment of testicular veins and the pressure in left renal vein not only in clin- and orthostasis or Valsalva maneuver, but in the six static positions is discussed; this can allow to register the violations of magistral renal blood flow at the early stages important for fertility disorders, improve the efficiency of diagnosis and treatment of patients with varicocele.


Dyspraxia in ASD: Impaired coordination of movement elements.
Children with autism spectrum disorders (ASD) have long been known to have deficits in the performance of praxis gestures; these motor deficits also correlate with social and communicative deficits. To date, the precise nature of the errors involved in praxis has not been clearly mapped out. Based on observations of individuals with ASD performing gestures, we hypothesized that the simultaneous execution of multiple movement elements is especially impaired in affected children. We examined 25 school-aged participants with ASD and 25 age-matched controls performing seven simultaneous gestures that required the concurrent performance of movement elements and nine serial gestures, in which all elements were performed serially. There was indeed a group × gesture-type interaction (P < 0.001). Whereas both groups had greater difficulty performing simultaneous than serial gestures, children with ASD had a 2.6-times greater performance decrement with simultaneous (vs. serial) gestures than controls. These results point to a potential deficit in the simultaneous processing of multiple inputs and outputs in ASD. Such deficits could relate to models of social interaction that highlight the parallel-processing nature of social communication. Autism Res 2016,. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 648-652. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.


Impact of a neuroscience intensive care unit on neurosurgical patient outcomes and cost of care: evidence-based support for an intensivist-directed specialty ICU model of care.
Analysis of patient data from a new neuroscience intensive care unit (NSICU) permitted evaluation of whether such a specialty ICU favorably altered clinical outcomes in critically ill neuroscience patients, and whether such a care model produced an efficient use of resources. A retrospective review was performed to compare (1) the clinical outcomes, as defined by percent mortality and disposition at discharge, between patients with a primary diagnosis of intracerebral hemorrhage treated in 1995 in medical or surgical ICUs and those treated in the same medical facility in an NSICU in 1997; and (2) the efficiency of care, as defined by length of ICU stay, total cost of care, and specific resource use, between patients treated in the NSICU and national benchmark standards for general ICUs during the 1997 fiscal year (FY). In the latter, extracted patient population data on neurosurgery patients requiring ICU treatment during FY 1997 were used with the following adjacent-disease related group (A-DRG)-coded diseases: craniotomy with and without coma or intracerebral hemorrhage, and skull fracture with and without coma lasting longer than 1 hour. Outcome measures of percent mortality and disposition at discharge in patients with intracerebral hemorrhage were significantly improved (P < .05), compared with those in a similar cohort treated 2 years earlier in a general ICU setting. Also, patients treated in the NSICU had shorter hospital stays (P < .01 ) and lower total costs of care (P < .01) than a national benchmark. The data suggest that a neuroscience specialty ICU arena staffed by specialty-trained intensivists and nurses is beneficial.


Marine algae and land plants share conserved phytochrome signaling systems.
Phytochrome photosensors control a vast gene network in streptophyte plants, acting as master regulators of diverse growth and developmental processes throughout the life cycle. In contrast with their absence in known chlorophyte algal genomes and most sequenced prasinophyte algal genomes, a phytochrome is found in Micromonas pusilla, a widely distributed marine picoprasinophyte (<2 µm cell diameter). Together with phytochromes identified from other prasinophyte lineages, we establish that prasinophyte and streptophyte phytochromes share core light-input and signaling-output domain architectures except for the loss of C-terminal response regulator receiver domains in the streptophyte phytochrome lineage. Phylogenetic reconstructions robustly support the presence of phytochrome in the common progenitor of green algae and land plants. These analyses reveal a monophyletic clade containing streptophyte, prasinophyte, cryptophyte, and glaucophyte phytochromes implying an origin in the eukaryotic ancestor of the Archaeplastida. Transcriptomic measurements reveal diurnal regulation of phytochrome and bilin chromophore biosynthetic genes in Micromonas. Expression of these genes precedes both light-mediated phytochrome redistribution from the cytoplasm to the nucleus and increased expression of photosynthesis-associated genes. Prasinophyte phytochromes perceive wavelengths of light transmitted farther through seawater than the red/far-red light sensed by land plant phytochromes. Prasinophyte phytochromes also retain light-regulated histidine kinase activity lost in the streptophyte phytochrome lineage. Our studies demonstrate that light-mediated nuclear translocation of phytochrome predates the emergence of land plants and likely represents a widespread signaling mechanism in unicellular algae.


Estimating Cure Rates From Survival Data: An Alternative to Two-Component Mixture Models.
This article considers the utility of the bounded cumulative hazard model in cure rate estimation, which is an appealing alternative to the widely used two-component mixture model. This approach has the following distinct advantages: (1) It allows for a natural way to extend the proportional hazards regression model, leading to a wide class of extended hazard regression models. (2) In some settings the model can be interpreted in terms of biologically meaningful parameters. (3) The model structure is particularly suitable for semiparametric and Bayesian methods of statistical inference. Notwithstanding the fact that the model has been around for less than a decade, a large body of theoretical results and applications has been reported to date. This review article is intended to give a big picture of these modeling techniques and associated statistical problems. These issues are discussed in the context of survival data in cancer.


Cancer-associated fibroblasts induce cancer cell apoptosis that regulates invasion mode of tumours.
In the process of cancer spreading, different modes of invasion exist. One is expansive invasion, in which a group of cancer cells gradually expands along with cancer cell proliferation. Invasion of cancer cells is also modified by their interaction with stromal cells including cancer-associated fibroblasts (CAFs). Cancer cells co-invade with CAFs, and invasion by CAFs frequently precede invasion by cancer cells, which indicates CAF-led cancer cell invasion. Here, we show that CAFs induce apoptosis in gastric cancer cells, which prevented expansive invasion by cancer cells and instead facilitated CAF-led invasion. Death receptor 4 and activation of caspase-8 in cancer cells mediated cancer cell apoptosis induced by CAFs, which was dependent on contact between cancer cells and CAFs. Apoptotic cancer cells in turn released apoptotic vesicles and stimulated invasion of CAFs. Accordingly, cancer cells followed the migrating CAFs. Treatment with a caspase inhibitor, ZVAD, or forced expression of a death domain fragment in cancer cells prevented cancer cell apoptosis induced by CAFs and increased expansive invasion by cancer cells in extracellular gel invasion assays, while the rate of cancer cell invasion led by CAFs was decreased. Death domain-fragment expression also prevented intramural invasion by gastric cancer cells in the stomach. Because CAF-led invasion is characterized by the movement of individual cancer cells away from the tumour, adequate cancer cell apoptosis may promote cancer dissemination.


Medical student perceptions of their knowledge and skills in pharmacology in their first and final clinical years.
This article was migrated. The article was marked as recommended. Medical student perceptions of their knowledge and skills in pharmacology in their first and final clinical years were investigated. An online survey investigated qualitative and quantitative data. Resources that the students relied on to support their knowledge in this area included pharmacists and the Australian Medicines Handbook. Suggested areas for curriculum review include having more formal teaching in this area and having more prescribing practice.


Some aspects of toxic contaminants in herbal medicines.
A World Health Organisation survey indicated that about 70-80% of the world populations rely on non-conventional medicine mainly of herbal sources in their primary healthcare. In recent years, we have witnessed the increasing growth in popularity of over-the-counter (OTC) health foods, nutraceuticals, and medicinal products from plants or other natural sources in developed countries. This indirectly indicates that the public is not satisfied with their orthodox medical (OM) treatment. Such increase in popularity has also brought concerns and fears over the professionalism of practitioners, and quality, efficacy and safety of their treatment methods and products from herbal and natural sources available in the market. Over the past decade several news-catching episodes in developed communities indicated adverse effects, sometimes life threatening, allegedly arisen consequential to taking of OTC herbal products or traditional medicines from various ethnic groups. These OTC products may be contaminated with excessive or banned pesticides, microbial contaminants, heavy metals, chemical toxins, and for adulterated with orthodox drugs. Excessive or banned pesticides, heavy metals and microbial contaminants may be related to the source of these herbal materials, if they are grown under contaminated environment or during collection of these plant materials. Chemical toxins may come from unfavourable or wrong storage conditions or chemical treatment due to storage. The presence of orthodox drugs can be related to unprofessional practice of manufacturers. Some of these environment related factors can be controlled by implementing standard operating procedures (SOP) leading to Good Agricultural Practice (GAP), Good Laboratory Practice (GLP), Good Supply Practice (GSP) and Good Manufacturing Practice (GMP) for producing these medicinal products from herbal or natural sources. The public's belief that herbal and natural products are safer than synthetic medicines can only be ascertained by imposing regulatory standards on these products that should be manufactured using these Good Practices. Using Chinese medicines, as examples, this paper illustrate how advances in chemical and biomedical analysis would help to detect intentional and unintentional toxic contaminants in herbal substances. The paper also summarises how modernization and progress are being carried out to get the best out of Chinese medicines for public healthcare.


Interface Engineering of Silver-Based Heterostructures for CO2 Reduction Reaction.
The production of CO from the CO2 reduction reaction (CO2RR) is of great interest in the renewable energy storage and conversion, the neutral carbon emission, and carbon recycle utilization. Silver (Ag) is one of the catalytic metals that are active for electrochemical CO2 reduction into CO, but the catalysis requires a large overpotential to achieve higher selectivity. Constructing a metal-oxide interface could be an effective strategy to boost both activity and selectivity of the catalysis. Herein, density functional theory (DFT) calculations were first conducted to reveal the chemical insights of the catalytic performance on the interface between metal oxide and Ag(111) (MOx/Ag(111)). The results show that the *COOH intermediates can be more stabilized on the surfaces of MOx/Ag(111) than pure Ag(111). The hydrogen evolution reaction on MOx/Ag(111) can be suppressed due to the significantly higher Gibbs free energy for hydrogen adsorption (ΔGH*), thereby enhancing the selectivity toward CO2RR. A series of MOx/Ag composites with the unique interface based on the DFT results were then introduced though a two-step approach. The as-obtained MOx/Ag catalysts boosted both the CO activity and selectivity at a relatively positive potential range, especially in the case of MnO2/Ag. The reduction current density on the MnO2/Ag catalyst can reach 4.3 mA cm-2 at -0.7 V (vs RHE), which is 21.5 times higher than that on pure Ag, and the overpotential of CO2 to CO (390 mV) possesses is much lower than that on pure Ag NPs (690 mV). This study proposes an effective design strategy to construct a metal-oxide interface for CO2RR based on the synergistic effect between metals and MOx.


Nestin-expressing cells divide and adopt a complex electrophysiologic phenotype after transient brain ischemia.
The intermediate filament nestin is upregulated in response to cerebral ischemia; the significance of this, however, is incompletely understood. Here, we used transgenic mice that express green fluorescent protein (GFP) under control of the nestin promotor to characterize the fate of nestin-expressing cells up to 8 weeks after 30 mins occlusion of the middle cerebral artery (MCAo) and reperfusion. The population of nestin-GFP+ cells increased in the ischemic lesion rim and core within 4 days, did not become TUNEL-positive, and was detectable up to 8 weeks in the lesion scar. Nestin-GFP+ cells proliferated in situ and underwent approximately one round of cell division. They were not recruited in large numbers from the subventricular zone (SVZ) as indicated by absence of colabeling with intracerebroventricularly injected dye DiI in the majority of nestin-GFP+ cells. Nestin-GFP+ cells expressed the chondroitin sulfate proteoglycan NG2 and nestin protein, but typically lacked mature astrocytic markers, that is, glial fibrillary acid protein (GFAP) or S100beta. Vice versa, the majority of GFAP+ cells lacked nestin-expression and surrounded the ischemic lesion by 4 days. Whole-cell patch-clamp recordings in acute brain slices from controls showed that only about half of nestin-GFP+ cells displayed complex membrane properties. In contrast, 4 days after the insult all nestin-GFP+ cells expressed these properties. We hypothesize that the change in physiologic properties induced by the ischemic insult is directed toward a specific function of nestin-expressing cells.


Chalcogenide-gold dual-layers coupled to gold nanoparticles for reconfigurable perfect absorption.
Recently, tunable high absorptance from various nanophotonic structures has been demonstrated. However, most of these structures require nano-lithography, which is expensive and slow. Lithography-free tuneable absorbers are rarely explored for tuneable visible and near-infrared photonics. Herein, we demonstrate a gold (Au)/chalcogenide dual-layer that is resonantly coupled to Au nanoparticles (NPs). The structure exhibits angle and polarisation-independent high absorptance. At resonance, waveguide cavity-like modes are excited between the film and NPs whilst gap plasmon modes are excited between the NPs. Coalescence of the waveguide cavity-like modes, the gap plasmon modes, and the highly absorbing chalcogenide semiconductor not only leads to perfect absorptance but also a reconfigurable response via reversible structural phase transitions in the chalcogenide film. In the amorphous state, the design provides nearly perfect absorptance for both p- and s-polarisation states at an incident angle of 20°. However, after switching to the crystalline state, the peak absorptance spectrally broadens and redshifts from 980 to 1520 nm. This experimental observation was theoretically validated by the finite element method. Thermal-electric modeling was performed to show that the structural transition from crystalline to amorphous states is possible in just 5 ns, thus allowing high-speed reconfigurable perfect absorbers.