Infant-initiated weaning from the breast in the first year.
Mothers of 50 healthy breast-fed infants for whom weaning had been completed by the first birthday were administered a maternal feeding and weaning questionnaire developed by the authors. A major purpose of the questionnaire was to investigate the phenomenon of infant-initiated weaning, which is commonly, but somewhat misleadingly referred to as 'self-weaning'. 46% of the infants were reported by their mothers to have initiated weaning. The onset of this behavior occurred most frequently at 5 and 9 months of age. Most mothers attributed it to their infants' increased exploratory and nutritional desires and a concomitant reduced interest in breast-feeding. It is suggested, that rather than being weaning behavior per se, this behavior (at least that which occurs between approximately 5 and 9 months of age) may actually be a common correlate of the cognitive and physical discontinuities or 'spurts' in development which are known to occur during this interval, but that it can, and often does indirectly lead to a relatively easy mutual weaning from the breast if met with appropriate and timely maternal intervention.


Influence of rice straw amendment on mercury methylation and nitrification in paddy soils.
Currently, rice straw return in place of burning is becoming more intensive in China than observed previously. However, little is known on the effect of returned rice straw on mercury (Hg) methylation and microbial activity in contaminated paddy fields. Here, we conduct a microcosm experiment to evaluate the effect of rice straw amendment on the Hg methylation and potential nitrification in two paddy soils with distinct Hg levels. Our results show that amended rice straw enhanced Hg methylation for relatively high Hg content soil, but not for low Hg soil, spiking the same additional fresh Hg. methylmercury (MeHg) concentration was significantly correlated to the dissolved organic carbon (DOC) content and relative abundance of dominant microbes associated with Hg methylation. Similarly, amended rice straw was found to only enhance the potential nitrification rate in soil with relatively high Hg content. These findings provide evidence that amended rice straw differentially modulates Hg methylation and nitrification in Hg contaminated soils possibly resulting from different characteristics in the soil microbial community. This highlights that caution should be taken when returning rice straw to contaminated paddy fields, as this practice may increase the risk of more MeHg production. Rice straw amendment enhanced both Hg methylation and nitrification potential in the relatively high, but not low, Hg soil.


Achondroplasia, hypochondroplasia and thanatophoric dysplasia: clinically related skeletal dysplasias that are also related at the molecular level.
This is the second of three articles on modern genetic concepts of a number of syndromes and disorders. Three short limb skeletal dysplasias with additional abnormalities of the skull are discussed. All are caused by mutations on fibroblast growth factor receptor 3 (FGFR3). A pathogenetic hypothesis is proposed to explain differences in the severity of short stature, midface deficiency, and craniosynostosis.


Studies on ATP: thiamine diphosphate phosphotransferase activity in rat brain.
The experiments described in this paper serve as a contribution to the solution of the discrepancies which exist in the assay of ATP:thiamine diphosphate phosphotransferase activity (EC 220.127.116.11), presently in use as a tool for the diagnosis of Leigh's disease (SNE, subacute necrotizing encephalomyelopathy). The results obtained with this phosphotransferase assay can, in part, be explained by the presence of thiamine triphosphate (ThTP) in the preparation of thiamine diphosphate (ThDP) used as a substrate, by the inhibition by ATP of the ThTP phosphohydrolase activity, present in fractions of rat brain homogenates, and by the stimulation by ThDP of the ATPase activity. When [2(-14)C-thiazole]thiamine was used for the synthesis of [14C]ThTP in fractions of rat brain, it was found that after chromatographic separation of thiamine and its phosphates, 14C radioactivity could be demonstrated in the ThTP fractions, even in the absence of an enzyme source. Probably a complex is formed between [14C]thiamine and a phosphate ester which behaves chromatographically as ThTP. It is concluded that the assay system for the measurement of ThTP synthesis in its present form is, in our hands, not suitable for diagnostic purposes.


Prehospital Resuscitation: What Should It Be?
Prehospital resuscitation is a dynamic field now being energized by new technologies and a shift in thinking regarding intravascular resuscitation. Growing evidence discourages use of intravenous (IV) crystalloid and colloid solutions in trauma, whereas blood products, particularly whole blood, are becoming preferred. Although randomized clinical trials validating definitive resuscitative protocols are still lacking, most preclinical and clinical indicators support this approach. In addition, emerging technologies such as external and endovascular hemorrhage control devices and extracorporeal perfusion are now being used routinely, even in the prehospital setting in many countries, generating new lines of emerging investigations for trauma specialists.


Determining the dimensionality in spatial representations of semantic concepts.
When multidimensional scaling solutions are used to study semantic concepts, the dimensionality of the optimal configuration has to be determined. Several strategies have been proposed to choose the appropriate dimensionality. In the present paper, the traditional dimensionality choice criteria were evaluated and compared to a method based on the prediction of an external criterion. Two studies were conducted in which typicality of an exemplar within a semantic concept was predicted from its distance to the concept centroid. In contrast to the low-dimensional solutions selected by the traditional methods, predictions of an external criterion improved with additional dimensions up till dimensionalities that were much higher than what is common in the literature. This suggests that traditional methods underestimate the richness of semantic concepts as revealed in spatial representations derived from similarity measures.


Blunt and penetrating cardiac trauma: a review.
Cardiologists' expertise in managing traumatic heart disease will be increasingly sought as the incidence of both firearm and motor vehicle accidents soars. Knowledge of mechanisms of injury, as well as appropriate use of diagnostic tools, will aid in rapid recognition of complications related to cardiac injury.


Behaviors and biochemical responses of macroinvertebrate Corbicula fluminea to polystyrene microplastics.
Microplastic, a well-documented emerging contaminant, is widespread in aquatic environments resulting from the production and fragmentation of large plastics items. The knowledge about the chronic toxic effects and behavioral toxicity of microplastics, particularly on freshwater benthic macroinvertebrates, is limited. In this study, adult Asian clams (Corbicula fluminea) were exposed to gradient microplastic solutions for 42 days to evaluate behavioral toxicity and chronic biotoxicity. The results showed that microplastics caused behavior toxicity, oxidative stress, and tissue damage in high-concentration treatments. Siphoning, breathing, and excretion was significantly inhibited (p < 0.05) at high-concentration treatments, suggesting that high-concentration microplastics induced behavioral toxicity in C. fluminea. Malondialdehyde content, superoxide dismutase, catalase, and glutathione reductase activities were significantly enhanced (p < 0.05) and the acetylcholinesterase was significantly inhibited (p < 0.05) throughout the exposure period in high-concentration treatments. Enzymes associated with energy supply were significantly higher at high-concentration microplastics treatments on D7 and D21. However, they recovered to a normal level on D42. The instability of the enzymes indicated that high-concentration microplastics induced oxidative stress and disorder in neurotransmission and energy supply. The gills of C. fluminea in treatments underwent cilia degeneration, which indicated that microplastics caused tissue damage in the gills. The analysis of integrated biomarker response values revealed that high-concentration microplastics led to long-term effects on the health of C. fluminea. In conclusion, continuous exposure to microplastics (10 mg L-1) would damage physical behavior and the antioxidant system of C. fluminea.


A simple preservation method for the storage of Aspergillus fumigatus and Scedosporium apiospermum filamentous fungi isolated from the sputum of patients with cystic fibrosis (CF).
A novel method is described for the laboratory storage of the filamentous fungi, Aspergillus fumigatus and Scedosporium apiospermum. These fungi were isolated directly from the sputum of patients with cystic fibrosis (CF) on previously described Medium B+ fungal selective agar. Medium B+ plates containing heavy growths of filamentous fungi were air dried to completeness and the resulting dehydrated agar containing fungi were hermetically sealed within A4 plastic lamination sheets using a domestic paper laminator. Fungi were successfully recovered and recultured post lamination. This method is simple, inexpensive, versatile and widely adaptable and requires minimum preparation/handling/processing, thereby encouraging the routine archiving of fungal isolates. Laminated fungal sheets may be catalogued and stored safely and securely in fireproof lockable filing cabinets in laboratories, thereby saving valuable bench- or freezer space.


Age-Dependent Reduction in Severity and Discrete Topographical Patterns in Rasmussen Encephalitis: A Link to Cortical Maturation?
Autopsy studies in Rasmussen encephalitis reveal areas of sparing within the affected hemisphere. Clinical progression and inflammation are milder with an older onset. We sought to demonstrate radiological corroboration for these patterns. In our retrospective study, 38 cases were dichotomized into severe pan-hemispheric (all lobes involved) and sub-hemispheric groups (others) to identify age demographics and other severity predictors. The extent and patterns of radiological pathology in the cortex and subcortical structures were assessed by structured visual grading. Relevant clinical data were also reported. Children with pan-hemispheric involvement were younger at onset (P < 0.001) and were more likely to present with status epilepticus (odds ratio 8.5, 95% confidence interval 1.5 to 50.0, P = 0.022). A history of perinatal asphyxia/hospitalization (P < 0.001) and delayed milestones (P = 0.013) were encountered exclusively in this group, and progression to a low-amplitude record background on electroencephalography, suggesting that cortical damage was identified frequently (P = 0.038, odds ratio = 5.7, 95% confidence interval 1.3 to 25.0). Visual grading revealed significant differences among both cortical (P < 0.001) and subcortical (P < 0.001) regions. On multivariate analysis, the odds for pan-hemispheric disease decreased per year of age at onset (P = 0.022, odds ratio 0.51, 95% confidence interval 0.085 to 0.725). Epilepsy surgery (n = 14) was associated with Engel Class 1 seizure control (P < 0.001). Immunosuppressive therapy (n = 20) did not demonstrate a significant seizure remission (P = 0.157, odds ratio 0.39, 95% confidence interval 0.10 to 1.55). Our case series confirms the presence of specific topographical patterns of macroscopic radiological pathology over the affected hemisphere with a marked age-associated reduction in the odds for severe pan-hemispheric disease.


Socio-Cultural Factors Contributing to Being an Organ Donor in Iranian Employees.
The purpose of this study was to use a culturally modified Organ Donation Model (ODM) to explore the significant factors and ways in which these factors could influence signing the donor card. This cross-sectional study was conducted among 600 employees from 57 offices in Hamadan, Iran, in 2018. Participants were selected randomly and surveyed on being a donor and their perceptions regarding signing the donor card. Structural equation modeling (SEM) was conducted to determine the inter-relationship between the studied variables. Participants' mean age was 39.5 (SD = 7.0). 20% of participants had a signed donor card. Descriptive norms (β = 0.53, p < 0.001), non-cognitive beliefs (β=-0.33, p < 0.001), anticipated regret (β = 0.28, p < 0.001) and subjective norms (β=-0.17, p < 0.01) had significant direct effects on signing the donor card. This study provides socio-culturally informed evidence on individuals' signing donor card. These factors could provide a guide to policymakers to develop the community-based interventions.


Multiway chemometric decomposition of EEM of fluorescence of CdTe quantum dots obtained as function of pH.
The effect of the pH (from 3 to 10) on the excitation emission matrices (EEMs) of fluorescence of CdTe quantum dots (QDs), capped with mercaptopropionic acid (MPA), were analyzed by multiway decomposition methods of parallel factor analysis (PARAFAC), a variant of the parallel factor analysis method (PARAFAC2) and multivariate curve resolution alternating least squares (MCR-ALS). Three different sized CdTe QDs with emission maximum at 555 nm (QDa), 594 nm (QDb) and 628 nm (QDc) were selected for analysis. The three-way data structures composed of sets of EEMs obtained as function of the pH (EEMs, pH) do not have a trilinear structure. A marked deviation to the trilinearity is observed in the emission wavelength order--the emission spectra suffers wavelength shift as the pH is varied. The pH-induced variation of the fluorescence properties of QDs is described with only one-component PARAFAC2 or MCR-ALS models--other components are necessary to model scattering and/or other background signals in (EEMs, pH) data structures. Bigger sized QDs are more suitable tools for analytical methodologies because they show higher Stokes shifts (resulting in simpler models) and higher pH range sensitivity. The pH dependence of the maximum wavelength of the emission spectra is particularly suitable for the development of QDs/EEMs wavelength-encoded pH sensor bioimaging or biological label methodologies when coupled to multiway chemometric decomposition.


Molecular characterization and expression of buffalo (Bubalus bubalis) DEAD-box family VASA gene and mRNA transcript variants isolated from testis tissue.
VASA is a member of the DEAD-box protein family that plays an indispensable role in mammalian spermatogenesis, particularly during meiosis. In the present study, we isolated, sequenced, and characterized VASA gene in buffalo testis. Here, we demonstrated that VASA mRNA is expressed as multiple isoforms and uses four alternative transcriptional start sites (TSSs) and four different polyadenylation sites. The TSSs identified by 5'-RNA ligase-mediated rapid amplification of cDNA ends (RLM-5'-RACE) were positioned at 48, 53, 85, and 88 nucleotides upstream relative to the translation initiation codon. 3'-RACE experiment revealed the presence of tandem polyadenylation signals, which lead to the expression of at least four different 3'-untranslated regions (209, 233, 239 and 605 nucleotides). The full-length coding region of VASA was 2190 bp, which encodes a 729 amino acid (aa) protein containing nine consensus regions of the DEAD box protein family. VASA variants are highly expressed in testis of adult buffalo. We found five variants, one full length VASA (729 aa) and four splice variants VASA 2, 4, 5, 6 (683, 685, 679, 703 aa). The expression level of VASA 1 was significantly higher than rest of all (P < 0.05) except VASA 6. The relative ratio for VASA 1:2:4:5:6 was 100:1.0:1.6:0.9:48.


Mechanisms of alcohol-associated cancers: introduction and summary of the symposium.
Chronic alcohol consumption is associated with an increased risk for cancers of many organs, such as oral cavity, pharynx, larynx, and esophagus; breast; liver; ovary; colon; rectum; stomach; and pancreas. An understanding of the underlying mechanisms by which chronic alcohol consumption promotes carcinogenesis is important for development of appropriate strategies for prevention and treatment of alcohol-associated cancers. The National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, Office of Rare Diseases, National Cancer Institute, National Institute on Drug Abuse, and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, sponsored an international symposium on Mechanisms of Alcohol-Associated Cancers in Bethesda, Maryland, USA, October 2004. The following is a summary of the symposium. Chronic ethanol consumption may promote carcinogenesis by (1) production of acetaldehyde, which is a weak mutagen and carcinogen; (2) induction of cytochrome P450 2E1 and associated oxidative stress and conversion of procarcinogens to carcinogens; (3) depletion of S-adenosylmethionine and, consequently, induction of global DNA hypomethylation; (4) induction of increased production of inhibitory guanine nucleotide regulatory proteins and components of extracellular signal-regulated kinase-mitogen-activated protein kinase signaling; (5) accumulation of iron and associated oxidative stress; (6) inactivation of the tumor suppressor gene BRCA1 and increased estrogen responsiveness (primarily in breast); and (7) impairment of retinoic acid metabolism. Nicotine may promote carcinogenesis through activation of extracellular signal-regulated kinase/cyclooxygenase-2/vascular endothelial growth factor signaling pathway.


Ultrastructural study of enteric ganglia in three patients with Rett syndrome.
In order to verify whether a pseudo-obstruction syndrome was associated with morphological changes in enteric ganglia, we performed an ultrastructural study on rectal biopsy specimens in three patients with Rett syndrome. Features of enteric neurons, detected to a different extent in all three biopsy specimens, included an abnormal dilatation of endoplasmic reticulum with a disorganization of cisternae of the Golgi apparatus, and masses of unidentified electron-dense granulo-filamentous material, probably of lipidic origin, observed in the perikaryon. Large electron-lucent membrane-bound vacuoles were found mostly within satellite glial cells. Sometimes, the axon terminals were swollen and showed intraxonal vacuolization. We conclude that the reported findings do not represent a specific sign of degeneration and do not constitute a significant morphological marker of disease.


Birth cohort differences in height, weight and BMI among Indian women aged 15-30 years: analyses based on three cross-sectional surveys.
To explore long-term trends in height, weight and BMI across birth cohorts among Indian women aged 15-30 years. Nationally representative cross-sectional surveys. Data from three National Family Health Surveys were conducted in 1998-1999, 2005-2006 and 2015-2016. Height and weight were modelled jointly, employing a multivariate regression model with age and birth cohorts as explanatory variables. The largest birth cohort (born 1988-1992) was the reference cohort. Stratified analyses by place of residence and by marital status and dichotomised parity were also performed. 437 753 non-pregnant women aged 15-30 years. The rate of increase in height, weight and BMI differed across birth cohorts. The rate of increase was much lower for height than weight, which was reflected in an increasing trend in BMI across all birth cohorts. In the stratified analyses, increase in height was found to be similar across urban and rural areas. Rural women born in the latest birth cohort (1998-2001) were lighter, whereas urban women were heavier compared to the reference cohort. A relatively larger increase in regression coefficients was observed among women born between 1978 and 1982 compared to women born between 1973 and 1977 when considering unmarried and nulliparous ever-married women and, one cohort later (1983-1987 v. 1978-1982), among parous ever-married women. As the rate of increase was much larger for weight than for height, increasing trends in BMI were observed across the birth cohorts. Thus, cohort effects show an important contributory role in explaining increasing trends in BMI among young Indian women.


Reservoirs of Staphylococcus aureus in meat sheep and dairy cattle.
The objective of the study was to investigate reservoirs and transmission of S. aureus in ewes and lambs in 3 meat sheep flocks. Repeated sampling of milk, teat skin, nasal- and vaginal mucous membranes was performed and samples were analysed for S. aureus. For comparison, samples were also collected from cows and young heifers in 3 dairy cattle herds. Selected isolates were compared by pulsed-field gel electrophoresis (PFGE). S. aureus was detected in 8 (1.5%) of 520 milk samples from ewes and in 38 (6.4%) of 588 milk samples from cows. From body site swabs, S. aureus was found in 394 (32.6%) of 1208 samples from sheep and in 67 (16.0%) of 420 samples from cattle. The proportion of S. aureus-positive nasal swabs from ewes and cows were 56.7% and 13.9%, respectively. From lambs, 58.2% of the nasal swabs were S. aureus-positive. In each flock, one S. aureus pulsotype predominated. Identical S. aureus pulsotypes were found in milk and from body sites. Paired S. aureus isolates from the nasal cavity of (i) ewes and their lambs, (ii) twins and (iii) from repeated swabs of individual ewes were compared by PFGE, and in the majority of cases the two isolates were identical. The results contribute new knowledge indicating frequent transmission of S. aureus between the dam and her lambs and within animals in a flock. In contrast to cattle, S. aureus is frequently present in the nose of sheep which may represent the primary reservoir of S. aureus in sheep flocks.


Role of ionic fluxes in the apoptotic cell death of cultured cerebellar granule neurons.
Cultured cerebellar granule neurons (CGC) increase survival in a medium containing 25 mM KCl (K25), and they die apoptotically when cultures are treated with staurosporine (St) or are transferred to a 5-mM KCl containing medium (K5). Apoptotic CGC show nuclear condensation and caspase-3 activation. Cell death induced by these conditions was partially prevented when cultures were maintained under alkaline conditions, which also induced a marked reduction of the caspase-3 activation. The acidification of the medium further increased cell death induced by both stimuli. Cultures transferred to K5 suffered an immediate intracellular alkalinization that remained constant during the time K5 was present. In contrast, St did not modify cytosolic pH at any of the evaluated times. On the other hand, DIDS, furosemide, and bumetanide prevented CGC death induced by K5 and St. Other drugs such as amiloride, EIPA, tamoxifen, NEM, or NPPB did not modify cell death induced by these conditions. Both DIDS and bumetanide markedly inhibited the processing and activation of caspase-3, and DIDS prevented the nuclear condensation induced by K5 and St. These findings suggest that pH is a condition that could contribute to the modulation of cell death induced by some stimuli and that other ions, such as potassium, could have a role in the initial phase of apoptotic death of CGC.


Combining autocorrelation signals with delay multiply and sum beamforming algorithm for ultrasound imaging.
Beamformer is one of the most important components in ultrasound imaging system. The delay and sum (DAS) beamforming algorithm has been widely used in recent decades due to its simplicity and robustness. However, it has poor impact on resolution and contrast. A new beamformer named filtered delay multiply and sum (F-DMAS) which was an alternative of delay multiply and sum (DMAS) was proposed to overcome these shortcomings of DAS. Although F-DMAS partially enhances the image quality, its performance still has room for improvement. Therefore, a novel beamformer named lag-based delay multiply and sum (L-DMAS) which combines autocorrelation signals with DMAS algorithm is proposed by us to improve its efficiency. Field II was employed to synthesize a point target phantom and a cyst phantom to compare the performance between DAS, F-DMAS, double stage delay multiply and sum (DS-DMAS), and L-DMAS. We also estimate the performance of four algorithms on experimental data and in vivo data. These results show that both DS-DMAS and L-DMAS are better than DAS and F-DMAS in each case. In some cases, DS-DMAS and L-DMAS have little difference in performance, but in other cases, L-DMAS outperforms DS-DMAS. Graphical Abstract.


Exploratory behavior, reaction to novelty, and proactive memory in rats with temporo-entorhinal connections disrupted.
The parahippocampal cortex is ascribed a key function in mediating reciprocal connections between neocortical association areas and the hippocampal formation. Within this complex the lateral entorhinal cortex (LEC) seems to stand out as an important interface exerting modulating influence upon cognition and memory by way of its connections with the hippocampal formation and temporal cortex (TC), respectively. The purpose of the present study was to compare effects of TC/LEC disruptions in a novelty test with results previously obtained in the same test following lateral perforant path (LPP) disruptions. Further, effects of TC/LEC lesions on proactive memory were examined, since a profound impairment in retroactive memory has previously been found. Rats bearing TC/LEC lesions or LPP lesions behaved differently in the novelty test. It was also shown that the impairment in proactive memory was less severe than the one seen in retroactive memory following TC/LEC lesions. The results are discussed in terms of a highly integrative role of LEC.


Re-excision rates after breast conserving surgery following the 2014 SSO-ASTRO guidelines.
In 2014, SSO-ASTRO published guidelines which recommended "no ink on tumor" as adequate margins for patients undergoing breast conservation for invasive breast cancer. In 2016, new SSO-ASTRO-ASCO guidelines recommended 2 mm margins for DCIS. We evaluated whether these guidelines affected re-excision rates at our institution. Patients treated with breast conservation surgery from January 1, 2010-March 1, 2016 were identified. Re-excision rates, tumor characteristics, and presence of residual disease were recorded. The 2016 guidelines were retrospectively applied to the same cohort and expected re-excision rates calculated. Re-excision rates did not significantly decline before and after 2014 guideline adoption (11.9% before, 10.9% after; p = 0.65) or when the 2016 guidelines were retrospectively applied (8.4%; p = 0.10). The 2014 and 2016 guidelines had minimal impact on our re-excision rates, as most re-excisions were done for DCIS and 2016 guidelines supported our prior institutional practices of 2 mm margins for these patients.


An international reference reagent for the detection of RHD and SRY DNA in plasma.
The determination of foetal RHD genotype using foetal DNA contained in the maternal circulation is increasingly used to manage pregnancies at risk of haemolytic disease of the foetus and newborn (HDFN) caused by maternal anti-D. The test is becoming increasingly reliable, and routine clinical services have been established in some centres. However, laboratories currently have no reference materials with which to determine the performance of their tests. This report describes the production and evaluation of a freeze-dried preparation of human plasma, code 07/222, containing RHD and SRY sequences which can be used as a minimum sensitivity reagent. RhD-positive male plasma was diluted in an excess of RhD-negative female plasma, and 1 ml aliquots were freeze-dried in glass ampoules. To characterise the material, 19 laboratories took part in an international collaborative study. The participants evaluated dilutions of the material using their in-house routine assays and recorded the highest dilution where the genes could be detected. When diluted 1 in 2, most laboratories were able to detect the presence of RHD and SRY sequences in the material and the participants agreed that this was an appropriate level to set as the minimum sensitivity required. In October 2010, the WHO Expert Committee on Biological Standardization approved the material 07/222 as an International Reference Reagent for the detection of RHD and SRY DNA in plasma.


Update on diagnostic approaches and therapeutic strategies in systemic mastocytosis.
Systemic mastocytosis is a rare disease which is being better recognized and managed. While the vast majority of patients have indolent disease with variable symptom burden, a small proportion evolve or present with aggressive disease. This may be due to increases in mast cell burden (leukemic, associated with tumour masses) or more commonly due to the presence of an additional hematologic neoplasm (SM-AHN). These patients with advanced systemic mastocytosis have poor outcome; however, recent advances in diagnosis, molecular genetics and treatment have changed the prognostic landscape for this group of patients. In this review we address the most topical questions related to diagnostics, classification, new disease entities, treatment and multiparameter prognostic scoring systems.


Pancreatic Elastase-1 Quick Test for rapid assessment of pancreatic status in cystic fibrosis patients.
At present, fecal elastase-1 ELISA determination is the most sensitive and specific tubeless pancreatic function test available. However, the results are not available the same day in routine clinical practice. This prospective study aims at evaluating the sensitivity and specificity of the Elastase-1 Quick™ Test by comparing the results with the ELISA test. The study was composed of three groups: the screening-diagnosed cystic fibrosis (CF) patients (n=28), the screened, but non-CF subjects (n=36) and non-screened CF patients (n=62). Pancreatic status (normal vs abnormal) was evaluated using the Pancreas Elastase-1 Quick™ Test. Fecal elastase-1 concentration was determined with a commercially available ELISA kit, used as reference. The cut-off for abnormal results was set at <200μg/g of stool. The Pancreatic Elastase-1 Quick Test™ showed the following sensitivities and specificities in the studied groups: 92.8% and 96.6% in all subjects, 90.5% and 100% in screening samples, and 92.8 and 90.5% in CF patients. Pancreatic Elastase-1 Quick Test™ proves to be a rapid and reliable option to qualitatively evaluate pancreatic function for diagnostic purposes in a clinical setting of CF care.


Annual reproductive cycle in the male red-sided garter snake, Thamnophis sirtalis parietalis: field and laboratory studies.
The reproductive cycle of male red-sided garter snakes (Thamnophis sirtalis parietalis) was studied in a laboratory-maintained population and in nature. Both populations exhibited a dissociated reproductive pattern in which spermatogenesis was initiated after the breeding season and sperm were stored in the vas deferens over winter. Although animals in both the laboratory and the field exhibited a dissociated reproductive pattern, temporal differences were evident in the two populations. Animals maintained in the laboratory initiated and completed spermiation much sooner than animals collected in the field. In the captive population, the renal sexual segment (RSS) could be identified but did not exhibit a seasonal fluctuation, indicating perhaps that androgen production was continuous, but at a reduced level. In nature, the RSS was hypertrophied at emergence, regressed following the breeding season, and again hypertrophied as circulating androgens increased in the fall, prior to hibernation. In both laboratory-maintained and field animals the circulating concentrations of testosterone and dihydrotestosterone at emergence were initially similar to the levels observed prior to hibernation but by 2 weeks postemergence had decreased to a relatively low level. Both the high androgen levels prior to hibernation and the rapid decrease during the spring courtship season may result from temperature influences on clearance rates. Plasma levels of corticosterone varied during the spring, first increasing upon emergence and then declining approximately 2 weeks following emergence.


The increasing incidence of gallbladder disease in children: A 20year perspective.
The incidence of cholecystectomy in the pediatric population has increased over the last 20years but has not been described in a Canadian population. We conducted the first province-wide study to describe the incidence of cholecystectomy in children in Ontario. A population-based, retrospective cohort using administrative databases in Ontario, Canada, was conducted. We included patients less than 18years of age who underwent cholecystectomy from 1993 to 2012. Trends in rates of cholecystectomy were assessed with the Cochrane-Armitage test. There were a total of 6040 pediatric cholecystectomies performed over the study period in Ontario. The mean age was 14.3years, and 79.6% of patients were females. The crude incidence per 100,000 person-years increased from 8.8 to 13.0 (p<0.001) from 1993 96-2009-12, respectively. The sex-specific incidence showed a larger increase in the female population from 14.7 to 21.1 per 100,000 person-years (p<0.001). The vast majority (82%) of surgeries were performed in 13-17year olds and were largely performed in the community (>75%). There has been a significant rise in the incidence of pediatric cholecystectomy in Ontario over the last 20years. The majority of surgeries are performed in the community, and pediatricians will likely see an increase of gallbladder disease in practice.


Adjunctive treatment with probiotics partially alleviates symptoms and reduces inflammation in patients with irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a functional bowel disorder. This study aimed to assess the effect of a probiotic product (containing Lactobacillus casei Zhang, Lactobacillus plantarum P-8, and Bifdobacterium animalis subsp. lactis V9) as an adjunct to a routine regimen in IBS management. Forty-five patients with IBS were randomized into the probiotic (n = 24) and control (n = 21) groups, receiving the routine regimen with or without probiotics for 28 days, respectively. Serum and fecal samples were collected and analyzed. The IBS-symptom severity score (P < 0.01), serum levels of IL-6 (P < 0.01) and TNF-α (P < 0.001) were significantly lower in the probiotic group than the control group at day 28. The probiotic adjunctive treatment resulted in significant decreases in some bacterial genera that worsen IBS, such as Bacteroides (P < 0.01), Escherichia (P < 0.05), and Citrobacter (P < 0.05), significant decreases were also observed in some beneficial genera in the control group, including Bifidobacterium (P < 0.05), Eubacterium (P < 0.05), Dorea (P < 0.01), and Butyricicoccus (P < 0.05). Furthermore, significant correlations were found between some monitored parameters and compositional changes in the fecal microbiota, suggesting that the clinical improvement of IBS was likely associated with gut microbiota modulation. The enterotype analysis revealed that the initial fecal microbiota composition could influence clinical outcomes. The adjunctive use of probiotics with a routine regimen showed additional clinical effectiveness compared to the routine regimen alone in managing IBS. A pretreatment gut microbiome analysis might help tailor a personalized probiotic regimen to optimize treatment effects.


A whole cell-based Matrix-assisted laser desorption/ionization mass spectrometry lipidomic assay for the discovery of compounds that target lipid a modifications.
Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) is a powerful analytical technique that has been applied to a wide variety of applications ranging from proteomics to clinical diagnostics. One such application is its use as a tool for discovery assays, such as monitoring the inhibition of purified proteins. With the global threat from antimicrobial-resistant (AMR) bacteria, new and innovative solutions are required to identify new molecules that could revert bacterial resistance and/or target virulence factors. Here, we used a whole cell-based MALDI-TOF lipidomic assay using a routine MALDI Biotyper Sirius system operating in linear negative ion mode combined with the MBT Lipid Xtract kit to discover molecules targeting bacteria that are resistant to polymyxins, which are considered last-resort antibiotics. A library of 1200 natural compounds was tested against an E. coli strain expressing mcr-1, which is known to modify lipid A by adding phosphoethanolamine (pETN), making the strain resistant to colistin. Using this approach, we identified 8 compounds that led to a decrease in this lipid A modification by MCR-1 and could potentially be employed to revert resistance. Taken together, as-proof-of-principle, the data we report here represent a new workflow based on the analysis of bacterial lipid A by routine MALDI-TOF for the discovery of inhibitors that could target bacterial viability and/or virulence.


The benefit of the Hemonetics cell saver apparatus during cardiac surgery.
This retrospective chart review of 155 patients having coronary artery bypass graft surgery (CABG) over a two-month period determined whether the use of a cell saver apparatus (CSA) (1) reduced or increased the requirements for homologous blood; (2) increased the incidence of post-surgical bleeding; (3) was cost-effective. Two groups of patients were identified. Group 1 (n = 99) received both CSA processed red blood cells and homologous blood components. Requirement for homologous blood products was reduced in the first 24 hr after surgery (0.5 +/- 1.0 vs 1.3 +/- 1.8 units; P less than 0.05) when compared with Group 2 (n = 56) in whom only homologous blood products were utilized. More patients in Group 1 had no transfusion requirements (45 vs 8; P less than 0.05) and there was no increased risk of major haemorrhage. When the capital costs are included, utilization of the CSA was not cost-effective. We conclude that utilisation of a CSA was safe, with no increased risk of bleeding, reduced requirements for homologous blood transfusions, but added to the cost of the procedure.


CT and MRI features of calvarium and skull base osteosarcoma (CSBO).
This study aims to assess the CT and MRI features of calvarium and skull base osteosarcoma (CSBO). The CT and MRI features and pathological characteristics of 12 cases of pathologically confirmed CSBO were analyzed retrospectively. 12 patients (age range 9-67 years; 3 male, 9 female) were included in the study. Tumours occurred in skull base (7, 58.3%), temporal (4, 33.3%) and frontal (1, 8.3%). Among all, six patients received radiotherapy for nasopharyngeal carcinoma. According to pathology, 11 out of 12 tumours were high-grade (91.7%). On CT, all the tumours had soft tissue mass penetrated into cortical bone with invasion of surrounding soft tissue. Six tumours were shown to have lytic density and six were mixed density. Matrix mineralization was present in 10 cases (83.3%). On MRI, tumours presented as soft-tissue masses measuring 5.9 ± 2.4 (3.9-8.0) cm. Five tumours showed low signal intensities on T1 weighted imaging with seven having heterogeneous signal intensities. One showed low signal intensity on T2 weighted imaging, two showed high signal intensities and nine heterogeneous signal intensities. All the tumours showed low signal intensities on diffusion-weighted imaging. On contrast enhanced images, seven cases showed heterogeneous enhancement, three showed peripheral enhancementand and two showed homogeneous enhancement. Dural tail sign were detected in nine cases. CSBO is rare, and is commonly associated with previous radiation exposure. A presumptive diagnosis for osteosarcoma should be considered when calvarium and skull base tumours with osteoid matrix and duraltail sign are found. CT and MR features of CSBO have not been reported. The study helps to identify CSBO and other sarcomas.


Dynamics of the wax bloom of a seasonal Namib Desert tenebrionid, Cauricara phalangium (Coleoptera: Adesmiini).
The dynamics of the extracuticular was bloom in a 'winter' species of tenebrionid beetle, Cauricara phalangium, from the Namib Desert were monitored in the field and under laboratory conditions. The beetles possessed a full complement of the white wax material after adult emergence. The amount of this material on the integument declined towards the end of the season. The wax bloom was regenerated in both the field and laboratory, with high temperatures and low humidities bringing about greatest renewal. End of the season decline appears tobe related to the senescence of these seasonal beetles. Water loss rates differed significantly for individuals collected in May, when fully bloomed, and in August when little or no wax bloom was present. The wax bloom material contributes to the protection of these diurnal beetles against the high temperatures and radiant heat loads in the Namib Desert.


Autoradiographic localization of 3H-glucocorticoids and 3H-cortexolone in mouse pituitary.
Autoradiograms of mouse pituitaries were prepared 30 min after injection of 3H-dexamethasone (3HDM), 3H-corticosterone (3HB) and 3H-cortexolone (3HS) either alone or in the presence of competing unlabelled steroids. 3H-dexamethasone accumulated in cell nuclei of both the pars distalis and the pars nervosa but not in those of the pars intermedia. This preferential accumulation (nuclear/cytoplasmic grain density, 4 : 1) was abolished by the concurrent administration of excess dexamethasone. 3H-corticosterone, to a much less marked extent than 3H-dexamethasone, accumulated in cell nuclei of the pars distalis but not in those of the pars intermedia and the pars nervosa. Excess unlabelled corticosterone diminished nuclear grain density in the pars distalis. After 3-h-cortexolone injection, preferential nuclear uptake was not observed. In a second series of experiments, excess dexamethasone (10 x, 100 x), corticosterone (100 x, 300 x) and cortexolone (100 x, 300 x) administered with 3H-dexamethasone were without effect on cytoplasmic grain density but totally abolished preferential nuclear accumulation. Parallel biochemical studies on kidney cytoplasmic preparations from the same animals showed no differences in total cytoplasmic radioactivity between treatments but marked differences in cytoplasmic bound 3H-dexamethasone. The results demonstrate: i) that dexamethasone binds specifically to cell nuclei of the pars distalis and the pars nervosa and that this nuclear concentration is abolished by competing corticosterone and cortexolone as well as dexamethasone; ii) that corticosterone localizes in cell nuclei of the pars distalis but much less markedly than dexamethasone; iii) that cortexolone fullfils the criteria of a glucocorticoid antagonist at the pituitary cell level.


Interleukin-20 plays a critical role in maintenance and development of psoriasis in the human xenograft transplantation model.
Interleukin (IL)-20 is a recently discovered cytokine displaying increased levels in psoriatic lesions. Interestingly, IL-20 levels decrease with antipsoriatic treatment, correlating with clinical improvement. However, the role of IL-20 in the aetiology of psoriasis is unknown. In this study, we investigate the effects both of blocking IL-20 signalling in psoriatic plaques and of adding IL-20 to nonlesional psoriasis skin. We employed the human skin xenograft transplantation model in which psoriatic plaques and nonlesional keratome skin biopsies obtained from donors with moderate to severe plaque psoriasis were transplanted on to immuno-deficient mice. The transplanted mice were treated with anti-IL-20 antibodies or recombinant human IL-20. We demonstrate that blocking IL-20 signalling with anti-IL-20 antibodies induces psoriasis resolution and inhibits psoriasis induction. We also demonstrate that continuous IL-20 infusion, together with injection of additional nonactivated leucocytes, promotes induction of psoriasis in nonlesional skin from patients with psoriasis. The results suggest that IL-20 plays a critical role in the induction and maintenance of psoriasis, and IL-20 is suggested as a new possible specific target in psoriasis treatment.


Analysis of pThr286-CaMKII and CaMKII immunohistochemistry in the hippocampus of patients with temporal lobe epilepsy.
Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates a variety of neuronal proteins, thereby, coordinating responses to changes of intracellular Ca2+ concentrations. Autophosphorylation at threonine286 generates an autonomously active form of CaMKII (pThr286-CaMKII), thus prolonging responses to transient increases in Ca2+. Our previous studies in hippocampi of temporal lobe epilepsy (TLE) patients revealed a significant up-regulation of CaMKII in dentate granule cells (DGCs) of specimens with Ammon's horn sclerosis (AHS). However, the functional status of the up-regulated enzyme remained unclear. Therefore, we performed double immunofluorescence staining for CaMKII and pThr286-CaMKII in hippocampi of TLE patients and controls. Furthermore, we analyzed the ratio of the relative fluorescence intensities pThr286-CaMKII: CaMKII in DGCs. CaMKII immunoreactivity was significantly increased in DGC bodies and their proximal dendrites in AHS. In contrast, immunostaining for pThr286-CaMKII was localized to the DGC bodies, revealing similar labeling intensities in all TLE and control specimens, and was not observed in the dendritic compartment of DGCs. Analysis of the ratio of the relative fluorescence intensities pThr286-CaMKII:CaMKII in DGC bodies revealed a significantly reduced ratio in AHS compared to lesion-associated TLE and controls. Thus, up-regulation of total CaMKII in DGCs of AHS specimens is not paralleled by an increase of its autonomously active form.


Early auditory evoked potentials (EAEPs) in the rabbit. Normative data and effects of lesions in the cerebello-pontine angle.
Early auditory evoked potentials (EAEPs) were measured in rabbits. After establishing normative data an operative method was developed to expose the cerebello-pontine angle. Compression of the VIIIth nerve and a reduction of blood supply to the cochlea via the labyrinthine artery altered the EAEP systematically. In all cases of an VIIIth nerve lesion wave 1 continued to be elicited whereas waves 2-5 disappeared. Circulatory disturbances had an effect upon wave 1. The results indicate that the generator of wave 1 is the unit cochlea/acoustic nerve and of waves 2-5 the auditory pathway within the brain stem. The resultant data help to understand wave alterations in patients with acoustic neuromas.


Arachidonic acid and endothelin potentiate Ca2+ transients in rat cardiac myocytes via inhibition of distinct K+ channels.
The release of arachidonic acid by phospholipases in response to cell surface receptor activation may be an important step in the initiation of inotropic events in cardiac muscle. Endothelin has been shown to activate phospholipase A2 and release arachidonic acid in isolated rat hearts. Endothelin also has a positive inotropic effect in cardiac muscle, suggesting that endothelin increases Ca2+ influx or the amount of Ca2+ released from the sarcoplasmic reticulum. We used suspensions of adult rat ventricular myocytes loaded with fura-2/AM to compare the effects of arachidonic acid and endothelin on Ca2+ transients evoked by extracellular ATP. We showed recently (Damron, D.S., and Bond, M. (1993) Circ. Res. 72, 376-386) that pretreatment of cardiac myocytes with arachidonic acid significantly potentiated the amplitude of the ATP-triggered Ca2+ transient. We now report that endothelin also enhances the ATP-triggered Ca2+ transient and that the effect of the combination of maximal doses of endothelin and arachidonic acid is additive. Neither endothelin nor arachidonic acid was found to affect the size of the sarcoplasmic reticulum Ca2+ store. The potentiating effects of both arachidonic acid and endothelin were sensitive to inhibitors of protein kinase C. Endothelin was also found to stimulate phospholipase C but not phospholipase A2. Application of arachidonic acid to individual cardiac muscle cells resulted in inhibition of the transient outward K+ current, whereas application of endothelin inhibited the delayed rectifier current. These effects of arachidonic acid and endothelin were additive, and both effects could be blocked by the protein kinase C inhibitor, staurosporine. Similarly, staurosporine inhibited endothelin-induced increases in isometric contractions in ventricular papillary muscle. We conclude that arachidonic acid and endothelin may be involved in the modulation of inotropic activity in cardiac muscle by means of protein kinase C-dependent inhibition of two distinct K+ channels. This would result in a prolongation of action potential duration and thus an increase in Ca2+ influx across the sarcolemma.


Effectiveness of an Internet-Based and Telephone-Assisted Training for Parents of 4-Year-Old Children With Disruptive Behavior: Implementation Research.
There is a lack of effectiveness studies when digital parent training programs are implemented in real-world practice. The efficacy of the internet-based and telephone-assisted Finnish Strongest Families Smart Website (SFSW) parent training intervention on the disruptive behavior of 4-year-old children was studied in a randomized controlled trial setting in Southwest Finland between 2011 and 2013. After that, the intervention was implemented nationwide in child health clinics from 2015 onwards. The main aim of this study was to compare the treatment characteristics and effectiveness of the SFSW parent training intervention between the families who received the intervention when it was implemented as a normal practice in child health clinics and the families who received the same intervention during the randomized controlled trial. The implementation group comprised 600 families who were recruited in the SFSW intervention between January 2015 and May 2017 in real-world implementation. The RCT intervention group comprised 232 families who were recruited between October 2011 and November 2013. The same demographic and child and parent measures were collected from both study groups and were compared using linear mixed-effect models for repeated measurements. The child psychopathology and functioning level were measured using the Child Behavior Checklist (CBCL) version 1.5-5 for preschool children, the Inventory of Callous-Unemotional Traits (ICU), and a modified version of the Barkley Home Situations Questionnaire. Parenting skills were measured using the 31-item Parenting Scale and the shorter 21-item Depression, Anxiety and Stress Scale (DASS-21). The estimated child and parent outcomes were adjusted for CBCL externalizing scores at baseline, maternal education, duration of the behavior problems, and paternal age. The baseline measurements of each outcome were used as covariates. The implementation group was more likely to complete the intervention than the RCT intervention group (514/600, 85.7% vs 176/232, 75.9%, respectively; P<.001). There were no significant differences between the implementation and RCT intervention groups with regard to child measures, including CBCL externalizing score (-0.2, 95% CI -1.3 to 1.6; P=.83), total score (-0.7, 95% CI -3.0 to 4.5; P=.70), internalizing score (-0.3, 95% CI -1.0 to 1.6; P=.64), and ICU total score (-0.4, 95% Cl -1.9 to 1.2; P=.64). No significant difference was detected in the Parenting Scale total score (0.0, 95% Cl -0.1 to 0.1; P=.50), while DASS-21 total score differed nearly significantly (2.5, 95% Cl 0.0-5.1; P=.05), indicating better improvement in the implementation group. The internet-based and telephone-assisted SFSW parent training intervention was effectively implemented in real-world settings. These findings have implications for addressing the unmet needs of children with disruptive behavior problems. Our initiative could also provide a quick socially distanced solution for the considerable mental health impact of the COVID-19 pandemic. ClinicalTrials.gov NCT01750996; https://clinicaltrials.gov/ct2/show/NCT01750996. RR2-10.1186/1471-2458-13-985.


[Principles of the genesis of pressure and flow pulse contours of the human carotid artery (author's transl)].
In order to clarify the genesis of the characteristic pressure and flow pulse contours of the common carotid artery of man, at first transcutaneous pulse recordings were carried out on healthy resting subjects during breathing of room air and of a mixture of 95% O2 and 5% CO2 (Carbogen). The latter was used to cause vasodilation of the cerebral resistance vessels and thus reducing the peripheral reflection coefficient. Secondly pulse constructions were performed by means of a theoretical inhomogeneous tube model using a digital computer. A side branch of this model represented the carotid artery. The pressure pulse of the aortic arch of the model was used as generating pulse for the carotid system. A satisfactory simulation of the carotid pressure and flow pulse contours under normal conditions and during peripheral vasodilation requires an intermediate reflection (positive for antegrade waves) at a site near the middle of the total transmission time of the carotid model system. The adequacy of the model is demonstrated by comparison of the recorded and constructed pulses.


Distinct manifestations of executive dysfunction in aged rats.
Different components of executive function such as working memory, attention, and cognitive flexibility can be dissociated behaviorally and mechanistically; however, the within-subject influences of normal aging on different aspects of executive function remain ill-defined. To better define these relationships, young adult and aged male F344 rats were cross-characterized on an attentional set-shifting task that assesses cognitive flexibility and a delayed response task that assesses working memory. Across tasks, aged rats were impaired relative to young; however, there was significant variability in individual performance within the aged cohort. Notably, performance on the set-shifting task and performance at long delays on the delayed response task were inversely related among aged rats. Additional experiments showed no relationship between aged rats' performance on the set-shifting task and performance on a hippocampal-dependent spatial reference memory task. These data indicate that normal aging can produce distinct manifestations of executive dysfunction, and support the need to better understand the unique mechanisms contributing to different forms of prefrontal cortical-supported executive decline across the lifespan.


Feeding and swallowing outcomes following mandibular distraction osteogenesis: an analysis of 22 non-isolated paediatric cases.
Patients with mandibular hypoplasia and upper airway obstruction are at an increased risk of feeding and swallowing difficulties. Little has been described regarding these outcomes following mandibular distraction. The aim of this study was to evaluate the effect of mandibular distraction on feeding and swallowing function. A retrospective study was performed on 22 patients with non-isolated mandibular hypoplasia and severe upper airway obstruction treated with mandibular distraction. Median age at first mandibular distraction was 3.1 years (interquartile range 2.3-6.0 years) and the median follow-up time was 3.5 years (interquartile range 2.0-9.4 years). Prior to mandibular distraction, feeding difficulties were present in 18 patients. Swallowing difficulties were present in 20 patients, all of whom had problems in the oral phase of swallowing, while 11 patients had additional problems in the pharyngeal phase. Following mandibular distraction, at the time of follow-up, feeding difficulties persisted in 13 patients. Swallowing difficulties in the oral phase remained present in all 20 patients, while pharyngeal phase problems persisted in seven patients. In conclusion, feeding and swallowing difficulties are highly prevalent in non-isolated patients and often persist following mandibular distraction. Moreover, these can be the reason that decannulation cannot be accomplished. Hence, awareness and close follow-up by a specialized speech therapist is of paramount importance.


Long-term neurobehavioral effects of mild poisonings with organophosphate and n-methyl carbamate pesticides among banana workers.
Organophosphate poisoning has been associated with chronic neurobehavioral dysfunction, but no epidemiologic data exist with regard to long-term consequences from carbamate poisoning. This cross-sectional study evaluated the neurobehavioral performances of 81 banana workers who, on average 27 months earlier, had received medical attention not requiring hospitalization for mild occupational poisoning by either an organophosphate or a carbamate pesticide. These performances were compared with those of 130 banana workers who had never sought medical attention for pesticide poisoning. Poisoned subjects did less well than controls on tests measuring psychomotor and visuomotor skills, language function, and affect, the differences being significant for coding skills on the Digit-Symbol test and two tests of neuropsychiatric symptoms. These deficits, in particular a marked increase of neuropsychiatric symptoms, occurred among the organophosphate-poisoned subjects, but small deficits in performance were also seen in the carbamate-poisoned subjects. The performances of the previously poisoned subjects who had had contact with cholinesterase inhibitors within three months before testing were particularly poor. These findings in workers with mild poisoning are consistent with previous findings of persistent damage to the central nervous system from organophosphate poisoning. The possibility of persistent neurobehavioral effects associated with poisonings by nmethyl carbamate insecticides cannot be excluded. Workers with histories of poisoning may be more susceptible to neurobehavioral effects with subsequent exposures.


Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer.
The tolerogenic hepatic microenvironment impedes clearance of viral infections but is an advantage in viral vector gene transfer, which often results in immune tolerance induction to transgene products. Although the underlying tolerance mechanism has been extensively studied, our understanding of antigen presentation to transgene product-specific CD4+ T cells remains limited. To address this, we administered hepatotropic adeno-associated virus (AAV8) vector expressing cytoplasmic ovalbumin (OVA) into wt mice followed by adoptive transfer of transgenic OVA-specific T cells. We find that that the liver-draining lymph nodes (celiac and portal) are the major sites of MHC II presentation of the virally encoded antigen, as judged by in vivo proliferation of DO11.10 CD4+ T cells (requiring professional antigen-presenting cells, e.g., macrophages) and CD4+CD25+FoxP3+ Treg induction. Antigen presentation in the liver itself contributes to activation of CD4+ T cells egressing from the liver. Hepatic-induced Treg rapidly disseminate through the systemic circulation. By contrast, a secreted OVA transgene product is presented in multiple organs, and OVA-specific Treg emerge in both the thymus and periphery. In summary, liver draining lymph nodes play an integral role in hepatic antigen presentation and peripheral Treg induction, which results in systemic regulation of the response to viral gene products.


DNA damage and cytotoxicity of nitracrine in cultured HeLa cells.
The effects of nitracrine (1-nitro-9-(3,3-N,N-dimethylaminopropylamino)acridine on DNA of cultured HeLa cells were studied. DNA strand breakage and interstrand cross-linking as well as DNA-protein cross-linking were measured by means of an alkaline elution technique and were compared with the cytotoxic effect of the drug. Interstrand cross-links were not detectable in the concentration range that inhibited cell growth up to 99%. DNA single-strand breaks were found when cells were treated with highly cytotoxic doses of the drug. DNA breakage was not reparable and exhibited a tendency to increase during incubation after drug removal. The only chromatin lesion induced by sublethal doses of nitracrine were DNA-protein cross-links which persisted for 24 h after drug treatment. It is concluded that DNA breaks represent degraded DNA from dying cells, whereas DNA-protein cross-links are specific cellular lesions, which may be responsible for the cell-killing effect of nitracrine.


Conditioning Dogs for an Active Lifestyle.
The aim of conditioning is to remodel body tissues in preparation for the physical demands of activity. Body tissues need strength to produce and withstand the forces generated during movement. Body tissues remodel in response to load, for example, training can remodel and increase the size of tendons, but this takes time. Training does more than just strengthening tissues; it also improves tissue response to exercise and recovery time. The National Sports Medicine Institute in the United Kingdom states "regular exercise increases muscle tone, facilitates good circulation, improves strength, agility and flexibility and improves the rate of waste product disposal."


Location and primary structure of a major antigenic site for poliovirus neutralization.
We have determined a major antigenic site for virus neutralization on the capsid protein VP1 of poliovirus type 3. Antigenic mutant viruses selected for resistance to individual monoclonal antibodies had point mutations concentrated in a region 277-294 bases downstream from the start of the region of viral RNA coding for VP1. These findings provide the basis for an improved understanding of the molecular basis of virus neutralization.


Contribution of nitric oxide-producing cells in normal and diabetic rat retina.
To examine the immunohistochemical localization of L-arginine and L-citrulline and determine where and how nitric oxide (NO) is produced in the normal and streptozotocin (STZ)-induced diabetic rat retinas. NO is produced when L-arginine is changed to L-citrulline by NO synthase (NOS). In normal and STZ-induced diabetic rats, using an immunohistochemical method, we examined the retinal distribution of L-arginine and L-citrulline after intracardiac perfusion. We studied the distribution of NOS after immersed fixation and analyzed the number of neuronal NOS (nNOS)-positive neurons. We observed L-arginine localization in the internal limiting membrane (ILM), the ganglion cell layer (GCL), and the inner nuclear layer (INL). L-Arginine immunoreactivity in the diabetic rat retinas was found in the inner plexiform layer (IPL), as well as in the normal retina. L-Citrulline immunoreactivity in the normal and diabetic retinas was observed in the ILM, the GCL, the IPL, and the INL. nNOS staining in the normal and diabetic rat retinas was observed in the GCL, the IPL and the INL. The number of nNOS-positive amacrine cells was less in the diabetic rat retinas. NO might be produced in the GCL and amacrine cells, which show immunoreactivity to L-arginine, L-citrulline, and nNOS. In the early stage of diabetic retinopathy in STZ rat retinas, diabetes disturbed the function of the nNOS-positive amacrine cells and reduced NO production via nNOS.


Autophagy-related chemoradiotherapy sensitivity in non-small cell lung cancer (NSCLC).
Lung cancer is one of the leading causes of tumor-related mortalities worldwide. NSCLC is the most common type of lung cancer. In recent years, advancements in chemoradiotherapy and immunotherapy have led to unprecedented survival benefits in some patients. However, conventional therapies such as radiation and chemotherapy are not effective in all patients due to the chemo or radioresistance mechanisms; as a result, there is an urgent need for understanding the resistant mechanism. Given that malignancies are caused by changes in cell homeostasis, autophagy may help chemo/radiosensitization by removing damaged compartments and enhancing tumor clearance. Autophagy, on the other hand, may help cancer cells survive by increasing the breakdown of cell cycle regulators. Considering these inconsistencies, this study aimed to overview the intricacy of autophagy in response to chemoradiotherapy in lung cancer.


Effects of acetyl- and proprionyl-L-carnitine on peripheral nerve function and vascular supply in experimental diabetes.
L-Carnitine metabolism is abnormal in diabetes mellitus, and treatment with acetyl-L-carnitine (ALC) improves the function of cardiac muscle, retina, and peripheral nerve in experimental models. The aim was to compare the effects of ALC and proprionyl-L-carnitine (PLC) on motor and sensory nerve conduction in streptozotocin-diabetic rats and to ascertain whether their action could be mediated by a vascular mechanism. ALC and PLC treatment for 2 months after diabetes induction attenuated the development of sciatic motor nerve conduction velocity (NCV) deficits by 59.4% +/- 4.4% and 46.9% +/- 3.2%, respectively. There was a similar level of protection for sensory saphenous NCV (42.9% +/- 6.6% and 47.8% +/- 6.0%, respectively). Neither ALC nor PLC prevented the development of resistance to hypoxic conduction failure (RHCF) in sciatic nerve from diabetic rats. A 46.5% +/- 3.4% deficit in sciatic endoneurial blood flow, measured by microelectrode polarography and hydrogen clearance, in diabetic rats was partially prevented by both ALC (48.7% +/- 6.4%) and PLC (69.4% +/- 10.1%). ALC had no significant effect on blood flow in nondiabetic rats. Thus, the data show that these L-carnitine derivatives have a similar efficacy in preventing nerve dysfunction, which depends on a neurovascular action.


Diastolic function in paced children with cardiac defects: septum vs apex.
In children with structural congenital heart disease (CHD), the effects of chronic ventricular pacing on diastolic function are not well known. On the other hand, the beneficial effect of septal pacing over apical pacing is still controversial.The aim of this study was to evaluate the influence of different right ventricular (RV) pacing site on left ventricular (LV) diastolic function in children with cardiac defects.Twenty-nine pediatric patients with complete atrioventricular block (CAVB) and CHD undergoing permanent pacing were prospectively studied. Pacing sites were RV apex (n = 16) and RV septum (n = 13). Echocardiographic assessment was performed before pacemaker implantation and after it, during a mean follow‑up of 4.9 years.Compared to RV septum, transmitral E-wave was significantly affected in RV apical pacing (95.38 ± 9.19 vs 83 ± 18.75, p = 0.038). Likewise, parameters at the lateral annular tissue Doppler imaging (TDI) were significantly affected in children paced at the RV apex. The E´ wave correlated inversely with TDI lateral myocardial performance index (Tei index) (R2= 0.9849, p ≤ 0.001). RV apex pacing (Odds ratio, 0.648; confidence interval, 0.067-0.652; p = 0.003) and TDI lateral Tei index (Odds ratio, 31.21; confidence interval, 54.6-177.4; p = 0.025) predicted significantly decreased LV diastolic function.Of the two sites studied, RV septum prevents pacing-induced reduction of LV diastolic function.


Perforating and deep lymphatic vessels in the knee region: an anatomical study and clinical implications.
To determine the relationship between the perforating and deep lymphatic vessels in the knee region for clinical implications. Four lower limbs from two unembalmed human cadavers were used. Under a surgical microscope, 6% hydrogen peroxide was employed to detect lymph vessels accompanying the small saphenous vein, anterior tibial, posterior tibial and fibular blood vessels all commencing from distal ends of specimens. Each lymphatic vessel was inserted by a 30-gauge needle and injected with a barium sulphate mixture. Each specimen was dissected, radiographed and photographed to determine the perforating and deep lymphatic vessels in the region. A perforating lymph vessel was observed in the popliteal fossa of each specimen. It arose from the superficial popliteal lymph node and terminated in the deep popliteal lymph node. The anterior tibial, posterior tibial and peroneal lymph vessels were discovered in the region travelling with the corresponding vascular bundles. After penetrating the vascular aperture of the interosseous membrane between the tibia and fibula, the anterior tibial lymph vessel entered directly into the deep popliteal lymph node or converged to either the posterior tibial or fibular lymph vessel, before entering the node. The posterior tibial and peroneal lymph vessels entered the deep popliteal lymph node. The efferent lymph vessel of the deep popliteal lymph node travelled with the femoral vascular bundle. The perforating and deep lymphatic vessels in the knee region has been presented and discussed. The information advances our anatomical knowledge and the results will benefit clinical management.


Seasonal changes in response ofSenecio ovatus to grazing by the chrysomelid beetleChrysomela speciosissima.
The response ofSenecio ovatus to herbivory byChrysomela speciosissima (Coleoptera, Chrysomelidae) was studied in the Krušné hory Mountains, Czechoslovakia. The following questions were addressed: (1) what is the impact of natural levels of insect herbivory on the performance of individual plants, (2) how do the levels of herbivory change during the growing period, and (3) what is the relative importance of direct and indirect effects of herbivory? Ten experimental plots sprayed with metathion and ten controls were established. Damage to plants was quantified in the period of maximum herbivore activity (June) and again at the end of the growing season (August). In the first half of the season, total leaf area in grazed ramets was reduced by 30.3% compared to ungrazed ramets; half of this reduction was due to beetle consumption and half was due to indirect effects. Individual leaf area was not significantly different between treatments. Insecticide-treated ramets were taller and heavier than the controls. During the second half of the growing period the differences in ramet weight and leaf area disappeared because of compensatory growth. However, the insecticide-treated ramets remained taller and had higher seed numbers per capitulum. Neither number of capitula per ramet nor seed weight were significantly different between treatments. In the grazed population, the leaf area reduction (30.3%) in June resulted in 36.5% reduction in fecundity at the end of August.


A facile synthesis of substituted 2-alkylquinolines through [3+3] annulation between 3-ethoxycyclobutanones and aromatic amines at room temperature.
An efficient single-step approach toward the synthesis of 2-alkylquinolines is described. Through a Lewis acid mediated [3+3] annulation reaction between 3-ethoxycyclobutanones and aromatic amines, a variety of multisubstituted 2-alkylquinoline derivatives were prepared regioselectively at room temperature.


Thinking, fast and slow on the autism spectrum.
What is already known about the topicDaniel Kahneman wrote a highly influential book titled 'thinking, fast and slow'. He proposes that people usually think in a rapid, automatic, intuitive style. When people realise their intuitive thinking may be wrong, a slower, effortful, deliberative style of thinking takes over. It has recently been proposed that thinking in autistic individuals can be characterised as usually thinking in the deliberative style (rather than the intuitive style that non-autistic people usually think in).What this paper addsAs intuitive thinking is fast and deliberative thinking is slow, this research manipulated the time available to complete a series of reasoning questions. These questions have been developed to have intuitive answers (which are incorrect) and deliberative answers (which are correct). For the first time, a fast time manipulation (you must answer quickly) and slow (you must think about your answer before responding) was undertaken with autistic individuals. Autistic participants did produce more deliberative answers than the non-autistic participants. However, both groups produced comparably more intuitive answers and less deliberative answers in the fast condition. This shows that while autistic people tend not to use their intuition, autistic people can be encouraged to use their intuition.Implications for practice, research or policyUsing rapid intuition can be useful in fast-changing contexts, such as some social situations. Future research can explore how to support autistic individuals to use their intuition when the need arises. In addition, the propensity for deliberation resulting in unbiased, correct responses reflects a strengths-based account of autism. This requires more mental effort and is less susceptible to bias and errors. This is called 'Dual Process Theory'.


Genomic Mechanisms Influencing Outcome in Chronic Myeloid Leukemia.
Chronic myeloid leukemia (CML) represents the disease prototype of genetically based diagnosis and management. Tyrosine kinase inhibitors (TKIs), that target the causal BCR::ABL1 fusion protein, exemplify the success of molecularly based therapy. Most patients now have long-term survival; however, TKI resistance is a persistent clinical problem. TKIs are effective in the BCR::ABL1-driven chronic phase of CML but are relatively ineffective for clinically defined advanced phases. Genomic investigation of drug resistance using next-generation sequencing for CML has lagged behind other hematological malignancies. However, emerging data show that genomic abnormalities are likely associated with suboptimal response and drug resistance. This has already been supported by the presence of BCR::ABL1 kinase domain mutations in drug resistance, which led to the development of more potent TKIs. Next-generation sequencing studies are revealing additional mutations associated with resistance. In this review, we discuss the initiating chromosomal translocation that may not always be a straightforward reciprocal event between chromosomes 9 and 22 but can sometimes be accompanied by sequence deletion, inversion, and rearrangement. These events may biologically reflect a more genomically unstable disease prone to acquire mutations. We also discuss the future role of cancer-related gene mutation analysis for risk stratification in CML.


A comprehensive estimation of acute myocardial infarct size using enzymatic, electrocardiographic and mechanical methods.
This prospective study compares the estimated size of acute myocardial infarction (AMI) by cumulative serum creatine kinase isoenzyme MB (CK-MB), Selvester QRS score, and 2-dimensional (2-D) echocardiographic dyssynergy of the left ventricle in 63 consecutive patients with their first anterior (n = 31) or inferior AMI (n = 32). The correlations among these parameters were good for patients with anterior AMI (r = 0.74 to 0.78, standard error of the estimate = 29 to 33%) but only fair for those with inferior AMI (r = 0.35 to 0.47, standard error of the estimate = 38 to 73%). Based on previous autopsy studies, estimates of CK-MB and QRS score were then converted to percent of infarcted left ventricle. Linear regression analyses between mean percent AMI size by cumulative CK-MB plus QRS score vs the number of dyssynergic segments by 2-D echocardiography were used to develop a comprehensive formula for estimating AMI size by a combination of all 3 techniques. Thus, a formula is proposed that may optimally estimate AMI size derived from leakage of cytosolic enzymes, changes in the sequence of myocardial depolarization, and irregularities of left ventricular contraction.


Role of Multiparametric MR Imaging in Malignancies of the Urogenital Tract.
Multiparametric MR imaging (mpMRI) combine different sequences that, properly tailored, can provide qualitative and quantitative information about the tumor microenvironment beyond traditional tumor size measures and/or morphologic assessments. This article focuses on mpMRI in the evaluation of urogenital tract malignancies by first reviewing technical aspects and then discussing its potential clinical role. This includes insight into histologic subtyping and grading of renal cell carcinoma and assessment of tumor response to targeted therapies. The clinical utility of mpMRI in the staging and grading of ureteral and bladder tumors is presented. Finally, the evolving role of mpMRI in prostate cancer is discussed.


The impact of COVID19 pandemic and government enforced lockdowns on levels of attendance and context of sexual assaults reported at Saint Marys Sexual Assault Referral Centre.
Globally, government enforced lockdowns were one measure introduced to reduce the transmission of COVID-19. The impact of these social movement restrictions on victims of sexual assault and their access of sexual assault services needed clarity. This study aimed to understand the impact of COVID-19 pandemic lockdowns on: Sexual Assault Referral Centres (SARC) attendance; characteristics of clients; characteristics of alleged perpetrators and nature of sexual assaults. Routinely collected data from the Saint Mary's SARC in the North West of England over two financial years, April 2019-March 2020 (pre-COVID-19) and April 2020-March 2021 (during COVID-19), were analysed. Compared to the pre COVID-19 year, monthly SARC attendance for children and adults decreased during national lockdowns and increased as restrictions lifted. Ethnicity of clients was significantly different during COVID-19 with more South Asian adults and more bi-racial children attending. Attendance of adults aged over 57 years also significantly increased during COVID-19. A significant increase in adults meeting alleged perpetrators online and a significant decrease in alleged perpetrators being a sex worker client were also identified. Finally, a significant increase in not-recorded data for health characteristics of adult and child clients was noted. While this study has illuminated some changes in the vulnerability profile of clients attending SARC during COVID-19 and its associated lockdowns, it has also highlighted shortcomings in changes to usual care introduced in the challenging and changing context of a global pandemic. These findings in parallel usefully recommend areas in need of service improvement.


Hydroxyl may not be indispensable for raltegravir: Design, synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors.
A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC(50) values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors.


Intrapulmonary mature cystic teratoma of the lung: case report of a rare entity.
Intrapulmonary teratoma (IPT) is a rare type of extra gonadal teratoma which often presents with non-specific symptoms and can be misdiagnosed as other diseases. Here we report a patient with IPT which was initially misdiagnosed as lung hydatid cyst versus abscess. We report an intrapulmonary teratoma in a 27-year-old female presenting with persistent chest pain and dyspnea since a few years prior to her admission with associated symptoms of cough and fever. Chest x-ray only showed left side massive pleural effusion and computed tomography scan of the lungs was suggestive of hydatid cyst or a lung abscess. She underwent lobectomy and postoperative histopathological study revealed IPT as the final diagnosis. Due to the non-specific symptoms and rarity, IPT can be easily misdiagnosed at first. It is essential that physicians take into account the possibility of IPT when approaching a new case of lung mass.


Centromere function in asymmetric cell division in Drosophila female and male germline stem cells.
The centromere is the constricted chromosomal region required for the correct separation of the genetic material at cell division. The kinetochore protein complex assembles at the centromere and captures microtubules emanating from the centrosome to orchestrate chromosome segregation in mitosis and meiosis. Asymmetric cell division (ACD) is a special type of mitosis that generates two daughter cells with different fates. Epigenetic mechanisms operating at the centromere have been proposed to contribute to ACD. Recent studies have shown that an asymmetric distribution of CENP-A-the centromere-specific histone H3 variant-between sister chromatids can bias chromosome segregation in ACD. In stem cells, this leads to non-random sister chromatid segregation, which can affect cell fate. These findings support the 'silent sister' hypothesis, according to which the mechanisms of ACD are epigenetically regulated through centromeres. Here, we review the recent data implicating centromeres in ACDs and cell fate in Drosophila melanogaster female and male germline stem cells.


Quantitative platelet disorders.
Thrombocytopenia may be caused by abnormal platelet production, accelerated removal owing to immunologic or nonimmunologic reasons, or sequestration of platelets in the spleen. Bleeding associated with thrombocytopenia usually presents as petechial or ecchymotic hemorrhages or epistaxis. Immunologic and nonimmunologic cases of thrombocytopenia may be diagnosed with routine hematology, bone marrow cytology, and platelet specific tests. Thrombocythemia may also be associated with platelet functional abnormalities, contrasting the normal platelet function noted in reactive thrombocytosis.


Independent and supplementary prescribing and PGDs.
Types of prescribing for non-medical staff are discussed and clarifications made regarding the current overlap in six forms of prescribing and administration of medication. Differences between independent and supplementary prescribing are explored and the distinction between patient group directions and extended formulary nurse prescribing outlined.


Pulmonary Campylobacter concisus infection in an immunocompromised patient with underlying mucormycosis.
Campylobacter concisus is a rarely encountered agent of human infection. The first isolation of C. concisus from a pulmonary abscess in an immunocompromised patient who underwent allogeneic stem cell transplantation is reported here. This unusual case demonstrates the pathogenic potential of this bacterium and outlines species-immanent difficulties in gaining a reliable diagnosis. Molecular methods were a cornerstone for definite identification of the organism grown on anaerobic culture from surgically excised tissue. Antimicrobial susceptibility testing revealed unusual quinolone and macrolide resistance, and therefore antimicrobial therapy was based on β-lactam antibiotics.


Critical review of factors governing data quality of integrative samplers employed in environmental water monitoring.
Integrative sampling enables the collection of analyte mass from environmental liquids over extended timeframes from hours to months. While the incentives to complement or replace conventional, time-discrete sampling have been widely discussed, the data quality implications of employing alternative, integrative methods have not yet been systematically studied. A critical analysis of contemporary literature reports showed the data quality of integrative samplers, whether active-advection or passive-diffusion, to be governed by uncertainty in both sampling rate and analyte recovery. Derivation of two lumped parameters, representing the coefficient of accumulation (α) of a contaminant from an environmental fluid and the coefficient of subsequent recovery (ρ) of its mass from the sampler, produced a conceptual framework for quantifying error sources in concentration data derived from accumulative samplers. Whereas the precision associated with recovery was found to be fairly consistent across eight passive-diffusion and active-advection devices (averaging 5-16% relative standard deviation, RSD), active-advection samplers effectively improve precision in sampling rate (analyte uptake), as determined for two active-advection devices (2-7% average RSD) and five passive devices (12-42% average RSD). In summary, an approach is presented whereby the data quality implications of integrative sampler design can be compared, which can inform the selection, optimization, and development of sampling systems to complement the state of the art.


[Original method of multivariate analysis, adapted for comparison of mean evoked potentials: E2 test].
This paper describes a multivariate statistical method of analysis for the comparison of 2 paired series. For such paired series, this test, called E2, is analogous to the generalized Hotteling T2 test, as epsilon test (pairing method) is analogous to Student's t test. Here we give an example of its application to a comparison of curves, in this particular case average auditory evoked potentials, picked up at symmetrical points on the scalp.


Demographic Factors Affect Ocular Comfort Ratings During Contact Lens Wear.
To determine if rating of ocular comfort during soft contact lens wear is affected by demographic factors. Retrospective analysis of ocular comfort ratings during soft contact lens wear extracted from 44 nonrandomized similar clinical trials (n = 986). Subjects wore one of seven daily wear silicone hydrogels (SiHy) in combination with one of nine lens care products (LCP), and two daily disposables lenses. The effects on comfort rating of demographic factors were examined after adjusting for lens and LCP effects using general linear model. Males reported lower comfort on insertion than females (7.9 ± 1.6 vs. 8.1 ± 1.6, p = 0.001). Over 45 years old had higher comfort ratings than those between 26 and 45 or <26 years old at insertion (8.7 ± 1.3 vs. 8.1 ± 1.6 vs. 7.8 ± 1.6, p < 0.001), during the day (8.6 ± 1.2 vs. 8.0 ± 1.6 vs. 8.2 ± 1.2, p < 0.001), and end of day (7.7 ± 1.6 vs. 6.8 ± 2.0 vs. 7.0 ± 1.6, p < 0.001). Neophytes reported lower comfort on insertion (7.3 ± 1.6 vs. 8.2 ± 1.5, p < 0.001) and during day (8.0 ± 1.3 vs. 8.3 ± 1.3, p = 0.020) than experienced wearers. Participants with Rx ≥-3.50D had higher comfort ratings than those with ≤-3.50D on insertion (8.3 ± 1.4 vs. 7.8 ± 1.6, p < 0.001), during the day (8.4 ± 1.3 vs. 8.1 ± 1.3, p = 0.010), and end of day (7.2 ± 1.7 vs. 6.9 ± 1.8, p = 0.046). Comfort during the day was different between participants of different ethnic origin (p = 0.024) with Asians reporting the lowest (8.1 ± 1.3). Demographic factors such as age, gender, lens wear experience, ethnicity, and refractive status can influence the rating of ocular comfort in clinical studies. The confounding effects of such demographic factors can be controlled by implementing randomization and appropriate multivariable statistical analysis.


External Oxidant-Dependent Reactivity Switch in Copper-Mediated Intramolecular Carboamination of Alkynes: Access to a Different Class of Fluorescent Ionic Nitrogen-Doped Polycyclic Aromatic Hydrocarbons.
An interesting case of external oxidant-controlled reactivity switch leading to a divergent set of ionic nitrogen-doped polycyclic aromatic hydrocarbons (N-doped PAHs), is presented here, which is quite unrecognized in copper-mediated reactions. In the current scenario, from the same pyridino-alkyne substrates, the use of the external oxidant PhI(OAc)2, in combination with Cu(OTf)2, gave N-doped spiro-PAHs via a dearomative 1,2-carboamination process; whereas, without the use of oxidant, an alkyne/azadiene [4 + 2]-cycloaddition cascade occurred to exclusively afford ionic N-doped PAHs. These newly synthesized N-doped PAHs further exhibit tunable emissions, as well as excellent quantum efficiencies.


Acute toxicity of chlorobenzenes in tetrahymena: estimated by microcalorimetry and mechanism.
The toxicity of chlorobenzenes to Tetrahymena growth metabolism was studied by microcalorimetry. The growth constant (k), peak time (T) and generation times (T(G)) were calculated. IC(50) of chlorobenzenes was obtained through the kinetic parameters. The results suggested that the order of toxicity was 1,2,4-trichlorobenzene>o-dichlorobenzene>p-dichlorobenzene>m-dichlorobenzene>chlorobenzene. ATR-FTIR spectra revealed that amide groups and PO(2)(-) of the phospholipid phospho-diester, both in the hydrophobic end exposed to the outer layer, were the easiest to be damaged. The relationship between IC(50) and chemicals structure parameters (E(LUMO), E(HOMO), logK(OW), ∑Q(R), ΔQ(πR) and ΔE), indicated that the more chlorine atoms were substituted, the greater the toxicity was. Chlorobenzenes have toxicity of non-polar narcosis. Their toxicity is proportional to their concentrations at the site of action, and caused by membrane perturbation.


Fluorescent Donor-Acceptor Psoralen Cruciforms by Consecutive Suzuki-Suzuki and Sonogashira-Sonogashira One-Pot Syntheses.
Two novel donor-acceptor cruciform topologies are efficiently synthesized by site-selective Suzuki-Suzuki and Sonogashira-Sonogashira multicomponent reactions starting from a bromo-triflato-functionalized psoralen scaffold. In addition to tunability of photophysical properties, such as absorption and emission, many derivatives possess partially high relative fluorescence quantum yields in solution and fluoresce strongly in the solid state. Additionally, the promising compounds show solvatochromism and acidochromic effects. In addition, 8-p-anisyl-5-p-cyanophenyl-substituted psoralen exhibits aggregation-induced emission properties. Experimentally (applying the Lippert-Mataga model) and computationally (TD-DFT calculations), the pronounced charge transfer character of the longest wavelength absorption band was confirmed.


Blood manganese and alcohol consumption interact on mood states among manganese alloy production workers.
Long-term exposure to manganese (Mn) can induce neurotoxic effects including neuromotor, neurocognitive and neuropsychiatric effects, but there is a great interpersonal variability in the occurrence of these effects. It has recently been suggested that blood Mn (MnB) may interact with alcohol use disorders, accentuating neuropsychiatric symptoms. The objective of the present study was to explore a possible interaction between alcohol consumption and MnB on mood states, using an existing data set on Mn exposed workers. Respirable Mn exposure in the plant averaged 0.23mg/m(3) and was correlated with MnB. All participants for whom all data on MnB concentration and mood (assessed with the Profile of Mood States (POMS)) were available and who reported currently drinking alcohol were included in the analyses (n=74). Workers were grouped according to their MnB concentration (<10 and > or =10 microg/l) and alcohol consumption (<400 and > or =400g per week). Two-way ANOVAs were performed on each POMS scale and Mann-Whitney tests were used to assess group differences. Workers in the higher alcohol consumption group had higher scores on three POMS scales: tension, anger and fatigue. There was no difference for POMS scale scores between MnB subgroups. Dividing the group with respect to alcohol consumption and MnB showed that the group with high alcohol consumption and high MnB displayed the highest scores. In the lower MnB category, those in the higher alcohol consumption group did not have higher scores than the others. The interaction term for alcohol consumption and MnB concentration was statistically significant (P<0.05) for the depression, anger, fatigue and confusion POMS scales. There was a tendency for tension (P<0.06), and it was not significant for vigor. This study shows the first evidence of an interaction between MnB and alcohol consumption on mood states among Mn exposed workers and supports the results from a previous population-based study.


Structure of the ovine pineal gland during prenatal development.
The structure of the pineal gland of 32 clinically healthy ovine embryos at different stages of development was studied. Embryos were arranged in four age groups, each containing eight embryos (four males and four females), defined in terms of the most relevant histological features: group 1 (27 to 69 days of prenatal development), group 2 (70 to 97 days), group 3 (98 to 116 days), and group 4 (117 to 150 days). At around 30 days of prenatal life, according to topographic criteria, the pineal outline begins to differentiate into a dorsal evagination of the diencephalic medium line, close to the anterior and posterior commissures. The growth of the pineal is biphasic. The ontogenic-proliferative phase begins at 30 days and includes the invasion of ependymal cells and the proliferation of the pineal parenchyma cells. The hypertrophic-differentiation phase includes the volume increment of the pinealoblasts and their differentiation into pinealocytes; this occurs at around 118 days. At around 98 days, the gland acquires its definitive compact appearance due to 1) glandular growth in constant volume and 2) the obliteration of pineal recess. The glandular structure displays a parenchyma made up of pinealoblasts, interstitial cells, and cells containing pigment. The pineal stroma is structured in pseudolobes formed by reticular and collagen fiber septae, which constitute together the interstitial cell prolongation net, which is the support structure of the whole glandular cytology. Capillaries are detected all over the glandular surface, being more abundant in the medullary zone. At around 98 days of prenatal development, VIP (Vasoactive Intestinal Peptide) positive fibers, distributed around blood vessels and among pinealoblasts were detected.


In vitro selection and differentiation of ivermectin resistant cyathostomin larvae.
Cyathostomins are considered to be the primary helminth pathogen of horses and macrocyclic lactones (ML) are the most frequently used anthelmintics. Therefore, ML resistance is a serious threat for the control of these parasites. In the present study ivermectin resistant cyathostomin L3 were in vitro selected, using a reiterative larval migration inhibition assay (rLMIA) and differentiated by reverse line blot (RLB). Larvae were obtained from two populations, one from a never treated, free-roaming horse population in the nature reserve Oostvaardersplassen (OVP) and the other from regularly ivermectin-treated ponies of Utrecht University (UU). In the rLMIA the proportion of larvae that migrated increased with each passage, demonstrating that the applied procedure indeed selects for larvae the least susceptible for ivermectin. This was further supported by the fact that glutamate addition to this procedure reversed the selection effect, which also suggests that glutamate-gated chloride channels (GluCls) play a role in the ivermectin resistance of the selected L3. In both populations the predominant species were Cyathostomum catinatum, Cylicostephanus longibursatus and Cylicocyclus nassatus. After in vitro selection in the rLMIA in the presence of ivermectin the predominant species became C. catinatum in both larval populations, while C. nassatus disappeared in the never treated OVP larval population but not in the regularly ivermectin-exposed UU population. It is concluded that the rLMIA and RLB can be used to study anthelmintic resistance in cyathostomin populations and to study differences and changes in species composition between populations with different anthelmintic exposure histories.


Large-scale interrogation of retinal cell functions by 1-photon light-sheet microscopy.
Visual processing in the retina depends on the collective activity of large ensembles of neurons organized in different layers. Current techniques for measuring activity of layer-specific neural ensembles rely on expensive pulsed infrared lasers to drive 2-photon activation of calcium-dependent fluorescent reporters. We present a 1-photon light-sheet imaging system that can measure the activity in hundreds of neurons in the ex vivo retina over a large field of view while presenting visual stimuli. This allows for a reliable functional classification of different retinal cell types. We also demonstrate that the system has sufficient resolution to image calcium entry at individual synaptic release sites across the axon terminals of dozens of simultaneously imaged bipolar cells. The simple design, large field of view, and fast image acquisition make this a powerful system for high-throughput and high-resolution measurements of retinal processing at a fraction of the cost of alternative approaches.


Normal myelination: a practical pictorial review.
MRI is currently the best imaging modality to assess myelin maturation in the human brain. Myelin is the insulator for nerves and is present in both the peripheral nervous system and the central nervous system (CNS). In the CNS, it is a modified extension of the oligodendrocyte cell and is made up of multiple sheaths of protein-lipid-protein-lipid-protein. Standard T1-weighted and T2-weighted sequences can be performed on any MR imaging platform and with knowledge of normal age-related myelin maturation, myelin delay can be detected. Myelination progresses in a constant predetermined pattern from bottom to top, central to peripheral and back to front.