Prevalence of osteoporosis and its associated factors among postmenopausal women in Kiambu County, Kenya: a household survey.
This household survey involved determining the bone mineral density of 254 postmenopausal African women in Kiambu County, Kenya. The prevalence of osteoporosis was 26.4%. A positive association between osteoporosis and advancing age, poverty, illiteracy, and being underweight was found. Osteoporosis is a worldwide health problem with high morbidity and mortality. In Kenya, there is paucity of information on the magnitude and risk profiles of those at risk. The objective of this study was to determine the prevalence and associated factors of osteoporosis among postmenopausal women in a Kenyan periurban population. This community-based cross-sectional survey involving 254 postmenopausal African women in Kiambu County, Kenya, was carried out between October 2017 and February 2018. Multi-stage random sampling approach was adopted where households were selected after sampling sub-counties and enumeration areas. A structured questionnaire was administered and physical examination done on recruited participants by the principal investigator and research assistants. Weight and height of the participants were measured and bone mineral density was determined using dual-energy X-ray absorptiometry (DXA). Data were analyzed using SPSS statistical software version 21.0, SPSS Inc. The mean age of the women was 64.6 years and ranging between 50 and 95 years. The prevalence of osteoporosis was 26.4%. Osteoporosis was associated with advancing age (p < 0.0001), low socioeconomic status (p = 0.007), lower education level (p < 0.0001), being underweight (BMI < 18.5) (p < 0.0001), family history of osteoporosis (p = 0.006), and caffeine intake (p = 0.002). The association between osteoporosis and occupation, marital status, age at menarche, and exercise was not statistically significant. The prevalence of osteoporosis among the select women in Kenya is high and is associated with advancing age, poverty, illiteracy, and being underweight. There is need to implement intervention strategies based on these findings to control osteoporosis in groups at risk.


Description of a Giardia varani-like flagellate from a water monitor, Varanus salvator, from Malaysia.
A Giardia varani Lavier, 1923-like flagellate was found in the feces of a captive water monitor, Varanus salvator, originally caught wild from an unknown location in Malaysia. The parasite is similar in size and shape to Giardia lamblia, except that median bodies are rare and cysts are binucleate. A description of both the trophozoite and cyst stage of this flagellate is provided.


Carbon extension in peptidylnucleoside biosynthesis by radical SAM enzymes.
Nikkomycins and polyoxins are antifungal peptidylnucleoside antibiotics active against human and plant pathogens. Here we report that during peptidylnucleoside biosynthesis in Streptomyces cacaoi and S. tendae, the C5' extension of the nucleoside essential for downstream structural diversification is catalyzed by a conserved radical S-adenosyl-L-methionine (SAM) enzyme, PolH or NikJ. This is distinct from the nucleophilic mechanism reported for antibacterial nucleosides and represents a new mechanism of nucleoside natural product biosynthesis.


Accelerating 4D flow MRI by exploiting vector field divergence regularization.
To improve velocity vector field reconstruction from undersampled four-dimensional (4D) flow MRI by penalizing divergence of the measured flow field. Iterative image reconstruction in which magnitude and phase are regularized separately in alternating iterations was implemented. The approach allows incorporating prior knowledge of the flow field being imaged. In the present work, velocity data were regularized to reduce divergence, using either divergence-free wavelets (DFW) or a finite difference (FD) method using the ℓ1-norm of divergence and curl. The reconstruction methods were tested on a numerical phantom and in vivo data. Results of the DFW and FD approaches were compared with data obtained with standard compressed sensing (CS) reconstruction. Relative to standard CS, directional errors of vector fields and divergence were reduced by 55-60% and 38-48% for three- and six-fold undersampled data with the DFW and FD methods. Velocity vector displays of the numerical phantom and in vivo data were found to be improved upon DFW or FD reconstruction. Regularization of vector field divergence in image reconstruction from undersampled 4D flow data is a valuable approach to improve reconstruction accuracy of velocity vector fields.


Endometriosis Nodule Causing Spontaneous Haemoperitoneum in Pregnancy: A Case Report and Literature Review.
Spontaneous haemoperitoneum in pregnancy (SHiP) due to endometriosis is a very rare condition and this is a case of a 41-year-old primigravida, who presented at 32 weeks with sudden onset of severe lower abdominal pain without any uterine activity. This was a dichorionic-diamniotic twin pregnancy, following in vitro fertilisation for subfertility secondary to severe endometriosis. On admission, pain score was eight, with ten being the maximum of the scale. The vital signs were stable. Abdominal palpation revealed generalised tenderness with no guarding or palpable contraction. There was no evidence of bleeding and the cervical os was closed on speculum examination. The cardiotocograph (CTG) was pathological and a plan was made to deliver the babies with emergency caesarean section. Intraoperatively, there was massive haemoperitoneum which was managed successfully with the involvement of multidisciplinary input from general surgeons and urologists with optimum maternal and fetal outcome.


Psoas abscess associated with infected total hip arthroplasty: a case report.
Psoas abscess (PA) is an uncommon disease and its diagnosis is difficult. It can be primary or secondary. Primary abscesses are of unknown origin and are presumably caused by haematogenous or lymphatic spread from a distant infectious focus. Secondary PA is caused by spreading from a contiguous infected structure, such as vertebrae (espondilodiscitis) or mesenteric abscesses (Crohns disease). PA infrequently has been associated with an infection of total hip arthroplasty (ITHA). The correct diagnosis in these cases is difficult due to the clinical similarities between PA and ITHA. Since connection between PA and ITHA is established through the acetabulum, we consider that computed tomography (CT) is the most accurate radiological test because of its efficacy in evaluating the bone structure, and the optimum therapeutic strategy is two-stage replacement surgery. We report one case of PA associated with ITHA and a review of the previous literature.


Possible existence of platelet aggregation inhibitor(s) in a gas-phase extract of cigarette smoke.
Present study demonstrated an existence of anti-aggregation factor(s) in water-soluble extract of a gas-phase of cigarette smoke, and studied chemical characteristics of the factor(s) evaluating its inhibitory potency on platelet aggregation of human and rabbit platelets. The water-soluble extract was prepared by passing mainstream smoke of one cigarette through a Cambridge glassfiber filter and then bubbling it through 1 ml of water. The inhibitory effects were similar in both human and rabbit platelets with the final concentrations of 1 to 5% of the aqueous extract, and were also non-specific irrespective of types of agonists such as collagen, arachidonic acid, STA2 (a stable analogue of thromboxane A2), ADP or nor-adrenaline. The inhibitory effect of water-soluble extract on platelet aggregation were not affected by treatment of the extract by erythrocytes, indicating that the factor(s) was different from the one that is adsorbed by hemoglobin, such as superoxide radicals, nitric oxide (NO), nitrogen oxides (Nox), hydrogen peroxide (H2O2), carbon monoxide (CO), aldehydes, trace elements (Cd2+, Cu2+) or carcinogenic nitrosocompounds. The inhibitor(s) was stable in acidic condition under 4 degrees C but unstable in basic condition under room temperature. The anti-platelet factor(s) was retained on a reversed phase chromatography column, and eluted with 50 to 60% methanol. The substance(s) was also adsorbed by H+ and OH- form ion exchange columns, but not by Cl- form, suggesting that the substance is both basic and acidic but not so strong as to be absorbed by Cl- form column. These facts suggest that the anti-platelet substance(s) in the water extract of cigarette smoke seems to be moderately non polar, both acidic and basic in water and not adsorbed by hemoglobin.


Function of 2-mercaptoethanol as a macrophage substitute in the primary immune response in vitro.
The mechanism by which 2-ME acts as a macrophage-substitute for the induction of a primary PFC response to SRC in vitro was studied in macrophage-depleted mouse spleen cell cultures. 2-ME could replace macrophages only in FCS-supplemented cultures. Evidence is presented that the function of 2-ME is independent of residual macrophages. Neither normal nor macrophage-depleted spleen cell cultures from congenitally athymic nude mice supplemented with 2-ME, with or without FCS, could give rise to a primary in vitro anti-SRC immune response. 2-ME, at an optimal concentration of 10(-5) M, induced DNA synthesis in normal and macrophage-depleted spleen cells in both FCS-containing and serum-free cultures. The peak response occurred on day 3. The stimulation was accompanied by a polyclonal B cell activation to antibody secretion which was much more pronounced in FCS-containing than in serum-free cultures. Spleen cells from nude mice showed a weaker DNA stimulation than did cells from normal mice in FCS-containing cultures, and nearly no response under serum-free conditions. T cells obtained by a nylon column adherence method from normal mouse spleen cells showed good DNA synthetic responses in FCS-containing, but no response in serum-free cultures. These results show that 2-ME has weak mitogenic activity for B cells, and in combination with FCS, strong mitogenic activity for T cells. Since the macrophage provides stimulation to the T cell in the primary anti-SRC PFC response in vitro, these results suggest that the direct mitogenic activity of 2-ME with FCS on T cells provides the functional substitution for macrophages.


Coupling amplified DNA from flow-sorted chromosomes to high-density SNP mapping in barley.
Flow cytometry facilitates sorting of single chromosomes and chromosome arms which can be used for targeted genome analysis. However, the recovery of microgram amounts of DNA needed for some assays requires sorting of millions of chromosomes which is laborious and time consuming. Yet, many genomic applications such as development of genetic maps or physical mapping do not require large DNA fragments. In such cases time-consuming de novo sorting can be minimized by utilizing whole-genome amplification. Here we report a protocol optimized in barley including amplification of DNA from only ten thousand chromosomes, which can be isolated in less than one hour. Flow-sorted chromosomes were treated with proteinase K and amplified using Phi29 multiple displacement amplification (MDA). Overnight amplification in a 20-microlitre reaction produced 3.7 - 5.7 micrograms DNA with a majority of products between 5 and 30 kb. To determine the purity of sorted fractions and potential amplification bias we used quantitative PCR for specific genes on each chromosome. To extend the analysis to a whole genome level we performed an oligonucleotide pool assay (OPA) for interrogation of 1524 loci, of which 1153 loci had known genetic map positions. Analysis of unamplified genomic DNA of barley cv. Akcent using this OPA resulted in 1426 markers with present calls. Comparison with three replicates of amplified genomic DNA revealed >99% concordance. DNA samples from amplified chromosome 1H and a fraction containing chromosomes 2H - 7H were examined. In addition to loci with known map positions, 349 loci with unknown map positions were included. Based on this analysis 40 new loci were mapped to 1H. The results indicate a significant potential of using this approach for physical mapping. Moreover, the study showed that multiple displacement amplification of flow-sorted chromosomes is highly efficient and representative which considerably expands the potential of chromosome flow sorting in plant genomics.


CXCL12-CXCR4 Interplay Facilitates Palatal Osteogenesis in Mice.
Cranial neural crest cells (CNCCs), identified by expression of transcription factor Sox9, migrate to the first branchial arch and undergo proliferation and differentiation to form the cartilage and bone structures of the orofacial region, including the palatal bone. Sox9 promotes osteogenic differentiation and stimulates CXCL12-CXCR4 chemokine-receptor signaling, which elevates alkaline phosphatase (ALP)-activity in osteoblasts to initiate bone mineralization. Disintegration of the midline epithelial seam (MES) is crucial for palatal fusion. Since we earlier demonstrated chemokine-receptor mediated signaling by the MES, we hypothesized that chemokine CXCL12 is expressed by the disintegrating MES to promote the formation of an osteogenic center by CXCR4-positive osteoblasts. Disturbed migration of CNCCs by excess oxidative and inflammatory stress is associated with increased risk of cleft lip and palate (CLP). The cytoprotective heme oxygenase (HO) enzymes are powerful guardians harnessing injurious oxidative and inflammatory stressors and enhances osteogenic ALP-activity. By contrast, abrogation of HO-1 or HO-2 expression promotes pregnancy pathologies. We postulate that Sox9, CXCR4, and HO-1 are expressed in the ALP-activity positive osteogenic regions within the CNCCs-derived palatal mesenchyme. To investigate these hypotheses, we studied expression of Sox9, CXCL12, CXCR4, and HO-1 in relation to palatal osteogenesis between E15 and E16 using (immuno)histochemical staining of coronal palatal sections in wild-type (wt) mice. In addition, the effects of abrogated HO-2 expression in HO-2 KO mice and inhibited HO-1 and HO-2 activity by administrating HO-enzyme activity inhibitor SnMP at E11 in wt mice were investigated at E15 or E16 following palatal fusion. Overexpression of Sox9, CXCL12, CXCR4, and HO-1 was detected in the ALP-activity positive osteogenic regions within the palatal mesenchyme. Overexpression of Sox9 and CXCL12 by the disintegrating MES was detected. Neither palatal fusion nor MES disintegration seemed affected by either HO-2 abrogation or inhibition of HO-activity. Sox9 progenitors seem important to maintain the CXCR4-positive osteoblast pool to drive osteogenesis. Sox9 expression may facilitate MES disintegration and palatal fusion by promoting epithelial-to-mesenchymal transformation (EMT). CXCL12 expression by the MES and the palatal mesenchyme may promote osteogenic differentiation to create osteogenic centers. This study provides novel evidence that CXCL12-CXCR4 interplay facilitates palatal osteogenesis and palatal fusion in mice.


Incidence of School-related Injuries among Students in A'Dakhiliyah Governorate Schools, Oman.
Childhood injuries are among the most significant causes of mortality and morbidity as estimated by the World Health Organization. We sought to assess the incidence of school-related injuries in A'Dakhiliyah governorate schools, with the secondary aim of addressing common causes, risk factors, and how the school environment contributes to injuries. We conducted a prospective cohort study involving all students in A'Dakhiliyah governorate schools during the 2015-2016 academic year. Data were collected using a questionnaire that was filled out by the school nurses or social workers at school health units. The incidence of school-related injuries was 2.3% per year. The majority of injured students were in grades 1-4 (63.7%) and 72.6% were boys. Improper school equipment and furniture accounted as a risk factor for 25.3% of injuries. The three most common mechanisms causing injury were falling (50.4%, n = 584), collision with an object (30.7%, n = 356), and collision with a person (18.8%, n = 218). Asphalt (59.5%, n = 295) and concrete (40.5%, n = 201) were the most common surfaces in the school environment to contribute to injuries. School-related injuries are not uncommon and can be prevented by improving the infrastructure of school buildings and supplying appropriate school stationary equipment for age. Our results are useful in developing a national injury prevention program aimed at enhancing safety in school environments.


Maximizing breast projection after free-nipple-graft reduction mammaplasty.
In 1922, Thorek described standard free-nipple reduction mammaplasty for gigantomastia. This technique provided a simple and effective way to perform reduction mammaplasty. However, the technique is frequently criticized for producing a breast and nipple with poor projection. Even with the standard modification of the original technique, the resultant breast and nipple may be wide and flat, with unpredictable nipple-areola pigmentation. To create a breast mound and nipple with projection and even pigmentation, the free-nipple-graft breast reduction technique is presented. The Wise pattern skin reduction markings and the superiorly based parenchymal reduction technique are used. After the nipple-areola complex is removed, as a free graft, the inferior pole of the breast is then amputated along the Wise pattern skin markings, leaving lateral and medial pillars of breast tissue, with the apex of the resection corresponding to the new nipple location. The lateral and medial pillars of the superiorly based breast mound are then sutured together. Key interrupted sutures are placed, beginning at the most inferior and posterior point of the pillars, while recruiting tissue centrally to increase the projection. The intersecting point of the inverted T, at 7 cm from the new nipple position, is then sutured to the fasciae of the pectoralis major muscle. If more central projection is desired, the vertical limb design can be lengthened. The tissue inferior to the 7-cm mark is de-epithelialized and tucked under the central breast, if needed, contributing further to the final breast parenchyma projection. The skin of the vertical limb of the Wise pattern is then closed with a dog-ear at the apex to further contribute to nipple projection. The nipple is replaced as a free, thick, split-thickness skin graft. The breast is temporarily closed, and the medial and lateral breast tissue excess is liposuctioned to create a more conical breast. Excessive medial and lateral skin is then resected, keeping the inframammary crease incision under the breast mound. Twenty-five patients underwent free-nipple-graft reduction mammaplasty using this technique between 1992 and 2000. An average of 1600 g of breast tissue per breast was removed. The average follow-up period was 36 months. Patient satisfaction has been very high.


Exploring a Possible Link between the Intestinal Microbiota and Feed Efficiency in Pigs.
Feed efficiency (FE) is critical in pig production for both economic and environmental reasons. As the intestinal microbiota plays an important role in energy harvest, it is likely to influence FE. Therefore, our aim was to characterize the intestinal microbiota of pigs ranked as low, medium, and high residual feed intake ([RFI] a metric for FE), where genetic, nutritional, and management effects were minimized, to explore a possible link between the intestinal microbiota and FE. Eighty-one pigs were ranked according to RFI between weaning and day 126 postweaning, and 32 were selected as the extremes in RFI (12 low, 10 medium, and 10 high). Intestinal microbiota diversity, composition, and predicted functionality were assessed by 16S rRNA gene sequencing. Although no differences in microbial diversity were found, some RFI-associated compositional differences were revealed, principally among members of Firmicutes, predominantly in feces at slaughter (albeit mainly for low-abundance taxa). In particular, microbes associated with a leaner and healthier host (e.g., Christensenellaceae, Oscillibacter, and Cellulosilyticum) were enriched in low RFI (more feed-efficient) pigs. Differences were also observed in the ileum of low RFI pigs; most notably, Nocardiaceae (Rhodococcus) were less abundant. Predictive functional analysis suggested improved metabolic capabilities in these animals, especially within the ileal microbiota. Higher ileal isobutyric acid concentrations were also found in low RFI pigs. Overall, the differences observed within the intestinal microbiota of low RFI pigs compared with that of their high RFI counterparts, albeit relatively subtle, suggest a possible link between the intestinal microbiota and FE in pigs.IMPORTANCE This study is one of the first to show that differences in intestinal microbiota composition, albeit subtle, may partly explain improved feed efficiency (FE) in low residual feed intake (RFI) pigs. One of the main findings is that, although microbial diversity did not differ among animals of varying FE, specific intestinal microbes could potentially be linked with porcine FE. However, as the factors impacting FE are still not fully understood, intestinal microbiota composition may not be a major factor determining differences in FE. Nonetheless, this work has provided a potential set of microbial biomarkers for FE in pigs. Although culturability could be a limiting factor and intervention studies are required, these taxa could potentially be targeted in the future to manipulate the intestinal microbiome so as to improve FE in pigs. If successful, this has the potential to reduce both production costs and the environmental impact of pig production.


Depression and Suicidal Behavior in Young Adult Men and Women With ADHD: Evidence From Claims Data.
This study used commercial claims data to examine the effects of ADHD and sex on the prevalence of depression, suicidal ideation, and suicide attempts in a sample of young adult men and women (aged 18-25 years) with and without attention-deficit/hyperactivity disorder (ADHD). Patterns of treatment use for these conditions was also explored. Young adults with ADHD (162,263 women and 225,705 men) having at least 2 claims with the International Classification of Diseases, Ninth Revision (ICD-9), code for ADHD and a sex- and age-matched group of young adults without an ICD-9 code for ADHD (162,263 women and 225,705 men) were identified. The prevalence of ICD-9 depression and suicidal behavior along with the use and cost of related treatment were compared between young adults with and without ADHD using 2014 claims data. Compared to young adults without ADHD, young adults with ADHD were more frequently identified with depression, suicidal ideation, and suicide attempts. Depression and suicidal ideation were identified more frequently among women with ADHD compared to all other groups. Young adults with ADHD were more frequently engaged in outpatient and inpatient mental health care compared to young adults without ADHD (P < .0001 in each instance). Furthermore, overall costs of outpatient and inpatient care were greater among young adults with ADHD compared to young adults without ADHD (P < .0001 in each instance). These findings highlight the substantial burden of depression and suicidal behavior among young adults with ADHD, particularly women, and underlie the need for more research focused on mitigating risk for depression and suicidal behavior among both men and women with ADHD.


Functional characterization of HFR1, a high-mannose N-glycan-specific wheat lectin induced by Hessian fly larvae.
We previously cloned and characterized a novel jacalin-like lectin gene from wheat (Triticum aestivum) plants that responds to infestation by Hessian fly (Mayetiola destructor) larvae, a major dipteran pest of this crop. The infested resistant plants accumulated higher levels of Hfr-1 (for Hessian fly-responsive gene 1) transcripts compared with uninfested or susceptible plants. Here, we characterize the soluble and active recombinant His(6)-HFR1 protein isolated from Escherichia coli. Functional characterization of the protein using hemagglutination assays revealed lectin activity. Glycan microarray-binding assays indicated strong affinity of His(6)-HFR1 to Manalpha1-6(Manalpha1-3)Man trisaccharide structures. Resistant wheat plants accumulated high levels of HFR1 at the larval feeding sites, as revealed by immunodetection, but the avirulent larvae were deterred from feeding and consumed only small amounts of the lectin. Behavioral studies revealed that avirulent Hessian fly larvae on resistant plants exhibited prolonged searching and writhing behaviors as they unsuccessfully attempted to establish feeding sites. During His(6)-HFR1 feeding bioassays, Drosophila melanogaster larvae experienced significant delays in growth and pupation, while percentage mortality increased with progressively higher concentrations of His(6)-HFR1 in the diet. Thus, HFR1 is an antinutrient to dipteran larvae and may play a significant role in deterring Hessian fly larvae from feeding on resistant wheat plants.


[Clinico-morphological characteristics of thymomegaly].
48 autopsy cases of thymomegaly in children up to 14 years and in adults from 18 to 55 years are studied. The patients died either from the acute or chronic infectious diseases resistant to the therapy or suddenly during or several hours after the diagnostic manipulations, small surgical interventions. Analysis of clinical data and morphological immunohistochemical and ultrastructural studies of the thymus and organs of the immune and endocrine system showed the thymomegaly in the majority of cases to be a local manifestation of the endocrine-immune deficiency syndrome. Primary (congenital) and secondary (acquired) thymomegaly are to be distinguished. A primary thymomegaly occurs in children and adults having congenital pluriglandular endocrinopathy with hypocortisism as well as an adrenal hypo- or aplasia with an antigenic stimulation. A secondary thymomegaly occurs in children of the first year of life and reflects the first phase of the thymic response in the activation of the immune T-system predominantly prolonged due to the immature state of the hypothalamico-hypophyseal-adrenal system. In the adults secondary thymomegaly occurs in cases of the acquired endocrinopathy with hypocortisism.


Further studies on the mechanism of action of human plasma in stimulating prostacyclin production by rat smooth muscle cells.
Human normal plasma stimulates prostacyclin (PGI2) production by vascular cells. This plasma activity may be greatly modified in different pathological conditions. The purpose of this study was to characterize some aspects of the mechanism of action of plasma in modulating PGI2 release. Cultured rat aortic smooth muscle cells were used. Citrated plasma from healthy donors stimulated PGI2 production in a concentration-dependent way. Plasma-derived serum containing increasing concentrations of platelets had the same PGI2 stimulating activity as citrated plasma. Plasma stimulation of PGI2 production was accompanied by release of endogenously incorporated arachidonic acid (AA) from the cell membrane. Similarly to AA, plasma induced PGI2 synthesis only once, a second or third challenge producing a reduced response from the cells. Cells stimulated twice with plasma responded to AA like unstimulated cells while cells stimulated twice with AA were poorly responsive to subsequent stimulation with plasma. When the cells were repeatedly stimulated with AA in the presence of plasma no refractoriness was apparent. This study suggests that plasma increases PGI2 synthesis by the release of endogenous substrate from the cell membrane and by protecting the cells from self-inactivation during AA conversion to prostaglandins.


Season of birth and childhood psychosis.
This paper reports a test of the hypothesis that winter birth is a risk factor for childhood psychosis. All psychotic children (n = 208) admitted to a day-treatment facility in Paris from 1960 through to 1986 were compared with 1040 controls matched by sex and year of birth. Risk ratio estimates were computed for each month, and a significant increase was observed for boys born in December. This association was stronger in some years than in others. The fact that there were no excesses in contiguous months detracts from the persuasiveness of this association.


A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease.
Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.


Differential effects of thyroid hormone on renin secretion, content, and mRNA in juxtaglomerular cells.
The effects of thyroid hormone on renin secretion, renin content, and renin mRNA levels in juxtaglomerular (JG) cells harvested from rat kidneys were determined by radioimmunoassays and reverse transcriptase-polymerase chain reaction. Despite a lack of immediate effect, incubation with triiodothyronine dose dependently increased renin secretion during the first 6 h and elevated renin content and renin mRNA levels during the subsequent period. Simultaneous incubation with triiodothyronine and the calcium ionophore A-23187 abolished the increase in renin secretion and attenuated the increase in renin content but did not affect the increase in renin mRNA levels. During simultaneous incubation with triiodothyronine and the adenylate cyclase inhibitor SQ-22536 or membrane-soluble guanosine 3',5'-cyclic monophosphate (cGMP), the increases in renin secretion, content, and mRNA were similar to those observed in the presence of triiodothyronine alone, except for a cGMP-induced attenuation of the increase in renin secretion. These findings suggest that thyroid hormone stimulates renin secretion by JG cells through the calcium-dependent mechanism, whereas the stimulation of renin gene expression by thyroid hormone does not involve intracellular calcium or cyclic nucleotides.


Hormonal regulation of calcium transport in thick ascending limb renal tubules.
Net calcium efflux (JCanet) was compared in isolated perfused cortical and medullary segments of the thick ascending limb of Henle of the rabbit kidney. In response to the addition of calcitonin to the bathing medium, cortical segments showed no change in JCanet, whereas in medullary segments JCanet increased significantly. Similar studies substituting 8-bromo-cyclic AMP (8-BrcAMP) in concentrations of 10(-4) M or lower in the bath showed no effect on JCanet in either segment. When the concentration of 8-BrcAMP in the bath was increased to 10(-3) M, JCanet rose significantly in both segments. These results indicate heterogeneity of response to calcitonin in the cortical and medullary segments of the thick ascending limb of Henle, but a similar response of calcium transport to cAMP. Because we have previously shown that parathyroid hormone stimulates net calcium efflux in the cortical but not in the medullary segments of the thick ascending limb of Henle, the present observations suggest that cAMP may be the mediator of the actions of both calcitonin and parathyroid hormone.


Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease.
The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7-30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.


Nitrite-stimulated Gastric Formation of S-nitrosothiols As An Antihypertensive Therapeutic Strategy.
Hypertension is usually associated with deficient nitric oxide (NO) bioavailability, and therefore stimulating NO activity is an important antihypertensive strategy. Recently, many studies have shown that both nitrite and nitrate anions are not simple products of NO metabolism and indeed may be reduced back to NO. While enzymes with nitrite-reductase activity capable of generating NO from nitrite may contribute to antihypertensive effects of nitrite, another mechanism involving the generation of NO-related species in the stomach from nitrite has been validated. Under the acidic conditions of the stomach, nitrite generates NO-related species that form S-nitrosothiols. Conversely, drugs that increase gastric pH may impair the gastric formation of S-nitrosothiols, which may mediate antihypertensive effects of oral nitrite or nitrate. Therefore, it is now becoming clear that promoting gastric formation of S-nitrosothiols may result in effective antihypertensive responses, and this mechanism opens a window of opportunity in the therapy of hypertension. In this review, we discuss the recent studies supporting the gastric generation of S-nitrosothiols as a potential antihypertensive mechanism of oral nitrite. We also highlight some drugs that increase S-nitrosothiols bioavailability, which may also improve the responses to nitrite/nitrate therapy. This new approach may result in increased nitrosation of critical pharmacological receptors and enzymes involved in the pathogenesis of hypertension, which tend to respond less to their activators resulting in lower blood pressure.


Vibrational spectrum of gamma-HNIW investigated using terahertz time-domain spectroscopy.
Experimental and theoretical investigations of the vibration spectrum of gamma-Hexanitrohexaazaisowurtzitane in the region of 0.2-2.5 terahertz are presented for the first time. The refraction index, absorption coefficient, and complex dielectric function of this sample are measured by terahertz time-domain spectroscopy. The simulated spectrum using density functional theory (DFT) is in agreement with the experimental data. The observed spectra features are assigned based on DFT calculation.


Nursing Cooperation Pattern for Patients With Advanced Pancreatic Cancer and Abdominal Pain Undergoing Endoscopic Ultrasound-guided Celiac Plexus Neurolysis.
Patients with pancreatic cancer (PC) at a late stage often suffer from severe abdominal pain due to the invasion of celiac plexus, and the analgesics they receive often have intolerable side effects. Endoscopic, ultrasound-guided, celiac plexus neurolysis (EUS-guided CPN) can have a good therapeutic effect. The study intended to evaluate the ability of two nursing cooperation patterns to reduce patients' pain, decrease operation times, increase operational efficiency, and increase nurses' satisfaction, for patients with advanced PC and abdominal pain who received EUS-guided CPN. The research team designed a retrospective controlled study. The study took place at the Shenzhen People's Hospital of the Second Clinical Medical College of Jinan University in Shenzhen, China, and at the Changhai Hospital of the Second Military Medical University in Shanghai, China. Participants were 40 patients with advanced PC who received EUS-guided CPN at one of the two hospitals between January 2019 and January 2020. Twenty participants at Changhai Hospital received the traditional nursing cooperation pattern and became the control group, and 20 participants at the Shenzhen People's Hospital received the new nursing cooperation pattern and became the intervention group. The study measured clinical data, nursing measures, diagnostic significance, and key points for the two patterns as well as compared the effects of the new nursing cooperation method to that of traditional nursing. If the measurement data met the requirements for normality, the team used the two independent sample t-test for the intergroup comparisons. If normality wasn't satisfied, the team used medians and interquartile ranges (IQRs) for expression and the rank sum test for the intergroup comparisons. Counting data were expressed using the constituent ratio, and team used the chi-square test for comparisons between groups. P < .05 was considered to be statistically significant. The operations were successful, and no complications occurred. No significant difference existed in the pain scores between the control group and the intervention group (P > .05), while a significant difference occurred in the nurses' operation times and satisfaction. Not only were the scores for operation times for the control group (97) and the intervention group (59) significantly different, but also the nurses' satisfaction was significantly higher for the intervention group postintervention, at 83.35 ± 5.25, than for the control group, at 62.25 ± 8.18 (P < .001). Such a new nursing cooperation method could assist in patient's rehabilitation and increase nurses' satisfaction. The new nursing cooperation method for patients with advanced PC and abdominal pain undergoing EUS-guided CPN can reduce operation time and improve nurses' satisfaction.


Adolescent obesity and social networks.
The prevalence of overweight among children worldwide is growing at an alarming rate. Social relationships may contribute to the development of obesity through the interaction of biological, behavioral, and environmental factors. Although there is evidence that early environment influences the expression of obesity, very little research elucidates the social context of obesity among children or adolescents. Social network approaches can contribute to research on the role of social environments in overweight and obesity and strengthen interventions to prevent disease and promote health. By capitalizing on the structure of the network system, a targeted intervention that uses social relationships in families, schools, neighborhoods, and communities may be successful in encouraging healthful behaviors among children and their families.


Interplay between epigenome and 3D chromatin structure.
Epigenetic mechanisms, primarily mediated through histone and DNA modifications, play a pivotal role in orchestrating the functional identity of a cell and its response to environmental cues. Similarly, the spatial arrangement of chromatin within the three-dimensional (3D) nucleus has been recognized as a significant factor influencing genomic function. Investigating the relationship between epigenetic regulation and 3D chromatin structure has revealed correlation and causality between these processes, from the global alignment of average chromatin structure with chromatin marks to the nuanced correlations at smaller scales. This review aims to dissect the biological significance and the interplay between the epigenome and 3D chromatin structure, while also exploring the underlying molecular mechanisms. By synthesizing insights from both experimental and modeling perspectives, we seek to provide a comprehensive understanding of cellular functions.


Sociocultural perspectives on physical activity in the lives of older African American and American Indian women: a cross cultural activity participation study.
Illuminating the diversity and sociocultural specificity of women's experiences may be important if healthy lifestyles and quality of life are to be achieved. The incidence of cardiovascular disease linked to physical inactivity is high among African American and American Indian women. If more is understood about the experience of physical activity involvement, healthier living might be encouraged. Therefore, the purpose of this study was to explore the sociocultural meanings of physical activity for older (over the age of 40 years) African American and American Indian women who participated in the Cross Cultural Activity Participation Study (CAPS). Through qualitative in-depth interviews, we explored how sociocultural perspectives are related to perceptions about physical activity. Gender and other sociocultural factors influenced physical involvement on a continuum from negligible to significant. Both groups interviewed showed evidence that opportunities for physical activity in their free time did not always exist for them. For African American women, history and daily living issues were important factors limiting their involvement. Marginality limited American Indian women, but their cultural pride was often a source of physical activity. The juxtaposition of cultural and personal values emerged as a determinant of physical activity involvement among the women in this study. A further expansion of cultural and personal life situation perspectives is recommended to help understand the complex dimensions of physical activity as it relates to healthy living.


Intraindividual Dynamic Network Analysis - Implications for Clinical Assessment.
A network analysis approach to psychopathology regards symptoms as mutually interacting components of a multifaceted system (Borsboom & Cramer, 2013). Although several studies using this approach have examined comorbidity between disorders using cross-sectional samples, a direct application of the network analysis approach to intraindividual dynamic relations between symptoms in a complex, comorbid case has not been reported. The current article describes an intraindividual dynamic network analysis (IDNA) approach to understanding the psychopathology of an individual using dynamic (over time) lead-lag interrelations between symptoms. Multivariate time series data were utilized to create and examine an intraindividual, lag-1 network of the partial, day-to-day relations of symptoms in an individual with comorbid mood and anxiety disorders. Characteristics of the network, including centrality indices, stability, dynamic processes between symptoms, and their implications for clinical assessment are described. Additional clinical implications and future directions for IDNA, including the potential incremental validity of this assessment approach for empirically-based idiographic assessment and personalized treatment planning, are discussed. This person-specific IDNA approach may be especially useful in complex and comorbid cases.


[Oral medicine 6. Ulcerations of the oral mucosa].
An ulcer can be defined as a superficial defect of the skin or the mucosa, caused by tissue degeneration, and having little tendency to heal. With a careful review of the medical history and the findings of inspection of the oral cavity, including palpation of the ulcer, the dentist will in many cases be able to determine the diagnosis and also the treatment. There are, however, also ulcerations which require referral to a specialist, most often the oral and maxillofacial surgeon.


T-Score Discordance of Bone Mineral Density in Patients with Atypical Femoral Fracture.
Although atypical femoral fracture (AFF) occurs more frequently in patients taking bisphosphonates and longer treatment is associated with higher risk, the causal relationship between AFF and bisphosphonates has not been established. Most patients with AFF have osteoporosis that is being treated with bisphosphonates, but we are not aware of any reports regarding the areal bone mineral density (aBMD) and discordance between the T-scores of the femur and spine in such patients. We investigated the prevalence of aBMD discordance and the characteristics of patients with AFF. Medical records for 63 consecutive patients treated for AFF were retrospectively evaluated, and 48 patients, all female, were eligible for the study. The average age at the time of fracture was 73.0 years, the average duration of bisphosphonate use was 68.5 months, and the average presumed age at bisphosphonate initiation was 67.2 years. We evaluated the prevalence of discordance, defined as a difference between the T-score categories of the femur and spine in the same individual as well as demographic differences between the discordance and concordance groups. We also compared the prevalence of discordance in patients with AFF with that in 114 female patients with intertrochanteric femoral fracture (ITFF). T-score concordance, minor discordance, and major discordance were seen in 14 (29%), 32 (67%), and 2 (4%) of the patients with AFF, respectively. The prevalence of discordance was significantly higher in those with AFF (71%) than in those with ITFF (23%) (p < 0.001). The average age at bisphosphonate initiation in the AFF group was lower in the discordance group (65.7 years) than in the concordance group (70.7 years) (p = 0.04). The prevalence of T-score discordance between the hip and lumbar spine was relatively high in patients with AFF, and the presumed age at the initiation of bisphosphonate therapy was younger in patients with discordant T-scores in this study. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Urban herring gulls use human behavioural cues to locate food.
While many animals are negatively affected by urbanization, some species appear to thrive in urban environments. Herring gulls (Larus argentatus) are commonly found in urban areas and often scavenge food discarded by humans. Despite increasing interactions between humans and gulls, little is known about the cognitive underpinnings of urban gull behaviour and to what extent they use human behavioural cues when making foraging decisions. We investigated whether gulls are more attracted to anthropogenic items when they have been handled by a human. We first presented free-living gulls with two identical food objects, one of which was handled, and found that gulls preferentially pecked at the handled food object. We then tested whether gulls' attraction to human-handled objects generalizes to non-food items by presenting a new sample of gulls with two non-food objects, where, again, only one was handled. While similar numbers of gulls approached food and non-food objects in both experiments, they did not peck at handled non-food objects above chance levels. These results suggest that urban gulls generally show low levels of neophobia, but that they use human handling as a cue specifically in the context of food. These behaviours may contribute to gulls' successful exploitation of urban environments.


Therapist Focus on Parent Involvement in Community-Based Youth Psychotherapy.
Parent involvement in the treatment of childhood disruptive behavior problems is a critical component of effective care. Yet little is known about the amount of time therapists are involving parents in treatment and factors that predict therapists' efforts to involve parents in routine care. The purpose of this study is to examine therapists' within-session involvement of parents in community-based outpatient mental health treatment. The data are from a larger longitudinal observational study of psychotherapy for children ages 4-13 with disruptive behavior problems and include videotaped psychotherapy sessions coded for the therapeutic strategies delivered as well as measures of child, parent/family, and therapist characteristics at baseline. Parent involvement is defined as the proportion of time in the session that therapists direct treatment strategies towards parents. Results indicated that therapists directed treatment strategies towards parents an average of 44% of the time within a session. Multilevel modeling was used to examine client-level (child, parent, and family functioning) and provider-level (therapist experience and background) predictors of parent involvement. Therapists involved parents more when the child had higher levels of behavior problems, when the parent reported higher levels of internalized caregiver strain, and when the therapist was more experienced. The results highlight potential areas to target in efforts to increase parent involvement, including training less experienced therapists to increase their focus on directing strategies towards parents.


Confirming the association between low serum 25OHD levels in girls with central precocious puberty and its severity.
To assess the differences in vitamin D levels in girls with rapidly progressive (RP) or slowly progressive (SP) central precocious puberty (CPP) and to compare whether the factors related to RP-CPP influenced the vitamin D status. A cross-sectional study was performed among girls with CPP classified as RP-CPP or SP-CPP. The baseline data, gonadotropin-releasing hormone (GnRH) stimulation test results, serum 25-hydroxyvitamin D (25OHD) levels, and season of sample collection were analyzed. The mean 25OHD level in 340 girls was 15.89 ± 6.87 ng/mL, of whom only 10 (2.9%) had normal levels (≥ 30 ng/mL). A total of 114 girls in the SP-CPP group and 226 in the RP-CPP group had similar chronological age, disease course, height SDS, bone mineral density, baseline follicle-stimulating hormone (FSH), peak FSH, and 25OHD levels. Developmental age, body mass index (BMI), BMI SDS, peak luteinizing hormone (LH)/FSH, insulin-like growth factor 1 (IGF-1), and IGF-1 SDS were independent risk factors for RP-CPP. Significant differences were observed among the different serum 25OHD levels in terms of season, disease course, IGF1 level, and BMI SDS (P < 0.05). Moreover, the sampling season was strongly correlated with serum 25OHD levels (r = 0.402, P < 0.001). The vitamin D levels were generally deficient or insufficient in girls with CPP, but were not related to the different types of CPP. High BMI levels, IGF1 levels, or peak LH/FSH ratio, but not vitamin D levels, could promote the progression of RP-CPP. Seasonal factors mainly influenced the vitamin D levels.


Fusion-negative rhabdomyosarcoma orthotopic tongue xenografts for study of invasion, intravasation and metastasis in live animals.
PAX3/7 Fusion-negative rhabdomyosarcoma (FN-RMS) is a childhood mesodermal lineage malignancy with a poor prognosis for metastatic or relapsed cases. Towards achieving a more complete understanding of advanced FN-RMS, we developed an orthotopic tongue xenograft model for studies of molecular basis of FN-RMS invasion and metastasis. The behavior of FN-RMS cells injected into murine tongue was examined using in vivo bioluminescence imaging, non-invasive intravital microscopy (IVM), and histopathology and compared to the prevailing hindlimb intramuscular and subcutaneous xenografts. FN-RMS cells were retained in the tongue and invaded locally into muscle mysial spaces and vascular lumen. While evidence of hematogenous dissemination to the lungs occurred in tongue and intramuscular xenografts, evidence of local invasion and lymphatic dissemination to lymph nodes only occurred in tongue xenografts. IVM and RNA-seq of tongue xenografts reveal shifts in cellular phenotype and differentiation state in tongue xenografts. IVM also shows homing to blood and lymphatic vessels, lymphatic intravasation, and dynamic membrane protrusions. Based on these findings, the tongue orthotopic xenograft of FN-RMS is a valuable model for tumor progression studies at the tissue, cellular and subcellular levels providing insight into kinetics and molecular bases of tumor invasion and metastasis and, hence, new therapeutic avenues for advanced FN-RMS.


Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly.
A 44 amino acid peptide with growth hormone-releasing activity has been isolated from a human tumor of the pancreas that had caused acromegaly. The primary structure of the tumor-derived peptide is H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala- Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly -Ala-Arg-Ala-Arg-Leu-NH2. The synthetic replicate has full biological activity in vitro and in vivo specifically to stimulate the secretion of immunoreactive growth hormone. The tumor-derived peptide is identical in biological activity and similar in physiochemical properties to the still uncharacterized growth hormone-releasing factor present in extracts of hypothalamic tissues.


Multiple Sclerosis in the Asia Pacific Region: A Systematic Review of a Neglected Neurological Disease.
Background: Multiple sclerosis is thought to be relatively uncommon in the Asia Pacific region with prevalence estimated between 0 and 20 per 100,000. There is reason to doubt these estimates due to the lack of data from many countries and the growing evidence of variability in prevalence across small geographic areas. This study was conducted to systematically review the population prevalence, incidence, mortality and disability progression estimates of MS within the Asia Pacific region. Methods: The systematic review was conducted on articles from 1985 till 31st July 2017 within the PubMed/MEDLINE, EMBASE, SCOPUS, and The Cochrane Library databases. The review included articles that were population-based studies conducted on patients with MS in the Asia Pacific region that reported either incidence, prevalence, mortality, or disease progression. Hospital-based studies and non-research articles were excluded to ensure that only information representative of the population was included for analysis. Data appraisal and extraction was done by independent reviewers. This review was registered with PROSPERO (ID: CRD42017082760). Findings: Of the 2,757 articles found, 16 studies were included. Information on 6 (18.75%) of 32 Asia Pacific countries was found, with data representing 8% of the total population. Prevalence estimates were available for 6 countries while estimates for incidence (3 countries), mortality (4 countries), and disease progression (2 countries) were limited. Interpretation: The lack of epidemiological data available in the Asia Pacific region creates a blind spot in the surveillance of MS which obscures the true burden of MS, causing patients to struggle to receive the resources and funding that they need.


Spirograph theory: a framework for calculations on digitized straight lines.
Using diagrams called ``spirographs'' a general theory is developed with which one can easily perform calculations on various aspects of digitized straight lines. The mathematics of the theory establishes a link between digitized straight lines and the theory of numbers (Farey series, continued fractions). To show that spirograph theory is a useful unification, we derive two previously known advanced results within the framework of the theory, and new results concerning the accuracy in position of a digitized straight line as a function of its slope and length.


A Community-Based Study of Cognitive Impairment Caregiving Outcomes Pre- and During the COVID-19 Pandemic.
The impact of the COVID-19 pandemic on informal caregiving was examined in a Mexican American (MA) and Non-Hispanic White (NHW) population-based cohort. 395 participants age > 65 years were recruited via door-to-door and phone recruitment as part of the Brain Attack Surveillance in Corpus Christi-Cognitive (BASIC-C) project. Both recipients and caregivers answered questions regarding the recipient's health and the COVID-19 pandemic. 15% of caregivers saw their caregiving recipient less than before the pandemic and 18% saw their recipient more than before. 55% of caregivers reported a slight to severe impact of the pandemic on their caregiving, and 45% reported no impact. For most caregivers, their caregiving role did not change markedly during the pandemic. MA and NHW caregivers had similar survey responses.


Hemodialysis adequacy and treatment in Iranian patients: a national multicenter study.
Assessment of the hemodialysis adequacy is one of the key factors in evaluating health service system. This would provide a good background for effective future planning by healthcare authorities. In this study, we aimed to evaluate the hemodialysis adequacy in Iran. One hundred and twenty-seven hemodialysis centers affiliated to 30 medical universities in Iran participated in this cross-sectional multicenter national study. All demographic data as well as hemodialysis prescription data, including blood flow rate, length of the hemodialysis session, hemodialysis membrane type, and composition of the dialysis solution were recorded for each patient. In addition, urea reduction ratio and Kt/V were calculated to determine the hemodialysis adequacy. A total of 4004 patients were included in this study, 2345 men (58.6%) and 1659 women (41.4%). Bicarbonate-based solutions and low-flux membranes were prescribed for 77.0% and 97.6% of the patients, respectively. The mean blood flow rate was 242.9 ± 39.2 mL/min. The mean length of hemodialysis session was 229.2 ± 22.2 minutes. The mean urea reduction ratio and Kt/V were calculated to be 61.0 ± 11.8% and 1.2 ± 0.4, respectively. A Kt/V less than 1.2 and a urea reduction ratio less than 65% were found in 56.7%, and 65.2% of the hemodialysis patients, respectively. This study showed a substantial inadequate hemodialysis in Iran as compared with the Kidney Disease Outcomes Quality Initiative guidelines. Considering the impact of dialysis adequacy on quality of life and survival rates, as well as healthcare costs, rigorous attempts to achieve the desired goals are necessary.


Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource.
Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development. Here, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and non-cancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/ .


Equivalence class formation: a method for teaching statistical interactions.
Many students struggle with statistical concepts such as interaction. In an experimental group, participants took a paper-and-pencil test and then were given training to establish equivalent classes containing four different statistical interactions. All participants formed the equivalence classes and showed maintenance when probes contained novel negative exemplars. Thereafter, participants took a second paper-and-pencil test. Participants in the control group received two versions of the paper-and-pencil test without equivalence-based instruction. All participants in the experimental group showed increased paper-and-pencil test scores after forming the interaction-indicative equivalence classes. Class-indicative responding also generalized to novel exemplars and the novel question format used in the paper-and-pencil test. Test scores did not change with repetition for control group participants. Implications for behavioral diagnostics and teaching technology are discussed.


Hepatitis C virus-infected patients report communication problems with physicians.
We examined the prevalence and nature of perceived problems in the interaction between physicians and patients diagnosed with hepatitis C virus (HCV) infection. This cross-sectional study included 322 outpatients diagnosed with chronic HCV infection and treated at a tertiary referral hospital's hepatology clinic. Patients were asked to provide demographic information and to complete a semistructured interview, the Sickness Impact Profile (SIP) and Hospital Anxiety Depression (HAD) scale. A team of two blinded coders analyzed the interviews. A total of 131 (41%) study patients reported communication difficulties with physicians involved in their care. The main difficulties were the poor communication skills of physicians (91 [28%]), physician incompetence regarding the diagnosis and treatment of HCV infection (74 [23%]), feelings of being misdiagnosed, misled, or abandoned (51 [16%]), or being stigmatized by their physician (29 [9%]). Patients were twice as likely to report difficulties with subspecialists as compared with generalists. Nonresponse with antiviral therapy correlated with perceived physician conflict even after adjusting for treatment in relation to the time of interview, whereas previous or ongoing substance abuse and mode of acquisition did not. In a multivariate model, patients' psychosocial problems were the best predictors of communication difficulties. In conclusion, a substantial number of patients with HCV infection report difficulties when interacting with physicians, which may be due to coexisting emotional or social problems. However, perceived stigmatization by physicians and a sense of abandonment reflect the need for further educational efforts. These should target both specialists and primary care providers to inform them about the psychosocial challenges facing these patients.


Lack of associations between two previously identified susceptible single nucleotide polymorphisms of interleukin-23 receptor gene and ankylosing spondylitis: a replication study in a Chinese Han population.
The human leukocyte antigen (HLA)-B27 gene is considered to be a major gene associated with predisposition to ankylosing spondylitis (AS); however, studies have demonstrated that non-HLA-B27 genes also contribute substantially to the susceptibility to AS. Two single nucleotide polymorphisms (SNPs), rs1004819 and rs10889677, of the interleukin-23 receptor (IL-23R) gene have been shown to be associated with AS susceptibility in European populations. However, ethnicity factors contribute to population splitting and genetic variation, and ethnic-specific genetic association studies are needed to validate these associations in patients from different ethnic backgrounds. This study therefore aimed to replicate the associations between these two SNPs and AS susceptibility in a Chinese Han population. A total of 195 AS patients and 203 normal controls were recruited in this study. Two IL-23R gene SNPs, rs1004819 and rs10889677 were selected. Genotyping was performed in all subjects using the TaqMan probe method. Genotype and allele frequencies were compared between AS patients and normal controls by χ2 tests. There were no significant differences in either the genotype frequencies (TT 36.4%, TC 48.7% and CC 14.9% in AS patients; TT 35.0%, TC 50.0% and CC 15.0% in normal controls) or allele frequencies (T 60.8% and C 39.2% in AS patients; T 60.0% and C 40.0% in normal controls) of rs1004819 between AS patients and normal controls (P > 0.05). In addition, both the genotype frequencies (AA 51.3%, AC 43.1% and CC 5.6% in AS patients; AA 57.6%, AC 35.5% and CC 6.9% in normal controls) and allele frequencies (A 72.8% and C 27.2% in AS patients; A 75.4% and C 24.6% in normal controls) of rs10889677 were also comparable between AS patients and normal controls (P > 0.05). This study found no evidence for an association between either of the two previously identified AS-susceptibility IL-23R SNPs (rs1004819 and rs10889677) and onset of AS, indicating a possible difference in pathogenesis of AS between Chinese and European patients.


Prognostic significance of hypoxic PET using (18)F-FAZA and (62)Cu-ATSM in non-small-cell lung cancer.
Tumor hypoxia is believed to have a strong correlation with the resistance to chemoradiotherapy. Noninvasive evaluation of hypoxic status in tumors using molecular imaging has the potential to characterize the tumor aggressiveness. We evaluated the clinical usefulness of newly-developed tumor hypoxic positron emission tomography (PET) tracers in localized non-small-cell lung cancer (NSCLC). Forty-seven patients with localized NSCLC received either or both hypoxic PETs using the tracers: (18)F-fluoroazomycin arabinoside ((18)F-FAZA) (n=45) and/or (62)Cu-diacetyl-bis (N4)-methylsemithiocarbazone ((62)Cu-ATSM) (n=22). All received (18)F-fluorodeoxyglucose ((18)F-FDG) PET tracer (n=47). We examined the correlation between uptake of three PET tracers and clinicopathological factors, and evaluated their impacts on survival after treatment retrospectively. A couple of commonly-identified unfavorable factors such as presence of vascular invasion and pleural invasion was significantly correlated with higher uptake of these hypoxic agents as well as that of (18)F-FDG. Larger tumor diameter, high neutrophil-to-lymphocyte ratio and advanced pathological stage were also associated with accumulation of hypoxic PETs ((18)F-FAZA, p<0.01; (62)Cu-ATSM, p<0.04), but not with that of (18)F-FDG. The patients with a higher accumulation had significantly poorer overall survival [(18)F-FAZA, HR (hazard ratio), 9.50, p<0.01; (62)Cu-ATSM, HR, 4.06, p<0.05] and progression free survival ((18)F-FAZA, HR, 5.28, p<0.01, (62)Cu-ATSM, HR, 2.72, p<0.05). Both (18)F-FAZA and (62)Cu-ATSM PET provide useful information regarding tumor aggressiveness and prediction of survival among NSCLC patients. We believe these hypoxic PETs could contribute to the establishment of the optimally individualized treatment of NSCLC.


Circulating autoantibodies in patients with extracapillary glomerulonephritis.
Circulating autoantibodies, namely c-ANCA, MPO-ANCA, anti-Goodpasture (anti-NC1), and anti-entactin antibodies were analysed in sera from 82 consecutive patients with crescentic involvement of more than 50% glomeruli in renal biopsy specimens. Sixty-eight (approximately 83%) patients possessed one or more of these autoantibodies. About two-thirds of all patients had ANCA (c-ANCA, MPO-ANCA or both). Most of the remaining positive patients had anti-NC1 antibodies. Very few patients had anti-entactin antibodies, thereby suggesting a poor association of these antibodies with extracapillary glomerulonephritis (ECGN). Thus two different categories of patients, one possessing ANCA and the other anti-NC1 antibodies, could be recognised. Patients with anti-NC1 antibodies were characterised by linear immune deposits along the glomerular basement membrane and the clinical outcome was invariably grim. On the other hand, despite no significant difference in renal morphology from patients with anti-NC1 antibodies, the disease in patients with ANCA, in general, had a milder course. Among patients with ANCA, those with c-ANCA mainly had systemic small-vessel vasculitis with widespread systemic manifestations, whereas most patients with renal restricted primary ECGN with non-linear immune deposits possessed MPO-ANCA. Furthermore, patients with c-ANCA had a more severe disease than those with MPO-ANCA. These observations indicate that a continuous spectrum of diseases exists between idiopathic small-vessel vasculitides and primary non-linear ECGN. Our study also demonstrates that the presence of auto-antibodies is a dominant feature of severe ECGN and that the type of immunological injury is more important than the extent of crescentic involvement of glomeruli in determining the course of illness in patients with ECGN.


[Glyphosate--a non-toxic pesticide?].
Glyphosate is currently the most commonly applied herbicide and its use is still growing. Nowadays, over 50 commercial preparations containing this compound are used, and these formulations are much more toxic than their active compound, glyphosate, owing to the presence of many surfactants and carrier compounds. Toxicological investigations provide evidence that glyphosate is an extremely "safe" herbicide for animals. This is why its use in agriculture is universal. In June 1991, the Environmental Protection Agency (EPA) categorized this compound into class E (according to EPA there are five categories of carcinogenicity), which means that it is probably not carcinogenic to humans. Unfortunately, the study carried out by Swedish oncologists in 2001 showed that glyphosate may induce cancer of the lymphatic system. The results of the Swedish study have changed our opinion about "safety" of this herbicide. Investigations concerning both its accumulation and toxic effect in animals and plants are now under way in many laboratories.


Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).
To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. ClinicalTrials.gov identifier: NCT02497287.


A mysterious clavicular swelling.
The clavicle or collarbone is a horizontal-axis bony structure located between the neck and thoracic area. Tumour metastasis at the clavicle is very rare. Due to its location at the border of the neck and chest area, a primary tumour could originate from both areas. We report the case of a 39-year-old man who presented with a painful right sternal-end clavicular mass and intermittent fever. Chest radiography was normal. Musculoskeletal ultrasound of the clavicle revealed a mass. Computed tomography (CT) thorax further identified a mass at the upper lobe of the right lung. CT-guided tissue biopsy confirmed that it was a lung adenocarcinoma. This case shows an atypical presentation of lung carcinoma and how musculoskeletal ultrasound helped in the diagnosis when other features and investigations were inconclusive.


Insights into the solvation and dynamic behaviors of a lithium salt in organic- and ionic liquid-based electrolytes.
New-generation lithium-ion batteries use ionic liquids (ILs) as electrolyte solutions, greatly enhancing the safety and energy storage capacity of the battery. Fundamental molecular insights are useful for understanding the advantages of high conductivity of IL solvent electrolytes over organic solvent ones. In this work, we computationally studied two organic solvents (DMC and DEC) and four IL solvents ([Cnmim][BF4] and [Cnmim][TFSI] (n = 2, 4)) to examine the physicochemical properties of high concentration electrolytes. As expected, the IL solvent electrolytes exhibit higher density and viscosity, and larger self-diffusion coefficients and conductivity than the organic solvent electrolytes. Further, the microstructures of the lithium salt LiTFSI in various solvent electrolytes were investigated to explore the effect of the organic and IL solvents on the ionic association of the ions Li+ and TFSI-. The structural analysis of LiTFSI revealed that the organic solvents restrict the free motion of the ions, reducing the conductivity of the electrolytes. The [BF4]-type IL electrolytes have higher conductivity than the [TFSI]-type IL electrolytes, especially [C4mim][BF4] with the highest conductivity among the IL-based electrolytes. More importantly, it was proved that the dissolution of LiTFSI in the IL solvents is an anion-driven process.


Robust fabrication of electrospun-like polymer mats to direct cell behaviour.
Currently, cell culture systems that include nanoscale topography are widely used in order to provide cells additional cues closer to the in vivo environment, seeking to mimic the natural extracellular matrix. Electrospinning is one of the most common techniques to produce nanofiber mats. However, since many sensitive parameters play an important role in the process, a lack of reproducibility is a major drawback. Here we present a simple and robust methodology to prepare reproducible electrospun-like samples. It consists of a polydimethylsiloxane mold reproducing the fiber pattern to solvent-cast a polymer solution and obtain the final sample. To validate this methodology, poly(L-lactic) acid (PLLA) samples were obtained and, after characterisation, bioactivity and ability to direct cell response were assessed. C2C12 myoblasts developed focal adhesions on the electrospun-like fibers and, when cultured under myogenic differentiation conditions, similar differentiation levels to electrospun PLLA fibers were obtained.


Heat accumulation during infrared stimulation impacts the response of ex vivo rat sciatic nerve.
Infrared neural stimulation (INS) is a neuromodulation technique that involves short optical pulses delivered to the neural tissue, resulting in the initiation of action potentials. In this work, we studied the compound neural action potentials (CNAP) generated by INS in five ex vivo sciatic nerves. A 1470 nm laser emitting a sequence of 0.4 ms light pulses with a peak power of 10 W was used. A single 4 mJ stimulus is not capable of eliciting a nerve response. However, repetition of the optical stimuli resulted in the induction of CNAPs. Heat accumulation induced by repetition rates as high as 10 Hz may be involved in the increase in CNAP amplitude. This sensitization effect may help to reduce the pulse energy required to evoke CNAP. In addition, these results highlight the importance of investigating the role of the slow nerve temperature dynamics in INS.


Cervical dysplasia on cervicovaginal Papanicolaou smear among HIV-1-infected pregnant and nonpregnant women. Women and Infants Transmission Study.
To assess the association of squamous intraepithelial lesions (SIL) on cervicovaginal Papanicolaou (Pap) smear among women infected with HIV-1 and their pregnancy status, and historical and clinical factors. Study enrollment Pap smears of 452 pregnant and 126 nonpregnant HIV-infected women had cytologic evaluation. The rates of SIL were compared with pregnancy status, immunosuppression, presence of sexually transmitted diseases (STDs) and demographic features. Rates of low grade SIL were similar for pregnant and nonpregnant HIV-1-infected women (17% and 23.8%, respectively; p = .09). Of them, 12 women, 9 pregnant and 3 nonpregnant, had high grade SIL. None had invasive cervical cancer. Low CD4 percentage (odds ratio, [OR] = 3.8; 95% confidence interval [CI], 2.0-7.3) and inflammation (OR = 2.8; 95% CI, 1.8-4.3) were associated with SIL. An association between herpes simplex and SIL (OR = 3.3; 95% CI, 1.1-9.5) was less certain due to clinical diagnosis and low prevalence of herpes simplex (17 of 456 women). Pap smears for a cohort of HIV-infected pregnant and nonpregnant women revealed a high prevalence of LGSIL but a low prevalence of HGSIL and no cases of cervical cancer. Although pregnancy may not affect the rate of Pap smear abnormalities, SIL is associated with immunosuppression, cervical inflammation, and herpes simplex. Closer surveillance of HIV-1-infected women with these risk factors may be warranted.


Short-term effect of levosimendan on free light chain kappa and lambda levels in patients with decompensated chronic heart failure.
To investigate the effects of levosimendan, a positive inotropic agent, on the new heart failure markers immunoglobulin free light chains kappa and lambda (FLC-kappa and FLC-lambda) in decompensated chronic heart failure (HF), 59 patients with New York Heart Association (NYHA) class III-IV HF were enrolled. Patients were randomized into levosimendan (n = 31) and standard HF treatment (n = 29) groups. Serum FLC-kappa and FLC-lambda, brain natriuretic peptide (BNP), and ejection fraction (EF) were measured before treatment and on the 5th day of treatment initiation. Forty-two percent of subjects were females (n = 25) and overall mean age was 64.1 +/- 10.7 years. FLC-kappa (P < 0.05) and FLC-lambda (P < 0.05) were significantly decreased in the levosimendan group compared to baseline, but no difference in either marker in the standard treatment group was observed. Pre- and post-treatment FLC-kappa/FLC-lambda ratios in both groups were similar, whereas FLC-kappa and FLC-lambda levels and the FLC-kappa/FLC-lambda ratio showed no significant correlation with NYHA class, brain natriuretic peptide (BNP) and ejection fraction (EF) levels; and BNP and EF changes after the treatment. Symptomatic improvement in the levosimendan group according to the NYHA class was significantly better than in the standard treatment group (P = 0.044). While 55.2% of patients in the levosimendan group showed a 1-degree shift to lower NYHA classes, 10.3% showed a 2-degree decrease. In conclusion, levosimendan caused short-term hemodynamic and symptomatic improvements, with a more pronounced decrease in FLC levels in patients with advanced decompensated HF.


Evaluation of neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-9 (MMP-9) and their complex MMP-9/NGAL in sera and urine of patients with kidney tumors.
Recent evidence suggests that neutrophil gelatinase-associated lipocalin (NGAL) is required for the development and/or progression of benign and malignant disease, and is overexpressed in several types of tumor. Matrix metalloproteinase-9 (MMP-9), by degrading components of the extracellular matrix and thus promoting the release of growth factors, is important in tumor growth and tumorigenicity. NGAL protects MMP-9 from proteolytic degradation and enhances its enzymatic activities by binding and forming the MMP-9/NGAL complex. Therefore, NGAL, MMP-9 and their complex MMP-9/NGAL have been proposed as soluble biomarkers for numerous malignancies. In the present study, we measured the concentration of these molecules in sera and urine of patients with kidney disease using ELISA. Of these patients, 16 had clear cell renal cell carcinoma (ccRCC) and 4 had oncocytoma. Sera and urine samples of 53 healthy patients were used as controls. In sera, MMP-9 was enhanced in ccRCC patients compared with oncocytoma patients. In urine, the most abundant molecule was NGAL and its mean value was higher in cancer patients. However, there was a broad overlap of the data and we did not identify any correlation with disease type, stage or grade. Therefore, these molecules may not be useful as biomarkers for predicting kidney carcinoma.


Complete genome sequence of classical Swine Fever virus genotype 2.2 strain bergen.
The complete genome sequence of the genotype 2.2 classical swine fever virus strain Bergen has been determined; this strain was originally isolated from persistently infected domestic pigs in the Netherlands and is characterized to be of low virulence.


IQ AND SOCIOECONOMIC DEVELOPMENT ACROSS REGIONS OF THE UK.
Cross-regional correlations between average IQ and socioeconomic development have been documented in many different countries. This paper presents new IQ estimates for the twelve regions of the UK. These are weakly correlated (r=0.24) with the regional IQs assembled by Lynn (1979). Assuming the two sets of estimates are accurate and comparable, this finding suggests that the relative IQs of different UK regions have changed since the 1950s, most likely due to differentials in the magnitude of the Flynn effect, the selectivity of external migration, the selectivity of internal migration or the strength of the relationship between IQ and fertility. The paper provides evidence for the validity of the regional IQs by showing that IQ estimates for UK nations (England, Scotland, Wales and Northern Ireland) derived from the same data are strongly correlated with national PISA scores (r=0.99). It finds that regional IQ is positively related to income, longevity and technological accomplishment; and is negatively related to poverty, deprivation and unemployment. A general factor of socioeconomic development is correlated with regional IQ at r=0.72.


Cockroach allergen exposure and risk of asthma.
Cockroach sensitization is an important risk factor for the development of asthma. However, its underlying immune mechanisms and the genetic etiology for differences in allergic responses remain unclear. Cockroach allergens identification and their expression as biologically active recombinant proteins have provided a basis for studying the mechanisms regarding cockroach allergen-induced allergic sensitization and asthma. Glycans in allergens may play a crucial role in the immunogenicity of allergic diseases. Protease-activated receptor (PAR)-2, Toll-like receptor (TLR), and C-type lectin receptors have been suggested to be important for the penetration of cockroach allergens through epithelial cells to mediate allergen uptake, dendritic cell maturation, antigen-presenting cell (APC) function in T-cell polarization, and cytokine production. Environmental pollutants, which often coexist with the allergen, could synergistically elicit allergic inflammation, and aryl hydrocarbon receptor (AhR) activation and signaling may serve as a link between these two elements. Genetic factors may also play an important role in conferring the susceptibility to cockroach sensitization. Several genes have been associated with cockroach sensitization and asthma-related phenotypes. In this review, we will discuss the epidemiological evidence for cockroach allergen-induced asthma, cockroach allergens, the mechanisms regarding cockroach allergen-induced innate immune responses, and the genetic basis for cockroach sensitization.


Association between change in cardiorespiratory fitness and incident hypertension in Swedish adults.
To explore how change in cardiorespiratory fitness is associated with incident hypertension in adults, and whether the association varies between sex, age, body mass index, cardiorespiratory fitness at baseline and follow-up time. A second aim is to study how change in other lifestyle-related variables affects the results. A total of 91,728 participants (48% women), normotensive at baseline, with two examinations from occupational health service screenings between 1982 and 2019 (mean duration 4.3 years) were included. Cardiorespiratory fitness was assessed as estimated maximal oxygen consumption using submaximal cycle testing. Change in cardiorespiratory fitness was expressed as the percentage change per year. Incident hypertension was defined as systolic blood pressure of 140 mmHg or greater or diastolic blood pressure of 90 mmHg or greater, or self-reported physician-diagnosed hypertension, at second examination. A large increase (≥3% annual change) in cardiorespiratory fitness was associated with a 11% lower risk of incident hypertension compared with maintainers (-1 to +1%), after multi-adjustment including change in smoking, body mass index, diet, stress and exercise habits. On the contrary, a small (-1 to -<3%) and large (≥-3%) decrease in cardiorespiratory fitness associated with a 21% and 25% higher risk compared with maintainers. Longer duration between the examinations was associated with stronger risk associations. Preserving, or changing to, risk level for the other lifestyle variables was associated with a higher risk of incident hypertension. However, a simultaneous maintenance of or increase in cardiorespiratory fitness attenuated the risk associated with smoking, and stress. Preserving or increasing cardiorespiratory fitness should be part of any long-term strategy to decrease the risk of incident hypertension.


Fluorescent markers to study membrane retrieval in antidiuretic hormone-treated toad urinary bladder.
Antidiuretic hormone (ADH) stimulation of toad urinary bladder causes fusion of intracellular vesicles called aggrephores with the apical plasma membrane of granular cells. Aggrephores contain intramembrane particle aggregates whose appearance in the apical membrane is believed to produce a large increase in its water permeability. ADH removal (ADH washout) is thought to cause the retrieval of aggrephores into granular cell cytoplasm. We studied granular cell uptake of dextran and horseradish peroxidase conjugated with fluorescein, rhodamine, or both during ADH washout. Granular cell uptake of fluorescent dextran was dependent on prior exposure to ADH, a linear function of dextran concentration, and increased by a transepithelial osmotic gradient. Immediately after removal of ADH, granular cell fluorescence was finely dispersed and located near the apical surface. Subsequently, it coalesced into larger bodies. This change was most apparent when a single bladder was subjected to two cycles of ADH stimulation and removal using a dextran containing a different fluorophore for each cycle. The ultrastructural correlate for these fluorescent patterns was identified using rhodamine-labeled horseradish peroxidase. Electron microscopy showed that after detachment from the apical membrane, label was initially in tubular-shaped vesicles near the apical surface. Later, these vesicles clustered near multivesicular bodies and transferred their label to these structures. These tubular vesicles closely resemble the morphology of aggrephores visualized by freeze-fracture electron microscopy. We conclude that these fluorescent compounds can be used as markers for the luminal contents of membrane retrieved during ADH washout and allow detailed study of its intracellular processing.


Does a longer delay in fixation of talus fractures cause osteonecrosis?
This retrospective study investigated active duty soldiers with delayed definitive fixation of combat-related talus fractures. The authors predicted a longer delay to internal fixation and a correlation between the timing of fixation and development of osteonecrosis and posttraumatic arthritis. The Joint Theater Trauma Registry was queried by ICD-9 codes for talus fractures. Soldiers, ages 18 to 40, with talus fracture between 2001 and 2008 were included. Radiographs identified the injury type, Hawkins sign, osteonecrosis, and posttraumatic arthritis. Mean time to fixation was 12.9 days. Hawkins sign was observed in 59% of fractures at a mean of 7 weeks. No correlation was found between osteonecrosis or posttraumatic arthritis and open fractures, comminuted fractures, or timing of fixation. Average follow-up was 16 months. This case series has the longest mean time to fixation by more than threefold. There was no correlation of delayed timing of fixation and development of osteonecrosis or posttraumatic arthritis.


Intranasal mucosal boosting with an adenovirus-vectored vaccine markedly enhances the protection of BCG-primed guinea pigs against pulmonary tuberculosis.
Recombinant adenovirus-vectored (Ad) tuberculosis (TB) vaccine platform has demonstrated great potential to be used either as a stand-alone or a boost vaccine in murine models. However, Ad TB vaccine remains to be evaluated in a more relevant and sensitive guinea pig model of pulmonary TB. Many vaccine candidates shown to be effective in murine models have subsequently failed to pass the test in guinea pig models. Specific pathogen-free guinea pigs were immunized with BCG, AdAg85A intranasally (i.n), AdAg85A intramuscularly (i.m), BCG boosted with AdAg85A i.n, BCG boosted with AdAg85A i.m, or treated only with saline. The animals were then infected by a low-dose aerosol of M. tuberculosis (M.tb). At the specified times, the animals were sacrificed and the levels of infection in the lung and spleen were assessed. In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study. Immunization with Ad vaccine alone had minimal beneficial effects. Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent. However, while BCG alone prolonged the survival of infected guinea pigs, the majority of BCG-immunized animals succumbed by 53 weeks post-M.tb challenge. In contrast, intranasal or intramuscular Ad vaccine boosting of BCG-primed animals markedly improved the survival rate with 60% of BCG/Ad i.n- and 40% of BCG/Ad i.m-immunized guinea pigs still surviving by 74 weeks post-aerosol challenge. Boosting, particularly via the intranasal mucosal route, with AdAg85A vaccine is able to significantly enhance the long-term survival of BCG-primed guinea pigs following pulmonary M.tb challenge. Our results thus support further evaluation of this viral-vectored TB vaccine in clinical trials.


In-layer stacking competition during ice growth.
When ice grows, the growth rates are unequal [corrected] along different growth directions and some layers contain planar defective regions. With the aim of helping to understand these phenomena, we report the molecular dynamics simulations of ice growth on the basal and prismatic faces of initial hexagonal ice, using the TIP5P-E water model. By presenting the time evolution of the two-dimensional density profiles of water molecules in each layer and the kinetics of layer formation during ice growth at the temperature of 11 K supercooling, we show that two forms of ice arrangements, hexagonal and cubic, develop competitively within the same ice layer on the basal face, whereas such in-layer stacking-competition is insignificant on the prismatic face. It is shown that, on the basal face, the occurrence of significant in-layer stacking competition in one of the layers significantly delays the layer formation in several overlying layers and explains the overall delay in ice growth on the basal face compared to that on the prismatic face. In addition, it is observed that large planar defects form on the basal face, as a consequence of the long-lasting in-layer stacking competition when the overlying layer grows rapidly.


Sleep Duration Is Associated with Academic Achievement of Adolescent Girls in Mathematics.
To examine the associations between objective measures of sleep during the school week and academic achievement in mathematics and languages in typically developing adolescent girls. Eighty adolescent girls aged 12-17 years (M=14.74, SD=1.3) participated. For five consecutive weeknights, sleep was assessed in the home environment using an actigraph. Academic achievement was assessed using report card grades. Girls who obtained on average less sleep than the recommended amount of 8 to 10 hrs per night had significantly lower grades in mathematics compared to girls who obtained the recommended amount (77.61 vs 86.16, respectively; ηp 2=0.11). Hierarchical regression analyses adjusted for age, pubertal status, and socioeconomic status revealed that longer average sleep time was significantly associated with higher grades in mathematics (B=4.78, 95% CI [2.03,7.53]). No significant associations were found between sleep variables and grades in languages. Longer average weekday sleep duration is associated with academic achievement of adolescent girls in mathematics.


The role of mass spectrometry in atomic weight determinations.
The 1914 Nobel Prize for Chemistry was awarded to Theodore Richards, whose work provided an insight into the history of the birth and evolution of matter as embedded in the atomic weights. However, the secret to unlocking the hieroglyphics contained in the atomic weights is revealed by a study of the relative abundances of the isotopes. A consistent set of internationally accepted atomic weights has been a goal of the scientific community for over a century. Atomic weights were originally determined by chemical stoichiometry--the so-called "Harvard Method," but this methodology has now been superseded by the "physical method," in which the isotopic composition and atomic masses of the isotopes comprising an element are used to calculate the atomic weight with far greater accuracy than before. The role of mass spectrometry in atomic weight determinations was initiated by the discovery of isotopes by Thomson, and established by the pioneering work of Aston, Dempster, and Nier using sophisticated mass spectrographs. The advent of the sector field mass spectrometer in 1947, revolutionized the application of mass spectrometry for both solids and gases to other fields of science including atomic weights. Subsequently, technological advances in mass spectrometry have enabled atomic masses to be determined with an accuracy better than one part in 10(7), whilst the absolute isotopic composition of many elements has been determined to produce accurate values of their atomic weights. Conversely, those same technological developments have revealed significant variations in the isotope abundances of many elements caused by a variety of physiochemical mechanisms in natural materials. Although these variations were initially seen as an impediment to the accuracy with which atomic weights could be determined, it was quickly realized that nature had provided a new tool to investigate physiochemical and biogeochemical mechanisms in nature, which could be exploited by precise and accurate isotopic measurements. Atomic weights can no longer be regarded as constants of nature, except for the monoisotopic elements whose atomic weights are determined solely by the relative atomic mass of that nuclide. Stable isotope geochemists developed mass spectrometric protocols by the adoption of internationally accepted reference materials for the light elements, to which measurements from various laboratories could be compared. Subsequently, a number of heavy elements such as iron, molybdenum and cadmium have been shown to exhibit isotope fractionation. The magnitude of such isotope fractionation in nature is less than for the light elements, but technological developments, such as multiple collector-inductively coupled plasma-mass spectrometry, have enabled such fractionation effects to be determined. Measurements of the atomic weights of certain elements affect the determination of important fundamental constants such as the Avogadro Constant, the Faraday Constant and the Universal Gas Constant. Heroic efforts have been made to refine the accuracy of the atomic weight of silicon, with the objective of replacing the SI standard of mass--the kilogram--with the Avogadro Constant. Improvements in these fundamental constants in turn affect the set of self-consistent values of other basic constants through a least-squares adjustment methodology. Absolute isotope abundances also enable the Solar System abundances of the s-, r-, and p-process of nucleosynthesis to be accurately determined, thus placing constraints on theories of heavy element nucleosynthesis. Future developments in the science of atomic weight determinations are also examined.