Effects of the N-methyl-D-Aspartate receptor antagonist dextromethorphan on vibrotactile adaptation.
Previous reports have demonstrated that short durations of vibrotactile stimuli (less than or equal to 2 sec) effectively and consistently modify both the perceptual response in humans as well as the neurophysiological response in somatosensory cortex. The change in cortical response with adaptation has been well established by a number of studies, and other reports have extended those findings in determining that both GABA- and NMDAR-mediated neurotransmission play a significant role in the dynamic response of somatosensory cortical neurons. In this study, we evaluated the impact that dextromethorphan (DXM), an NMDAR antagonist, had on two distinct vibrotactile adaptation tasks. All subjects, both those that ingested 60 mg DXM and those that ingested placebo, were evaluated for their amplitude discriminative capacity between two simultaneously delivered vibrotactile stimuli both with and without 3 conditions of pre-exposure to adapting stimulation. The results demonstrated that the perceptual metrics of subjects who ingested 60 mg DXM were significantly altered from that of controls when the amplitude discrimination task followed one of the conditions of adapting stimulation. Without the condition of pre-exposure to an adapting stimulus (or stimuli), there was little difference between the observations obtained from the subjects that ingested DXM and controls. Peak impact on subject response occurred at 60 min post-ingestion, whereas the scores of controls who ingested placebo were not impacted. The results - that DXM blocks vibrotactile adaptation - is consistent with the suggestion that NMDAR-mediated neurotransmission plays a significant role in the perceptual adaptive response. This finding is also consistent with neurophysiological findings that report observations of the effects of NMDAR block on the SI cortical response to repetitive vibrotactile stimulation.


General practitioners' provision of end-of-life care and associations with dying at home: a registry-based longitudinal study.
General practitioners (GPs) may play an important role in providing end-of-life care to community-dwelling people. To investigate patients' contacts with GPs, GPs' interdisciplinary collaboration, out-of-hours services and hospitalizations in the last 13 weeks of life and associations with dying at home. Second, investigate whether GP contacts were associated with fewer out-of-hours contacts or days hospitalized. Individually linked data from the Norwegian Cause of Death Registry, Norwegian Patient Registry, Statistics Norway and Control and Payment of Reimbursement to Health Service Providers database for all 80 813 deceased people in Norway within 2012-13. Outcomes were analyzed with logistic regression and negative binomial multilevel mixed-effect models. Overall, 1% of people received GP home visits in Week 13 and 4.6% in the last week before death. During the last 4 weeks of life, 9.2% received one or more GP home visits. Altogether, 6.6% received one or more home visits when the GP had one or more interdisciplinary collaborations during the last 4 weeks, of which <3% died at home. GP office consultations decreased towards the end of life. The likelihood of home death versus another location increased in relation to GP home visits [one home visit odds ratio (OR) 1.92, confidence interval (CI) 1.71-2.15; two or more OR 3.49, CI 3.08-3.96] and GP interdisciplinary collaboration (one contact OR 1.76, CI 1.59-1.96; two or more OR 2.52, CI 2.32-2.74). GPs play a role in enabling people to die at home by performing home visits and collaborating with other health care personnel. Only a minority received such services in Norway.


Augmentation of pituitary thyrotrophin response to thyrotrophin releasing hormone during subphysiological tri-iodothyroinine therapy in hypothyroidism.
Five hypothyroid patients are reported with increased pituitary TSH response to TRH during administration of T3. In one patient treated with intravenous T3, 50 micrograms daily for 10 days, the peak serum TSH and total pituitary TSH reserve after TRH increased coincident with increases in serum T3 and T4 levels and a decrease in the basal TSH concentration. In four patients treated with oral T3, the peak serum TSH and total pituitary TSH reserve after TRH increased during administration of subphysiological doses of T3. Peak serum T3 levels occurred 4 h after ingestion and increased progressively with increasing T3 doses. Serum TSH levels decreased modestly with the nadir at 4 h after T3 ingestion and then returned to basal levels at 24 h. Augmentation of TSH responses to TRH occurred simultaneously with decreases in serum cholesterol, as well as increases in the pituitary prolactin response to TRH, and increase in the GH and cortisol response to insulin induced hypoglycaemia where these responses could be studied. These data demonstrated a positive effect of subphysiological T3 therapy in these hypothyroid patients on the TSH response to TRH as well as increases in the responses of other pituitary hormones to stimulation.


Rotavirus VP4 and VP7 genotypes circulating in Cameroon: Identification of unusual types.
Rotavirus remains a priority candidate for vaccine development, because it is the major cause of viral diarrhea in children worldwide. This study characterized rotavirus strains in 195 stool specimens collected from children <5 years of age with diarrhea, in the Southwest Province and Western Province of Cameroon during 1999-2000. The predominant G type was G1 (detected in 44.9% of specimens) and the most predominant P type was P[8] (in 82.7%). The most common G-P combination detected was G1P[8] (in 37.1% of specimens), followed by G9P[8] (in 14%). Rotavirus strains with unusual G-P combinations, such as G1P[4], G2P[8], G8P[8], G9P[4], G5P[8], and G10P[8], were also observed in significant numbers. Analysis of the age distribution showed that G1P[8] was found circulating in all age groups except in infants <6 months old. Strains G2P[4] and G3P[8] were identified in children >37 months and 19-24 months of age, respectively. Strain G9P[8] was found circulating among children >25 months of age. Unusual strains and mixed infections were found circulating in the different age groups, albeit at lower levels. The high prevalence of mixed infections and diversity of rotavirus strains detected in this first study based on genotyping of Cameroonian strains reinforce the need to continue with surveillance programs in Africa, where a high diversity of strains has been reported.


Oxygen fugacities of extrasolar rocks: Evidence for an Earth-like geochemistry of exoplanets.
Oxygen fugacity is a measure of rock oxidation that influences planetary structure and evolution. Most rocky bodies in the Solar System formed at oxygen fugacities approximately five orders of magnitude higher than a hydrogen-rich gas of solar composition. It is unclear whether this oxidation of rocks in the Solar System is typical among other planetary systems. We exploit the elemental abundances observed in six white dwarfs polluted by the accretion of rocky bodies to determine the fraction of oxidized iron in those extrasolar rocky bodies and therefore their oxygen fugacities. The results are consistent with the oxygen fugacities of Earth, Mars, and typical asteroids in the Solar System, suggesting that at least some rocky exoplanets are geophysically and geochemically similar to Earth.


Religion as a predictor of psychological distress in two religious communities.
Although spirituality and religion play a role in the lives of many North Americans, the relationship of these variables to symptoms of affective disorders has not been rigorously studied. The authors, therefore, evaluated the extent to which religious factors predicted symptoms of distress in a large community sample of 354 individuals (120 Christian and 234 Jewish). Results indicated that religious denomination was a poor predictor of distress. However, general religiousness (e.g. importance of religion), religious practices (e.g. frequency of prayer), and positive religious core beliefs predicted lower levels of worry, trait anxiety, and depressive symptoms, whereas negative religious core beliefs predicted increased symptoms. These variables accounted for a small but significant portion of the variance in reported symptoms after controlling for covariates. These findings are taken to indicate that religion is an important factor to consider when evaluating and treating distress in religious individuals. Implications for clinical practice of empirically supported treatments with religious individuals are explored.


Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial.
Whether hydrocortisone, vitamin C, and thiamine treatment can reduce the mortality of patients with sepsis is controversial. To evaluate the efficacy and safety of hydrocortisone, vitamin C, and thiamine combination treatment for patients with sepsis or septic shock (HYVCTTSSS). This single-blind, randomized controlled trial evaluated treatment with hydrocortisone (50 mg every 6 h for 7 days), vitamin C (1.5 g every 6 h for 4 days), and thiamine (200 mg every 12 h for 4 days) vs placebo (normal saline) in patients with sepsis. The intention-to-treat analysis was used. Primary outcome was 28-day all-cause mortality, and secondary outcomes were organ protection, procalcitonin reduction, and adverse events related to hydrocortisone, vitamin C, and thiamine. Eighty patients were randomized to receive combination treatment (n = 40) or normal saline (n = 40). No difference in 28-day all-cause mortality was observed (27.5% vs 35%, respectively; P = .47); however, treatment was associated with a significant improvement of 72-h change in Sequential Organ Failure Assessment score (P = .02). In adverse events analysis, the treatment group exhibited more incidents of hypernatremia (P = .005). In prespecified subgroup analysis, patients of the treatment subgroup diagnosed with sepsis within 48 h showed lower mortality than those in the control subgroup (P = .02). The study was terminated after the midterm analysis. Among patients with sepsis or septic shock, the combination of hydrocortisone, vitamin C, and thiamine did not reduce mortality compared with placebo. ClinicalTrials.gov; No.: NCT03258684; URL: www.clinicaltrials.gov.


[Child battering and adult psychopathology: an empiric study].
Childhood trauma and battering have been associated with adult psychopathology. To explore the relationship between childhood trauma, somatization, post traumatic stress disorder (PTSD), affective disorder and borderline personality disorder in hospitalized patients of four Chilean hospitals. Five hundred five patients were screened by a short seven item trauma recollection scale (70 from San Bernardo Hospital, 193 from Salvador Hospital, 97 from El Trabajador Hospital and 147 from Curico Hospital). A random sample of 85 cases was studied in depth using the CIDI 2.1, depression, PTSD and somatization scales, Inventory of Personality Organization (IPO) and the OQ 45.2 scale. Forty five percent of patients did not report traumatic experiences, 38.4% recalled one or two events and 16.3% three or more traumatic experiences. The most remembered event was physical punishment (28.7%), followed by traumatic separation from parents (27.1%), alcohol and drug use by an adult at home (22%) and presence of family violence (22%). Thirty two percent of the 85 selected cases met CIDI criteria for affective disorder, 20% for post traumatic stress disorder and 11.8% for somatization disorder. There were statistically significant correlations between the frequence of trauma and post traumatic stress disorder (p <0.001), as well as somatization and depressive disorder (p <0.007 and 0.008). This study supports the concept that traumatic psychosocial environments during childhood are a risk factor for diverse psychiatric syndromes during adulthood.


Curcumin Improves the Tumoricidal Effect of Mitomycin C by Suppressing ABCG2 Expression in Stem Cell-Like Breast Cancer Cells.
Cancer cells with stem cell-like properties contribute to the development of resistance to chemotherapy and eventually to tumor relapses. The current study investigated the potential of curcumin to reduce breast cancer stem cell (BCSC) population for sensitizing breast cancer cells to mitomycin C (MMC) both in vitro and in vivo. Curcumin improved the sensitivity of paclitaxel, cisplatin, and doxorubicin in breast cancer cell lines MCF-7 and MDA-MB-231, as shown by the more than 2-fold decrease in the half-maximal inhibitory concentration of these chemotherapeutic agents. In addition, curcumin sensitized the BCSCs of MCF-7 and MDA-MB-231 to MMC by 5- and 15-fold, respectively. The BCSCs could not grow to the fifth generation in the presence of curcumin and MMC. MMC or curcumin alone only marginally reduced the BCSC population in the mammospheres; however, together, they reduced the BCSC population in CD44+CD24-/low cells by more than 75% (29.34% to 6.86%). Curcumin sensitized BCSCs through a reduction in the expression of ATP-binding cassette (ABC) transporters ABCG2 and ABCC1. We demonstrated that fumitremorgin C, a selective ABCG2 inhibitor, reduced BCSC survival to a similar degree as curcumin did. Curcumin sensitized breast cancer cells to chemotherapeutic drugs by reducing the BCSC population mainly through a reduction in the expression of ABCG2.


C-reactive protein and hormones but not IL-6 are associated to body mass index in first trimester of pregnancy.
To investigate if body mass index (BMI) is related to inflammatory markers and hormones in early pregnancy. A prospective study with 190 pregnant women evaluated at 10 weeks when leptin, insulin, homeostatic model assessment-insulin resistance (HOMA-IR), C-reactive protein (CRP) and interleukin-6 (IL-6) were measured. Median and inter-quartile values of hormones and inflammatory markers are presented according to BMI quintiles. Spearman correlations and Kruskal-Wallis analysis of variance were implemented followed by Mann-Whitney post hoc pair-wise tests. Leptin (P < 0.001), insulin (P = 0.005), HOMA-IR (P = 0.015), and CRP (P = 0.026) assumed higher and significantly median values as BMI quintiles increases, but no differences were observed for IL-6 (P = 0.859). Pair-wise comparisons among quintiles (Q) of BMI were significant for leptin (Q1 × Q3, Q1 × Q4, Q1 × Q5, Q2 × Q4, Q2 × Q5, Q3 × Q5), insulin (Q1 × Q5, Q2 × Q5, Q3 × Q5, Q4 × Q5) and for CRP (Q1 × Q4, Q1 × Q5, Q2 × Q5). Spearman correlation coefficients between BMI showed significant results for leptin (r (s) = 0.58, P < 0.001), insulin (r (s) = 0.19, P = 0.018), HOMA-IR (r (s) = 0.22, P = 0.007), CRP (r (s) = 0.26, P < 0.001), but not for IL-6 (r (s) = -0.06, P = 0.526). Median (mg/L) values of CRP were higher in overweight (35.26) than in normal weight women (21.28, P = 0.051). The present investigation provides evidences on the positive relationship between BMI, leptin, insulin, HOMA-IR and CRP in early pregnancy. CRP but not IL-6 demonstrated a strong relation with overweight in pregnant women, as early as the tenth week.


Sequence and chemistry requirements for a novel aptameric oligonucleotide inhibitor of EGF receptor tyrosine kinase activity.
We have previously identified a phosphorothioate oligonucleotide (PS-ODN) that inhibited epidermal growth factor receptor tyrosine kinase (TK) activity both in cell fractions and in intact A431 cells. Since ODN-based TK inhibitors may have anti-cancer applications and may also help understand the non-antisense mediated effects of PS-ODNs, we have further studied the sequence and chemistry requirements of the parent PS-ODN (sequence: 5'-GGA GGG TCG CAT CGC-3') as a sequence-dependent TK inhibitor. Sequence deletion and substitution studies revealed that the 5'-terminal GGA GGG hexamer sequence in the parent compound was essential for anti-TK activity in A431 cells. Site-specific substitution of any G with a T in this 5'-terminal motif within the parent compound caused a significant loss in anti-TK activity. The fully PS-modified hexameric motif alone exhibited equipotent activity as the parent 15-mer whereas phosphodiester (PO) or 2'-O-methyl-modified versions of this motif had significantly reduced anti-TK activity. Further, T substitutions within the two 5'-terminal G residues of the hexameric PS-ODN to produce a sequence, TTA GGG, representing the telomeric repeats in human chromosomes, also did not exhibit a significant anti-TK activity. Multiple repeats of the active hexameric motif in PS-ODNs resulted in more potent inhibitors of TK activity than the parent ODN. These results suggested that PS-ODNs, but not PO or 2'-O-methyl modified ODNs, containing the GGA GGG motif can exert potent anti-TK activity which may be desirable in some anti-tumor applications. Additionally, the presence of this previously unidentified motif in antisense PS-ODN constructs may contribute to their biological effects in vitro and in vivo and should be accounted for in the design of the PS-modified antisense ODNs.


Resilience or detachment? Coping strategies among termination of pregnancy health care providers in two South African provinces.
There is global recognition that competent and willing health care providers remain the most important determinant of safe abortion or termination of pregnancy services. The psychosocial well-being of providers is critical to the provision of responsive termination of pregnancy services. In light of the dearth of scholarly attention on termination of pregnancy providers' coping strategies in low- and middle-income countries, this paper explores coping strategies among these providers in the urban Gauteng and the mixed rural-urban North West provinces of South Africa. During 2015, in-depth interviews were conducted with 30 termination of pregnancy providers working at abortion facilities in these provinces. Questions focused on providers' lived experiences of abortion service provision, the meanings they attached to their work and their reported coping strategies. Interpretative phenomenological analysis was used to analyse the interviews. Interviewees' mean age was 45.8 years, all were professional nurses and the majority were female (82%), working for an average of 3.6 years in abortion services. Four overlapping themes emerged in relation to reported coping strategies: silence and concealing emotions; seeking support; detachment or disengagement; and belief systems. Study findings point to the need for effective, sustainable employee wellness programmes, within an overall context of positive practice environments.


Variability in modified Rankin scoring across a large cohort of international observers.
The modified Rankin scale (mRS) is the most commonly used outcome measure in stroke trials. However, substantial interobserver variability in mRS scoring has been reported. These studies likely underestimate the variability present in multicenter clinical trials, because exploratory work has only been undertaken in single centers by a few observers, all of similar training. We examined mRS variability across a large cohort of international observers using data from a video training resource. The mRS training package includes a series of "real-life" patient interviews for grading. Training data were collected centrally and analyzed for variability using kappa statistics. We examined variability against a standard of "correct" mRS grades; examined variability by country; and for UK assessors, examined variability by center and by professional background of the observer. To date, 2942 assessments from 30 countries have been submitted. Overall reliability for mRS grading has been moderate to good with substantial heterogeneity across countries. Native English language has had little effect on reliability. Within the United Kingdom, there was no significant variation by profession. Our results confirm interobserver variability in mRS assessment. The heterogeneity across countries is intriguing because it appears not to be related solely to language. These data highlight the need for novel strategies to improve reliability.


Historical introgression and the persistence of ghost alleles in the intermediate horseshoe bat (Rhinolophus affinis).
Phylogenetic conflicts between genetic markers can help to disentangle complex histories of phylogeography and introgression among taxa. We previously proposed that the Chinese mainland subspecies of the intermediate horseshoe bat Rhinolophus affinis himalayanus colonized Hainan Island to form the subspecies R. a. hainanus. Subsequent recolonization of the mainland formed a third taxon, R. a macrurus, and a secondary contact zone with the ancestral himalayanus. To test for historical and recurrent genetic exchange between these mainland subspecies, we sampled populations of each from two parapatric zones and undertook analyses using one mtDNA marker, three nuclear genes and 14 microsatellites. Nuclear DNA, echolocation call frequencies and morphological data all recovered two taxa; however, a mtDNA phylogeny revealed two himalayanus clades, of which one clustered with macrurus, as well as some shared or related mtDNA haplotypes in eastern populations. Isolation-with-migration (IM) models suggested some mtDNA gene flow from macrurus to himalayanus. However, strong population structure in himalayanus raises the possibility that macrurus captured mtDNA from a coastal population of himalayanus that has since become rare or extinct. To reconcile these two sets of results, we suggest that the IM estimates might reflect historical mtDNA gene flow among populations of himalayanus, before mtDNA was subsequently captured by macrurus. Finally, microsatellite-based ABC analyses supported the island origin of macrurus; however, mtDNA-based ABC analyses suggest this taxon might have evolved on the mainland. Our findings highlight the importance of understanding population history and structure for interpreting hybridization and introgression events.


The hedgehog receptor patched is involved in cholesterol transport.
Sonic hedgehog (Shh) signaling plays a crucial role in growth and patterning during embryonic development, and also in stem cell maintenance and tissue regeneration in adults. Aberrant Shh pathway activation is involved in the development of many tumors, and one of the most affected Shh signaling steps found in these tumors is the regulation of the signaling receptor Smoothened by the Shh receptor Patched. In the present work, we investigated Patched activity and the mechanism by which Patched inhibits Smoothened. Using the well-known Shh-responding cell line of mouse fibroblasts NIH 3T3, we first observed that enhancement of the intracellular cholesterol concentration induces Smoothened enrichment in the plasma membrane, which is a crucial step for the signaling activation. We found that binding of Shh protein to its receptor Patched, which involves Patched internalization, increases the intracellular concentration of cholesterol and decreases the efflux of a fluorescent cholesterol derivative (BODIPY-cholesterol) from these cells. Treatment of fibroblasts with cyclopamine, an antagonist of Shh signaling, inhibits Patched expression and reduces BODIPY-cholesterol efflux, while treatment with the Shh pathway agonist SAG enhances Patched protein expression and BODIPY-cholesterol efflux. We also show that over-expression of human Patched in the yeast S. cerevisiae results in a significant boost of BODIPY-cholesterol efflux. Furthermore, we demonstrate that purified Patched binds to cholesterol, and that the interaction of Shh with Patched inhibits the binding of Patched to cholesterol. Our results suggest that Patched may contribute to cholesterol efflux from cells, and to modulation of the intracellular cholesterol concentration. This activity is likely responsible for the inhibition of the enrichment of Smoothened in the plasma membrane, which is an important step in Shh pathway activation.


Elephantid Genomes Reveal the Molecular Bases of Woolly Mammoth Adaptations to the Arctic.
Woolly mammoths and living elephants are characterized by major phenotypic differences that have allowed them to live in very different environments. To identify the genetic changes that underlie the suite of woolly mammoth adaptations to extreme cold, we sequenced the nuclear genome from three Asian elephants and two woolly mammoths, and we identified and functionally annotated genetic changes unique to woolly mammoths. We found that genes with mammoth-specific amino acid changes are enriched in functions related to circadian biology, skin and hair development and physiology, lipid metabolism, adipose development and physiology, and temperature sensation. Finally, we resurrected and functionally tested the mammoth and ancestral elephant TRPV3 gene, which encodes a temperature-sensitive transient receptor potential (thermoTRP) channel involved in thermal sensation and hair growth, and we show that a single mammoth-specific amino acid substitution in an otherwise highly conserved region of the TRPV3 channel strongly affects its temperature sensitivity.


Increased oestradiol in hepatitis E virus-infected pregnant women promotes viral replication.
Hepatitis E virus (HEV) infection causes subclinical diseases, leading to high mortality (>25%) in pregnant women. HEV replication is aggressively escalated in pregnant women, especially in the third trimester of pregnancy. Oestrogen plays an important role in pregnancy. However, the pathogenesis of HEV in pregnant women or immunosuppressive pregnant women (such as HIV-infected or organ-transplanted pregnant women) remains unclear. We investigated the role of oestradiol in HEV infection in a cell culture system. HEV-infected pregnant women had significantly higher oestradiol levels compared with uninfected individuals. HEV infection was significantly increased in cells treated with analogues of oestradiol, diethylstilbestrol (DES) or 17β-oestradiol in a dose-dependent way. However, tamoxifen, an antagonist oestrogen, inhibited HEV replication. HEV infection inhibits oestrogen receptor (ER-α) expression. Immunofluorescence and co-immunoprecipitation assays indicated that ER-α interacted with the helicase of HEV ORF1 indirectly. More importantly, HEV infection was exacerbated in immunosuppressive cells treated with an inhibitor of PI3K-AKT-mTOR signal pathway (LY296004) and supplemented with pregnant women serum with high oestradiol simultaneously. These results strongly suggest that pregnant women with high oestradiol and/or immunosuppression will be vulnerable to HEV infection.


The effect of serum magnesium levels and serum endothelin-1 levels on bone mineral density in protein energy malnutrition.
An inadequate and imbalanced intake of protein and energy results in protein-energy malnutrition (PEM). It is known that bone mineral density and serum magnesium levels are low in malnourished children. However, the roles of serum magnesium and endothelin-1 (ET-1) levels in the pathophysiology of bone mineralization are obscure. Thus, the relationships between serum magnesium and ET-1 levels and the changes in bone mineral density were investigated in this study. There was a total of 32 subjects, 25 of them had PEM and seven were controls. While mean serum ET-1 levels of the children with kwashiorkor and marasmus showed no statistically significant difference, mean serum ET-1 levels of both groups were significantly higher than that of the control group. Serum magnesium levels were lower than normal value in 9 (36%) of 25 malnourished children. Malnourished children included in this study were divided into two subgroups according to their serum magnesium levels. While mean serum ET-1 levels in the group with low magnesium levels were significantly higher than that of the group with normal magnesium levels (p < 0.05), mean bone mineral density and bone mineral content levels were significantly lower (p < 0.05). In conclusion, many factors play a role in the pathophysiology of changes in bone mineral density in malnutrition. Our study suggested that lower magnesium levels and higher ET-1 levels might be important factors in changes of bone mineral density in malnutrition. We recommend that the malnourished patients, especially with hypomagnesaemia, should be treated with magnesium early.


Genotyping of human papillomavirus in paraffin embedded cervical tissue samples from women in Ethiopia and the Sudan.
Cervical cancer is the most frequent female malignancy in most developing countries. Previous studies have demonstrated a strong association of human papillomavirus (HPV) infection with dysplasia and carcinoma of the uterine cervix. The objective of this study was to identify the prevailing HPV genotypes responsible for the development of cervical cancer among women in Ethiopia and the Sudan. A molecular characterization of HPV was done on 245 paraffin embedded cervical biopsy samples collected from the two countries. Amplification of HPV and subsequent genotyping was done using SPF10 primers and Line probe assay. Of samples collected from Ethiopian patients, 93% (149/160) and 13% (21/160) had high risk and low risk HPV genotypes, respectively. Among samples collected from the Sudan, 94% (80/85) harbored high risk and 11.7% (10/85) low risk HPV genotypes. Human papillomavirus 16 was the most frequent genotype identified in samples from Ethiopia (91%, 136/149) and the Sudan (82.5%, 66/80). HPV 52, 58, and 18 were the second, third and fourth common genotypes identified in Ethiopia, whereas HPV 18, 45, and 52 were the second, third, and fourth genotypes identified in samples collected from the Sudan. Thus, individuals living in different geographical localities should receive vaccines based on the specific genotypes circulating in the area and a vaccine targeting HPV 16, 18, 45, 52, and 58 may be optimal for the control of cervical cancer in the two countries.


Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.
1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.


Ischemic neuronal cell death and organellae damage.
The brain is an organ that consumes much energy. This is partially due to the character of neurons; they possess excitable plasma membrane and a large amount of ATP is indispensable for maintaining ion gradient. Once neurons experience energy failure, calcium accumulates in the intracellular space as a result of disturbed ion homeostasis. This, in turn, activates many cellular processes, which culminate in cell death. In this cellular catastrophic cascade, many organelles play important roles. In addition to the plasma membrane, cytosol is the 'organelle' that first becomes exposed to the increased level of calcium. Many proteases, kinases and lipases are localized here, and are activated directly or indirectly by the ischemic insult. Some enzymes are pro-apoptotic ones, while others are anti-apoptotic. It was reported that neurons that would die later showed activated pro-apoptotic enzymes, but ones that would survive possessed activated anti-apoptotic molecules. Mitochondria is the organelle that plays the central role for intrinsic pathways of apoptosis. The release of cytochrome c from this organelle is the key step in apoptotic cascade in the ischemic neurons. However, the exact molecular mechanism of cytochrome c release remains uncertain. In addition, expression of genes essential for mitochondrial function changes in neurons after ischemia, which further indicates the crucial role of this organelle in cell death. Endoplasmic reticulum (ER) not only mediates proteins processing, but also regulates intracellular calcium homeostasis and cell death signal activation. Recent reports indicate that dysfunction of this organelle occurs at an early stage after ischemia and might be the initial step of apoptotic cascades in neurons. Golgi apparatus and lysosomes are organelles that are involved in apoptotic cell death in some situations. There have been no reports that demonstrated active role of these organelles in ischemic neuronal cell death. Further investigation would be desired about this issue. Nucleus is the organelle that contains genomic DNA. Many studies demonstrated DNA breakage in the neurons that would die later, but whether this is the cause or merely the result of the insult remains uncertain. If the more precise role of each organelle in neuronal cell death are disclosed, we should be able to think about new means of therapy for ischemic stroke.


A mammalian mitochondrial RNA processing activity contains nucleus-encoded RNA.
Ribonuclease mitochondrial RNA processing, a site-specific endoribonuclease involved in primer RNA metabolism in mammalian mitochondria, requires an RNA component for its activity. On the basis of copurification and selective inactivation with complementary oligonucleotides, a 135-nucleotide RNA species, not encoded in the mitochondrial genome, is identified as the RNA moiety of the endoribonuclease. This finding implies transport of a nucleus-encoded RNA, essential for organelle DNA replication, to the mitochondrial matrix.


Congenital exercise ability ameliorates muscle atrophy but not spinal cord recovery in spinal cord injury mouse model.
Spinal cord injury (SCI) can cause loss of mobility in the limbs, and no drugs, surgical procedures, or rehabilitation strategies provide a complete cure. Exercise capacity is thought to be associated with the causes of many diseases. However, no studies to date have assessed whether congenital exercise ability is related to the recovery of spinal cord injury. High congenital exercise ability (HE) and low congenital exercise ability (LE) mice were artificially bred from the same founder ICR mice. The HE and LE groups still exhibited differences in exercise ability after 13 generations of breeding. Histological staining and immunohistochemistry staining indicated no significant differences between the HE and LE groups on recovery of the spinal cord. In contrast, after SCI, the HE group exhibited better mobility in gait analysis and longer endurance times in the exhaustive swimming test than the LE group. In addition, after SCI, the HE group also exhibited less atrophy than the LE group, and no inflammatory cells appeared. In conclusion, we found that high congenital exercise ability may reduce the rate of muscle atrophy. This result can be applied to sports science and rehabilitation science as a reference for preventive medicine research.


Role of beta-1 adrenergic receptors in the control of the heterogeneity of O2 saturation in small myocardial veins.
The role of beta adrenergic receptors in the control of venous O2 saturation heterogeneity was studied in the left ventricular free wall of 24 anesthetized open-chest dogs. Venous and arterial O2 saturation was obtained microspectrophotometrically and combined with radioactive microsphere blood flow determinations to calculate regional myocardial O2 consumption. The mean and variance of venous O2 saturation were determined under six experimental conditions designed to produce graded levels of beta adrenergic activity. Regional O2 consumption, extraction and flow were also determined. Propranolol, 2 mg/kg, significantly lowered the O2 saturation variance in both small subepicardial and subendocardial veins compared to control. Isoproterenol, 10 micrograms/kg/min, did not alter the variance of venous O2 saturation. Isoproterenol, 10 micrograms/kg/min, in the presence of 2 mg/kg of propranolol was able to prevent the reduction in variance of venous O2 saturation seen with propropranolol alone. However, 0.1 microgram/kg/min of isoproterenol did not prevent this fall in venous O2 saturation variance with propranolol. Practolol, 1 mg/kg, also caused a significant fall in venous O2 saturation variance in the subepicardium and subendocardium. From this it can be concluded that there is an inhomogeneous distribution in beta-1 adrenergic receptor population and/or activity in the left ventricle. Thus, there appear to be small regions in the heart with high O2 consumption and extraction related to beta-1 adrenergic activity and/or distribution.


Variation in center-level frailty burden and the impact of frailty on long-term survival in patients undergoing elective repair for abdominal aortic aneurysms.
Frailty is increasingly recognized as a key determinant in predicting postoperative outcomes. Centers that see more frail patients may not be captured in risk adjustment, potentially accounting for poorer outcomes in hospital comparisons. We aimed to (1) determine the effect of frailty on long-term mortality in patients undergoing elective abdominal aortic aneurysm (AAA) repair and (2) evaluate the variability in frailty burden among centers in the Vascular Quality Initiative (VQI) database. Patients undergoing elective open and endovascular AAA repair (2003-2017) were identified, and those with complete data on component variables of the VQI-derived Risk Analysis Index (VQI-RAI) and centers with ≥10 AAA repairs were included. VQI-RAI characteristics are sex, age, body mass index, renal failure, congestive heart failure, dyspnea, preoperative ambulation, and functional status. Frailty was defined as VQI-RAI ≥35 based on prior work in surgical patients using other quality improvement databases. This corresponds to the top 12% of patients at risk in the VQI. Center-level VQI-RAI differences were assessed by analysis of variance test. Relationships between frailty and survival were compared by Kaplan-Meier analysis and the log-rank test for open and endovascular procedures. Multivariable hierarchical Cox proportional hazards regression models were calculated with random intercepts for center, controlling for frailty, race, insurance, AAA diameter, procedure type, AAA case mix, and year. A total of 15,803 patients from 185 centers were included. Mean VQI-RAI scores were 27.6 (standard deviation, 5.9; range, 4-56) and varied significantly across centers (F = 2.41, P < .001). The percentage of frail patients per center ranged from 0% to 40.0%. In multivariable analysis, frailty was independently associated with long-term mortality (hazard ratio, 2.88; 95% confidence interval, 2.6-3.2) after accounting for covariates and center-level variance. Open AAA repair was not associated with long-term mortality after adjusting for frailty (hazard ratio, 0.98; 95% confidence interval, 0.86-1.13). There was a statistically significant difference in the percentage of frail patients compared with nonfrail patients who were discharged to a rehabilitation facility or nursing home after both open (40.5% vs 17.8%; P < .0001) and endovascular repair (17.7% vs 4.6%; P < .0001). There is considerable variability of preoperative frailty among VQI centers performing elective AAA repair. Adjusting for center-level variation, frailty but not procedure type had a significant association with long-term mortality; however, frailty and procedure type were both associated with nonhome discharge. Routine measurement of frailty preoperatively by centers to identify high-risk patients may help mitigate procedural and long-term outcomes and improve shared decision-making regarding AAA repair.


Clustering of Syk is sufficient to induce tyrosine phosphorylation and release of allergic mediators from rat basophilic leukemia cells.
In mast cells, antigen-mediated aggregation of the high-affinity receptor for immunoglobulin E, Fc epsilon RI, stimulates tyrosine phosphorylation and activation of multiple signaling pathways leading to the release of several classes of mediators of the allergic response. Early events induced upon cross-linking of Fc epsilon RI include tyrosine phosphorylation of Fc epsilon RI subunits and activation of the tyrosine kinase p72syk (Syk), which binds to tyrosine-phosphorylated Fc epsilon RI. Clustering of Syk, as a result of its interaction with aggregated Fc epsilon RI, may play a role in activating one or more of the signaling pathways leading to mediator release. To test this possibility, Syk was introduced into a model mast cell line (rat basophilic leukemia cells) as part of a chimeric transmembrane protein containing the extracellular and transmembrane domains of CD16 and CD7, respectively. Clustering of the Syk chimera, using antibodies against CD16, was found to be sufficient to stimulate early and late events normally induced by clustering of Fc epsilon RI. Specifically, aggregation of Syk induced degranulation, leukotriene synthesis, and expression of cytokine genes. Induction of mediator release was dependent on the kinase activity of Syk. Consistent with this finding, clustering of Syk also induced the tyrosine phosphorylation of a profile of proteins, including phospholipase C-gamma 1 and mitogen-activated protein kinase, similar to that induced upon clustering of Fc epsilon RI. These results strongly suggest that Syk is an early and critical mediator of multiple signaling pathways that emanate from the Fc epsilon RI receptor and give rise to the allergic response.


Immune control of food intake: enteroendocrine cells are regulated by CD4+ T lymphocytes during small intestinal inflammation.
Gastrointestinal inflammation reduces food intake but the biological mechanisms explaining suppressed feeding during inflammation are unknown. We have used a model of upper gut infection (Trichinella spiralis in the mouse) to study the effect of inflammation on food intake, and explored the role of a key enteroendocrine cell (EEC) in the regulation of feeding by the immune response. Food intake of NIH mice infected with the intestinal nematode Trichinella spiralis was measured. Duodenal cholecystokinin (CCK) cells were counted. Plasma CCK was measured. Infected mice were treated with a specific CCK1 receptor antagonist, and food intake reassessed. The influence of the immune response on food intake and CCK was mechanistically examined by treating mice with CD4 or mast cell neutralising antibodies. The role of the T helper 2 response was further explored in mice genetically deficient for interleukin (IL)-4, IL-13, or IL-4Ralpha (receptor alpha subunit). Food intake of infected mice was significantly reduced at the temporal peak of intestinal inflammation. CCK expressing EEC were upregulated in infected mice, and plasma CCK levels were increased. A CCK1 receptor antagonist restored the food intake of infected mice to a significant degree. Furthermore, suppression of food intake was completely abolished in the absence of CD4+ T lymphocytes or IL-4Ralpha. The data show for the first time that intestinal inflammation results in reduced food intake due to upregulation of CCK. Moreover, following infection, food intake and CCK expressing cells are under the specific control of CD4+ T-cells, via release of IL-4 and IL-13.


Screening for bipolar disorder.
Bipolar disorder is a recurrent and sometimes chronic illness involving episodes of depression and mania or hypomania. The most frequent presentation is depression: more than 1 of 5 primary care patients with depression have bipolar disorder. The symptoms of bipolar depression often differ from those of unipolar depression. Age of onset for bipolar disorder is usually the late teens; slightly older for bipolar II subtype. Nearly all patients with bipolar disorder suffer from a comorbid psychiatric disorder, most frequently an anxiety disorder. Although the most dramatic presentation of bipolar disorder is the acutely manic patient who presents to the emergency department, this presentation is much less frequently encountered in physicians' offices, both primary care and psychiatric. Bipolarity is often missed in these situations. About half of bipolar patients have consulted 3 or more professionals before receiving a correct diagnosis, and the average time to first treatment is 10 years. It is imperative that clinicians carefully assess patients for bipolar disorder, especially those presenting with depression. In addition to patient and family history, administration of a screening instrument can be very helpful. The most widely used screening tool is the Mood Disorder Questionnaire. This screening tool will be discussed in this article regarding its use in outpatient clinics and the community.


X-ray Structures of the Sun during the Importance 1N Flare of 8 June 1968.
High-resolution solar x-ray images were obtained with a rocket-borne grazing incidence telescope. The x-ray flare is large in extent, has fine strulctuire, and follows a neutral magnetic line. X-ray emitting coronal links interconnect active regions. The general coronal emission at the limb and several faint regions on the disc are observed.


Pharmacologic action of oseltamivir on the nervous system.
Oseltamivir, an antiviral drug used for the treatment of influenza, contains the L-glutamic acid motif in its chemical structure. We focused on this structural characteristic of oseltamivir and examined the pharmacologic effects of the drug on the nervous system in invertebrate and vertebrate animal models. Injection of oseltamivir or L-glutamic acid into silkworm (Bombyx mori) larvae induced muscle relaxation. Oseltamivir and L-glutamic acid inhibited kainate-induced rapid muscle contraction, but neither drug affected insect cytokine paralytic peptide-induced slow muscle contraction. In the mammalian system, mice (Mus musculus) treated intracerebrally with oseltamivir developed convulsive seizures. Hydrolyzed oseltamivir, the active form containing a carboxylic acid, evoked epileptiform firing of hippocampal neurons in rat (Rattus norvegicus) organotypic hippocampal slice cultures. These results are the first to demonstrate that oseltamivir exerts pharmacologic effects on the nervous system in insects and mammals.


Technology for assessment and treatment of justice-involved youth: A systematic literature review.
We conducted a systematic literature review of e-mental health technologies in juvenile justice contexts. Our exploratory research questions were as follows: First, what types of e-mental health exist for justice-involved youth, their caregivers, and juvenile justice professionals? Second, what are the characteristics of studies that have examined these technologies? Third, what have studies found about the effectiveness, reliability, or validity of e-mental health in treating and assessing juvenile justice populations? And fourth, what advantages and disadvantages exist for e-mental health use in juvenile justice? We screened 759 articles and retained 36 for review. We included articles that investigated e-mental health for the assessment or treatment of justice-involved youth and their caregivers. We excluded technologies not directly related to assessment or treatment as well as samples of at-risk youth with no justice involvement. We identified four types of e-mental health technologies: Interventions with technology-facilitated interpersonal communication (e.g., telehealth and mHealth), digitized intervention programs, simulation games, and computerized assessments. Most study designs were experimental/quasi-experimental or qualitative/descriptive, followed closely by repeated measures/pretest-posttest. A majority of evidence suggested that e-mental health technologies were potentially effective or valid for treatment and assessment, especially telehealth. Advantages included positive opinions of users, increased access to care, and efficiency; disadvantages included barriers to accessing technology, privacy concerns, and lack of clear effectiveness, reliability, or validity data. Although the available evidence for e-mental health for juvenile justice is promising, the current literature base appears generally underdeveloped and nuanced. Worthwhile future directions include continued development of technologies and more rigorously conducted studies to support further implementation of e-mental health for juvenile justice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Physical Activity, Sport Participation, and Perceived Barriers to Engagement in First-Year Canadian University Students.
Background: Physical activity (PA) declines during early adulthood with higher rates of inactivity in university students. The authors aimed to examine the frequency, intensity, time, type of PA, and the barriers to PA participation in Canadian students during the first year of university. Methods: Questionnaires assessing PA variables were administered to 301 first-year students at the beginning and end of the academic year. Results: PA decreased over a year. Males engaged in more vigorous activity minutes, more strength training, and more organized sports than females (P < .05). Females participated in more fitness activities than males (P < .05). Intramural (noncompetitive and school organized) sport participation remained constant throughout the year. Significant intrapersonal barriers to PA engagement included stress and perceived self-skill; significant interpersonal barriers included lack of friends and peer influence; and significant structural barriers included homework, class schedule, and overcrowded facilities. Conclusion: PA and sport participation declined, and some differences existed between the sexes. Focus should be placed on reducing the barriers that students' experience that may impact their PA. Interventions/programming to promote different aspects of PA should focus on noncompetitive sport and recreation activities, as well as activities that students can do on their own time. Ensuring the availability of adequate campus facilities is also important.


Immunoglobulin A nephropathy. Quantitative immunohistomorphometry of the tonsillar plasma cells evidences an inversion of the immunoglobulin A versus immunoglobulin G secreting cell balance.
Primary IgA nephropathy (Berger's disease) is characterized by renal deposits of IgA, the origin of which is still unknown. However, several clinical and biological findings suggest that these immunoglobulins might have a mucosal origin, and that such patients should present mucosal abnormalities. This paper reports the results of the immunohistomorphometrical analysis of tonsillar plasma cells from seven patients suffering from Berger's disease and seven controls also with recurrent tonsillitis. IgG, IgA, and IgM-secreting cells were enumerated after immunofluorescent staining of serial frozen-cut sections from 20 tonsils. In controls, a predominance of the IgG-secreting population, similar to this reported in the literature was observed (65% of IgG secreting cells and 29% of IgA plasma cells), while an inversion in the patients' plasma cells percentages was evidenced (IgG:37%, IgA:56%). This increment in the IgA population was paralleled by an augmentation of the number of dimeric IgA-secreting cells (75% of IgA plasma cells), stained both for cytoplasmic IgA and J chain. In controls, the latter cells were in similar proportions as previously reported by others (45% of IgA plasma cells). These results demonstrate an imbalance in the IgA-producing system of patients with Berger's disease, which is in keeping with the hypothesis favoring a mucosal origin for the mesangial IgA present in their kidneys.


Emotional and biological stress measures in Katrina survivors relocated to Oklahoma.
The authors assessed relocated Hurricane Katrina survivors' emotional and biological stress measures 20 months postdisaster to understand effects of both hurricane exposure and forced relocation on emotional and physical health. Psychiatric diagnoses, post-traumatic stress disorder (PTSD) and depressive symptoms, and biological stress measures were compared for total survivor and control groups and subgroups by PTSD diagnoses and lifetime trauma. Outpatient university psychiatry clinics in Oklahoma City and Tulsa. Thirty-four healthy adult Katrina survivors relocated to Oklahoma, and 34 healthy, demographically matched Oklahoma comparison participants. Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, assessed Axis I psychiatric disorders. Clinician-Administered PTSD Scale and Beck Depression Inventory quantified PTSD and depression symptoms. Biological stress measures were physiologic reactivity (heart rate and blood pressure responses to a trauma interview), interleukin-2 (IL-2; cell-mediated immunity), and interleukin-6 (IL-6; proinflammatory cytokine). Both groups had high lifetime trauma exposure. Among survivors, current hurricane-related and predisaster PTSD were diagnosed in 35.3 and 11.8 percent. Controls had current (11.8 percent) and lifetime (14.7 percent) PTSD. Survivors' PTSD and depression symptom levels were higher than controls and within illness ranges. The survivors had higher IL-6 than nontraumatized controls, higher IL-6 in the presence of PTSD, and higher baseline heart rates and mean arterial blood pressure reactivity than controls. Higher IL-6 and autonomic measures for several Katrina survivor subgroups than control subgroups may confer future cardiovascular risks. The results are discussed relative to increased myocardial infarct rates in New Orleans after Katrina. Even healthy survivors should be assessed for cardiovascular risks and mental health sequelae.


Experimental Validation of a Fundamental Model for PCR Efficiency.
Recently a theoretical analysis of PCR efficiency has been published by Booth et al., (2010). The PCR yield is the product of three efficiencies: (i) the annealing efficiency is the fraction of templates that form binary complexes with primers during annealing, (ii)the polymerase binding efficiency is the fraction of binary complexes that bind to polymerase to form ternary complexes and (iii)the elongation efficiency is the fraction of ternary complexes that extend fully. Yield is controlled by the smallest of the three efficiencies and control could shift from one type of efficiency to another over the course of a PCR experiment. Experiments have been designed that are specifically controlled by each one of the efficiencies and the results are consistent with the mathematical model. The experimental data has also been used to quantify six key parameters of the theoretical model. An important application of the fully characterized model is to calculate initial template concentration from real-time PCR data. Given the PCR protocol, the midpoint cycle number (where the template concentration is half that of the final concentration) can be theoretically determined and graphed for a variety of initial DNA concentrations. Real-time results can be used to calculate the midpoint cycle number and consequently the initial DNA concentration, using this graph. The application becomes particularly simple if a conservative PCR protocol is followed where only the annealing efficiency is controlling.


New insights in diagnostics and therapies in syncope: a novel approach to non-cardiac syncope.
This article aims to give advice on how to identify and manage patients with syncope who are at risk of severe outcomes, that is, at risk of trauma, potentially life-threatening episodes or frequent recurrences reducing quality of life. The first step of syncope diagnostic assessment is to identify patients with cardiac syncope, and once established, these patients must receive the adequate mechanism-specific treatment. If cardiac syncope is unlikely, reflex (neurally mediated) syncope and orthostatic hypotension are the most frequent causes of transient loss of consciousness. For these presentations, efficacy of therapy is largely determined by the mechanism of syncope rather than its aetiology or clinical features. The identified mechanism of syncope should be carefully assessed and assigned either to hypotensive or bradycardic phenotype, which will determine the choice of therapy (counteracting hypotension or counteracting bradycardia). The results of recent trials indicate that 'mechanism-specific therapy' is highly effective in preventing recurrences. Established mechanism-specific treatment strategies include withdrawal of hypotensive drugs, applying fludrocortisone and midodrine for the hypotensive phenotype and cardiac pacing in the bradycardic phenotype.


Multivitamins in the prevention of cancer in men: the Physicians' Health Study II randomized controlled trial.
Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality. To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men. A large-scale, randomized, double-blind, placebo controlled trial (Physicians" Health Study II) of 14 641 male US physicians initially aged 50 years or older (mean [SD] age, 64.3 [9.2] years), including 1312 men with a history of cancer at randomization, enrolled in a common multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011. Daily multivitamin or placebo. Total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points. During a median (interquartile range) follow-up of 11.2 (10.7-13.3) years, there were 2669 men with confirmed cancer, including 1373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (multivitamin and placebo groups, 17.0 and 18.3 events, respectively, per 1000 person-years; hazard ratio [HR], 0.92; 95% CI, 0.86-0.998; P=.04). There was no significant effect of a daily multivitamin on prostate cancer (multivitamin and placebo groups, 9.1 and 9.2 events, respectively, per 1000 person-years; HR, 0.98; 95% CI, 0.88-1.09; P=.76), colorectal cancer (multivitamin and placebo groups, 1.2 and 1.4 events, respectively, per 1000 person-years; HR, 0.89; 95% CI, 0.68-1.17; P=.39), or other site-specific cancers. There was no significant difference in the risk of cancer mortality (multivitamin and placebo groups, 4.9 and 5.6 events, respectively, per 1000 person-years; HR, 0.88; 95% CI, 0.77-1.01; P=.07). Daily multivitamin use was associated with a reduction in total cancer among 1312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56-0.96; P=.02), but this did not differ significantly from that among 13 329 men initially without cancer (HR, 0.94; 95% CI, 0.87-1.02; P=.15; P for interaction=.07). Conclusion In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer. clinicaltrials.gov Identifier: NCT00270647.


Long non-coding RNAs in neurodevelopmental disorders.
Recent studies have emphasized an important role for long non-coding RNAs (lncRNA) in epigenetic regulation, development, and disease. Despite growing interest in lncRNAs, the mechanisms by which lncRNAs control cellular processes are still elusive. Improved understanding of these mechanisms is critical, because the majority of the mammalian genome is transcribed, in most cases resulting in non-coding RNA products. Recent studies have suggested the involvement of lncRNA in neurobehavioral and neurodevelopmental disorders, highlighting the functional importance of this subclass of brain-enriched RNAs. Impaired expression of lnRNAs has been implicated in several forms of intellectual disability disorders. However, the role of this family of RNAs in cognitive function is largely unknown. Here we provide an overview of recently identified mechanisms of neuronal development involving lncRNAs, and the consequences of lncRNA deregulation for neurodevelopmental disorders.


Ascorbate-induced oxidative stress mediates TRP channel activation and cytotoxicity in human etoposide-sensitive and -resistant retinoblastoma cells.
There are indications that pharmacological doses of ascorbate (Asc) used as an adjuvant improve the chemotherapeutic management of cancer. This favorable outcome stems from its cytotoxic effects due to prooxidative mechanisms. Since regulation of intracellular Ca2+ levels contributes to the maintenance of cell viability, we hypothesized that one of the effects of Asc includes disrupting regulation of intracellular Ca2+ homeostasis. Accordingly, we determined if Asc induced intracellular Ca2+ influx through activation of pertussis sensitive Gi/o-coupled GPCR which in turn activated transient receptor potential (TRP) channels in both etoposide-resistant and -sensitive retinoblastoma (WERI-Rb1) tumor cells. Ca2+ imaging, whole-cell patch-clamping, and quantitative real-time PCR (qRT-PCR) were performed in parallel with measurements of RB cell survival using Trypan Blue cell dye exclusion. TRPM7 gene expression levels were similar in both cell lines whereas TRPV1, TRPM2, TRPA1, TRPC5, TRPV4, and TRPM8 gene expression levels were downregulated in the etoposide-resistant WERI-Rb1 cells. In the presence of extracellular Ca2+, 1 mM Asc induced larger intracellular Ca2+ transients in the etoposide-resistant WERI-Rb1 than in their etoposide-sensitive counterpart. With either 100 µM CPZ, 500 µM La3+, 10 mM NAC, or 100 µM 2-APB, these Ca2+ transients were markedly diminished. These inhibitors also had corresponding inhibitory effects on Asc-induced rises in whole-cell currents. Pertussis toxin (PTX) preincubation blocked rises in Ca2+ influx. Microscopic analyses showed that after 4 days of exposure to 1 mM Asc cell viability fell by nearly 100% in both RB cell lines. Taken together, one of the effects underlying oxidative mediated Asc-induced WERI-Rb1 cytotoxicity stems from its promotion of Gi/o coupled GPCR mediated increases in intracellular Ca2+ influx through TRP channels. Therefore, designing drugs targeting TRP channel modulation may be a viable approach to increase the efficacy of chemotherapeutic treatment of RB. Furthermore, Asc may be indicated as a possible supportive agent in anti-cancer therapies.


Involvement of caldesmon at the actin-myosin interface.
Addition of myosin subfragment 1 (S-1) to the actin-caldesmon binary complex, which forms bundles of actin filaments resulted in the formation of actin/caldesmon-decorated filaments [Harricane, Bonet-Kerrache, Cavadore & Mornet (1991) Eur. J. Biochem. 196, 219-224]. The present data provide further evidence that caldesmon and S-1 compete for a common actin-binding region and demonstrate that a change occurs in the actin-myosin interface induced by caldesmon. S-1 digested by trypsin, which has an actin affinity 100-fold weaker than that of native S-1, was efficiently removed from actin by caldesmon, but not completely dissociated. This particular ternary complex was stabilized by chemical cross-linking with carbodi-imide, which does not have any spacer arm, and revealed contact interfaces between the different protein components. Cross-linking experiments showed that the presence of caldesmon had no effect on stabilization of actin-(20 kDa domain), whereas the actin-(50 kDa domain) covalent association was significantly decreased, to the point of being virtually abolished.


Detection of rectal antibodies to HIV-1 by a sensitive chemiluminescent western blot immunodetection method.
Western blot with a time-dependent enhanced chemiluminescence immunodetection method (ECL-WB) was shown to be 100-fold more sensitive than standard commercial colorimetric Western blots (WB) for detecting serum IgG to human immunodeficiency virus type 1 (HIV-1). ECL-WB was then used to test rectal secretions from 15 HIV-1 infected subjects (HIV+) and 7 uninfected subjects (HIV-) to document local IgG, IgA, and secretory component-associated immunoglobulin (SC-Ig) to HIV-1 proteins. Fourteen of 15 HIV+ subjects had rectal IgA to at least 1 HIV-1 protein, most often to gp41 (80%) or p24 (60%) and 14 (93%) had IgG to gp160, gp120, or gp41. Of seven HIV- subjects, none had detectable bands to HIV-1 proteins. SC-Ig to HIV-1 proteins was detected in all five rectal samples tested. However, the antibody profiles differed from those of rectal IgA, suggesting more than one source of rectal IgA to HIV. ECL-WB requires individual optimization and interpretation for each specimen as well as expensive reagents and is, therefore, not currently applicable to screening assays. However, the method offers promise as a sensitive method to characterize low-level immune responses (IgG, IgA, and SC-Ig) to HIV-1 proteins at local sites such as rectal mucosae.


Raman imaging of carious lesions using a hollow optical fiber probe.
Raman spectroscopy using a hollow optical fiber probe with a glass ball lens at the distal end is proposed for detection of early caries lesions. Raman spectroscopy on carious lesions of extracted teeth showed that the probe enables measurement with a high signal-to-noise ratio when combined with a ball lens with a high refractive index. The proposed probe and lens combination detects changes in Raman spectra caused by morphological differences between sound and carious enamel. We also obtained a high-contrast image of an early carious lesion by scanning the tooth surface with the probe.


Flexible cognitive strategies during motor learning.
Visuomotor rotation tasks have proven to be a powerful tool to study adaptation of the motor system. While adaptation in such tasks is seemingly automatic and incremental, participants may gain knowledge of the perturbation and invoke a compensatory strategy. When provided with an explicit strategy to counteract a rotation, participants are initially very accurate, even without on-line feedback. Surprisingly, with further testing, the angle of their reaching movements drifts in the direction of the strategy, producing an increase in endpoint errors. This drift is attributed to the gradual adaptation of an internal model that operates independently from the strategy, even at the cost of task accuracy. Here we identify constraints that influence this process, allowing us to explore models of the interaction between strategic and implicit changes during visuomotor adaptation. When the adaptation phase was extended, participants eventually modified their strategy to offset the rise in endpoint errors. Moreover, when we removed visual markers that provided external landmarks to support a strategy, the degree of drift was sharply attenuated. These effects are accounted for by a setpoint state-space model in which a strategy is flexibly adjusted to offset performance errors arising from the implicit adaptation of an internal model. More generally, these results suggest that strategic processes may operate in many studies of visuomotor adaptation, with participants arriving at a synergy between a strategic plan and the effects of sensorimotor adaptation.


Genomic analysis of organismal complexity in the multicellular green alga Volvox carteri.
The multicellular green alga Volvox carteri and its morphologically diverse close relatives (the volvocine algae) are well suited for the investigation of the evolution of multicellularity and development. We sequenced the 138-mega-base pair genome of V. carteri and compared its approximately 14,500 predicted proteins to those of its unicellular relative Chlamydomonas reinhardtii. Despite fundamental differences in organismal complexity and life history, the two species have similar protein-coding potentials and few species-specific protein-coding gene predictions. Volvox is enriched in volvocine-algal-specific proteins, including those associated with an expanded and highly compartmentalized extracellular matrix. Our analysis shows that increases in organismal complexity can be associated with modifications of lineage-specific proteins rather than large-scale invention of protein-coding capacity.


Preanalytical stability of HIV-1 and HCV RNA: impact of storage and plasma separation from cells on blood donation testing by NAT.
The aim of this study was to evaluate the optimal preanalytical conditions prior to nucleic acid amplification technology (NAT) for human immunodeficiency virus-1 (HIV-1) or Hepatitis C virus (HCV) RNA in pools of 96 plasma specimens with regard to storage temperature, time and plasma separation in a blood donation environment. Changes in viral nucleic acid concentration of HIV-1 and HCV were observed for 5 days according to the Paul-Ehrlich-Institute's (PEI) guidelines that demand 95%-detection limit of at least 10 000 IU mL(-1) for HIV-1 RNA and 5000 IU mL(-1) for HCV RNA within a single donor blood specimen. Ninety-five per cent detection limits of HIV-1 RNA over 3 days after storage at either 5 or 21 °C were evaluated by using standardised HIV-1 RNA-positive plasma. HCV RNA in whole blood samples proved to be more stable than HIV-1 RNA. Whole blood storage at 21 °C was shown to decrease the detectability of HIV-1 RNA even after only 18 h. Plasma samples once used for NAT at time 18 h did not alter viral stability up to 48 h after donation. Ninety-five per cent detection limits of HIV-1 RNA were securely below 10 000 IU mL(-1) for 24 h after whole blood storage at 5 °C. These results may lead to a discussion around the most suitable preanalytical conditions in blood donation environments. Contrary to the current PEI guidelines that allow storage of whole blood specimens up to 18 h at 21 °C, these results suggest that immediate storage in a 5 °C container after blood donation is more suitable and would permit storage of whole blood up to 24 h prior to the separation of plasma from cells.


Primary care, economic barriers to health care, and use of colorectal cancer screening tests among Medicare enrollees over time.
Colorectal cancer (CRC) screening remains underutilized. The objective of this study was to examine the impact of primary care and economic barriers to health care on CRC testing relative to the 2001 Medicare expansion of screening coverage. Medicare Current Beneficiary Survey data were use to study community-dwelling enrollees aged 65 to 80 years, free of renal disease and CRC, and who participated in the survey in 2000 (n = 8,330), 2003 (n = 7,889), or 2005 (n = 7,614). Three outcomes were examined: colonoscopy/sigmoidoscopy within 5 years (recent endoscopy), endoscopy more than 5 years previously, and fecal occult blood test (FOBT) within 2 years. Endoscopy use increased and FOBT use decreased during the 6-year period, with no significant independent differences between those receiving care from primary care physicians and those receiving care from other physicians. Beneficiaries without a usual place of health care were the least likely to undergo CRC testing, and that gap widened with time: adjusted odds ratio (AOR) = 0.27 (95% confidence interval [CI], 0.19-0.39) for FOBT, and AOR = 0.35 (95% CI, 0.27-0.46) for endoscopy in 2000 compared with AOR = 0.18 (95% CI, 0.11-0.30) for FOBT and AOR = 0.22 (95% CI, 0.17-0.30) for endoscopy in 2005. Disparities in use of recent endoscopy by type of health insurance coverage in both 2000 and 2005 were greater for enrollees with a high school education or higher than they were for less-educated enrollees. There were no statistically significant differences by delayed care due to cost after adjustment for health insurance. Despite expanding coverage for screening, complex CRC screening disparities persisted based on differences in the usual place and cost of health care, type of health insurance coverage, and level of education.


Thromboembolic complications in atrial fibrillation.
I review the present understanding of thromboembolic complications and their prevention in patients with nonrheumatic atrial fibrillation. Chronic atrial fibrillation carries an annual 3-6% risk of thromboembolic complications, which is 5-7 times greater than that of controls with sinus rhythm. Paroxysmal atrial fibrillation is associated with a lower risk of thromboembolic complications than chronic atrial fibrillation. Heart failure and systemic hypertension seem to be significant clinical risk factors for stroke in patients with atrial fibrillation, but disagreement persists, and, with few exceptions, subgroups at particular risk have not been convincingly identified. The risk of stroke in persons with thyrotoxic atrial fibrillation seems to be lower than believed previously. Clinical studies have shown that left atrial dilatation is a consequence of the duration of atrial fibrillation rather than a cause, but the relation of left atrial enlargement to stroke is uncertain. Cerebral blood flow may be reduced during atrial fibrillation but seems to increase after cardioversion to sinus rhythm. A high prevalence of silent cerebral infarction has been detected in patients with chronic atrial fibrillation, but there seems to be a low risk of silent cerebral infarction in persons with paroxysmal atrial fibrillation. The one prospective study published to date on stroke prevention in patients with nonrheumatic chronic atrial fibrillation showed that anticoagulation with warfarin significantly reduced the incidence of thromboembolic complications.


Tunable Single-Cell Extraction for Molecular Analyses.
Because of cellular heterogeneity, the analysis of endogenous molecules from single cells is of significant interest and has major implications. While micromanipulation or cell sorting followed by cell lysis is already used for subsequent molecular examinations, approaches to directly extract the content of living cells remain a challenging but promising alternative to achieving non-destructive sampling and cell-context preservation. Here, we demonstrate the quantitative extraction from single cells with spatiotemporal control using fluidic force microscopy. We further present a comprehensive analysis of the soluble molecules withdrawn from the cytoplasm or the nucleus, including the detection of enzyme activities and transcript abundances. This approach has uncovered the ability of cells to withstand extraction of up to several picoliters and opens opportunities to study cellular dynamics and cell-cell communication under physiological conditions at the single-cell level.


High prevalence of antithyroid peroxidase and antiparietal cell antibodies among patients with type 1 diabetes mellitus attending a tertiary diabetes centre in South Africa.
Data on the prevalence of autoimmune thyroid disease (AITD) and gastric autoimmunity in type 1 diabetes mellitus (T1DM) in Africa are limited. The aim of this study was to assess the prevalence of antithyroid peroxidase (TPO-A) and antiparietal cell antibody (PCA) in patients with T1DM at a tertiary diabetes clinic in Durban, South Africa. This was a cross-sectional observational study among subjects attending the adult T1DM clinic at Inkosi Albert Luthuli Hospital. Information about history and clinical examination was collected. Blood tests included glutamic acid decarboxylase antibody (GADA), TPO-A, PCA, vitamin B12, folate, ferritin, thyroid stimulating hormone (TSH), free thyroxine, lipids and HbA1c. A total of 202 (M:F, 90:112) patients were recruited. The ethnic composition was African (black) (56.4%; n=114), Indian (31.7%; n=64), white (4.5%; n=9) and coloured (mixed race) (7.4%; n=15). Mean age and mean duration of diabetes were 26.4±11.4 and 10.7±9.1 years, respectively. Mean body mass index was 21.6±6.3 kg/m2. GADA was positive in 63.37% (n=128). The prevalence of TPO-A was 18.9% (n=39) and PCA 8.9% (n=17). The prevalence of overt hypothyroidism, subclinical hypothyroidism and Graves' disease was 10.9%, 2.5% and 1.5%, respectively; vitamin B12 deficiency was noted in 3.5% (n=7) and iron deficiency in 19.3% (n=39). Among patients with T1DM in this study, there was a high prevalence of coexistent AITD and gastric autoimmunity. Screening for hypothyroidism and thyroid autoimmunity should be undertaken in all patients at initial presentation. However, to assess the feasibility and optimal timing of subsequent testing in the African setting with limited resources, more collaborative research with longitudinal studies is required.


The Contribution of Multiparametric Pelvic and Whole-Body MRI to Interpretation of 18F-Fluoromethylcholine or 68Ga-HBED-CC PSMA-11 PET/CT in Patients with Biochemical Failure After Radical Prostatectomy.
Our purpose was to assess whether the addition of data from multiparametric pelvic MRI (mpMR) and whole-body MRI (wbMR) to the interpretation of 18F-fluoromethylcholine (18F-FCH) or 68Ga-HBED-CC PSMA-11 (68Ga-PSMA) PET/CT (=PET) improves the detection of local tumor recurrence or of nodal and distant metastases in patients after radical prostatectomy with biochemical failure. Methods: The current analysis was performed as part of a prospective, multicenter trial on 18F-FCH or 68Ga-PSMA PET, mpMR, and wbMR. Eligible men had an elevated level of prostate-specific antigen (PSA) (>0.2 ng/mL) and high-risk features (Gleason score > 7, PSA doubling time < 10 mo, or PSA > 1.0 ng/mL) with negative or equivocal conventional imaging results. PET was interpreted with mpMR and wbMR in consensus by 2 radiologists and compared with prospective interpretation of PET or MRI alone. Performance measures of each modality (PET, MRI, and PET/mpMR-wbMR) were compared for each radiotracer and each individual patient (for 18F-FCH, or 68Ga-PSMA for patients who had 68Ga-PSMA PET) and to a composite reference standard. Results: There were 86 patients with PET (18F-FCH [n = 76] and/or 68Ga-PSMA [n = 26]) who had mpMR and wbMR. Local tumor recurrence was detected in 20 of 76 (26.3%) on 18F-FCH PET/mpMR, versus 11 of 76 (14.5%) on 18F-FCH PET (P = 0.039), and in 11 of 26 (42.3%) on 68Ga-PSMA PET/mpMR, versus 6 of 26 (23.1%) on 68Ga-PSMA PET (P = 0.074). Per patient, PET/mpMR was more often positive for local tumor recurrence than PET (P = 0.039) or mpMR (P = 0.019). There were 20 of 86 patients (23.3%) with regional nodal metastases on both PET/wbMR and PET (P = 1.0) but only 12 of 86 (14%) on wbMR (P = 0.061). Similarly, there were more nonregional metastases detected on PET/wbMR than on PET (P = 0.683) or wbMR (P = 0.074), but these differences did not reach significance. Compared with the composite reference standard for the detection of disease beyond the prostatic fossa, PET/wbMR, PET, and wbMR had sensitivity of 50%, 50%, and 8.3%, respectively, and specificity of 97.1%, 97.1%, and 94.1%, respectively. Conclusion: Interpretation of PET/mpMR resulted in a higher detection rate for local tumor recurrence in the prostatic bed in men with biochemical failure after radical prostatectomy. However, the addition of wbMR to 18F-FCH or 68Ga-PSMA PET did not improve detection of regional or distant metastases.


Understanding the financial cost of robotic lobectomy: calculating the value of innovation?
The advantages of a minimally-invasive surgical approach compared to conventional open thoracotomy for lung resection have been previously described. While robot-assisted thoracoscopic surgery (RATS) has shown comparable clinical outcomes for lobectomy as compared with video-assisted thoracic surgery (VATS), the cost and inherent value associated with the robotic technology remains a main concern. We conducted a systematic review of the literature on the cost of RATS lobectomy using studies published prior to December 2017 on MEDLINE and EMBASE. Six observational studies met our inclusion criteria. Median cost of RATS lobectomy ranged from $15,440 to $22,582. Operating room (OR) cost was a major contributing factor to overall cost. The lowest per-procedure cost was reported by the highest volume center. Cost definitions were highly variable among studies. The total cost of RATS was similar or lower to open lobectomy, and higher than that of VATS, with cost difference ranging from $2,901 to $4,708. Assessment of cost for RATS lobectomy varies significantly. High OR costs may be offset by improved outcomes as compared with open lobectomy, but currently the costs exceed that of VATS lobectomy. Further work is needed to define the cost and actual value parameters for RATS lobectomy.


Radiofrequency treatment of vaginal laxity after vaginal delivery: nonsurgical vaginal tightening.
All women who have given birth vaginally experience stretching of their vaginal tissue. Long-term physical and psychological consequences may occur, including loss of sensation and sexual dissatisfaction. One significant issue is the laxity of the vaginal introitus. To evaluate safety and tolerability of nonsurgical radiofrequency (RF) thermal therapy for treatment of laxity of the vaginal introitus after vaginal delivery. We also explored the utility of self-report questionnaires in assessing subjective effectiveness of this device. Pilot study to treat 24 women (25-44 years) once using reverse gradient RF energy (75-90 joules/cm(2) ), delivered through the vaginal mucosa. Post-treatment assessments were at 10 days, 1, 3, and 6 months. Pelvic examinations and adverse event reports to assess safety. The author modified Female Sexual Function Index (mv-FSFI) and Female Sexual Distress Scale-Revised (FSDS-R), Vaginal Laxity and Sexual Satisfaction Questionnaires (designed for this study) to evaluate both safety and effectiveness, and the Global Response Assessment to assess treatment responses. No adverse events were reported; no topical anesthetics were required. Self-reported vaginal tightness improved in 67% of subjects at one month post-treatment; in 87% at 6 months (P<0.001). Mean sexual function scores improved: mv-FSFI total score before treatment was 27.6 ± 3.6, increasing to 32.0 ± 3.0 at 6 months (P < 0.001); FSDS-R score before treatment was 13.6 ± 8.7, declining to 4.3 ± 5.0 at month 6 post-treatment (P < 0.001). Twelve of 24 women who expressed diminished sexual satisfaction following their delivery; all reported sustained improvements on SSQ at 6 months after treatment (P = 0.002). The RF treatment was well tolerated and showed an excellent 6-month safety profile in this pilot study. Responses to the questionnaires suggest subjective improvement in self-reported vaginal tightness, sexual function and decreased sexual distress. These findings warrant further study.


Incidence of repeat procedures and healthcare utilization following surgery, radiosurgery, and percutaneous procedures in elderly patients with trigeminal neuralgia.
Management of trigeminal neuralgia (TN) in elderly patients poses significant challenges. The impact of different treatment modalities (surgery, radiosurgery [RS], and percutaneous techniques [PTs]) on healthcare utilization is not well defined in the management of TN in elderly patients. The aim of this study was to compare the long-term healthcare utilization metrics of different interventions in the management of elderly patients with TN. The MarketScan database was queried using the International Classification of Diseases, Ninth Revision and Current Procedural Terminology, from 2000 to 2016. TN patients ≥ 65 years of age managed using surgery, RS, and PTs with at least 5 years of follow-up after the index procedure were included. Outcomes analyzed were hospital admissions, outpatient services, and medication refills. Of 993 patients, 43% (n = 430) underwent RS, 44% (n = 432) had PTs, and only 13% (n = 131) underwent surgery for TN. Overall, the median age of patients was 74 years old, 64% were females, 90% had Medicare insurance, and 17% had an Elixhauser index ≥ 3. Patients in the surgery group were younger (median age 71 years) with a higher comorbidity index (≥ 3; 24%) compared with patients undergoing RS and PTs (13% and 17%, respectively). At 1, 2, and 5 years after the index procedure, 41%, 48%, and 57% of patients in the PT cohort underwent any repeat procedure compared with 11%, 18%, and 29% for the RS cohort, and 6%, 9%, and 11% for the surgical cohort, respectively. Also, patients in the PT cohort incurred 1.8, 1.9, and 2.0 times the combined payment at 1, 2, and 5 years, respectively, compared with the surgery cohort. Similarly, patients who underwent RS for TN incurred 1.4, 1.5, and 1.5 times the combined payment at 1, 2, and 5 years, respectively, compared with the surgery cohort. At 5 years after the index procedure, combined payments for the PT cohort were $79,753 (IQR $46,013, $144,064) compared with $61,016 (IQR $27,114, $117,097) for the RS cohort and $41,074 (IQR $25,392, $87,952) for the surgery cohort (p < 0.0001). PTs followed by RS were the common procedures used in the majority of elderly patients with TN. However, surgery for TN resulted in durable control with the least need for reoperations up to 5 years after the index procedure, followed by RS and PTs. PTs for TN resulted in the highest utilization of healthcare resources and need for reoperations at all time points. These findings should be considered in clinical decision-making when selecting appropriate treatment modalities in elderly patients with TN.


An elevated basal FSH reflects a quantitative rather than qualitative decline of the ovarian reserve.
Many cycling women with elevated basal FSH level have been discouraged from undergoing IVF treatment. This is because elevated basal FSH is associated with poorer assisted reproduction treatment outcome. It has been argued that high FSH reflects not only reduced ovarian reserve but also poor oocyte quality. The aim of this study is to assess the value of treating cycling women who have elevated basal FSH and to assess the reasons for the reduction in both pregnancy rate (PR) and live birth rate (LBR). Between January 1997 and December 2001, 2057 patients underwent 3401 consecutive IVF/ICSI cycles in which the basal level of FSH (days 2-4) was determined at an earlier cycle. Analysis, however, was only performed for a single cycle per patient. All cases were divided into four cohorts according to FSH levels: group A, FSH <10 IU/ml; group B, 10.1-15 IU/ml; group C, 15.1-20 IU/ml; and group D, FSH >20 IU/ml. Each group was stratified further into subgroups according to age, < or =38 and >38 years. Both PR (A, 32.3%; B, 19.8%; C, 17.5%; and D, 3%) and LBR (A, 24.7%; B, 13.2%; C, 13.8%; and D, 3%) were significantly reduced in the higher FSH level groups. LBR was significantly higher in the younger subgroups (A, 32.2%; B, 21.8%; C, 20%; and D, 16.7%) as compared with the older subgroups (A, 12.1%; B, 8.3%; C, 10.5%; and D, 0%). Higher levels of FSH were significantly associated with more cycle cancellation, a larger amount of gonadotrophin required to achieve follicular maturity, and a lower number of eggs collected, embryos available and embryos transferred. In all cases, however, there was no significant correlation between FSH levels and fertilization rate or miscarriage rate. Younger cycling women with elevated FSH had significantly higher LBR compared with older women with normal FSH (21.2% versus 12.1%). Furthermore, the cumulative LBR after three cycles in these younger patients with elevated FSH levels was 49.3%. Although there is a reduction in both PR and LBR associated with higher levels of basal FSH, it is clear that in cycling women, high basal FSH is not a contraindication to IVF treatment, and a respectable PR and LBR can be achieved especially in young women. The reduction in PR and LBR is due to reduced reserve rather than poor oocyte quality. Clinics refusing to treat cycling women with elevated basal FSH levels may be denying these women a reasonable, albeit low, chance of achieving a birth with their own genetic material. Clinicians should use basal FSH levels as a guide to advise patients about their chances of achieving a live birth, not to exclude patients with a predicted lower success rate from a treatment programme.


Increased oral sodium chloride intake in humans amplifies selectively postprandial GLP-1 but not GIP, CCK, and gastrin in plasma.
Human studies have demonstrated that physiologically relevant changes in circulating glucagon-like peptide-1 (GLP-1) elicit a rapid increase in renal sodium excretion when combined with expansion of the extracellular fluid volume. Other studies support the involvement of various gastrointestinal hormones, e.g., gastrin and cholecystokinin (CCK) in a gut-kidney axis, responsible for a rapid-acting feed-forward natriuretic mechanism. This study was designed to investigate the hypothesis that the postprandial GLP-1 plasma concentration is sensitive to the sodium content in the meal. Under fixed sodium intake for 4 days prior to each experimental day, 10 lean healthy male participants were examined twice in random order after a 12-hr fasting period. Arterial blood samples were collected at 10-20-min intervals for 140 min after 75 grams of oral glucose + 6 grams of oral sodium chloride (NaCl) load versus 75 grams of glucose alone. Twenty-four-hour baseline urinary sodium excretions were similar between study days. Arterial GLP-1 levels increased during both oral glucose loads and were significantly higher at the 40-80 min period during glucose + NaCl compared to glucose alone. The postprandial arterial responses of CCK, gastrin, and glucose-dependent insulinotropic polypeptide as well as glucose, insulin, and C-peptide did not differ between the two study days. Arterial renin, aldosterone, and natriuretic peptides levels did not change within subjects or between study days. Angiotensin II levels were significantly lower at the time GLP-1 was higher (60-80 min) during glucose + NaCl. Sodium intake in addition to a glucose load selectively amplifies the postprandial GLP-1 plasma concentration. Thus, GLP-1 may be part of an acute feed-forward mechanism for natriuresis.


Pollutant loading from low-density residential neighborhoods in California.
This paper presents a comparison of pollutant load estimations for runoff from two geographically distinct residential suburban neighborhoods in northern and southern California. The two neighborhoods represent a single urban land use type: low-density residential in small catchments (<0.3 km2) under differing regional climates and irrigation practices. Pollutant loads of pesticides, nutrients, and drinking water constituents of concern are estimated for both storm and non-storm runoff. From continuous flow monitoring, it was found that a daily cycle of persistent runoff that peaks mid-morning occurs at both sites. These load estimations indicate that many residential neighborhoods in California produce significant non-storm pollutant loads year-round. Results suggest that non-storm flow accounted for 47-69% of total annual runoff and significantly contributed to annual loading rates of most nutrients and pesticides at both sites. At the Southern California site, annual non-storm loads are 1.2-10 times higher than storm loads of all conventional constituents and nutrients with one exception (total suspended solids). At the Northern California site, annual storm loads range from 51 to 76% of total loads for all conventional constituents and nutrients with one exception (total dissolved solids). Non-storm yields of pesticides at the Southern California site range from 1.3-65 times higher than those at the Northern California site. The disparity in estimated pollutant loads between the two sites indicates large potential variation from site-to-site within the state and suggests neighborhoods in drier and milder climates may produce significantly larger non-storm loads due to persistent dry season runoff and year-round pest control.


Wastewater surveillance of antibiotic-resistant bacterial pathogens: A systematic review.
Infectious diseases caused by antibiotic-resistant bacterial (ARB) pathogens are a serious threat to human and animal health. The active surveillance of ARB using an integrated one-health approach can help to reduce the emergence and spread of ARB, reduce the associated economic impact, and guide antimicrobial stewardship programs. Wastewater surveillance (WWS) of ARB provides composite samples for a total population, with easy access to the mixed community microbiome. This concept is emerging rapidly, but the clinical utility, sensitivity, and uniformity of WWS of ARB remain poorly understood especially in relation to clinical evidence in sewershed communities. Here, we systematically searched the literature to identify studies that have compared findings from WWS of ARB and antibiotic resistance genes (ARG) with clinical evidence in parallel, thereby evaluating how likely WWS of ARB and ARG can relate to the clinical cases in communities. Initially, 2,235 articles were obtained using the primary search keywords, and 1,219 articles remained after de-duplication. Among these, 35 articles fulfilled the search criteria, and an additional 13 relevant articles were included by searching references in the primary literature. Among the 48 included papers, 34 studies used a culture-based method, followed by 11 metagenomics, and three PCR-based methods. A total of 28 out of 48 included studies were conducted at the single sewershed level, eight studies involved several countries, seven studies were conducted at national or regional scales, and five at hospital levels. Our review revealed that the performance of WWS of ARB pathogens has been evaluated more frequently for Escherichia coli, Enterococcus spp., and other members of the family Enterobacteriaceae, but has not been uniformly tested for all ARB pathogens. Many wastewater-based ARB studies comparing the findings with clinical evidence were conducted to evaluate the public health risk but not to relate with clinical evidence and to evaluate the performance of WWS of ARB. Indeed, relating WWS of ARB with clinical evidence in a sewershed is not straightforward, as the source of ARB in wastewater cannot be only from symptomatic human individuals but can also be from asymptomatic carriers as well as from animal sources. Further, the varying fates of each bacterial species and ARG within the sewerage make the aim of connecting WWS of ARB with clinical evidence more complicated. Therefore, future studies evaluating the performance of many AMR pathogens and their genes for WWS one by one can make the process simpler and the interpretation of results easier.


Assessment of potential asbestos exposures from jet engine overhaul work.
Asbestos fibers have been used in a wide variety of products and numerous studies have shown that exposures from the use or manipulation of these products can vary widely. Jet engines contained various components (gaskets, clamps, o-rings and insulation) that contained asbestos that potentially could release airborne fibers during routine maintenance or during an engine overhaul. To evaluate the potential exposures to aircraft mechanics, a Pratt & Whitney JT3D jet engine was obtained and overhauled by experienced mechanics using tools and work practices similar to those used since the time this engine was manufactured. This study has demonstrated that the disturbance of asbestos-containing gaskets, o-rings, and other types of asbestos-containing components, while performing overhaul work to a jet engine produces very few airborne fibers, and that virtually none of these aerosolized fibers is asbestos. The overhaul work was observed to be dirty and oily. The exposures to the mechanics and bystanders were several orders of magnitude below OSHA exposure regulations, both current and historic. The data presented underscore the lack of risk to the health of persons conducting this work and to other persons in proximity to it from airborne asbestos.


Dose-related effects of alcohol on cognitive functioning.
We assessed the suitability of six applied tests of cognitive functioning to provide a single marker for dose-related alcohol intoxication. Numerous studies have demonstrated that alcohol has a deleterious effect on specific areas of cognitive processing but few have compared the effects of alcohol across a wide range of different cognitive processes. Adult participants (N = 56, 32 males, 24 females aged 18-45 years) were randomized to control or alcohol treatments within a mixed design experiment involving multiple-dosages at approximately one hour intervals (attained mean blood alcohol concentrations (BACs) of 0.00, 0.048, 0.082 and 0.10%), employing a battery of six psychometric tests; the Useful Field of View test (UFOV; processing speed together with directed attention); the Self-Ordered Pointing Task (SOPT; working memory); Inspection Time (IT; speed of processing independent from motor responding); the Traveling Salesperson Problem (TSP; strategic optimization); the Sustained Attention to Response Task (SART; vigilance, response inhibition and psychomotor function); and the Trail-Making Test (TMT; cognitive flexibility and psychomotor function). Results demonstrated that impairment is not uniform across different domains of cognitive processing and that both the size of the alcohol effect and the magnitude of effect change across different dose levels are quantitatively different for different cognitive processes. Only IT met the criteria for a marker for wide-spread application: reliable dose-related decline in a basic process as a function of rising BAC level and easy to use non-invasive task properties.