Age grading Anopheles arabiensis: their gorging and surviving responses using a membrane feeding system.
Literature on artificial membrane feeding has traditionally supported the notion that mosquitoes have to be enough old to present a high gorging rate and enough young to present a high surviving rate. In order to know the best mosquito age to perform a Plasmodium sp. experimental infection revealed by oocyst examination, Anopheles arabiensis of known ages were fed on baudruche membrane with fresh human blood thermostated at 37 degrees C. The response was evaluated in term of gorging after ten minutes in contact with the membrane feeder and, for engorged females, in term of survival eight days after the engorgement. Two strains of mosquitoes were used, one wild, collected at larval stages in the city of Dakar and the other, originating from the same place but reared in our insectary since three years. The two strains showed their highest gorging rate at 3-4 days after emergence (39.4% for the wild strain and 63.3% for the insectary strain). The survival rate of the wild strain was highest at 2-3-4 days after emergence (64.8%) and those of the insectary strain at four days (65.6%). In conclusion, the gorging mosquitoes would have to be aged of 3-4 days after emergence for the wild strain and of four days for the insectary strain in order to obtain eight days after the engorging the best output of fed and surviving mosquitoes.


Predicting the development of diabetic nephropathy and its progression.
Diabetes remains the number one cause of end-stage renal disease worldwide. Only about one third of diabetic patients develop nephropathy, and the risk appears to be, in part, genetically determined. In this article, we review clinical and genetic markers for the development and progression of diabetic nephropathy. Microalbuminuria remains the best available predictor of the subsequent development of nephropathy, even though in recent years it has become clear that less than 50% of individuals with type 1 diabetes progress to overt proteinuria over a period of less than 10 years. It is of great interest for early recognition of risk of nephropathy that small elevations in nighttime blood pressure predict microalbuminuria in type 1 diabetes. Genetic markers for diabetic nephropathy have not been conclusively identified. The occurrence of renal events in diabetic patients, however, appears to be influenced by the angiotensin-converting enzyme (ACE) genotype, with a dominant deleterious effect of the D allele (D/D or I/D) versus I/I genotype. Some patients with the DD genotype also appear less susceptible to the renoprotective effects of conventional doses of ACE inhibitors, suggesting that ACE genotyping might be useful in selecting those patients that could benefit from higher doses of ACE inhibitors and more aggressive treatment to prevent or delay disease progression.


A fluctuation analysis of the rate of reexpression of the metastatic potential in a nonmetastatic mutant of the MDAY-D2 murine tumor.
A fluctuation analysis was performed on cell populations of a nonmetastatic, wheat germ agglutinin-resistant mutant (MDW4-1) of the murine MDAY-D2 tumor in order to determine the spontaneous frequency of occurrence of metastatic revertants during in vitro proliferation. A number of clones derived from the MDW4-1 mass culture were expanded in vitro and equal samples were inoculated intravenously into groups of DBA/2 mice. The number of metastatic cells present in each clonal population was estimated on the basis of the mean survival time per animal group, by making reference to a standard dose-response relationship. The final calculation indicated that metastatic cells arise randomly in vitro at a rate of 2 X 10(-5) cell per MDW4-1 cell per generation (upper estimate). The lower estimate of the rate reveals that only few metastatic revertants preexisted prior to inoculation when wheat germ agglutinin-sensitive cells are counterselected in the presence of the lectin. We conclude that the reexpression of the metastatic potential in the MDW4-1 tumor cell line may occur spontaneously, outside the host-selective environment, and may be linked to the loss of the wheat germ agglutinin-resistance phenotype.


Chronic idiopathic pseudo-obstructive bowel disease.
An illness characterized by recurrent episodes of small bowel obstruction is described. The patient, a 79-year old gentleman has been followed for 20 years. During this time he has hospitalized 19 times. Extensive investigation, including three exploratory laparotomies, have failed to show a cause of the bowel dysfunction. The clinical findings have been similar on each admission. Cramping abdominal pain, vomiting, obstipation often followed by diarrhea, tender distended abdomen, high pitched bowel sounds and abdominal x-rays revealed dilatation of small and large intestine and delayed gastric emptying on various admissions. The failure to demonstrate a recognized etiology for the repeated bowel obstruction over a long period of time warrants a clinical diagnosis of chronic idiopathic intestinal pseudo-obstruction (C.I.I.P.). The age of the patient at the onset of symptoms and the duration of the dysfunction prompted a review of the literature. Twenty-seven reported cases allowed a comparison of this case with the clinical features previously described. Symptomatic therapy, consisting of small bowel decompression by intestinal intubation during the acute episode, was followed by the use of elemental diets given slowly and continuously during the convalescing period. The patient continues to be comfortable and able to maintain his body weight between episodes which, however, seem to be increasing in frequency.


Mitochondrial DNA, a Powerful Tool to Decipher Ancient Human Civilization from Domestication to Music, and to Uncover Historical Murder Cases.
Mitochondria are unique organelles carrying their own genetic material, independent from that in the nucleus. This review will discuss the nature of mitochondrial DNA (mtDNA) and its levels in the cell, which are the key elements to consider when trying to achieve molecular identification in ancient and degraded samples. mtDNA sequence analysis has been appropriately validated and is a consistent molecular target for the examination of biological evidence encountered in forensic cases-and profiling, in certain conditions-especially for burnt bodies and degraded samples of all types. Exceptional cases and samples will be discussed in this review, such as mtDNA from leather in Beethoven's grand piano, mtDNA in mummies, and solving famous historical criminal cases. In addition, this review will be discussing the use of ancient mtDNA to understand past human diet, to trace historical civilizations and ancient trade routes, and to uncover geographical domestication origins and lineage relationships. In each topic, we will present the power of mtDNA and how, in many cases, no nuclear DNA was left, leaving mitochondrial DNA analysis as a powerful alternative. Exploring this powerful tool further will be extremely useful to modern science and researchers, due to its capabilities in providing us with previously unattainable knowledge.


Influences of diet and vaccination on colonisation of pigs by the intestinal spirochaete Brachyspira (Serpulina) pilosicoli.
The purpose of this study was to determine whether methods used to control swine dysentery (SD), caused by the intestinal spirochaete Brachyspira (Serpulina) hyodysenteriae, would also be effective in controlling porcine intestinal spirochaetosis (PIS) caused by the related spirochaete Brachyspira (Serpulina) pilosicoli. Weaner pigs in Groups I (n=8) and II (n=6) received a standard weaner pig diet based on wheat and lupins, whilst Group III (n=6) received an experimental diet based on cooked white rice and animal protein. Pigs in Group II were vaccinated intramuscularly twice at a 3-week-interval with a formalinised bacterin made from B. pilosicoli porcine strain 95/1000 resuspended in Freund's incomplete adjuvant. Eleven days later pigs in all groups were infected orally with 10(10) cells of strain 95/1000 on three successive days. One control pig in Group I developed acute diarrhoea, and at post-mortem had a severe erosive colitis with end-on attachment of spirochaetes to the colonic epithelium. All other pigs developed transient mild diarrhoea and had moderate patchy colitis at post-mortem 3 weeks later. B. pilosicoli was isolated from the faeces of all pigs, except for one fed rice, and was isolated from the mesenteric nodes of three pigs from Group I and from one vaccinated pig in Group II. Consumption of the rice-based diet, but not vaccination, delayed and significantly (p<0.001) reduced the onset of faecal excretion of B. pilosicoli after experimental challenge. Vaccination induced a primary and secondary serological response to B. pilosicoli, as measured using sonicated whole cells of strain 95/1000 as an ELISA plate coating antigen. Antibody titres in the vaccinated pigs then declined, despite intestinal colonisation by B. pilosicoli. Both groups of unvaccinated animals also failed to develop a post-infection increase in circulating antibody titres.


Achieving a unified clinical science requires a meta-theoretical solution: Comment on Melchert (2016).
Timothy Melchert's vision for a unified clinical science that transcends the specific theoretical orientations and is grounded in the science of human psychology is a laudable goal. However, his solution to achieve this goal via reliance on evolutionary theory, neuroscience, and empirically verifiable research findings is not sufficient. The way forward is to recognize that the field of psychology is fragmented and lacks a clear meta-theoretical perspective. Conceptual work is needed to develop such a perspective, which can then allow for clearly defining the field and effectively integrating and assimilating the key concepts from the various theoretical orientations into a coherent whole. (PsycINFO Database Record


Comparison of two recombinant systems for expression of cholera toxin B subunit from Vibrio cholerae.
The aim of this study was to assess the production of recombinant cholera toxin B subunit (rCTB) protein in two different expression systems (pAE_ctxB and pQE_ctxB constructs) in Escherichia coli BL21 (DE3). The ctxB fragment was amplified from Vibrio cholerae O 1 ATCC14035 and cloned in pGETM-T easy vector after which it was transformed to E. coli Top 10F' and grown on LB-ampicillin agar medium. Sequence analysis confirmed the complete ctxB gene sequence in the construct which was further subcloned to pQE-30 vector. The construct was subsequently transformed to E. coli M15 (pREP4). The recombinant pAE_ctxB and pQE_ctxB were transformed to competent E. coli BL21 (DE3) cells to express CTB protein. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed the maximum expression of rCTB in both systems at 5 h after induction and western blot analysis confirmed the presence of recombinant CTB in blotting membranes. Expression of rCTB in pAE_ctxB construct was more efficient (15-fold) than pQE_ctxB, and it seems that Lac UV5 in E. coli BL21 (DE3) is more compatible with the former construct. This expression system can be used to produce recombinant CTB in high yield which may enable us to study the oral tolerance or mucosal adjuvant properties of rCTB using animal models.


Targeted sequencing approach to identify genetic mutations in Nasu-Hakola disease.
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Premortem molecular diagnosis of NHD requires genetic analysis of both TYROBP and TREM2, in which 20 distinct NHD-causing mutations have been reported. Due to genetic heterogeneity, it is often difficult to identify the exact mutation responsible for NHD. Recently, the revolution of the next-generation sequencing (NGS) technology has greatly advanced the field of genome research. A targeted sequencing approach allows us to investigate a selected set of disease-causing genes and mutations in a number of samples within several days. By targeted sequencing using the TruSight One Sequencing Panel, we resequenced genetic mutations of seven NHD cases with known molecular diagnosis and two control subjects. We identified homozygous variants of TYROBP or TREM2 in all NHD cases, composed of a frameshift mutation of c.141delG in exon 3 of TYROBP in four cases, a missense mutation of c.2T>C in exon 1 of TYROBP in two cases, or a splicing mutation of c.482+2T>C in intron 3 of TREM2 in one case. The results of targeted resequencing corresponded to those of Sanger sequencing. In contrast, causative variants were not detected in control subjects. These results indicate that targeted sequencing is a useful approach to precisely identify genetic mutations responsible for NHD in a comprehensive manner.


Main results and clinical interpretations from the TRANSCEND study.
Angiotensin-converting enzyme (ACE) inhibitors are useful drugs for preventing cardiovascular disease and death in patients at risk. However, a significant proportion of patients experience side effects, mainly cough or less frequently angioedema, when treated with ACE inhibitors. Angiotensin receptor blockers (ARBs) are also useful drugs for treatment of hypertension, diabetic nephropathy and patients with left ventricular dysfunction or cardiac failure who are intolerant to ACE inhibitors. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) study examined the effect of a long-acting ARB, telmisartan, on cardiovascular events in a group of patients at high-risk for cardiovascular disease who were intolerant to ACE inhibitors. Five thousand nine hundred twenty-six patients with known intolerance to ACE inhibitors were randomized to telmisartan or placebo added to current treatments. The primary composite endpoint, a sum of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to heart failure was nonsignificantly reduced in telmisartan-treated patients with respect to placebo (15.7 vs. 17%; relative risk reduction 8%). The key secondary endpoint (the primary endpoint excluding heart failure hospitalization) was reduced in telmisartan-treated patients by 13% (13 vs. 14.8%; P = 0.046). In conclusion, telmisartan reduces cardiovascular events in high-risk patients with the exception of heart failure hospitalization and can be considered as the first-line therapy in those intolerant to ACE inhibitors.


[Female incontinence: problems with assessment of prevalence and severity].
Incontinence raises a problem of increasing relevance. Estimates of prevalence and severity are presented in a wide range. Valid assessment instruments are sparse or based on varying definitions. Therefore, existing data of incontinence rates are likely to be overestimated. To exemplify this problem, we reviewed epidemiological articles on female incontinence.


The monophyletic origin of freshwater crayfish estimated from nuclear and mitochondrial DNA sequences.
Despite their widespread use as model organisms, the phylogenetic status of the around 520 species of freshwater crayfish is still in doubt. One hypothesis suggests two distinct origins of freshwater crayfish as indicated by their geographical distribution, with two centres of origin near the two present centres of diversity; one in south-eastern United States and the other in Victoria, Australia. An alternative theory proposes a single (monophyletic) origin of freshwater crayfish. Here we use over 3000 nucleotides from three different gene regions in estimating phylogenetic relationships among freshwater crayfish and related Crustacea. We show clear evidence for monophyly of freshwater crayfish and for the sister-group relationship between crayfish and clawed lobsters. Monophyly of the superfamilies Astacoidea and Parastacoidea is also supported. However, the monophyly of the family Cambaridae is questioned with the genus Cambaroides being associated with the Astacidae.


[Cytogenetic study of thyroid patients treated with external irradiation or radioiodine].
Where clinically permitted, either external irradiation or radioiodine therapy is usually recommended for the treatment of differentiated thyroid cancer patients. This paper describes an attempt to clarify the radiation burden and the distribution of radiation doses on the lymphocytes in consequence of these two therapeutic modalities, and the circumstances of the applicability of biological dosimetry. Thyrotoxic patients with intact thyroid glands underwent 131I therapy were also analysed for this purpose. An analysis was made of the extent to which exposure to local neck irradiation (50 Gy) or radioiodine therapy (1734-2600 MBq) causes chromosomal aberrations in the lymphocytes of thyroid disease patients after total or subtotal thyroidectomy, or thyrotoxic patients with intact thyroid glands (185-595 MBq). The irradiated volume of lymphatic tissues played the most important role in the formation of chromosomal aberrations. External irradiation caused 10-times more aberrant cells than 131I therapy did in cancer patients. In thyrotoxic patients the lower therapy doses of radioiodine caused a significantly higher frequency of aberrations than that observed in thyroid cancer patients. Selective radiosensitivity of lymphocytes was supported by the analysis of the Poisson distribution of aberrations, which suggested a homogeneous dose distribution only in 131I-treated and thyroidectomized cancer patients. In conclusion, we suggest that the results of studies of the genetic alterations in the lymphocytes exposed to radioiodine, under well-defined circumstances should not be ignored before the mode of radiation treatment is chosen. On the other hand, in the modelling of accidental environmental radioiodine exposure, only thyrotoxic patients with an intact thyroid gland and heterogeneous dose-distribution are a suitable group.


Cancer drugs with high repositioning potential for Alzheimer's disease.
Despite the recent full FDA approval of lecanemab, there is currently no disease modifying therapy (DMT) that can efficiently slow down the progression of Alzheimer's disease (AD) in the general population. This statement emphasizes the need to identify novel DMTs in the shortest time possible to prevent a global epidemic of AD cases as the world population experiences an increase in lifespan. Here, we review several classes of anti-cancer drugs that have been or are being investigated in Phase II/III clinical trials for AD, including immunomodulatory drugs, RXR agonists, sex hormone therapies, tyrosine kinase inhibitors, and monoclonal antibodies. Given the overall course of brain pathologies during the progression of AD, we express a great enthusiasm for the repositioning of anti-cancer drugs as possible AD DMTs. We anticipate an increasing number of combinatorial therapy strategies to tackle AD symptoms and their underlying pathologies. However, we strongly encourage improvements in clinical trial study designs to better assess target engagement and possible efficacy over sufficient periods of drug exposure.


Sedative and cardiorespiratory effects of low doses of xylazine with and without acepromazine in Nordestino donkeys.
Information on appropriate protocols for sedation of Nordestino donkeys is scarce. To evaluate the sedative and cardiorespiratory effects of low doses of intravenous (i.v.) xylazine with and without acepromazine in 'Nordestino' donkeys. Seven healthy female Nordestino donkeys (150 ± 18 kg) were included in this blinded, randomised, crossover experiment. Four treatments were administered, consisting of two i.v. injections, at baseline (T0, 1st injection) and 15 min later (T15, 2nd injection). Treatments included acepromazine 0.05 mg/kg bwt + saline (AS), saline + xylazine 0.5 mg/kg bwt (SX0.5), acepromazine + xylazine 0.25 mg/kg bwt (AX0.25) or acepromazine + xylazine 0.5 mg/kg bwt (AX0.5). Sedative and cardiorespiratory parameters were evaluated before T0 and 15, 20, 30, 45, 60, 75 and 90 min after treatment. Degree [height of head above ground (HHAG)] and quality of sedation [ataxia, responses to stimuli and visual analogue scale (VAS) scoring] and respiratory rate were evaluated by the main investigator in situ, and heart rate was measured by an assistant investigator. Three experienced evaluators assessed vídeos for ataxia and responses to stimuli. Normal data were analysed by repeated measures ANOVA, and non-normal by Kruskal-Wallis (P<0.05). HHAG was lower than baseline for 15 min after xylazine administration in AX0.25 and for 30 min in SX0.5 and AX0.5 groups. All treatments with xylazine increased VAS and ataxia scores in situ for 15 min after xylazine administration, with no differences between groups. Ataxia scores in situ were higher in SX0.5 and AX0.5 groups than AS for 15 and 30 min after xylazine administration, respectively. Absence of a negative control group (saline-saline). Acepromazine added to xylazine at 0.25 mg/kg bwt produced briefer and milder sedation than xylazine at 0.5 mg/kg bwt.


Phylogenetic relationships of three Italian merino-derived sheep breeds evaluated through a complete mitogenome analysis.
In Italy, the crisis of the wool industry triggered the necessity to reconvert the two traditional Merino-derived breeds, Gentile di Puglia and Sopravissana, to meat production, by creating the Merinizzata Italiana. The aim of the present study was to assess the genetic diversity of these three Italian Merino-derived (IMd) breeds by examining the molecular information encoded in the maternally-inherited mitochondrial DNA (mtDNA). A parallel molecular investigation was performed on the putative paternal and maternal breeds, the Merino from Spain and the Appenninica from Italy, respectively, as well as on three unrelated dairy breeds (Sarda and Comisana from Italy, and Lacaune from France). Firstly, the mtDNA control region of 291 samples was analyzed. When comparing the overall genetic distances among the eight stocks, the three IMd breeds clustered together close to the Appenninica, thus confirming its parental role. Among the 90 IMd samples, 82 different haplotypes were observed, almost all belonging to haplogroup B, and only one to A. For 23 mtDNAs, including nine IMd, the analysis was then brought to the level of entire mitogenomes. Three distinct sub-haplogroups within B were found to encompass the IMd samples, with one clade (B1a2a1) apparently restricted to those sheep. Thus, despite experiencing a drastic reduction in number (mainly due to changes in breeding practices driven by the economy), the IMd breeds still represent a reservoir of distinctive mitochondrial variants, which could potentially contribute to the development of conservation and management programs of Italian sheep breeds.


Efficacy and safety of a hexanic extract of Serenoa repens (Permixon® ) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies.
To comprehensively evaluate the efficacy and safety of the hexanic extract of Serenoa repens (HESr, Permixon® ; Pierre Fabre Médicament, Castres, France), at a dose of 320 mg daily, as monotherapy for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective observational studies in patients with LUTS/BPH identified through searches in Medline, Web of Knowledge (Institute for Scientific Information), Scopus, the Cochrane Library, and bibliographic references up to March 2017. Articles studying S. repens extracts other than Permixon were excluded. Data were collected on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ), nocturia, quality of life, prostate volume, sexual function, and adverse drug reactions (ADRs). Data obtained from RCTs and observational studies were analysed jointly and separately using a random effects model. A sub-group analysis was performed of studies that included patients on longer-term treatment (≥1 year). Data from 27 studies (15 RCTs and 12 observational studies) were included for meta-analysis (total N = 5 800). Compared with placebo, the HESr was associated with 0.64 (95% confidence interval [CI] -0.98 to -0.31) fewer voids/night (P < 0.001) and an additional mean increase in Qmax of 2.75 mL/s (95% CI 0.57 to 4.93; P = 0.01). When compared with α-blockers, the HESr showed similar improvements on IPSS (weighted mean difference [WMD] 0.57, 95% CI -0.27 to 1.42; P = 0.18) and a comparable increase in Qmax to tamsulosin (WMD -0.02, 95% CI -0.71 to 0.66; P = 0.95). Efficacy assessed using the IPSS was similar after 6 months of treatment between the HESr and 5α-reductase inhibitors (5ARIs). Analysis of all available published data for the HESr showed a mean improvement in IPSS from baseline of -5.73 points (95% CI -6.91 to -4.54; P < 0.001). HESr did not negatively affect sexual function and no clinically relevant effect was observed on prostate-specific antigen. Prostate volume decreased slightly. Similar efficacy results were seen in patients treated for ≥1 year (n = 447). The HESr had a favourable safety profile, with gastrointestinal disorders being the most frequent ADR (mean incidence of 3.8%). The present meta-analysis, which includes all available RCTs and observational studies, shows that the HESr (Permixon) reduced nocturia and improved Qmax compared with placebo and had a similar efficacy to tamsulosin and short-term 5-ARI in relieving LUTS. HESr (Permixon) appears to be an efficacious and well-tolerated therapeutic option for the long-term medical treatment of LUTS/BPH.


The Trends in Utilizing Nonvitamin K Antagonist Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation: A Real-Life Experience.
Dabigatran and rivaroxaban are novel nonvitamin K antagonist oral anticoagulants (NOACs) approved for thromboprophylaxis in atrial fibrillation (AF). In Turkey, like other countries, the efficacy of translation of the clinical trial results and current guideline recommendations into daily clinical practice is yet to be discovered. Using data from medical records of three tertiary care cardiology centers, we identified patients with nonvalvular AF on dabigatran or rivaroxaban treatment. Baseline characteristics and utilization trends were compared between dabigatran and rivaroxaban groups. Secondarily, clinical events including ischemic stroke and/or transient ischemic attack, systemic embolism, and bleeding were evaluated. Among 294 patients with AF included, dabigatran was utilized in 177 (60.2%) and rivaroxaban in 117 (39.8%). Overall, 76% of patients had received long-term warfarin therapy. The use of 110 mg twice a day (55.4%) was the prevailing strategy in dabigatran group, whereas in rivaroxaban group 20 mg every day (67.5%) was the preferred option. Of the patients, 37.3% had severe valvular disease in which mitral regurgitation was the predominant valve abnormality. Scores of CHADS2, CHA2DS2VASc, and HAS-BLED were similar in both the groups. Of the patients, 24% in dabigatran group and 13.7% in rivaroxaban group were prescribed the lower dose inappropriately. The two NOACs did not differ significantly in terms of clinical events. The results of this study indicate that in daily practice, the physicians' behavior in utilizing the NOACs is shaped by the clinical trials and the guideline recommendations. On the other hand, in dose selection, this adherence is not of high quality.


Neferine alleviates P2X3 receptor in rat dorsal root ganglia mediated neuropathic pain.
Chronic neuropathic pain is caused by tissue damage or nervous system inflammation and is characterized by sensitivity to painful stimuli. P2X3 receptors play an important role in facilitating pain transmission. Neferine is a bisbenzylisoquinline alkaloid isolated from seed embryos of lotus, which has anti-inflammatory and anti-oxidation pharmacological functions. The present research investigated whether neferine relieves neuropathic pain related to the P2X3 receptor in rat dorsal root ganglia (DRGs). Chronic contraction injury (CCI) in rats was used as a model for neuropathic pain. The results indicated that the expression of P2X3 receptor was significantly increased in the DRGs of CCI rats and that mechanical allodynia and thermal hyperalgesia were also enhanced in CCI rats. Neferine markedly lowered the upregulated P2X3 receptor and interleukin-1beta, inhibited the phosphorylation and activation of ERK1/2 in the DRGs of CCI rats, and relieved neuropathic pain. Therefore, neferine alleviates neuropathic pain by downregulating the expression of P2X3 receptor.


Thyroid function and plasma cyclic AMP response to intravenous glucagon.
The glucagon stimulated increase in plasma cyclic AMP has been studied in 17 healthy subjects, in 13 hyperthyroid and in 14 hypothyroid patients. Six hyperthyroid and 2 hypothyroid patients were re-investigated after at least 15 months of treatment. The results show: 1) The glucagon stimulated cyclic AMP response is significantly increased in hyperthyroid patients considered as a group, and is reduced in patients with hypothyroidism. 2) Three hyperthyroid and 4 hypothyroid patients showed a normal response to iv glucagon, indicating that the plasma cyclic AMP response to iv glucagon is not a sensitive test for the evaluation of peripheral thyroid states. This suggests that the effects of thyroid hormones in the liver does not necessarily follow the effects in other tissues. 3) Re-investigation of treated patients showed that the cyclic AMP response can be normalized by treatment, both in hyperthyroidism and hypothyroidism. However, in patients treated for hyperthyroidism a hyper-response to glucagon can continue after blood levels of thyroid hormones are reduced to normal. This suggests an inertia in the loss of the hyper-response to glucagon, once a hyperfunction has been induced. A similar inertia in the loss of glucagon sensitivity in hypothyroidism could explain the large number of normal tests in hypothyroid patients.


The space shuttle program: a policy failure?
The 5 January 1972 announcement by President Richard Nixon that the United States would develop during the 1970's a new space transportation system-the space shuttle-has had fundamental impacts on the character of U.S. space activities. In retrospect, it can be argued that the shuttle design chosen was destined to fail to meet many of the policy objectives established for the system; the shuttle's problems in serving as the primary launch vehicle for the United States and in providing routine and cost-effective space transportation are in large part a result of the ways in which compromises were made in the 1971-72 period in order to gain White House and congressional approval to proceed with the program. The decision to develop a space shuttle is an example of a poor quality national commitment to a major technological undertaking.


DG Connect Funded Projects on Information and Communication Technologies (ICT) for Old Age People: Beyond Silos, CareWell and SmartCare.
Information and communication technologies (ICT) are promising for the long-term care of older and frequently frail people. These innovations can improve health outcomes, quality of life and efficiency of care processes, while supporting independent living. However, they may be disruptive innovations. As all European member states are facing an increasing complexity of health and social care, good practices in ICT should be identified and evaluated. Three projects funded by DG CNECT are related to Active and Healthy Ageing (AHA) and frailty: (i) BeyondSilos, dealing with independent living and integrated services, (ii) CareWell, providing integrated care coordination, patient empowerment and home support and (iii) SmartCare, proposing a common set of standard functional specifications for an ICT platform enabling the delivery of integrated care to older patients. The three projects described in this paper provide a unique pan-European research field to further study implementation efforts and outcomes of new technologies. Below, based on a description of the projects, the authors display four domains that are in their views fundamental for in-depth exploration of heterogeneity in the European context: 1. Definition of easily transferable, high level pathways with solid evidence-base; 2. Change management in implementing ICT enabled integrated care; 3. Evaluation and data collection methodologies based on existing experience with MAST and MEDAL methodologies; and 4. Construction of new models for delivery of health and social care. Understanding complementarity, synergies and differences between the three unique projects can help to identify a more effective roll out of best practices within a varying European context.


Chronic ethanol consumption prior to retrovirus infection alters cytokine production by thymocytes during murine AIDS.
Chronic ethanol (EtOH) consumption may be a cofactor in the development of acquired immune deficiency syndrome (AIDS). As the thymus is an unique site for T cell maturation, we investigated whether thymocytes from EtOH consuming mice were more predisposed to aberrant cytokine production due to retrovirus infection. Adult female C57BL/6 mice were fed 4.5% (v/v) in liquid diet or control liquid diet without EtOH for 10 weeks. All diets contained nutrients at only the recommended daily intake level for mice. Then all mice were infected LP-BM5 retrovirus and were fed control liquid diets without EtOH. The body and thymus weights were not affected by EtOH consumption. However, thymocyte number and proliferation, which had been reduced during murine AIDS, were significantly further reduced by EtOH use. The production of IL-2 and IL-6 by thymocytes, which was lessened during retrovirus infection, were significantly further suppressed by dietary EtOH at 6 weeks postinfection, whereas levels of IL-4 and IFN-gamma by thymocytes, which were elevated during retrovirus infection, were significantly and slightly further increased by EtOH-treated mice prior to retrovirus infection, respectively. These data suggest that dietary EtOH consumption can modulate cytokine production by thymocytes, adversely affecting T cell differentiation, especially during retrovirus infection. These results provide additional evidence that EtOH consumption should be a cofactor during development of AIDS via producing altered cytokine production and then disrupting T cell differentiation.


Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis.
To examine the association between mitochondrial mutagenesis and the proinflammatory microenvironment in patients with inflammatory arthritis. Fifty patients with inflammatory arthritis underwent arthroscopy and synovial tissue biopsies, synovial fluid and clinical assessment were obtained. Fifteen patients pre/post-TNFi therapy were also recruited. Normal synovial biopsies were obtained from 10 subjects undergoing interventional arthroscopy. Macroscopic synovitis/vascularity was measured by visual analogue scale. Cell-specific markers CD3 (T cells) and CD68 (macrophages) were quantified by immunohistology. TNFα, IL-6, IFNγ and IL-1β were measured in synovial fluids by MSD multiplex assays. Synovial tissue mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay (RMCA). The direct effect of TNFα on oxidative stress and mitochondrial function was assessed in primary cultures of rheumatoid arthritis synovial fibroblast cells (RASFCs). Mitochondrial mutagenesis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and mitochondrial mass (MM) were quantified using the RMCA and specific cell fluorescent probes. A significant increase in mtDNA mutation frequency was demonstrated in inflamed synovial tissue compared with control (p<0.05), an effect that was independent of age. mtDNA mutations positively correlated with macroscopic synovitis (r=0.52, p<0.016), vascularity (r=0.54, p<0.01) and with synovial fluid cytokine levels of TNFα (r=0.74, p<0.024) and IFNγ (r=0.72, p<0.039). mtDNA mutation frequency post-TNFi therapy was significantly lower in patients with a DAS<3.2 (p<0.05) and associated with clinical and microscopic measures of disease (p<0.05). In vitro TNFα significantly induced mtDNA mutations, ROS, MM and MMP in RASFCs (all p<0.05). High mitochondrial mutations are strongly associated with synovial inflammation showing a direct link between mitochondrial mutations and key proinflammatory pathways.


[Topographic anatomy of human thoracic organs in the early fetal period].
The purpose of the present investigation was to evaluate the holotopy, skeletotopy and sintopy of human heart, trachea and esophagus in the early fetal period. The quantitative evaluation of the topography of these organs was given as a result of study of 100 human fetuses aged 16-24 week with the modification of N.I. Pirogov method and using the multiplane histotopographical sections in the multidimensional coordinate system. The horizontal sections were selected, that could be proposed as the standard ones. he results of this investigation may be recommended for the improvement of the ultrasonographic and magnetic resonance tomographic diagnosis and fetal surgery development.


Genome-wide identification of MAXs genes for strigolactones synthesis/signaling in solanaceous plants and analysis of their potential functions in tobacco.
The more axillary growth (MAX) gene family is a group of key genes involved in the synthesis and signal transduction of strigolactones (SLs) in plants. Although MAX genes play vital roles in plant growth and development, characterization of the MAX gene family has been limited in solanaceous crops, especially in tobacco. In this study, 74 members of the MAX family were identified in representative Solanaceae crops and classified into four groups. The physicochemical properties, gene structure, conserved protein structural domains, cis-acting elements, and expression patterns could be clearly distinguished between the biosynthetic and signal transduction subfamilies; furthermore, MAX genes in tobacco were found to be actively involved in the regulation of meristem development by responding to hormones. MAX genes involved in SL biosynthesis were more responsive to abiotic stresses than genes involved in SL signaling. Tobacco MAX genes may play an active role in stress resistance. The results of this study provide a basis for future in-depth analysis of the molecular mechanisms of MAX genes in tobacco meristem development and stress resistance.


Expression levels of Rab2, a G protein, and Bag-1, a Bcl-2 binding protein are controlled by withdrawal of nicotine from cultured pheochromocytoma PC12 cells.
We previously reported that nicotine withdrawal up-regulates transcription of some immediately early genes (IEGs), c-fos (Ichino et al., 1999) and egr1, nur77 (Ichino et al., 2002) in cultures of pheochromocytoma PC12 cells, which are of neuronal lineage. In the present study we aimed at further elucidating the effects of nicotine withdrawal on the expression of the genes downstream of IEGs. We examined the changes in the protein levels of 2 GTP-binding proteins, Rab2 (Ras-related protein) and Rac1. PC12 cells were cultured in the presence of nicotine for 24 hours, and then the nicotine was removed from the medium. The protein level of Rab2 was low in the presence of nicotine, but was rapidly increased after nicotine withdrawal. In contrast, that of Rac1 did not change after the withdrawal. Considering the neuroprotective effect of nicotine, we also examined the level of Bag-1 protein, which is a binding protein for Bcl-2, an anti-apoptotic factor, and found a slight increase in the gene expression of Bag-1 following nicotine withdrawal. Among 56-kDa, 50-kDa, and 36-kDa protein components of the Bag-1 protein complex, the levels of 56-kDa and 50-kDa proteins were not changed by the addition or withdrawal of nicotine; but the level of the 36-kDa protein, which had been increased in the presence of nicotine, was markedly decreased after nicotine withdrawal. The present results suggest that such changes may also occur in individuals during abstaining from smoking and be related to the withdrawal symptoms experienced after smokers stop smoking.


Mechanical Performance of Three-Dimensional Printed Lattice Structures: Assembled Versus Direct Print.
Lattice structures are composed of a collection of struts with different orientations. During slicing, the inclined struts generate multiple disjoint contours along the build direction in additive manufacturing (AM). These contours are substantially smaller in size due to the narrow cross-section of the individual lattice struts, and they can lead to contour plurality in AM processes. Contour plurality reduces the amount of continuous contact region between two successive layers, thus resulting in poor interlayer adhesion, structural integrity, and mechanical properties of the printed lattice structure. A new interlocking and assemble-based lattice structure building approach is investigated by increasing continuity in layers and avoiding support structure to minimize contour plurality. Two lattice configurations in the form of cubic and octet lattice structures are examined. The compressive performance of the designed lattice structures is compared with the traditional single-build direct three-dimensional printed lattice structures. The mechanical performance (e.g., peak stress, specific energy absorption) of the assembled structures is found to be generally better than their direct print counterparts. The empirical constants of Ashby-Gibson power law are found to be larger than their suggested values in both direct print and assembly techniques. However, their values are more compliant for octet assembled structures, which are less susceptible to manufacturing imperfections.


Pharmacokinetics and sputum penetration of ciprofloxacin in patients with cystic fibrosis.
Levels of ciprofloxacin in serum and sputum were studied for eight patients with cystic fibrosis who were infected with Pseudomonas aeruginosa. Patients were studied in a steady state on a dosage of 500 mg every 8 h. Peak levels in serum ranged from 1.27 to 5.6 mg/liter (mean, 3.16 +/- 1.27), and absorption was rapid, the time to peak concentration ranging from 0.5 to 3.0 h (mean, 1.5 +/- 0.9). The antibiotic penetrated sputum well, achieving areas under the curve of approximately 46% of those obtained in serum.


Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial.
Rationale exists for combined treatment with immune checkpoint inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors in a variety of solid tumours. This study aimed to investigate the safety and antitumour effects of pamiparib, an oral PARP 1/2 inhibitor, combined with tislelizumab, a humanised anti-PD-1 monoclonal antibody, in patients with advanced solid tumours and to determine the optimum doses for further evaluation. We did a multicentre, open-label, phase 1a/b study at five academic sites or community oncology centres in Australia. We recruited adults (aged ≥18 years) with advanced solid tumours who had received one or more previous lines of therapy, with an Eastern Cooperative Oncology Group performance score of 1 or less, and a life expectancy of 12 weeks or more. Patients were enrolled into one of five dose-escalation cohorts, with dose-escalation done in a 3 + 3 design. Cohorts 1-3 received intravenous tislelizumab 2 mg/kg every 3 weeks plus 20, 40, or 60 mg oral pamiparib twice daily, respectively; cohorts 4 and 5 received 200 mg intravenous tislelizumab every 3 weeks plus 40 or 60 mg oral pamiparib twice daily, respectively. The primary endpoints of the phase 1a dose-escalation part of the study were safety and tolerability, including the occurrence of dose-limiting toxicities and determination of the maximum tolerated dose and recommended phase 2 dose. All primary endpoints were analysed in the safety analysis set, which included all patients who received at least one dose of tislelizumab or pamiparib, with the exception of the occurrence of dose-limiting toxicities, which was analysed in the dose-limiting toxicity analysis set, which included all patients who received at least 90% of the first scheduled tislelizumab dose and at least 75% of scheduled pamiparib doses, or who had a dose-limiting toxicity event during cycle 1. Reported here are results of the phase 1a dose-escalation stage of the trial. This trial is registered with ClinicalTrials.gov, number NCT02660034, and is ongoing. Between Jan 22, 2016, and May 16, 2017, we enrolled 49 patients (median age 63 years [IQR 55-67]), all of whom received at least one dose of pamiparib or tiselzumab. Four patients had dose-limiting toxicities (intractable grade 2 nausea [n=1] and grade 3 rash [n=1] in cohort 4, and grade 2 nausea and vomiting [n=1] and grade 4 immune-mediated hepatitis [n=1] in cohort 5). The recommended phase 2 dose was tislelizumab 200 mg every 3 weeks plus pamiparib 40 mg twice daily (the dose given in cohort 4). The most common treatment-emergent adverse events were nausea (in 31 [63%] of 49 patients), fatigue (26 [53%]), diarrhoea (17 [35%]), and vomiting (15 [31%]). 23 (47%) of 49 patients had immune-related adverse events, of whom nine (39%) had asymptomatic grade 3-4 hepatic immune-related adverse events, which were reversible with corticosteroid treatment. The most common adverse event of grade 3 or worse severity was anaemia (in six [12%] patients) and no grade 5 adverse events were reported. Hepatitis or autoimmune hepatitis was the only serious adverse event to occur in two or more patients (in four [8%] patients). At a median follow-up of 8·3 months (IQR 4·8-12·8), ten (20%) of 49 patients achieved an objective response according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, including two complete responses and eight partial responses. Pamiparib with tislelizumab was generally well tolerated and associated with antitumour responses and clinical benefit in patients with advanced solid tumours supporting further investigation of the combination of pamiparib with tislelizumab. BeiGene.


Molecular Simulations of Phase Equilibria and Transport Properties in a Model CO2-Expanded Lithium Perchlorate Electrolyte.
Carbon-dioxide (CO2)-expanded liquids, in which a significant mole fraction of CO2 is dissolved into an organic solvent, have been of significant interest, especially as catalytic support media. Because the CO2 mole fraction and density can be controlled over a significant range by changing the CO2 partial pressure, the transport properties of these solvents are highly tunable. Recently, these liquids have garnered interest as potential electrolyte solutions for catalytic electrochemistry; however, little is currently known about the influence of the electrolyte on CO2 expansion. In the present work, we use molecular-dynamics simulations to study diffusion and viscosity in a model lithium perchlorate electrolyte in CO2-expanded acetonitrile and demonstrate that these properties are highly dependent on the concentration of the electrolyte. Our present results indicate that the electrolyte slows down diffusion of both CO2 and MeCN, and that the slowed diffusion in the former is driven by changes in the activation entropy, whereas slowed diffusion in the latter is driven by changes in the activation energy.


Development of standard estrogen and progesterone receptor immunohistochemical assays for selection of patients for antihormonal therapy.
Estrogen receptor (ER) and progesterone receptor (PR) status in breast carcinomas are considered validated predictive factors for selecting patients for antihormonal therapy. Published surveys have shown a significant rate of disagreement and lack of reproducibility of immunohistochemistry (IHC) results from laboratories around the world. To address these limitations IHC assays for ER and PR were developed using characterized reagents, after careful calibration of the sensitivity and specificity to match established assays previously validated in large clinical studies. The ER assay uses a cocktail of 2 mouse monoclonal antibodies (1D5 and ER-2-123) and the PR assay uses 1 mouse monoclonal antibody (PgR 1294); both are followed by a polymer-peroxidase-based detection system. All antibodies were tested for specificity by epitope mapping. The sensitivity of the new assays was calibrated to be equivalent to previously validated IHC assays followed by a comparison with the validated assays in a concordance study involving over 200 specimens. All slides were scored with the "Allred Score," also used for scoring of the original validated assays. The overall concordance between the new and the established IHC assays was nearly perfect (99%). The concordance study demonstrated greater than 98% positive agreement and 100% negative agreement of the new IHC assays with the previously validated IHC assays. This equivalence establishes the clinical validation of the assays and, as they are based on newer generation reagents and are produced and tested under stringent quality control conditions to ensure their consistency, they add additional advantages to the user and patients.


Human Urinary mRNA as a Biomarker of Cardiovascular Disease.
Background mRNA in urine supernatant (US-mRNA) might encode information about renal and cardiorenal pathophysiology, including hypertension. H, whether the US-mRNA transcriptome reflects that of renal tissues and whether changes in renal physiology are detectable using US-mRNA is unknown. Methods We compared transcriptomes of human urinary extracellular vesicles and human renal cortex. To avoid similarities attributable to ubiquitously expressed genes, we separately analyzed ubiquitously expressed and highly kidney-enriched genes. To determine whether US-mRNA reflects changes in renal gene expression, we assayed cell-depleted urine for transcription factor activity of mineralocorticoid receptors (MR) using probe-based quantitative polymerase chain reaction. The urine was collected from prehypertensive individuals (n=18) after 4 days on low-sodium diet to stimulate MR activity and again after suppression of MR activity via sodium infusion. Results In comparing this US-mRNA and human kidney cortex, expression of 55 highly kidney-enriched genes correlated strongly (rs=0.82) while 8457 ubiquitously expressed genes correlated moderately (rs=0.63). Standard renin-angiotensin-aldosterone system phenotyping confirmed the expected response to sodium loading. Cycle threshold values for MR-regulated targets ( SCNN1A, SCNN1G, TSC22D3) changed after sodium loading, and MR-regulated targets ( SCNN1A, SCNN1G, SGK1, and TSC22D3) correlated significantly with serum aldosterone and inversely with urinary sodium excretion. Conclusions RNA-sequencing of urinary extracellular vesicles shows concordance with human kidney. Perturbation in human endocrine signaling (MR activation) was accompanied by changes in mRNA in urine supernatant. Our findings could be useful for individualizing pharmacological therapy in patients with disorders of mineralocorticoid signaling, such as resistant hypertension. More generally, these insights could be used to noninvasively identify putative biomarkers of disordered renal and cardiorenal physiology.


Efficacy of fluconazole in experimental invasive aspergillosis.
The efficacy of fluconazole against Aspergillus fumigatus was evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Fluconazole was given at a dosage of 60 mg/kg twice daily and was compared with amphotericin B given intravenously at a dosage of 1.5 mg/(kg.d). Fluconazole reduced the tissue burden of Aspergillus from that in untreated controls by 10- to 100-fold in liver, kidney, and lung. However, at these doses amphotericin B was more effective in sterilizing tissues and in reducing the tissue burden of Aspergillus in those organs. Both fluconazole and amphotericin B decreased or eliminated circulating Aspergillus antigen and improved survival over that of untreated controls. Thus fluconazole shows activity in this rabbit model of invasive aspergillosis and should be further evaluated for use in the treatment of this disease.


Can natural fibers be a silver bullet? Antibacterial cellulose fibers through the covalent bonding of silver nanoparticles to electrospun fibers.
Natural cotton was dissolved in a room-temperature ionic liquid 1-ethyl-3-methyl acetate and wet-jet electrospun to obtain nanoscale cotton fibers with a substantially reduced diameter-and therefore an increased surface area-relative to natural cotton fibers. The resulting nano-cotton fibers were esterified with trityl-3-mercaptopropionic acid, which after selective de-tritylation afforded nano-cotton fibers containing reactive thiol functionality. Silver nanoparticles that were covalently attached to these sulfhydryl groups were assembled next. The microstructure of the resulting nanocomposite was characterized, and the antibacterial activity of the resulting nano-cotton Ag-nanoparticle composite was also studied. This nanocomposite showed significant activity against both Gram-negative and Gram-positive bacteria.


Hydrogen production from glucose and sorbitol by sorption-enhanced steam reforming: challenges and promises.
Concerning energy and environmental sustainability, it is appealing to produce hydrogen from sugars or sugar alcohols that are readily obtained from the hydrolysis of cellulosic biomass. Nevertheless, the conversion of such compounds for hydrogen production poses great technical challenges. In this paper, we report that hydrogen purity and yield can be significantly improved by integrating in situ CO(2) capture into the steam reforming reaction of the model compounds-glucose and sorbitol. The experimental assessment was conducted at a steam-to-carbon ratio of 1.8 for sorbitol and 6 for glucose from 450-625 °C. As predicted by thermodynamic analysis, combining CO(2) capture and reforming reactions at favorable operating conditions yielded very high purity hydrogen, for instance, 98.8 mol % from sorbitol and 99.9 mol % from glucose. However, there are trade-offs between hydrogen purity and yield in practice. The lower operating temperatures in the examined range helped to increase the hydrogen purity and reduce the CO content in the gas product, whereas a high hydrogen yield was more likely to be obtained at higher temperatures. Coupling CO(2) capture lowered the risk of coke formation during the steam reforming of glucose. Coke accumulated in the reactor for the sorption-enhanced steam reforming of glucose was mostly from the slow pyrolysis of glucose before it came into contact with the catalyst-acceptor bed. This problem may be solved by improving heat transfer or reconstructing the reactor, for instance, by using a fluidized-bed reactor.


Test of a theory relating to the cross-linking of IgE antibody on the surface of human basophils.
Recent mathematical models of bivalent hapten-induced histamine release from basophils predict that under appropriate conditions histamine release is maximum when cross-link formation is maximum, at a hapten concentration equal to 1/(2Ka), where Ka is the average affinity constant of the hapten for a single IgE binding site. To test this prediction we sensitized human basophils with a monoclonal anti-dinitrophenol IgE and generated histamine release dose-response curves with a bivalent hapten, alpha, epsilon-DNP-lysine. The monoclonal IgE has a published affinity constant of 7.1 X 10(7) M-1 for epsilon-DNP-lysine as determined by equilibrium dialysis. From the position of the maximum of the histamine dose-response curves, both in the presence and in the absence of monovalent DNP hapten, we determine that the sensitizing IgE has an intrinsic affinity constant of 6.9 +/- 0.5 X 10(7) M-1 for epsilon-DNP-lysine and 1.2 +/- 0.6 X 10(6) M-1 for alpha-DNP-lysine. The agreement between the two estimates of the epsilon-DNP-lysine affinity constant, one from histamine release experiments involving surface bound IgE and one from binding experiments involving IgE free in solution, 1) is consistent with a central prediction of the theory of cross-linking and 2) indicates that the hapten-binding properties of the IgE are unaffected by its being bound to Fc epsilon receptors on the basophil surface.


Enantioselective binding interaction of the metolachlor pesticide enatiomers with bovine serum albumin--a spectroscopic analysis study.
Enantioselective binding interaction of the pesticides, metolachlor (RAC-metolachlor) and its S-enantiomer (S-metolachlor), with bovine serum albumin (BSA) was investigated by fluorescence and UV-vis absorption spectroscopy. Both RAC- and S-metolachlors quenched the intrinsic fluorescence of BSA via a static mechanism, and various binding parameters indicated that electrostatic forces were involved in the binding of both of these compounds. Site marker competitive experiments demonstrated that S-metolachlor bound to site I of BSA, while R-metolachlor bound to site II, indicating the importance of enantiomeric factors for binding site selection. Further experiments showed that S-metolachlor had a higher binding affinity to BSA than R-metolachlor. The obtained spectral data were resolved with use of the multivariate curve resolution-alternating least squares method (MCR-ALS), and the extracted concentration profiles of the reacting species in the interaction were obtained. These profiles indicated that S-metolachlor was the main active constituent of RAC-metolachlor for binding with BSA, and these findings have significant implications in providing an explanation why S-metolachlor is the preferred herbicide in practice than RAC-metolachlor.


Comforting children during radiotherapy.
By keeping comfort as a central theme to guide interventions and practice, the radiation oncology nurse truly can address one of the high-incidence problem areas experienced by children receiving radiotherapy and by their families. More oncology nursing research is needed to identify the exact nurse behaviors and interventions that are deemed most comforting to children and their parents during a cancer diagnosis work-up, cancer therapies (including symptom management), and short- and long-term follow-up care. The global concept of comfort is alive in oncology nursing, but it must be continued, it must be cherished, it should be validated as part of a nurse's job performance, and it should be fostered in the oncology nursing and medical literature.


Transplant tolerance: a new role for IL-34.
Immune-suppressive cell populations, including Tregs and suppressor monocytes, have been implicated in long-term survival of allografts in both human transplant recipients and animal models. The factors that drive differentiation and function of these cell populations are not completely understood. In this issue, Bézie and colleagues identify IL-34 as an important mediator of allograft tolerance in a rat model of heart transplantation. Their data support a model in which IL-34 production by Tregs promotes a population of suppressive macrophages that in turn promote Treg differentiation. The results of this study support further exploration of the immunosuppressive properties of IL-34.


Mice lacking L1 have reduced CGRP fibre in-growth into spinal transection lesions.
Repair strategies for spinal cord injury often focus on promoting regeneration of injured axons and stimulating subsequent functional recovery. Although many of these strategies have proven their merits, less is known about potential unwanted side-effects, such as sprouting of nociceptive CGRP immunoreactive axons, which may bring about pain-related behavior. Sprouting of CGRP axons into lesion sites spontaneously occurs after spinal cord injury (SCI). Using L1-deficient mice we show a reduction of such CGRP growth response. This reduction was specific for CGRP axons since the overall neurofilament positive fibre in-growth into the spinal lesion site was not affected. Our results may have important implications on the development and assessment of repair strategies that should not only stimulate functional recovery, but also prevent the development of pain or autonomic dysreflexia.


Sex role stereotypes, gender identity and parental relationships in male homosexuals and heterosexuals.
The sex-role stereotypes held by heterosexual and homosexual men were examined by comparing their Repertory Grid scores. It was found that homosexual men held less rigid sex-role stereotypes than heterosexuals. Degree of opposite-sex identification was marginally greater in homosexuals, but neither group showed strong masculine or feminine stereotypic identification. Homosexual men perceived themselves as psychologically more distant from their fathers than did their heterosexual counterparts; this was probably an effect of homosexuality rather than a cause.


What puts women at risk of violence from their husbands? Findings from a large, nationally representative survey in Turkey.
A large, nationally representative, cross-sectional survey was conducted in Turkey in 2008. In this survey, which used the WHO (World Health Organization) study module on violence, information about lifetime and current violence (past 12 months) was obtained using weighted, stratified, and multistage cluster sampling. This article describes factors associated with physical or sexual violence experienced by ever-married women, aged 15 to 49, from their current or most recent husbands in the 12 months before the survey. Logistic regression analysis is used to describe the risk and protective factors from a considerable range of explanatory variables. The findings confirm that many factors are similar to the experiences of other countries. The physical or sexual violence experienced by ever-married women from their husbands was 15.1%. The violence experienced by women is significantly positively associated with early childhood abuse experiences of both women and their husbands; marriages decided by families or others; husband's behaviors such as drunkenness, adultery, controlling women's behavior, and preventing contact with women's family and friends. The age of the women, their contribution to the household income, support from women's families, women's acceptance of male authority, and nonpartner violence experience as well as regional differentials also affect the risk of violence. No significant associations were found with the employment status of women and men or education difference. This study, as one of the largest surveys ever conducted on the issue of domestic violence using face-to-face interviews, demonstrated how the patriarchal family structure still affects women's lives in Turkey. This is particularly significant, given Turkey's setting between traditional and modern values.


Correlation of transmitter release with membrane properties of the presynaptic fiber of the squid giant synapse.
Depolarization of the presynaptic terminal by current produced a postsynaptic potential (PSP) which increased with increasing presynaptic polarization and then reached a plateau. Iontophoretic injection of tetraethylammonium ions (TEA) into the presynaptic axon near the terminal produced a prolonged presynaptic spike. The resulting PSP is increased in size and its time course closely followed that of the presynaptic spike. The presynaptic fiber no longer exhibited rectification and strong depolarizations revealed that the PSP reached a maximum with about 110 mv depolarization. Further depolarization produced a decrease in PSP amplitude and finally transmission was blocked. However, a PSP then always appeared on withdrawal of the depolarizing current. Under the conditions of these experiments, the PSP could be considered a direct measure of transmitter release. Bathing the TEA-injected synapse with concentrations of tetrodotoxin (TTX) sufficient to block spike activity in both pre- and postsynaptic axons did not greatly modify postsynaptic electrogenesis. However, doubling TTX concentration reversibly blocked PSP. Thus the permeability changes to Na and K accompanying the spike do not appear necessary for transmitter release. Some other processes related to the level of presynaptic polarization must be involved to explain the data. The inhibition of transmitter release by strong depolarizations appears to be related to Ca action. A membrane Ca current may also be necessary for normal transmitter release.


Patient-controlled sedation with propofol/remifentanil versus propofol/alfentanil for patients undergoing outpatient colonoscopy, a randomized, controlled double-blind study.
Many techniques are used for sedation of colonoscopies. Patient-controlled sedation (PCS) is utilizing many drugs or drug combinations. The aim of this study is to compare the safety and feasibility of propofol/remifentanil versus propofol/alfentanil given to sedate patients undergoing outpatient colonoscopies through a patient-controlled technique. Controlled randomized and double-blind study. A total of 80 patients were randomly divided into two groups; PA group received a combination of propofol/alfentanil and PR group received propofol/remifentanil combination. Patients were monitored for heart rate (HR), blood pressure (BP), oxygen saturation, and Ramsay sedation scale (RSS). Times of the following events were recorded; initiation of sedation, insertion and removal of the colonoscope, recovery and discharge. Five intervals were calculated; time to sedation, procedure time, postprocedure time, procedure room time, and postanesthesia care unit (PACU) time. Endoscopist and patient satisfaction scores were obtained. Unpaired Student's t-test was used to compare between the two groups. Paired Student's t-test was used to compare baseline readings with readings after 30 min of sedation in the same group when needed. Both groups showed slowing of the HR and decrease in mean arterial BP. HR and mean arterial BP were significantly lower 5 and 10 min after initiation of sedation in PR group when compared with PA group. Both HR and mean arterial BP returned to presedation readings 30 min after initiation of sedation in PR group but not in PA group. No differences between the two groups concerning oxygen saturation, RSS, endoscopist and patient satisfaction scores. Postprocedure and PACU times were significantly prolonged in PA group. PCS with either remifentanil/propofol or alfentanil/propofol for patients undergoing outpatient colonoscopy is safe and feasible. Remifentanil/proofol has more beneficial advantages in this setting secondary to its more rapid clearance.


Cyclosporine A impairs bone repair in critical defects filled with different osteoconductive bone substitutes.
The aim of this study was to assess the influence of cyclosporine administration on the repair of critical-sized calvaria defects (CSDs) in rat calvaria filled with diverse biomaterials. Sixty animals were divided into two groups: the control (CTR) group (saline solution) and the cyclosporine (CCP) group (cyclosporine, 10 mg/kg/day). These medications were administered daily by gavage, beginning 15 days before the surgical procedure and lasting until the day the animals were euthanized. A CSD (5 mm Ø) was made in the calvaria of each animal, which was allocated to one of 3 subgroups, according to the biomaterial used to fill the defect: coagulum (COA), deproteinized bovine bone (DBB), or biphasic calcium phosphate ceramics of hydroxyapatite and β-phosphate tricalcium (HA/TCP). Euthanasia of the animals was performed 15 and 60 days after the surgical procedure (n = 5 animals/period/subgroup). Bone repair (formation) assessment was performed through microtomography and histometry, while the analyses of the expression of the BMP2, Osteocalcin, and TGFβ1 proteins were performed using immunohistochemistry. The CSDs not filled with biomaterials demonstrated lower bone formation in the CCP group. At 15 days, less bone formation was observed in the CSDs filled with DBB, a smaller volume of mineralized tissue was observed in the CSDs filled with HA/TCP, and the expression levels of BMP2 and osteocalcin were lower in the CCP group compared to the CTR group. The use of cyclosporine impaired bone repair in CSD, and this effect can be partially explained by the suppression of BMP2 and osteocalcin expression.


The use of intraaortic balloon counterpulsation as an adjunct to reperfusion therapy in cardiogenic shock.
Modern coronary care unit interventions have not reduced the high mortality rate associated with cardiogenic shock due to acute myocardial infarction. Results with thrombolytic therapy have also been disappointing because of poor infarct artery patency rates in a low coronary flow state. Percutaneous transluminal coronary angioplasty appears to be a beneficial intervention, but the technique is not available at most hospitals. Intraaortic balloon counterpulsation provides temporary hemodynamic and clinical improvement in the majority of patients with cardiogenic shock. The use of intraaortic counterpulsation to augment patency rates with thrombolytic therapy or to stabilize patients for transfer to a hospital with angioplasty services appears to be a promising strategy for hospitals without an interventional cardiac catheterization laboratory.


Two-eyed seeing: a framework for understanding indigenous and non-indigenous approaches to indigenous health research.
This article presents two-eyed seeing as a theoretical framework that embraces the contributions of both Indigenous and Western "ways of knowing" (world-views). It presents key characteristics and principles of these different perspectives and suggests ways in which they might be used together to answer our most pressing questions about the health of Indigenous people and communities. Presenting a critique of positivism, which has historically undermined and/or dismissed Indigenous ways of knowing as "unscientific," it discusses the origins of both Western and Indigenous approaches to understanding health; the importance of giving equal consideration to diverse Indigenous and non-Indigenous worldviews such that one worldview does not dominate or undermine the contributions of others; and how balanced consideration of contributions from diverse worldviews, embraced within a two-eyed seeing framework, can reshape the nature of the questions we ask in the realm of Indigenous health research.


Comparison of 3D intraoperative digital subtraction angiography and intraoperative indocyanine green video angiography during intracranial aneurysm surgery.
During the last decade, improvements in real-time, high-resolution imaging of surgically exposed cerebral vasculature have been realized with the successful introduction of intraoperative indocyanine green video angiography (ICGVA) and technical advances in intraoperative digital subtraction angiography (DSA). With the availability of 3D intraoperative DSA (3D-iDSA) in hybrid operating rooms, the present study offers a contemporary comparison for rates of accuracy and discordance. In this retrospective study of prospectively collected data, 140 consecutive patients underwent microsurgical treatment of intracranial aneurysms (IAs) in a hybrid operating room. Variables analyzed included patient demographics, aneurysm-specific characteristics, intraoperative ICGVA and 3D-iDSA findings, and the need for intraoperative clip readjustment. The authors defined the discordance rate of the two modalities as a false-negative finding that necessitated clip repositioning after 3D-iDSA. In 120 patients, ICGVA and 3D-iDSA were used to evaluate 134 IA obliterations. Of 215 clips used, 29 (14%) were repositioned intraoperatively, improving the surgical result in all 29 patients (24%). Repositioning was prompted by visual inspection and microvascular Doppler ultrasonography in 8 (28%), ICGVA in 13 (45%), and 3D-iDSA in 7 (24%) patients. Clip repositioning was needed in 7 patients (6%) based on 3D-iDSA, yielding an ICGVA accuracy rate of 94%. Five (71%) of the ICGVA-3D-iDSA discordances that prompted clip repositioning occurred at the anterior communicating artery complex. A combination of vascular monitoring techniques most often achieved correct intraoperative interpretation of complete IA occlusion and parent artery integrity. Compared with 3D-iDSA imaging, ICGVA demonstrated high accuracy. Despite the relatively low discordance rate, iDSA was confirmed to be the gold standard. Improved imaging quality, including 3D-iDSA, supports its routine use in IA surgery, obviating the need for postoperative DSA.


Ultrafast charge carrier dynamics in quantum confined 2D perovskite.
We studied the charge carrier dynamics in 2D perovskite NBT2PbI4 by ultrafast optical pump-THz probe spectroscopy. We observed a few ps long relaxation dynamics that can be ascribed to the band to band carrier recombination, in the absence of any contribution from many-body and trap assisted processes. The transient conductivity spectra show that the polaron dynamics is strongly modulated by the presence of a rich exciton population. The polarization field resulting from the exciton formation acts as the source of a restoring force that localizes polarons. This is revealed by the presence of a negative imaginary conductivity. Our results show that the dynamics of excitons in 2D perovskites at room temperature can be detected by monitoring their effect on the conductivity of the photoinduced polaronic carrier.


Porous Ionic Network/CNT Composite Separator as a Polysulfide Snaring Shield for High Performance Lithium-Sulfur Battery.
Lithium-sulfur (Li-S) battery features a high theoretical energy density, but the shuttle of soluble polysulfides between the two electrodes often results in a rapid capacity decay. Herein, a straightforward electrostatic adsorption strategy based on a cross-linked polyimidazolium separator as a snaring shield of polysulfides is reported, which suppresses the undesirable migration of polysulfides to the anode. The porous ionic network (PIN)-modified carbon nanotubes (CNTs) are successfully prepared and coated onto a commercial porous polypropylene membrane in a vacuum-filtration step. The favorable affinity of the imidazolium ring toward polysulfide via the polar interaction and the electrostatic effect of ions mitigates the undesirable shuttle of polysulfides in the electrolyte, improving the Li─S battery in terms of rate performance and cycling life. Compared to the reference PIN-free CNT-coated separator, the PIN/CNT-coated one has an increased initial capacity of 1.3 folds (up to 1394.8 mAh g-1 for PIN/CNT/PP-3) at 0.1 C.


Comparison of ultrasonographic and radiographic findings in cows with traumatic reticuloperitonitis.
The radiographic and ultrasonographic findings in 26 cows with traumatic reticuloperitonitis were compared. The cows were divided into three groups based on the radiographic findings; the first group consisted of 12 cows in which the principal radiographic finding was a foreign body penetrating the reticulum; the second group contained four cows in which the principal radiographic finding was gas shadows or a gas-fluid interface, the third group consisted of 10 cows that had no reliable radiographic evidence of traumatic reticuloperitonitis, such as an abnormal contour, position or shape of the reticulum. In no case could the foreign bodies be visualised by ultrasonography. In all the cows except one with radiographic evidence of abnormal gas inclusions and gas-fluid interfaces, ultrasonography revealed echogenic, partitioned and capsulated structures with central hypoechogenic cavities. In addition, in some of the cows with no radiographic evidence of the condition, severe changes indicative of inflammatory processes were visible by ultrasonography.


The convergence of neuropsychological testing and clinical ratings of cognitive impairment in patients with schizophrenia.
This study examined the relationship between clinical rating of cognitive symptoms and performance on neuropsychological tests in acute and chronic samples of patients with schizophrenia. Two separate studies examined patients who varied widely in their lifetime functional outcome, including 263 elderly poor-outcome inpatients and 20 acutely admitted patients. In the first study, six cognitive performance measures were collected, and in the second study, five different measures were collected. Correlations with different symptom models of cognitive and negative symptoms were examined. In both samples, cognitive symptoms were never more highly correlated with cognitive test performance than with negative symptoms. When cognitive and negative symptom ratings were combined, they never accounted for as much as half of the variance in performance on the cognitive tests in both samples. These data suggest that clinical assessment of symptoms is not a viable alternative to neuropsychological testing to obtain information about cognitive functioning in schizophrenia. These results may also be specific to the clinical rating scale used, the Positive and Negative Syndrome Scale (PANSS).


Review article: lymphatic vessel pumping and inflammation--the role of spontaneous constrictions and underlying electrical pacemaker potentials.
The lymphatic circulation is important in maintaining tissue fluid homeostasis. It removes fluid, proteins and other particles from tissue spaces and returns them to the blood stream. This function is achieved by rhythmical contractions of the collecting lymphatic vessels. The contractile mechanism is intrinsic to the smooth muscles present in the vessel wall and consequent to action potentials. The underlying electrical mechanism has been proposed to be due to rhythmic synchronization of Ca2+-dependent spontaneous transient depolarizations. The lymphatic pumping activity adapts to changes in fluid load and has been observed to augment during inflammatory reactions to help resolve the associated oedema. This beneficial action has been generally attributed to the increase in interstitial pressure consequent to the oedema. However, little attention has been paid to the possible role inflammatory mediators that are present in the lymphatic vessel environment, could play in directly affecting the lymphatic contractile mechanism. This review article discusses our current knowledge on the mechanism and initiation of lymphatic pumping and how these events are modulated during inflammatory conditions.


[Screening of mentally retarded persons for "fragile" X-chromosome].
112 mentally weak persons aged from 2 to 18 with different degree of oligophrenia have been examined. Cultivation of blood lymphocytes was performed on medium 199 containing 5% of cattle serum. 9 persons with "fragile" X-chromosome are revealed. High frequency of autosomes fragility among the examined contingent of patients is found. A supposition is advanced on interrelation between homozygosity of "fragile" parts of autosomes and oligophrenia.


Endemic mycoses in AIDS: a clinical review.
Histoplasmosis and coccidioidomycosis are serious opportunistic infections in patients with AIDS who reside in areas of endemicity of the United States and Central and South America. Blastomycosis, although less common, also must be recognized as an opportunistic infection in patients with AIDS. Prompt diagnosis requires knowledge of the clinical syndromes and diagnostic tests as well as a high index of suspicion. Histoplasmosis and blastomycosis respond well to antifungal treatment, but relapse is common without chronic suppressive therapy. Improvements in treatment are needed in coccidioidomycosis. Research is needed to identify preventive strategies for patients at risk. These strategies may include use of prophylactic antifungal therapy or vaccination.


Development of Parallel Reaction Monitoring Assays for the Detection of Aggressive Prostate Cancer Using Urinary Glycoproteins.
Recently, we have found that two urinary glycoproteins, prostatic acid phosphatase (ACPP) and clusterin (CLU), combined with serum prostate-specific antigen (PSA) can serve as a three-signature panel for detecting aggressive prostate cancer (PCa) based on a quantitative glycoproteomic study. To facilitate the translation of candidates into clinically applicable tests, robust and accurate targeted parallel reaction monitoring (PRM) assays that can be widely adopted in multiple labs were developed in this study. The developed PRM assays for the urinary glycopeptides, FLN*ESYK from ACPP and EDALN*ETR from CLU, demonstrated good repeatability and a sufficient working range covering three to four orders of magnitude, and their performance in differentiating aggressive PCa was assessed by the quantitative analysis of urine specimens collected from 69 nonaggressive (Gleason score = 6) and 73 aggressive (Gleason ≥ 8) PCa patients. When ACPP combined with CLU, the discrimination power was improved from an area under a curve (AUC) of 0.66 to 0.78. By combining ACPP, CLU, and serum PSA to form a three-signature panel, the AUC was further improved to 0.83 (sensitivity: 84.9%, specificity: 66.7%). Since the serum PSA test alone had an AUC of 0.68, our results demonstrated that the new urinary glycopeptide PRM assays can serve as an adjunct to the serum PSA test to achieve better predictive power toward aggressive PCa. In summary, our developed PRM assays for urinary glycopeptides were successfully applied to clinical PCa urine samples with a promising performance in aggressive PCa detection.


Pregnancy and neonatal outcomes of COVID-19: coreporting of common outcomes from PAN-COVID and AAP-SONPM registries.
Few large cohort studies have reported data on maternal, fetal, perinatal and neonatal outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy. We report the outcome of infected pregnancies from a collaboration formed early during the pandemic between the investigators of two registries, the UK and Global Pregnancy and Neonatal outcomes in COVID-19 (PAN-COVID) study and the American Academy of Pediatrics (AAP) Section on Neonatal-Perinatal Medicine (SONPM) National Perinatal COVID-19 Registry. This was an analysis of data from the PAN-COVID registry (1 January to 25 July 2020), which includes pregnancies with suspected or confirmed maternal SARS-CoV-2 infection at any stage in pregnancy, and the AAP-SONPM National Perinatal COVID-19 registry (4 April to 8 August 2020), which includes pregnancies with positive maternal testing for SARS-CoV-2 from 14 days before delivery to 3 days after delivery. The registries collected data on maternal, fetal, perinatal and neonatal outcomes. The PAN-COVID results are presented overall for pregnancies with suspected or confirmed SARS-CoV-2 infection and separately in those with confirmed infection. We report on 4005 pregnant women with suspected or confirmed SARS-CoV-2 infection (1606 from PAN-COVID and 2399 from AAP-SONPM). For obstetric outcomes, in PAN-COVID overall and in those with confirmed infection in PAN-COVID and AAP-SONPM, respectively, maternal death occurred in 0.5%, 0.5% and 0.2% of cases, early neonatal death in 0.2%, 0.3% and 0.3% of cases and stillbirth in 0.5%, 0.6% and 0.4% of cases. Delivery was preterm (< 37 weeks' gestation) in 12.0% of all women in PAN-COVID, in 16.1% of those women with confirmed infection in PAN-COVID and in 15.7% of women in AAP-SONPM. Extreme preterm delivery (< 27 weeks' gestation) occurred in 0.5% of cases in PAN-COVID and 0.3% in AAP-SONPM. Neonatal SARS-CoV-2 infection was reported in 0.9% of all deliveries in PAN-COVID overall, in 2.0% in those with confirmed infection in PAN-COVID and in 1.8% in AAP-SONPM; the proportions of neonates tested were 9.5%, 20.7% and 87.2%, respectively. The rates of a small-for-gestational-age (SGA) neonate were 8.2% in PAN-COVID overall, 9.7% in those with confirmed infection and 9.6% in AAP-SONPM. Mean gestational-age-adjusted birth-weight Z-scores were -0.03 in PAN-COVID and -0.18 in AAP-SONPM. The findings from the UK and USA registries of pregnancies with SARS-CoV-2 infection were remarkably concordant. Preterm delivery affected a higher proportion of women than expected based on historical and contemporaneous national data. The proportions of pregnancies affected by stillbirth, a SGA infant or early neonatal death were comparable to those in historical and contemporaneous UK and USA data. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN-COVID study, although not in the AAP-SONPM study. The data presented support strong guidance for enhanced precautions to prevent SARS-CoV-2 infection in pregnancy, particularly in the context of increased risks of preterm delivery and maternal mortality, and for priority vaccination of pregnant women and women planning pregnancy. Copyright © 2021 ISUOG. Published by John Wiley & Sons Ltd.


Strigolactones are involved in root response to low phosphate conditions in Arabidopsis.
Strigolactones (SLs) are plant hormones that suppress lateral shoot branching, and act to regulate root hair elongation and lateral root formation. Here, we show that SLs are regulators of plant perception of or response to low inorganic phosphate (Pi) conditions. This regulation is mediated by MORE AXILLARY GROWTH2 (MAX2) and correlated with transcriptional induction of the auxin receptor TRANSPORT INHIBITOR RESPONSE1 (TIR1). Mutants of SL signaling (max2-1) or biosynthesis (max4-1) showed reduced response to low Pi conditions relative to the wild type. In max4-1, but not max2-1, the reduction in response to low Pi was compensated by the application of a synthetic strigolactone GR24. Moreover, AbamineSG, which decreases SL levels in plants, reduced the response to low Pi in the wild type, but not in SL-signaling or biosynthesis mutants. In accordance with the reduced response of max2-1 to low Pi relative to the wild type, several phosphate-starvation response and phosphate-transporter genes displayed reduced induction in max2-1, even though Pi content in max2-1 and the wild type were similar. Auxin, but not ethylene, was sufficient to compensate for the reduced max2-1 response to low Pi conditions. Moreover, the expression level of TIR1 was induced under low Pi conditions in the wild type, but not in max2-1. Accordingly, the tir1-1 mutant showed a transient reduction in root hair density in comparison with the wild type under low Pi conditions. Therefore, we suggest that the response of plants to low Pi is regulated by SLs; this regulation is transmitted via the MAX2 component of SL signaling and is correlated with transcriptional induction of the TIR1 auxin receptor.


Photoperiod nonresponsive Siberian hamsters: effect of age on the probability of nonresponsiveness.
Groups from three different breeding lines of Siberian hamsters (UNS = general colony animals, PNRa = selected for photoperiod nonresponsiveness as adults, PNRj = selected for photoperiod nonresponsiveness as juveniles) were exposed to short days at weaning and again as adults (Experiment 1) or only as adults (Experiment 2). The proportion of photoperiod nonresponsive individuals in each line was determined by measuring testis length after 6 weeks of exposure to short days (juveniles) or by paired testis weights after 12 weeks in short photoperiod (adults). Adults were blood sampled on the day of sacrifice (Experiment 1) or on Weeks 3, 4, 5, 6, 8, 10, and 12 (Experiment 2) for determination of serum prolactin (PRL) and follicle-stimulating hormone (FSH) concentrations. Nonresponsive individuals were present in all three lines of hamsters. Furthermore, all three lines of hamsters showed an increase in the proportion of nonresponders with age; some individuals are responsive to short days as juveniles, but become nonresponsive in adulthood. The two PNR lines exhibited a greater proportion of nonresponders at both ages compared to the UNS line, with the PNRj line exhibiting the greatest proportion of nonresponders at each age. During exposure to short days, nonresponders exhibited significantly higher serum PRL and FSH concentrations that did the UNS line; nonresponders also exhibited larger testis size, and fewer animals molted to winter-type pelage. The results indicate that (a) in all three lines, a significantly higher proportion of animals are nonresponsive to short photoperiod as adults than as juveniles; (b) selection for nonresponsiveness as juveniles can produce a line of hamsters that, as adults, are nearly all nonresponsive to short days; and (c) some individuals from each line are responsive to short photoperiod early in life, but become nonresponsive as adults.


A comparative study of the peripheral doses from a linear accelerator with a multileaf collimator system.
This study presents a comparison of peripheral doses (PDs) measured using an ionisation chamber with treatment planning system (TPS) data and a Monte Carlo (MC) simulation of a 6-MV photon beam. The ion chamber measurements and MC simulation produced similar results for all out-of-field distances and field sizes considered in this study. For the 0° and 90° collimation angles, the average local per cent dose differences between the MC and TPS calculations were 2.7 % (range: -2.4, +22.6) and -1.7 % (range: -12.2, +10.8), respectively. The corresponding differences between the MC calculations and the ion chamber measurements were 2.2 % (range: -2.4, 24.7) and -1.8 % (range: -17, 15.2) for all field sizes and depths, respectively. Whereas the PDs increased with field sizes, the variations with depth were negligible at large distances. The TPS calculations usually yielded higher PDs than ion chamber measurements at distances close to the field edge. In contrast, at the farther distances, the TPS results indicated lower doses than both the ion chamber and the MC data. TPS data are not sufficient for use in calculating the out-of-field doses. These results can be used to estimate non-target organ doses to patients.


Self-reported symptoms among cancer survivors in the Women's Health Initiative (WHI) Life and Longevity after Cancer (LILAC) cohort.
Due to cancer survivors living longer and morbidity associated with cancer treatments, it is necessary to understand symptoms experienced by cancer survivors. This study will analyze the symptom burden among a large cohort of survivors across multiple cancer sites. Data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study were used to examine the symptom burden of older cancer survivors. Poisson regression with robust standard errors was utilized to determine differences in symptoms by cancer site, treatment, and other covariates. The most frequently reported symptoms among cancer survivors were fatigue (15.8%) and feeling sad or depressed (14.1%). Multivariable analyses indicated that more symptoms were reported among survivors who were younger (p = 0.002), divorced or separated (p = 0.03), and had a combination of public and private insurance (p = 0.01). Survivors who received chemotherapy (p < 0.001), radiation (p = 0.01), or hormone therapy (p = 0.02) reported more symptoms than survivors who did not receive these treatments. Survivors diagnosed with cancer < 5 years ago reported fewer symptoms than longer-term survivors, particularly those diagnosed > 10 years ago (p = 0.02). Results indicate that common physical and psychological symptoms are reported across cancer types. Cancer survivors diagnosed with cancer 10 or more years ago reported more symptoms than those recently diagnosed. This suggests that symptoms may remain a problem for some survivors decades after their diagnosis. Future research should focus on implementing active surveillance of cancer survivors. Healthcare providers and those who care for cancer survivors should understand that the symptom burden associated with cancer may persist even decades following diagnosis.


Prolonged Disability following Re-Exposure after Complete Recovery from Aerotoxic Syndrome: A Case Report.
Aerotoxic syndrome is a rarely recognized and poorly defined illness resulting from exposure to products of oil combustion in commercial aircraft bleed air systems. The pathophysiology of this syndrome is not well understood. A 42-year-old male pilot developed duty-limiting symptoms consistent with aerotoxic syndrome following exposure to airline cabin fumes and recurrence of symptoms following re-exposure despite apparent full recovery from the initial exposure event. Given his persistent symptoms and concern for immediate debilitation/incapacitation if re-exposed, the pilot was deemed medically unqualified for return to commercial piloting duties and a disability determination was made. Consideration of aerotoxic syndrome in aircrew members with unusual or episodic symptoms of neuro/cognitive dysfunction is essential for further characterizing this occupational illness, guiding medical management, and understanding its impact on aviation workforce health.


A Defect Engineered Electrocatalyst that Promotes High-Efficiency Urea Synthesis under Ambient Conditions.
Synthesizing urea from nitrate and carbon dioxide through an electrocatalysis approach under ambient conditions is extraordinarily sustainable. However, this approach still lacks electrocatalysts developed with high catalytic efficiencies, which is a key challenge. Here, we report the high-efficiency electrocatalytic synthesis of urea using indium oxyhydroxide with oxygen vacancy defects, which enables selective C-N coupling toward standout electrocatalytic urea synthesis activity. Analysis by operando synchrotron radiation-Fourier transform infrared spectroscopy showcases that *CO2NH2 protonation is the potential-determining step for the overall urea formation process. As such, defect engineering is employed to lower the energy barrier for the protonation of the *CO2NH2 intermediate to accelerate urea synthesis. Consequently, the defect-engineered catalyst delivers a high Faradaic efficiency of 51.0%. In conjunction with an in-depth study on the catalytic mechanism, this design strategy may facilitate the exploration of advanced catalysts for electrochemical urea synthesis and other sustainable applications.


Environmental factors associated with physical activity in childcare centers.
Child care centers influence physical activity levels among children, yet little is known about the specific aspects of the environment that support generous amounts of activity. The purpose of this study was to examine the practices, and environmental aspects of the child care center that are associated with children's moderate and vigorous physical activity. Thirty-five child care centers serving 389 3 to 5 year old children were assessed for: 1) environmental characteristics of the center; and 2) staff practices related to child physical activity. Children's physical activity was measured using accelerometers over a single day in child care. Fourteen percent (an average of 9 minutes per waking hour) were spent in moderate to vigorous physical activity (MVPA). The strongest environmental predictors of MVPA were: time spent in outdoor play, suitability of indoor play space, and teacher encouragement of (but not participation in) indoor play. In order to reach the U.S. recommended 120 minutes of physical activity per day, significant changes will need to occur in the child care setting, including increased time outdoors and more opportunities for indoor physical activity.


A generalized theory of carcinogenesis due to chronodisruption.
For two decades, research has been suggested and conducted into the causation and development of cancers in seemingly diverse and unrelated populations such as blind individuals, shift-workers, flight personnel, Arctic residents and subsets of sleepers. One common denominator of these investigations is "melatonin". Another common denominator is that all these studies implicitly pursued the validity of the so-called "melatonin hypothesis", of a corollary and of associated predictions which can be united in our proposed theory of "carcinogenesis due to chronodisruption". The new theory suggests that the various predictions investigated between 1987 and 2008 represent different aspects of the same problem. Indeed, abundant experimental evidence supports the notion that the final common cause of many cases of cancer may be what has been termed chronodisruption (CD), a relevant disturbance of the temporal organization or order of physiology, endocrinology, metabolism and behaviour. While melatonin as a key time messenger and time keeper can be a marker of CD, it is probably only partially related to the differential cancer occurrence apparent in individuals who chronically or frequently experience an excess or deficit of chronodisruption.