Detection of reassortant avian influenza A (H11N9) virus in environmental samples from live poultry markets in China.
Avian influenza viruses have caused human infection and posed the pandemic potential. Live poultry markets are considered as a source of human infection with avian influenza viruses. Avian influenza routine surveillance of live poultry markets is taken annually in China. We isolated the 2 H11N9 influenza virus from the surveillance program. To better understand the risk caused by these new viruses, we characterize the genetic and pathogenicity of the two viruses. Viral isolation was conducted with specific pathogen-free (SPF) embryonated chicken eggs. Whole genome was sequenced, and phylogenetic analysis was conducted. Two H11N9 viruses were identified, with all 8 segments belonging to the Eurasian lineage. The HA, NA, M, NS and PA genes were similar to virus isolates from ducks, and the NP, PB2 and PB1 gene segments were most similar to those viruses from wild birds, indicating that the H11N9 viruses might represent reassortant viruses from poultry and wild birds. The HA receptor binding preference was avian-like, and the cleavage site sequence of HA showed low pathogenic. The NA gene showed 94.6 % identity with the novel H7N9 virus that emerged in 2013. There was no drug resistance mutation in the M2 protein. The Asn30Asp and Thr215Ala substitutions in the M1 protein implied a potentially increased pathogenicity in mice. Both viruses were low-pathogenic strains, as assessed by the standards of intravenous pathogenicity index (IVPI) tests. Two reassortant H11N9 avian influenza viruses were detected. These viruses showed low pathogenicity to chickens in the IVPI test. Public health concern caused by the reassortant H11N9 viruses should be emphasized during the future surveillance.


De novo biosynthesis of nucleotides and of nucleic acids in different regions of developing rat brain: effect of undernutrition.
The effect of undernutrition on the de novo biosynthesis of nucleic acids in cerebral hemispheres, cerebellum, and brain stem of rats at different days of postnatal development was studied. The experiments were carried out in vitro by measuring the incorporation of [14C]-formate into the adenine nucleotide of the acid-soluble fraction of RNA and DNA, as well as into the thymine of DNA. The results obtained indicate that undernutrition during fetal and postnatal development impairs the de novo synthesis of the purine nucleotides of RNA and DNA at 5 days of age and delays it thereafter in the various brain regions examined, particularly in the cerebellum.


Retracted: Analysis of Clinicopathological Factors Associated with Radiation-Induced Cystitis in Patients with Cervical Cancer.
[This retracts the article DOI: 10.1155/2022/6216072.].


The challenges of pain management in primary care: a pan-European survey.
The OPENMinds Primary Care group is a group of European primary care physicians (PCPs) with an interest in pain management, formed to improve the understanding and management of chronic pain in primary care. A survey was conducted to assess the challenges of chronic nonmalignant pain (CNMP) management in primary care in Europe, focusing particularly on pain assessment, opioid therapy, and educational needs. A questionnaire was developed for online use by PCPs in 13 European countries (Belgium, Denmark, France, Germany, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the UK). A total of 1309 PCPs completed the questionnaire, approximately 100 from each country. Most PCPs (84%) perceived CNMP to be one of the most challenging conditions to treat, yet a low priority within healthcare systems. Only 48% of PCPs used pain assessment tools, and 81% considered chronic pain and its impact on quality of life to be underassessed in primary care. PCPs were less confident about prescribing strong opioids for CNMP than for use in cancer pain. Most PCPs (84%) considered their initial training on CNMP was not comprehensive, with 89% recognizing a need for more education on the topic. These findings reveal that PCPs in Europe find CNMP a challenge to treat. Areas to address with training include underuse of pain assessment tools and lack of confidence in use of opioid therapy. Guidelines on CNMP management in primary care would be welcomed. The insights gained should provide the basis for future initiatives to support primary care management of chronic pain.


Interpersonal problem solving: a theoretical perspective and methodology for the evaluation of residency education and its' relationship to health care processes and outcomes.
The study conceptualizes and implements an interaction model of interpersonal problem solving in the clinical milieu. This method of representing the interpersonal problem solving process and its relation to patient adherence is shown as an important tool for the evaluation of residency programs.


Hepatitis B virus genotypes in southwest Iran: molecular, serological and clinical outcomes.
To investigate the associations of hepatitis B virus (HBV) genotype with HBeAg and anti-HBe status, alanine aminotransferase (ALT) levels and HBV-DNA detection in different groups of HBV-infected patients in southwest Iran. A total of 89 HBsAg-positive serum samples were collected from the same number of patients. All sera were then investigated to determine HBV DNA and serological markers. For all the polymerase chain reaction (PCR)-positive samples, biochemical, histopathological assays and genotyping were also performed. Genotype D was the only type of HBV found in different clinical forms of acute and chronic infections. There was a high prevalence of HBeAg-negative HBV-infected patients with chronic hepatitis (52.7%). Out of 55 patients with chronic hepatitis, seven (12.7%) were diagnosed with cirrhosis. A significant association between the presence of anti-HBe antibody and an increase in ALT level, among either HBeAg-negative (P = 0.01) or HBeAg-positive (P = 0.026) patients, was demonstrated. No significant differences were observed between the clinical outcomes of HBeAg-positive and -negative individuals (P = 0.24). Genotype D has been recognized as the only type of HBV found in different clinical forms of HBV infections, including cirrhosis, among the residents of southwest Iran. Anti-HBe possibly plays a role in disease progression in some patients with chronic hepatitis, at least for a period of disease.


The Acceptance and Use of the e-Health Instrument 'The Personal Health Check' in Four Dutch Municipalities: Lessons Learned.
This pilot study assessed the acceptance and use of the e-Health instrument "the Personal Health Check" (PHC) among clients and professionals in primary care settings. By filling in the online PHC instrument, participants were provided insights into their health and lifestyle. When results revealed an increased health risk, participants were advised to undertake additional lab tests measuring blood pressure and haemaglobin levels. Based on the online questionnaire and optional lab tests, participants then received a report that included individually-tailored feedback from the e-Health application about personal health risks and suggestions for health interventions. The PHC was implemented in 2016 in four Dutch municipalities that determined which neighbourhood(s) the PHC targeted and how participants were invited. The Unified Theory of Acceptance and Use of Technology was used as a theoretical framework to address our research questions. Methods used to assess acceptance were: PHC instrument data, data from additional questionnaires completed by PHC participants, focus groups with PHC participants and professionals in primary care, and telephone interviews with non-responders to the invitation to participate in the online PHC. Of the 21,735 invited, 12% participated. Our results showed that participants and professionals in this pilot were predominantly positive about the PHC. Participants reported that they made an effort to apply the PHC lifestyle advice they received. Almost all had the knowledge and resources needed to use the PHC online instrument. Invitations from general practitioners almost doubled participation relative to invitations from the sponsoring municipalities. The overall low response rate, however, suggests that the PHC is unsuitable as a foundation on which to develop local public health policy.


Inhibited sexual desire in women.
A multifaceted study was conducted to identify differences in biopsychosocial characteristics between a clinical group of 59 married women who complained of inhibited sexual desire (ISD) and 31 married women who expressed normal sexual desire (non-ISD). Areas of examination included personality, endocrine, relationship, and sexual dimensions. Instruments of data collection included the MMPI, Dyadic Adjustment Scale, radioimmunoassay of testosterone and prolactin levels, and a questionnaire which focused on demographic, relationship, and sexual information. Statistical analyses indicated nonsignificant between-group differences on demographic characteristics, personality variables, and hormonal evaluation. Statistically significant differences were found between the two groups with regard to sexual history and several marital and sexual dimensions. The ISD group reported significantly greater dissatisfaction with these areas than the non-ISD group. Implications for clinical practice and research are discussed.


Isolation and characterization of polymorphic microsatellite loci from the invasive plant Solidago canadensis (Asteraceae).
Solidago canadensis, a clonal herb originally from North America (common name: Canada goldenrod), is an invasive species in many countries. We developed microsatellite primers for this species. Eleven polymorphic loci were generated and primers were designed. Polymorphism of these 11 loci was assessed in 35 plants from two populations (Wuhan and Shanghai) in China. The number of alleles per locus ranged from 3 to 14. The observed and expected heterozygosities varied from 0.0732 to 0.7391 and from 0.1177 to 0.8687, respectively. These microsatellite markers will be useful tools for studies of population genetics in the native and invasive range of this species.


Affinity of antithrombin III for insoluble modified polystyrene.
In previous papers we described insoluble polystyrenes grafted with L-arginyl methyl ester (PAOM) which exhibit a high affinity for thrombin. Based on their specific interaction with the protease, the resin has been used as stationary phases for affinity chromatographic procedure of thrombin in affinity chromatography (AC) and high performance liquid affinity chromatography (HPLAC). A slight adsorption of antithrombin III (AT III) was shown in AC. In this paper we study the interaction of AT III for PAOM resin in batch procedure. The adsorption is measured using purified protein and corresponds to a monolayer adsorbed on the surface of the polymer. The affinity constant is evaluated kAT = 3.10(5) 1.M-1. Furthermore, insoluble sulfonated polystyrenes grafted with different amino acid were shown to possess an heparin-like behaviour and catalyse the generation of thrombin-AT III complex. So, compared to one of the resin previously mentioned, it could be concluded that PAOM is not heparin-like. When thrombin is adsorbed on the surface of the polymer, AT III cannot interact with the specific seryl residue of the enzyme.


Bereavement and suicide bereavement as an antecedent of suicide in children and young people: Prevalence and characteristics.
There is limited research into bereavement and suicide bereavement as an antecedent of suicide in young people. We extracted information on the antecedents of suicide from official reports, primarily coroner inquests, on a 3-year national consecutive case series of all UK deaths by suicide in people aged 10-19. Between 2014 and 2016, there were 595 suicides by young people. 134 (25%) had been previously or recently bereaved; 51 (9%) by suicide, mainly of a friend or acquaintance. This is equivalent to 1 in 4 and 1 in 11, respectively, of all young people who die by suicide. Bereavement added to existing adversities - many antecedents of suicide were more likely in young people who were bereaved compared to those who were not, but there were few differences in the experiences of young people bereaved by suicide compared to other causes. This was an observational, not a risk factor study, and we did not use a control group. It is difficult to obtain data on non-suicide controls due to the ethical implications in contacting families, and the fact of suicide itself, its impact on disclosure and the reluctance of potential controls distorting any comparisons. Lasting bereavement support needs to be routinely and immediately available for young people, including those who have experienced the death of a friend or acquaintance. Vigilance of agencies for bereaved young people is required, especially if there is evidence of other adversities.


The Effects of Stochasticity at the Single-Cell Level and Cell Size Control on the Population Growth.
Establishing a quantitative connection between the population growth rate and the generation times of single cells is a prerequisite for understanding evolutionary dynamics of microbes. However, existing theories fail to account for the experimentally observed correlations between mother-daughter generation times that are unavoidable when cell size is controlled for, which is essentially always the case. Here, we study population-level growth in the presence of cell size control and corroborate our theory using experimental measurements of single-cell growth rates. We derive a closed formula for the population growth rate and demonstrate that it only depends on the single-cell growth rate variability, not other sources of stochasticity. Our work provides an evolutionary rationale for the narrow growth rate distributions often observed in nature: when single-cell growth rates are less variable but have a fixed mean, the population will exhibit an enhanced population growth rate as long as the correlations between the mother and daughter cells' growth rates are not too strong.


Treatment of acromegaly with octreotide-LAR: extensive experience in a Brazilian institution.
Somatostatin analogues have become the mainstay of the medical treatment of acromegaly. The aim of our study was to evaluate the efficacy and tolerability of octreotide-LAR (OCT-LAR) treatment in acromegalic patients. Prospective open trial. Eighty acromegalic patients (46 women; 18-80 years) were treated with OCT-LAR. Mean +/- SD duration of follow-up was 16.6 +/- 6.6 months (6-24 months). Twenty-eight patients received OCT-LAR as primary treatment. The target was to achieve normal IGF-I levels. Clinical activity was evaluated by symptom score and fasting samples for GH and IGF-I serum concentrations, obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging of the sella. A tumour volume reduction of at least 25% was considered significant. Clinical improvement was attained in most patients. Fifty-nine (74%) of them attained mean GH < 2.5 ng/ml and 33 (41%) achieved normal IGF-I by the 24th month of treatment. GH and IGF-I control increased throughout treatment. Regarding the 46 patients treated for at least 12 months there was a significant decrease of GH and IGF-I levels by the third month compared to basal levels, persisting with no subsequently variation. In the patient group that achieved normal serum IGF-1 during treatment (controlled group: n = 43) 20 patients maintained normal levels up to the latest follow-up, whereas 23 of them once again showed altered serum IGF-1-values of some measurements during follow-up, despite dose maintenance or elevation. Baseline percentage of the upper limit of IGF-I normal range, GH levels by the third month and length of treatment were predictive factors of IGF-I normalization. Tumour shrinkage occurred in 76% of primary patients. Among 21 diabetic patients, four worsened and five improved glycaemic control, based on glycated haemoglobin. One previously intolerant patient progressed to overt diabetes. Nine patients developed gall bladder sludge, other nine patients acquired microlithiasis and one patient developed gallstone pancreatitis. OCT-LAR is an effective agent in alleviating symptoms, suppressing GH, normalizing IGF-I and inducing tumour shrinkage in many acromegalic patients. Overall, OCT-LAR is well tolerated and should be recommended for nonsurgically cured acromegalics, and also be considered as primary therapy for selected cases, mainly for those with a low probability of surgical cure.


Prenatal tobacco exposure, birthweight, and offspring psychopathology.
Although prenatal tobacco exposure (PTE) is associated with several adverse offspring mental health outcomes, mechanisms remain unclear. We test whether associations between PTE and offspring psychopathology are explained by birthweight, one of the earliest-occurring outcomes of PTE. The analysis focuses on 238 offspring from a family study of depression with (1) collected prenatal histories and (2) at least one clinical interview in adulthood to assess psychiatric problems. Exposure was categorized by maternal smoking of ≥10 cigarettes daily/nearly daily; diagnostic outcomes were confirmed by clinicians using the best-estimate procedure, blind to exposure. After adjusting for potential confounders, PTE was associated with 0.7lb(9%) lower birthweight (p=0.0002), increased rates of disruptive behavior disorders [males: OR=2.66(1.15,6.16), and (trend) substance use disorders [females: OR=2.23(0.98,5.09)], and decreased rates of mood disorders (males: OR=0.42(0.17,0.98)]. Birthweight was not independently associated with diagnoses and did not mediate the association between exposure and psychopathology. Maternal smoking has long-term adverse consequences for offspring. Although birthweight cannot be manipulated, smoking is a modifiable risk factor. Thus, cessation efforts focused on pregnant women may not only improve maternal wellbeing, but also mitigate adverse proximal (e.g., birthweight) and long-term (psychopathology) outcomes in offspring.


Feasibility study of student telehealth interviews.
The COVID-19 pandemic has led to medical students being taught remote clinical communication modalities (telephone and video). Junior students have not generally been included in this and have had less patient contact than previously. This study aimed to examine the feasibility from the junior student viewpoint of conducting both modalities of patient telehealth interviews. An electronic questionnaire was used to discover Year 1 student reasons for their preferred modality after they had conducted one telephone and one video interview in pairs with a patient volunteer. Student views on the challenge and benefits of each were also sought. A total of 55 (32.7% of the cohort) responded, of whom 82% preferred video consultation, 75.6% of those stating being able to see their patient/partner was a key factor. About 5% preferred telephone interview, and 13% had no preference. Telephone interviews were perceived as the more challenging (40% versus 12.7%); however, challenge did not directly link with lack of comfort. There were some technical/connectivity issues with both modalities, and the telephone call system was more complex to set up. Turn-taking was more difficult by telephone without visual cues. This is the first direct comparison study in junior medical students of real patient interviews by video or telephone. Students embraced the challenge and, although preferring video and finding telephone more challenging, valued each as an educational experience. Telehealth interviews with patients for junior students are feasible, give needed patient exposure, practical insights into remote modalities and consolidate communication skills learnt in the classroom.


mTOR inhibition potentiates cytotoxicity of Vγ4 γδ T cells via up-regulating NKG2D and TNF-α.
γδ T cells play a critical role in early anti-tumor immunity and perform cytotoxicity via NKG2D for recognition and multiple cytotoxic factors for tumor killing. Recent studies have demonstrated pivotal roles of mTOR-mediated metabolism in the maturation, differentiation, and effector function of diverse immune cells, including DCs, NK cells, CD4+ T cell subsets, and CD8+ T cells, but the role of mTOR signaling in γδ T cells is barely known. Here, we showed that suppressing mTOR signaling in in vitro-expanded Vγ4 γδ T cells via the mechanistic inhibitor rapamycin enhanced their cytotoxicity against multiple tumor cell lines, and these cells performed better tumor-suppressing effects upon adoptive therapy. Further investigation revealed that elevated cytotoxicity was a result of up-regulation of NKG2D and TNF-α. Moreover, rapamycin treatment significantly decreased the expression of CISH and increased pSTAT5. The inhibition of STAT5 pathways via siRNA interference or a specific inhibitor eliminated the up-regulation of NKG2D and TNF-α in rapamycin-treated Vγ4 γδ T cells. These results uncovered an important role of mTOR signaling in the cytotoxic effector function of γδ T cells and provided a potential strategy to improve γδ T cell-based cancer immunotherapy.


Acute myelofibrosis in progressive systemic sclerosis. Report of a case developing during long term chlorambucil therapy and discussion of pathogenetic factors.
A case of acute myelofibrosis occurring in the course of long-term chlorambucil therapy for cardiac manifestations of progressive systemic sclerosis (PSS) is reported. Although hematologic malignancies have been known to develop consequent to long-term use of alkylating agents, and bone marrow suppression is well known, acute myelofibrosis has not, to our knowledge, been reported as a complication of this therapy, nor has any specific myeloproliferative syndrome been described consequent to such therapy in a patient with PSS. As abnormal fibroblastic proliferation is central to both PSS and myelofibrosis, it may be speculated that the patient with scleroderma may be predisposed to this particular expression of hematologic dyscrasia. The roles of fibroblastic proliferation, and immunologic and vascular factors in these two illnesses are currently poorly understood.


Assessment of snout analysis of Himalayan glaciers: impact studies on Pindari, Kafni, Sundardhunga, and Baljuri base camp glaciers.
There are several causes for the increasing rate of deglaciation, such as global warming, increase in the concentration of black carbon, and extensive use of fossil fuels which causes the change in the overall climate system and shifting glacier ecosystem. This study was conducted on Pindari valley glaciers part of lesser Himalaya in Uttarakhand. This study investigates to (1) monitor and map change in the frontal length or the snout region of a glacier that can be studied with the help of remote sensing techniques and (2) evaluate the decadal and annual retreat rate of the glacier from 1972 to 2018. The study applies both the maximum likelihood classifier and NDSI spectral indices based classification for extracting the glacier region for different periods. This study reveals a significant amount of retreats taking place in the selected glaciers, Pindari, Sundardhunga, Kafni, and Baljuri base camp glaciers, from 1972 to 2018 as 1719.95 m, 1751.21 m, 1057.01 m, and 810.78 m, respectively. The highest amount of change is noticed in Pindari and Sundardhunga glaciers, higher than ~ 1700 m. The study analyses temporal variation of the annual and decadal retreat rate in the Pindari valley glaciers, which would be helpful for the further study of the other glaciers.


Combined effects of nanoparticles and other environmental contaminants on human health - an issue often overlooked.
Air pollution is considered as a major public health issue worldwide. It consists of a complex mixture of pollutants including nanoparticles to which we are increasingly exposed to due to the dramatic development of the nanotechnologies and their incidental or intentional release in the environment. Consequently, some concerns have raised about the combined toxicity of air particulates and other air pollutants on human health. However, the interactions between the contaminants and their resulting combined toxicity are often overlooked. Indeed, the biological effects triggered by nanoparticles are usually assessed focusing on individual nanoparticles, while their interaction with co-contaminants can deeply impact, either positively or negatively, their biodistribution, fate in the organism and toxicological profile (additive, synergistic or antagonistic responses). This paper presents a bibliographic review on the combined toxicity of nanoparticles and co-pollutants and discusses the underlying mechanisms. It also highlights the scarcity of data in the current literature, arguing for an urgent need to take into account the mixture effects to be more representative of real-life conditions for a better and accurate human health risk assessment and management.


[Biocompatibility of implants with and without fluorohydrocarbon glow polymer coating. 4. Recommendations for the histocompatibility (repair) index for the evaluation of various implant materials].
The measurement of the thickness of the fibrous capsula around implant materials to different titmes and the material dependent speed of the subsidence process of the tissue reaction were formed to an index. The derivation of the index is described by a course study with 4 materials about 5 periods. The determination of the index is represented simply mathematically and also delineating-geometrically. The index should be determined between 50 and 200 days, better between 90 and 150 days. Individual wound reactions superimpose the material effect before and the final state of the tissue reaction hinders the speed interpretation of the quickness of subsidence prgcess after this period.


Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose.
To determine whether high-dose fish oil is superior to low-dose supplementation for symptomatic and structural outcomes in knee osteoarthritis (OA). A randomised, double-blind, multicentre trial enrolled 202 patients with knee OA and regular knee pain. They were randomised 1:1 to high-dose fish oil (4.5 g omega-3 fatty acids) 15 mL/day or (2) low-dose fish oil (blend of fish oil and sunola oil; ratio of 1:9, 0.45 g omega-3 fatty acids) 15 mL/day. The primary endpoints were Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score at 3, 6, 12 and 24 months, and change in cartilage volume at 24 months. Secondary outcomes included WOMAC function, quality of life, analgesic and non-steroidal anti-inflammatory drug use and bone marrow lesion score. Although there was improvement in both groups, the low-dose fish oil group had greater improvement in WOMAC pain and function scores at 2 years compared with the high-dose group, whereas between-group differences at 1 year did not reach statistical significance. There was no difference between the two groups in cartilage volume loss at 2 years. For other secondary endpoints, there was no difference between the two groups at 2 years. In people with symptomatic knee OA, there was no additional benefit of a high-dose fish oil compared with low-dose fish oil. The combination comparator oil appeared to have better efficacy in reducing pain at 2 years, suggesting that this requires further investigation. Australian New Zealand Clinical Trials Registry (ACTRN 12607000415404).


Epidemiology of cancer-related fatigue in the Swedish twin registry.
Estimates of the prevalence of cancer-related fatigue (CRF) are wide, and data suggest that fatigue is more prevalent among cancer patients than among the general population. However, most studies examining the prevalence of CRF have been hospital-based or clinic-based studies, which often are subject to bias. Point prevalence and prevalence odds ratios of fatigue were estimated using data from a large, population-based cohort that was screened for fatigue and linked with national registry-based data about cancer. Prevalence odds ratios and 95% confidence intervals were calculated using logistic regression with general estimating equations. Approximately 23% of cancer registrants reported abnormal fatigue in the previous 6 months, 19% reported abnormal fatigue that lasted for at least 1 month, 14% reported abnormal fatigue that lasted at least 6 months, and 11% reported abnormal fatigue that lasted at least 6 months and caused significant functional impairment. Individuals who were listed in the cancer registry within the last 5 years were more likely to report experiencing fatigue than individuals who were not listed. There was an elevated prevalence of fatigue among those who were registered with carcinomas of the lung, uterine cervix, colon-rectum, ovaries, and prostate. Both women and men who were listed recently in the cancer registry were more likely to experience any level of fatigue than the comparison group. However, a greater proportion of women experienced fatigue relative to men. A greater proportion of individuals who were listed in a national cancer registry reported experiencing fatigue compared with individuals in the general population.


Recent Advances in Renal Tumors with TSC/mTOR Pathway Abnormalities in Patients with Tuberous Sclerosis Complex and in the Sporadic Setting.
A spectrum of renal tumors associated with frequent TSC/mTOR (tuberous sclerosis complex/mechanistic target of rapamycin) pathway gene alterations (in both the germline and sporadic settings) have recently been described. These include renal cell carcinoma with fibromyomatous stroma (RCC FMS), eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT). Most of these entities have characteristic morphologic and immunohistochemical features that enable their recognition without the need for molecular studies. In this report, we summarize recent advances and discuss their evolving complexity.


On GABAergic mechanisms in the optokinetic nystagmus of the frog: effects of bicuculline, allylglycine and SR 95103, a new GABA antagonist.
In a monocular situation, an intravitreal injection of the GABA antagonists, bicuculline or SR 95103 provoked both the suppression of the optokinetic nystagmus (OKN) related to the injected eye and the appearance of a Nasal-Temporal (N-T) component in the OKN triggered by the contralateral non-injected eye (this N-T component being absent in control OKN). These two effects were added in a binocular condition. Similar results were obtained with L-C allylglycine which reduces the endogenous GABA level, but these effects were delayed when compared to those of GABA antagonists. All these data are roughly analogous to those previously obtained with picrotoxin (a non-competitive GABA antagonist) and thus confirm that GABA mechanisms are involved in the control of the frog OKN. Furthermore, SR 95103 acted in this model as a potent selective GABA antagonist, as has been demonstrated in another system.


Preparation and characterization of starch-based nanocomposites reinforced by graphene oxide self-assembled on the surface of silanecouplingagent modified cellulose nanocrystals.
The dispersion of cellulose nanocrystal (CNC) in starch matrix limited its application. In this study, CNC modified by silanecouplingagent before graphene oxide (GO) self-assembled on the surface of modified CNC, then CNC-GO as a filler was used to prepare starch-based nanocomposite films (CS/CNC-GO). The structure of CNC-GO and CS/CNC-GO films and the properties of CS/CNC-GO films were studied by FT-IR, Raman, SEM, surface potential, UV-Vis, moisture absorption and tensile tests. The results showed that GO was successfully self-assembled on the surface of CNC modified by silanecouplingagent. CNC-GO was superior to CNC in reinforcing the strength of starch film, improving the transmittance of starch film and decreasing moisture rate of starch film. Tensile strength, elongation at break and transmittance of CS/CNC-GO film with 5 wt% CNC-GO reached maximum, which was 53.96 MPa, 3.72% and 38.76%, respectively. Moisture rate of CS/CNC-GO film with 3 wt% CNC-GO reached minimum that was 12.13%. These were assigned to the more uniform dispersion of CNC-GO in the starch matrix and the stronger interfacial interaction between starch and CNC-GO.


[Expression of SDHB, EPAS1 and MIB-1 in Zuckerkandl paragangliomas].
To explore the significance of succinate dehydrogenase B (SDHB) mutation and EPAS1 overexpression in Zuckerkandl paragangliomas (PGL) and examine their correlations with malignant infiltration and metastasis. From March 2008 to July 2011, the clinical profiles of 16 Zuckerkandl PGL patients were analyzed retrospectively. For increased diagnostic specificity, a complex immunohistochemical panel of tissue microarray was performed for SDHB, EPAS1 and MIB-1. Positive expression identified as a granular cytoplasmic staining. Greater than or equal to 50% as strongly positive (+++), 1% to 10% as weakly positive (+). Tissue microarray immunohistochemical staining showed SDHB immunoreactivity in the cytoplasm, whereas EPAS1 and MIB-1 in the nuclear of tumor cells. Positive expression of EPAS1 in which 13 cases of Zuckerkandl PGL. And high expression strongly associated with malignancy. SDHB mutation of 7 cases are all EPAS1 positive staining. Non-gene mutation 9 cases tumor specimens, 6 cases were EPAS1 positive expression (P < 0.05). CgA positive expression in 11 cases benign Zuckerkandl PGL, strongly positive in 4 malignant cases (4/4). MIB-1 below 1% in 12 cases of benign Zuckerkandl PGL. And in 4 malignant cases, MIB-1 was about 3%. Malignant neoplasms had significantly higher EPAS1, CgA and MIB-1 expression compared to benign counterparts (P < 0.05). The SDHB mutation causes the EPAS1 over expression in PGL and correlation with higher positive expression of CgA and MIB-1. It may be one of the mechanisms of malignant invasiveness and metastasis in PGL.


Programmable ribozymes for mischarging tRNA with nonnatural amino acids and their applications to translation.
Here we describe a novel technology that allows users to charge nonnatural amino acids onto any tRNA. This technology is based on a resin-immobilized ribozyme system, called Flexiresin. It enables users to readily and rapidly synthesize misacylated tRNAs with a wide variety of phenylalanine analogs. Since Flexiresin is reusable and little effort is necessary for regeneration, it is economical and convenient. Moreover, it can adapt to virtually any tRNA chosen by the user, and can therefore be applied to not only a single site mutation but also multiple sites with designated nonnatural amino acids when both the amber and programmed frame-shift mutations are utilized. The original ribozyme utilized for Flexiresin was artificially generated in vitro, and thus the technology in principle could be broadened from Phe analogues to essentially any amino acid.


Screening for Duchenne muscular dystrophy in Germany, 1977-2011: A personal story.
This article by Dr. Günter Scheuerbrandt is a fascinating personal account and historical narrative of the birth and development of a screening program for Duchenne Muscular Dystrophy in Germany, beginning 40 years ago. As the author notes, approval of an institutional review board or ethics committee was not required for this type of scientific investigation in one's field at the time this program was begun, but we have removed all personal data from any of the materials presented in here in order to conform to current concepts of ethical publication. This article is about the screening of 528,410, mostly 4-6-week-old, boys in Germany between 1977 and 2011 for high levels of creatine kinase (CK) to identify those with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). During these 34 years of infant screening, 147 boys with confirmed, probable, and possible DMD (incidence 1:3,600 male births) and 33 boys with confirmed, probable, and possible BMD (incidence 1:15,500 male births) were found. Research reports about DMD were sent to families and pediatricians participating in the screening, and, on request, to families and scientists everywhere. It is hoped that screening programs used as the basis for future therapies will be able to modify the natural history of boys with DMD. New dystrophin mutations will continue to occur, necessitating screening and early therapy. Abstract Submitted for Presentation at the 10th International Society for Neonatal Screening-Asia Pacific Regional Meeting, August 2017, Ulaanbataar, Mongolia. Muscle Nerve 57: 185-188, 2018.


Evolution of the American College of Surgeons Children's Surgery Verification Program: Implications for optimizing multidisciplinary surgical care of the pediatric patient.
The Children's Surgery Verification Program of the American College of Surgeons began in 2016 based on the standards created by the Task Force for Children's Surgery. This program seeks to improve the surgical care of children by assuring the appropriate resources and robust performance improvement programs at participating centers. Three levels of centers with defined scopes of practice and matching resources are defined. Since its inception more than 50 center have been verified. A specialty hospital program was launched in 2019. The standards for all hospitals were revised in 2021 based on lessons learned. In this article the leaders of the program discuss the development, areas of greatest impact and future directions of the program.


Ontogenic modifications in the effect of the GABAergic system on the hypothalamic excitatory amino acids: its relationship with GABAergic control of gonadotrophin secretion during sexual maturation in female rats.
Aminooxyacetic acid (AOAA), an inhibitor of gamma-aminobutyric transaminase, stimulates the in vitro GABA release by medial and anterior preoptic hypothalamic areas in prepubertal female rats (6, 15 and 30 days of age). This increase of GABA release at 15 days of age, was accompanied by a significant increase (P<0.01) in the hypothalamic release of glutamate (GLU) and aspartate (ASP), the excitatory amino acids involved in N-methyl-D-aspartate neurotransmission and a decrease in the release of these excitatory amino acids at 6 and 30 days of age (P<0.01). The increase in the hypothalamic release of GLU and ASP at 15 days of age was accompanied by a significant increase of the plasmatic LH and FSH concentration, while the hypothalamic decrease of excitatory amino acids release induced by AOAA also decreased LH and FSH plasmatic levels at 6 and 30 days of age. In summary, the present results show that in female rats there are differences in the effect of GABAergic system the hypothalamic release of GLU and ASP and on gonadotrophin secretion at different ages of prepubertal period, i.e. an inhibitory effect at 6 and 30 days of age and a stimulatory one at 15 days of age. It is proposed that the different effects of GABA on gonadotrophin secretion in prepubertal rats previously described are connected with ontogenic changes in the interrelationships between GABAergic and NMDA neurotransmission systems during sexual maturation of the hypothalamus in female rats. It is probable that these ontogenic modifications are connected with the maturation of interneuronal connection and/or new receptors activity.


Development, organization, and remodeling of phoronid muscles from embryo to metamorphosis (Lophotrochozoa: Phoronida).
The phoronid larva, which is called the actinotrocha, is one of the most remarkable planktotrophic larval types among marine invertebrates. Actinotrochs live in plankton for relatively long periods and undergo catastrophic metamorphosis, in which some parts of the larval body are consumed by the juvenile. The development and organization of the muscular system has never been described in detail for actinotrochs and for other stages in the phoronid life cycle. In Phoronopsis harmeri, muscular elements of the preoral lobe and the collar originate in the mid-gastrula stage from mesodermal cells, which have immigrated from the anterior wall of the archenteron. Muscles of the trunk originate from posterior mesoderm together with the trunk coelom. The organization of the muscular system in phoronid larvae of different species is very complex and consists of 14 groups of muscles. The telotroch constrictor, which holds the telotroch in the larval body during metamorphosis, is described for the first time. This unusual muscle is formed by apical myofilaments of the epidermal cells. Most larval muscles are formed by cells with cross-striated organization of myofibrils. During metamorphosis, most elements of the larval muscular system degenerate, but some of them remain and are integrated into the juvenile musculature. Early steps of phoronid myogenesis reflect the peculiarities of the actinotroch larva: the muscle of the preoral lobe is the first muscle to appear, and it is important for food capture. The larval muscular system is organized in differently in different phoronid larvae, but always exhibits a complexity that probably results from the long pelagic life, planktotrophy, and catastrophic metamorphosis. Degeneration of the larval muscular system during phoronid metamorphosis occurs in two ways, i.e., by complete or by incomplete destruction of larval muscular elements. The organization and remodeling of the muscular system in phoronids exhibits the combination of protostome-like and deuterostome-like features. This combination, which has also been found in the organization of some other systems in phoronids, can be regarded as an important characteristic and one that probably reflects the basal position of phoronids within the Lophotrochozoa.


Increased serum aldosterone in diabetic pregnancy.
Serum levels of aldosterone and cortisol were measured by radioimmunoassay in 15 patients with gestational diabetes, in 18 patients with Type 1 (insulin-dependent) diabetes, in 36 pregnant control women and in 10 non-pregnant control women. All subjects, on habitual sodium and potassium intake, were sampled in a supine position at 09.00 hours. Pregnant women were examined twice, during gestational week 32-34 and at delivery. Serum levels of aldosterone and cortisol were also measured in the umbilical cord blood of newborn babies of these diabetic and non-diabetic mothers. Serum levels of aldosterone in both gestational and Type 1 pregnant diabetic women were found to be consistently above the reference values of non-diabetic pregnant women. Abnormal serum levels of aldosterone were also observed in newborn infants of diabetic mothers. In contrast, serum levels of cortisol were not increased.


A nonlinear epidemiological model considering asymptotic and quarantine classes for SARS CoV-2 virus.
In this article, we develop a mathematical model considering susceptible, exposed, infected, asymptotic, quarantine/isolation and recovered classes as in case of COVID-19 disease. The facility of quarantine/isolation have been provided to both exposed and infected classes. Asymptotic individuals either recovered without undergo treatment or moved to infected class after some duration. We have formulated the reproduction number for the proposed model. Elasticity and sensitivity analysis indicates that model is more sensitive towards the transmission rate from exposed to infected classes rather than transmission rate from susceptible to exposed class. Analysis of global stability for the proposed model is studied through Lyapunov's function.


Synthesis of ternary copper antimony sulfide via solventless thermolysis or aerosol assisted chemical vapour deposition using metal dithiocarbamates.
Copper antimony sulfide (Cu-Sb-S) has recently been proposed as an attractive alternative photovoltaic material due to the earth-abundant and non-toxic nature of the elements, high absorption coefficients and band gaps commensurate with efficient harvesting of solar photonic flux across multiple phases of Cu-Sb-S. These materials are therefore highly desirable and sustainable and scalable deposition techniques to produce them are of interest. In this paper, we demonstrate two facile, low-temperature and inexpensive techniques (solventless thermolysis and aerosol-assisted chemical vapor deposition (AACVD)) for the preparation of binary digenite (Cu1.8S), chalcocite (Cu2S) and stibnite (Sb2S3) and several phases of ternary copper-antimony-sulfide (Cu2xSb2(1-x)Sy, where 0 ≤ x ≤ 1). It was found that by utilising these different techniques and varying the ratio of Cu:Sb, pure phases of ternary chalcostibite (CuSbS2), fematinite (Cu3SbS4) and tetrahedrite (Cu12Sb4S13) can be achieved. Two single-source precursors were investigated for this purpose, namely the diethyldithiocarbamate (DTC) complexes of copper and antimony Cu(DTC)2 and Sb(DTC)3. These were decomposed both individually (to produce binary materials) and combined (to produce ternary materials) at different ratios. From the solventless thermolysis and AACVD methods, either particulate or thin film material was formed, respectively. These materials were then characterised by powder XRD, SEM, EDX and Raman spectroscopies to determine the crystalline phase, material morphology and uniformity of elemental composition. This analysis demonstrated that as the Cu-content increases, the phase of the ternary material changes from chalcostibite (CuSbS2) and fematinite (Cu3SbS4) at a low Cu:Sb ratio to tetrahedrite (Cu12Sb4S13) at a high Cu:Sb ratio.


Dermatomyositis: observations on the use of immunosuppressive therapy and review of literature. Cairo--Glasgow study group.
Seven young adults, six of whom were male, all suffering from dermatomyositis unassociated with malignancy are described. These patients were not adequately controlled with high doses of corticosteroids but all responded when immunosuppressive therapy was also given.


The impact of dietary fructose on gut permeability, microbiota, abdominal adiposity, insulin signaling and reproductive function.
The excessive intake of fructose in the regular human diet could be related to global increases in metabolic disorders. Sugar-sweetened soft drinks, mostly consumed by children, adolescents, and young adults, are the main source of added fructose. Dietary high-fructose can increase intestinal permeability and circulatory endotoxin by changing the gut barrier function and microbial composition. Excess fructose transports to the liver and then triggers inflammation as well as de novo lipogenesis leading to hepatic steatosis. Fructose also induces fat deposition in adipose tissue by stimulating the expression of lipogenic genes, thus causing abdominal adiposity. Activation of the inflammatory pathway by fructose in target tissues is thought to contribute to the suppression of the insulin signaling pathway producing systemic insulin resistance. Moreover, there is some evidence that high intake of fructose negatively affects both male and female reproductive systems and may lead to infertility. This review addresses dietary high-fructose-induced deteriorations that are obvious, especially in gut permeability, microbiota, abdominal fat accumulation, insulin signaling, and reproductive function. The recognition of the detrimental effects of fructose and the development of relevant new public health policies are necessary in order to prevent diet-related metabolic disorders.


Child organ trafficking: global reality and inadequate international response.
In organ transplantation, the demand for human organs has grown far faster than the supply of organs. This has opened the door for illegal organ trade and trafficking including from children. Organized crime groups and individual organ brokers exploit the situation and, as a result, black markets are becoming more numerous and organized organ trafficking is expanding worldwide. While underprivileged and vulnerable men and women in developing countries are a major source of trafficked organs, and may themselves be trafficked for the purpose of illegal organ removal and trade, children are at especial risk of exploitation. With the confirmed cases of children being trafficked for their organs, child organ trafficking, which once called a "modern urban legend", is a sad reality in today's world. By presenting a global picture of child organ trafficking, this paper emphasizes that child organ trafficking is no longer a myth but a reality which has to be addressed. It argues that the international efforts against organ trafficking and trafficking in human beings for organ removal have failed to address child organ trafficking adequately. This chapter suggests that more orchestrated international collaboration as well as development of preventive measure and legally binding documents are needed to fight child organ trafficking and to support its victims.


Earthquake exposure during adolescence and later-life depressive symptoms: A national cross-sectional survey.
This study aimed to examine the association between exposure to the 1976 Great Tangshan Earthquake (GTE) in adolescence and later-life depressive symptoms and to investigate the potential mechanisms underlying this association. Data were from the 2015 China Health and Retirement Longitudinal Study (CHARLS). The 10-item short form of the Center for Epidemiologic Studies Depression scale (CESD-10) was chosen to measure depressive symptoms. We used the difference-in-difference (DID) method, binary logistic regression models, and multilevel logistic regression models to explore the association of earthquake exposure during adolescence with later-life depressive symptoms. Additionally, multilevel mediation analysis with structural equation modeling (MMSEM) was conducted to investigate potential mechanisms. We identified that adolescent exposure to earthquakes was related to a lower risk of depressive symptoms in later life (OR = 0.90, P = 0.019; OR = 0.48, P = 0.031; OR = 0.47, P = 0.034, respectively). However, this significant association was observed only in females (OR = 0.83, P = 0.028; OR = 0.46, P = 0.053; OR = 0.42, P = 0.037, respectively). Moreover, social activity participation played a mediating role in the association between exposure to earthquakes in adolescence and later-life depressive symptoms. We observed a lower risk of depressive symptoms in later life in survivors of earthquake exposure during adolescence. Further, we found the mediating role of social participation in the association between earthquake exposure in adolescence and later-life depressive symptoms, which gives support for the posttraumatic growth (PTG) theory. Our findings imply that, in order to lower the risk of depression in later life following exposure to a natural disaster in adolescence, it is necessary to take into account the buffering effect of social participation.


Physician e-mail and telephone contact after emergency department visit improves patient satisfaction: a crossover trial.
Enhancing emergency department (ED) patient satisfaction has wide-ranging benefits. We seek to determine how postvisit patient-physician contact by e-mail or telephone affects patients' satisfaction with their emergency physician. We undertook this crossover study from May 1, 2010, to June 30, 2010, at 2 community EDs. Forty-two physicians either e-mailed or telephoned their patients within 72 hours of the ED visit for 1 month; in the alternate month, they provided no contact, serving as their own controls. Patients received satisfaction surveys after their ED visit. Patient satisfaction is reported as a percentage of those responding very good or excellent on a 5-point Likert scale for 3 questions about their emergency physician's skills, care, and communication. We calculated differences between patient groups (noncontact versus contact) using an intention-to-treat analysis. The mean patient satisfaction score was 79.4% for the 1,002 patients in the noncontact group and 87.7% for the 348 patients in the contact group (difference 8.3%; 95% confidence interval 4.0% to 12.6%). Patient satisfaction scores were similar for e-mail and telephone contact: 89.3% for the e-mail group and 85.2% for the telephone group (difference 4.1%; 95% confidence interval -2.3% to 10.5%). Patient satisfaction was higher when emergency physicians contacted patients briefly after their visit, either by e-mail or by telephone. Higher patient satisfaction was observed equally among patients contacted by e-mail and those contacted by telephone. Postvisit patient-physician contact could be a valuable practice to improve ED patient satisfaction.


Out of hours care in Germany - High utilization by adult patients with minor ailments?
Family practitioners (FPs) who work in Out-Of-Hours Care (OOHC) - especially in rural areas - complain about high workload related to low urgency and potentially unnecessary patient presentations with minor ailments. The aim of this study was to describe Reasons for Encounter (RFEs) in primary OOHC taken into account the doctor's perspective in the context of high workload without knowing patients' motives for visiting an OOHC-centre. Within this descriptive study, OOHC data from 2012 were evaluated from a German statutory health insurance company in the federal state of Baden-Wuerttemberg. 1.53 Million of the 10.5 Million inhabitants of Baden-Wuerttemberg were covered. The frequency of the ICD-10 diagnoses was determined at the three- and four-digit-level. The rate of hospitalizations was used to estimate the severity of the evaluated cases. Taken as a whole, 163,711 reasons for encounter with 1,174 ICD-10 single diagnoses were documented, of these 62.2% were on weekends. Less than 5.0% of the examined patients were hospitalized. Low back pain-dorsalgia (M54) was the most common diagnosis in OOHC, with 10,843 cases. Injuries were found twelve times in the list of the 30 most frequent diagnoses. The most frequent infectious disease was acute upper respiratory infection of multiple and unspecified sites (J06). By analysing the ICD codes to four-digits and looking at the rate of hospitalizations, it can be assumed that many RFEs were of less urgency in terms of the prompt need for medical treatment. While it is acknowledged that it can be difficult to make an exact diagnosis in an OOHC setting, after analysing the ICD-10 diagnoses, the majority of reasons for encounter in OOHC were determined to be of low urgency, meaning that patients could have waited until regular consultation hours. In the OOHC setting, it is important to understand RFEs from both the patient perspective and the family practitioner perspective. Additionally, results like these can be used in staff education especially improving triage methods and medical recommendations and in developing specific guidelines for OOHC in Germany. Analysis of routine data, such as in this study, contributes to this understanding and contributes to resolving problems of coding.


Imaginary worlds are attractive because they simulate multiple adaptive problems and encode real-world information.
Organisms don't explore for exploration's sake: exploratory psychology is regulated by inputs from multiple adaptations dedicated to processing information from different domains of ancestral adaptive relevance. As holistic representations of environments, imaginary worlds simulate multiple adaptive problems, solutions, and outcomes, thereby engaging numerous emotional systems and providing potentially useful information. Their popularity is thus best understood in terms of the full spectrum of information domains they comprise.


Experimental intraocular lens implantation in the rabbit eye and in the mouse peritoneal space. Part II: Morphological stages of the macrophage on the implanted lens surface.
Macrophages appearing on implanted intraocular lenses (IOLs) in the rabbit eye and in the mouse peritoneal space were observed using Wolter's implant cytology staining and scanning and transmission electron microscopy. In response to the implanted IOL, macrophages in the mouse peritoneal space displayed an activated form with marked ruffles on the surface. They were attached to the IOL with a broad base (sessile macrophage). The macrophages metamorphosed gradually to the flat shape of so-called epithelioid cells with many processes. They showed a tendency to fuse together or become more flat by extending the cytoplasmic lamellipodia and finally disappeared, leaving a thin membrane or a fibrous matrix. Phagocytic activity of macrophages and related cells was also observed. However, those observed on the IOL implanted in the rabbit eye showed less surface structure and appeared to adhere weakly to the IOL.


Physical examination to screen for peripheral artery disease in a defined Primary Care population: A diagnostic accuracy study.
Peripheral arterial disease (PAD) is an underdiagnosed prevalent disease which implies high cardiovascular risk. Professionals usually depend on physical examination to screen for PAD. To assess the diagnostic accuracy of physical examination to screen for PAD in a rural Primary Care population and to evaluate the nurse-physician level of agreement in pedal pulse palpation. Diagnostic accuracy study in which two experienced professionals (physician-nurse) prospectively performed pedal pulse palpation (grading as absent, reduced, normal, or bounding), femoral bruit auscultation and calf circumference (index tests) comparing with Doppler ABI (reference test, positive cut-off: 0.9 ≥ ABI ≥ 1.4) in 158 consecutive subjects. presence of diabetes, dyslipidaemia, hypertension, smoking habit (current or former), or age ≥ 65. Of 315 legs included, PAD was confirmed in 38 (12.1%) legs. Absent dorsalis pedis (DP) and posterior tibial (PT) pulses were found in 37 (11.7%) and 67 (21.3%) legs, respectively. Regarding nurse evaluation, when a positive test was set if DP or PT were absent (more sensitive cut-off), sensitivity was = 86.8 (95% CI: 74.8-98.9), specificity = 82.7 (95% CI: 78.0-87.3), likelihood ratio+ = 5.01 (95% CI: 3.77-6.67), likelihood ratio- = 0.16 (95% CI: 0.07-0.36), and diagnostic odds ratio (dOR) = 31.5 (95% CI: 11.7-84.8). Age, diabetes, and calcification (ABI ≥ 1.4) influenced the rate of a false negative finding in pedal palpation. Physician-nurse weighted kappa coefficient was = 0.649 (95% CI: 0.599-0.699). The presence of a femoral bruit auscultation had a dOR = 3.8 (95% CI: 1.1-13.1), and a calf circumference <34.55 cm had a dOR = 3.2 (95% CI: 1.6-6.4). In a mainly asymptomatic Primary Care population, pedal pulse palpation was by far the best diagnostic test, with good diagnostic accuracy and inter-rater agreement. In view of a high sensitivity and capacity to rule out the disease, pedal pulse palpation could be performed as a screening test for PAD and individuals at high cardiovascular risk.


Peripheral nerve conduction velocity in normal infants and children.
Maximum motor conduction velocity of the median, ulnar and peroneal nerves and maximum sensory conduction velocity of the median nerve have been studied in 635 children, below 12 years of age, free from peripheral nervous system disease. The children fell into four age-group: from 0 to 1 year; from 1 to 3 years: from 3 to 6 years; from 6 to 12 years. No normal values were recorded for the sensory conduction velocity of the median nerve under the age of one year. The motor conduction velocity values significantly rise for the median and ulnar nerves up to 1 year, for the peroneal nerve up to 3 years. The sensory conduction velocity values of median nerve increase significantly up to 6 years.


Localization of urokinase-type plasminogen activator in human eyes: an immunocytochemical study.
We investigated the presence of urokinase-type plasminogen activator (u-PA) in various structures of the human eye by using a biotin-strepavidin complex immunoperoxidase technique with a monoclonal antibody specific for human u-PA. A moderate to intense reaction product was seen in the corneal endothelium, episclera, sclera, iris muscles, lens equator and posterior capsule, peripheral vitreous, epithelium of pars plana, retinal pigment epithelium, axons, uveal fibroblasts, optic nerve fibers, and extraocular muscles. A weak reaction product was seen in the conjunctival and corneal epithelium, the trabecular meshwork, melanocytes and stroma of the iris and choroid, and the posterior layers of the retina. u-PA was not localized in the corneal stroma, conjunctival goblet cells, and certain parts of the lens. Comparison of the present results with those of our previous study (Tripathi, Geanon and Tripathi, 1987, Ophthalmology, 94, 1434-8) on the localization of tissue plasminogen activator (t-PA) in the eye indicate that the distribution of u-PA and t-PA overlaps in many tissues, but differs significantly in others, and that this finding may be related to their complementary and specific roles. As in other body systems, u-PA in ocular tissues is probably involved in processes such as fibrinolysis, wound healing, turnover of intra- and extracellular macromolecules, muscles and neuromuscular regeneration, synapse formation, and maintenance of general neuronal function.


Syndrome X and endothelial dysfunction.
Syndrome X (angina, normal coronary arteriogram and positive exercise test) remains an enigma with unexplained features and apparent conflicts of evidence. The present study addressed whether (i) the Syndrome is characterised by generalised flow-related endothelial dysfunction, (ii) myocardial thallium201 defects reflect myocardial or microvascular dysfunction, (iii) endothelial dysfunction and its consequences can be improved by oral L-arginine. Flow-mediated brachial artery dilatation was measured by ultrasonic 'wall-tracking' in 7 Syndrome X patients, further characterised as having thallium201 defects and no known cause of endothelial dysfunction, and a normal control group. Syndrome X patients entered a 4-week randomised double-blind placebo-controlled cross-over trial of oral L-arginine (7 g twice daily), with brachial artery studies, exercise tests and technetium99 tetrafosmin scans. Flow-mediated dilatation was absent in Syndrome X vs. normal. Stress technetium99 tetrafosmin and thallium201 scans showed similar defects. Flow-mediated dilatation, symptom-limited exercise duration and peak oxygen consumption (VO2max) were increased but rate-pressure-product (RPP) and radionuclide defects were unchanged after L-arginine vs. placebo. The study supports coronary microvascular rather than myocardial dysfunction and shows loss of flow-mediated dilatation in systemic arteries. Oral L-arginine improved flow-mediated dilatation, exercise capacity and VO2max (by ca. 17%) despite unchanged RPP. The findings support generalised endothelial dysfunction. The arginine effects imply NO-mediated improvement of skeletal muscle perfusion suggesting improved homogeneity of microvascular distribution.


Phenotypic Characterization and Comparative Genomics of the Melanin-Producing Yeast Exophiala lecanii-corni Reveals a Distinct Stress Tolerance Profile and Reduced Ribosomal Genetic Content.
The black yeast Exophiala lecanii-corni of the order Chaetothyriales is notable for its ability to produce abundant quantities of DHN-melanin. While many other Exophiala species are frequent causal agents of human infection, E. lecanii-corni CBS 102400 lacks the thermotolerance requirements that enable pathogenicity, making it appealing for use in targeted functional studies and biotechnological applications. Here, we report the stress tolerance characteristics of E. lecanii-corni, with an emphasis on the influence of melanin on its resistance to various forms of stress. We find that E. lecanii-corni has a distinct stress tolerance profile that includes variation in resistance to temperature, osmotic, and oxidative stress relative to the extremophilic and pathogenic black yeast Exophiala dermatitidis. Notably, the presence of melanin substantially impacts stress resistance in E. lecanii-corni, while this was not found to be the case in E. dermatitidis. The cellular context, therefore, influences the role of melanin in stress protection. In addition, we present a detailed analysis of the E. lecanii-corni genome, revealing key differences in functional genetic content relative to other ascomycetous species, including a significant decrease in abundance of genes encoding ribosomal proteins. In all, this study provides insight into how genetics and physiology may underlie stress tolerance and enhances understanding of the genetic diversity of black yeasts.


Lithium clearance during the paradoxical natriuresis of hypotonic expansion in man.
Tubular sodium handling in humans undergoing hypotonic expansion due to the administration of antidiuretic hormone was studied using the clearance of lithium as an index of distal filtrate and sodium delivery. Clearance studies were performed in the morning in eight normal subjects before and on the fourth day of intranasal I-desamino-8-D-arginine vasopressin (dDAVP) administration. Fluid intake was kept constant at 25 ml/kg body weight. After dDAVP body weight increased (2.5 +/- 0.4 kg), plasma sodium fell (from 143 +/- 1 to 128 +/- 5 mmol/liter) and a progressive natriuresis developed. Sodium balance remained negative up to the second clearance study, when the cumulative sodium loss amounted to 148 +/- 96 mmol. Plasma renin activity fell significantly, but plasma aldosterone did not. Inulin clearance rose from 110 +/- 14 to 135 +/- 23 ml/min and lithium clearance from 30.9 +/- 7.6 to 48.9 +/- 15.1 ml/min. Fractional reabsorption of uric acid, phosphate and calcium decreased. Together these changes suggest that the negative sodium balance in hypotonic expansion with dDAVP results from increased filtered sodium load, decreased fractional reabsorption in the proximal tubules, and increased distal delivery. Estimated fractional reabsorption in the distal nephron remained unaltered. The plasma concentration of lithium, of which 10.8 mmol was ingested on the eve of the clearance studies, was not lower during the dDAVP-clearance study. This indicates that the tubular adaptations mentioned are present intermittently, in particular during daytime.


Carrier frequency of a common mutation of carnitine palmitoyltransferase 1A deficiency and long-term follow-up in Finland.
To assess the long-term clinical course of carnitine palmitoyltransferase 1A (CPT1A) deficiency, caused by the c.1364A>C (p.K455T) mutation, and the carrier frequency of this mutation in Finland. This was a long-term follow-up of patients in whom the common mutation was detected. Between 1999 and 2010, 6 cases of CPT1A deficiency were diagnosed and treated with a high-carbohydrate, low-fat diet. The patients experienced their first symptoms during the first years of life, provoked by viral illness and/or fasting. The clinical features included hypoketotic hypoglycemia, hepatopathy, and loss of consciousness, ranging from transient unconsciousness to prolonged hyperlipidemic coma. Five cases carried a homozygous c.1364A>C (p.K455T) mutation, whereas 1 case had a compound c.1364A>C/c.1493A>C (p.Y498S) mutation. During dietary therapy, the patients had few transient decompensations. No carriers of mutation c.1364A>C were detected by minisequencing of 150 control samples. Even though CPT1A deficiency may be life-threatening and lead to prolonged coma, the long-term prognosis is good. A genotype-phenotype correlation implies that the mutations detected are disease-causing. Despite Finland's location close to the Arctic polar region, the carrier frequency of the c.1364A>C mutation in Finland is far lower than that of the variants found in Alaskan, Canadian, and Greenland native populations.


Lower prevalence of subsegmental pulmonary embolism after application of the YEARS diagnostic algorithm.
The rate of identified isolated subsegmental pulmonary embolism (ssPE) has doubled with advances in computed tomography pulmonary angiography (CTPA) technology, but its clinical relevance is debated. The YEARS diagnostic algorithm was shown to safely reduce the number of required CTPAs in the diagnostic management of PE. We hypothesized that the higher threshold for performing CTPA in YEARS was associated with a lower prevalence of ssPE compared to the conventional diagnostic algorithm. We compared 2291 consecutive patients with suspected PE managed according to YEARS to 3306 consecutive control patients managed according to the Wells score for the prevalence of isolated ssPE. In the YEARS cohort, 52% were managed without CTPA, 12% had pulmonary embolism (PE) of which 10% were isolated ssPE, and the 3-month diagnostic failure rate was 0·35%. In the control cohort, 32% were managed without CTPA, 20% had PE of which 16% were isolated ssPE, and the 3-month failure rate was 0·73%. The isolated ssPE prevalence was significantly lower in YEARS (absolute difference 6·2% (95% confidence interval [CI] 1·4-10), Odds Ratio 0·58 (95% CI 0·37-0·90). In conclusion, YEARS is associated with a lower prevalence of isolated ssPE, due to reduction in CTPAs by the higher D-dimer threshold. This was however not associated with a higher risk of recurrent VTE during follow-up.


Extrahepatic portal vein aneurysm after orthotopic liver transplantation: a case with 9-year ultrasound observations.
We report a case of extrahepatic portal vein aneurysm (PVA) in the late postoperative period after orthotopic liver transplantation (OLT). A 46-year-old man underwent OLT in 2001 for treatment of hepatitis B virus-induced cirrhosis and received ultrasound follow-up for 9 years. The long-term ultrasound observations showed that the diameter of the main portal vein had progressively increased from 12 mm in 2001 to 34 mm in 2007, and then remained at 34 mm from 2007 to 2010. The patient did not show any symptoms or complications that required surgical treatment during the clinical follow-up. Our case suggests that PVA after OLT can remain without a sign of deterioration for a long time, and careful observation by ultrasound may be one of the options in the clinical management.


Predictors of longitudinal ABA treatment outcomes for children with autism: A growth curve analysis.
Autism spectrum disorder (ASD) is a developmental disorder that causes lifelong disability. Applied Behavior Analysis (ABA) is one of the most empirically studied and validated approaches for treating children diagnosed with ASD. Due to the heterogeneity of ASD, it is important to ascertain who will most benefit from treatment. In this study, 35 participants, with a mean entry age of 3 years, received ABA therapy. Children were assessed at intake and every 6 months thereafter using the Developmental Profile-3 (DP-3) to measure their communication, social-emotional, adaptive behavior, and physical development (2-6 measures per participant). Using a growth curve analysis, we investigated if age, diagnosis severity, cognitive functioning, treatment hours, gender, parent education level, or primary language spoken at home significantly predicted the growth trajectories of ABA treatment outcomes. Our findings indicated that higher cognitive functioning significantly predicted faster growth across all four developmental domains, age at entry predicted initial status, and other variables only predicted growth rates in one or two domains. Knowing the predictors of treatment outcome is important information for customizing treatment and this study demonstrated how longitudinal analyses can illuminate how participant characteristics affect the course of ABA therapy.


Exploring the adsorption ability with sensitivity and reactivity of C12-B6N6, C12-Al6N6, and B6N6-Al6N6 heteronanocages towards the cisplatin drug: a DFT, AIM, and COSMO analysis.
The DFT study on the adsorption behaviour of the C24, B12N12, and Al12N12 nanocages and their heteronanocages towards the anticancer drug cisplatin (CP) was performed in gas and water media. Among the three pristine nanocages, Al12N12 exhibited high adsorption energy ranging from -1.98 to -1.63 eV in the gas phase and -1.47 to -1.39 eV in water media. However, their heterostructures C12-Al6N6 and B6N6-Al6N6 showed higher interaction energies (-2.22 eV and -2.14 eV for C12-Al6N6 and B6N6-Al6N6) with a significant amount of charge transfer. Noteworthy variations in electronic properties were confirmed by FMO analysis and DOS spectra analysis after the adsorption of the cisplatin drug on B12N12 and B6N6-Al6N6 nanocages. Furthermore, an analysis of quantum molecular descriptors unveiled salient decrement in global hardness and increments in electrophilicity index and global softness occurred after the adsorption of CP on B12N12 and B6N6-Al6N6. On the other hand, the above-mentioned fluctuations are not so noteworthy in the case of the adsorption of CP on Al12N12, C12-B6N6, and C12-Al6N6. Concededly, energy calculation, FMO analysis, ESP map, DOS spectra, quantum molecular descriptors, dipole moment, COSMO surface analysis, QTAIM analysis, and work function analysis predict that B12N12 and B6N6-Al6N6 nanocages exhibit high sensitivity towards CP drug molecules.


Antibiotic-Induced Gut Microbiota Depletion Accelerates the Recovery of Radiation-Induced Oral Mucositis in Rats.
Due to its pivotal role in the modulation of immune and inflammatory responses, the gut microbiota has emerged as a key modulator of cancer treatment-induced gastrointestinal mucositis. However, it is not clear yet how it affects radiation therapy-induced oral mucositis (OM). As such, this study aimed to explore the gut microbiota's role in the pathogenesis of radiation-induced OM in rats. Male Sprague Dawley rats were treated with 20 Gy x-ray radiation (Rx) delivered to the snout, with or without antibiotic-induced microbiota depletion (AIMD). OM severity was assessed, and tongue tissues were collected on day 9 and 15 postradiation for tissue injury and inflammatory markers assessment. AIMD+Rx had a significantly shorter duration of severe OM compared with Rx alone group. Macroscopically, the tongue ulcer-like area was smaller in AIMD+Rx compared with the Rx group. Microscopically, a smaller percentage of the mucosal ulcer was observed in the dorsal tongue of AIMD+Rx compared with the Rx group. AIMD+Rx also had significantly lower levels of interleukin 6, interleukin 1 beta, and toll like receptor 4 in the tongue tissues than the Rx group. The gut microbiota plays a role in OM pathogenesis, mainly in the recovery phase, through the modulation of proinflammatory pathways. Future microbiota-targeted interventions may improve OM in clinical settings.


Effects of Deep Brain Stimulation on Postural Trunk Deformities: A Systematic Review.
Deep brain stimulation (DBS) effects on postural deformities are still poorly explored. Systematic review in accord with the Preferred Reporting Items for Systematic review and Meta-Analysis guidelines (PRISMA). All 38 studies that met predefined eligibility criteria had high risk of bias attributed to retrospective analysis of heterogeneous populations with variable and incompletely reported demographic and clinical characteristics, definitions, outcomes, DBS indications, targets, and settings. Five patient groups were identified in the 35 studies with individual data available: (1) parkinsonian camptocormia (n = 96): 89 patients underwent subthalamic (STN) and 7 globus pallidus pars interna (GPi) DBS. Camptocormia was the indication in 3 patients. After DBS, camptocormia improved in 57 of 96 patients (4.3-100% improvement) and remained stable or worsened in 39 of 96 patients (2-100% worsening). (2) dystonic camptocormia (n = 16): All underwent GPi-DBS. They were younger and with shorter disease duration, but longer deformity duration, compared with parkinsonian camptocormia. After GPi-DBS, camptocormia improved in all patients (50-100% improvement). (3) Parkinsonian Pisa syndrome (n = 14): 11 patients underwent STN-DBS for motor fluctuations whereas Pisa syndrome was the indication for pedunculopontine and GPi-DBS in 2 patients. After DBS, Pisa improved in 10 of 14 patients (33.3-66.7% improvement). (4) Dystonic opisthotonus: 2 young patients remarkably responded to GPi-DBS. (5) Parkinsonian anterocollis: There were variable responses in 3 patients after STN-DBS for motor fluctuations. Low-quality level of evidence suggests that dystonic camptocormia and opisthotonus improve after GPi-DBS. Parkinsonian camptocormia, Pisa syndrome, and anterocollis have variable responses, and their dystonic features should be further explored.


Event-related potentials recorded from the scalp and nasopharynx. I. N1 and P2.
Event-related potentials were recorded from the scalp and nasopharynx during a signal-detection task. These responses were evaluated with respect to the effects of interstimulus interval, intensity, frequency, attention and modality. Our results indicate the existence of at least 4 distinct processes occurring in the 75-150 msec latency range following auditory stimuli. The first process is indexed in the vertex-N1b/temporal-N1a component. This component does not reverse in polarity below the sylvian fissure and is not seen in nasopharyngeal recordings. The location of its generator is not known. Probably there are two or more sources active at this latency. The second process finds reflection in the N1c/PgP120 component. This component is recorded with maximum amplitude on the side contralateral to the ear of delivery. A source in the lateral surface of the temporal lobe is a likely generator. The third process corresponds to Wolpaw and Penry's (1975) Ta positivity. How much of this represents the underside of a vertically oriented dipole and how much a surface positivity is unknown. Finally, during attention, a lateralized processing negativity seems to overlap these components at the scalp, but not at the nasopharynx. The auditory vertex N1 peak is quite distinct from the visual N1 which is more posteriorly recorded on the scalp and which is associated with a definite nasopharyngeal positive wave. The P2 peak is quite similar across auditory and visual modalities. In both modalities it is maximally recorded from the vertex and has no nasopharyngeal concomitant.


Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.
Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).


Coagulation Factor IIIa (f3a) Knockdown in Zebrafish Leads to Defective Angiogenesis and Mild Bleeding Phenotype.
Tissue factor (TF) is crucial for embryogenesis, as mice lacking TF are embryonically lethal (E10.5). This lethality may be attributed to defects in vascular development and circulatory failure, suggesting additional roles for TF in embryonic development beyond coagulation. In this study, we characterized the role of one of the TF paralogs (f3a) using a zebrafish model. The expression of f3a during embryonic developmental stages was determined by RT-PCR. Spatiotemporal expression pattern of f3a revealed (high expression from 28 to 36 hpf) the role of in the development of the yolk sac, circulation, and fins. Morpholinos (MO), an antisense-based oligonucleotide strategy, was used to knockdown f3a and examined for defects in morphological appearance, bleeding, and vascular patterning. f3a MO-injected embryos showed morphological abnormalities, including shorter body lengths and crooked tails. O-dianisidine staining showed f3a MO-injected embryos exhibited bleeding in the trunk (5.44%) and head (9.52%) regions. Imaging of endothelial-specific transgenic lines (flk1:egfp-NLS/kdrl:mCherry-CAAX) showed a 3-fold decreased caudal vein plexus (CVP) in f3a morphants versus controls at 48 hpf, suggesting a potential role for f3a in angiogenesis. These findings confirm that f3a is essential for angiogenesis, in addition to its involvement in hemostasis.


Craniopagi: anatomical characteristics and classification.
The incidence, embryology, anatomical features of the site of junction, associated abnormalities, and survival of the 79 craniopagi reported from 1496 to 1987 have been reviewed. All craniopagi upon whom sufficient information is available have been classified on the basis of the deepest shared anatomical structure.


A systematic review of non-pharmacological treatments for apathy in dementia.
Apathy is one of the most frequent neuropsychiatric symptoms encountered in dementia. Early diagnosis and timely treatment of apathy in dementia are crucial because apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress. Extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies which have investigated the effect of non-pharmacological treatments of apathy in dementia. Quality of the studies was appraised. A total of 1303 records were identified and 120 full-texts assessed. Forty-three unique studies were reviewed. A variety of interventions were found to be effective in reducing apathy in demented patients, particularly when provided in a multidisciplinary manner. However, quantification of the effect was limited by the marked methodological heterogeneity of the studies and the small number of studies where apathy was the primary outcome measure. Treatment of apathy in dementia is a complex and underexplored field. Certain studies suggest promise for a variety of non-pharmacological interventions. Standardized and systematic efforts primarily focusing on apathy may establish a benefit from individualized treatments for specific disease groups.


Modeling Safe Infant Sleep in the Hospital.
Despite reductions in the rate of sudden infant death syndrome (SIDS) over the last 25 years, over 3000 infant deaths annually in the US are attributable to sleep-related causes. We aimed to improve safe sleep practice (SSP) adherence by healthcare providers working with infants admitted to an inpatient pediatric unit in an urban academic center specifically increasing compliance on five core SSP (supine, alone in the crib, no objects in crib, appropriate bundling, and flat crib). This Quality Improvement project evaluated a staff education intervention using a pre- and post-design. Surveys of providers determined baseline SSP knowledge. Adherence to SSP in the hospital was audited before and after education. One hundred pre-intervention infant sleep placement observations were recorded and 123 were collected post-intervention. Surveyed providers had appropriate knowledge of SSP; however, baseline audits indicated that no patients met all SSP practices in the hospital. Post-intervention adherence to SSP showed significant (p < .05) improvements in keeping the crib flat, removing objects from the crib, and avoiding over-bundling. Overall, SSP adherence increased by 12.5% post-intervention. This quality improvement project suggests that the inpatient setting provides opportunities for providers to demonstrate SSP but that healthcare providers often do not follow SSP in practice. Continued education can lead to improvements in SSP adherence ensuring that hospitals are modeling SSP for the families of infants. Limited improvements to SSP adherence illustrate the complexities of modifying provider behaviors in the absence of formal policy.


Impaired oligodendroglial development by decabromodiphenyl ether in rat offspring after maternal exposure from mid-gestation through lactation.
Pregnant Sprague-Dawley rats were given diet containing decabromodiphenyl ether (DBDE) either at 0, 10, 100, or 1000 ppm from gestation day (GD) 10 until day 20 after delivery (PND 20). No significant alterations were observed in maternal and offspring reproductive parameters. At PND 20, serum triiodothyronine concentrations examined in males were slightly reduced at 1000 ppm (84.2% of the control value), and incidence of thyroid follicular cell hypertrophy was increased in both sexes with significant difference in males at 1000 ppm. Diffuse liver cell hypertrophy accompanying increased relative liver weight and increased cytoplasmic eosinophilia of the renal proximal tubules were observed in both sexes with significant difference from 10 ppm in males and females, respectively. At postnatal week 11, serum thyroxine concentrations examined in males were slightly reduced at 1000 ppm (85.9% of the control value), and the incidence of thyroid follicular cell hypertrophy was non-significantly increased from 10 ppm in males. There were reductions in the corpus callosum area and density of 2',3'-cyclic nucleotide 3'-phosphodiesterase-immunoreactive oligodendrocytes in the cingulate deep cortex in males from 100 ppm. Conversely, NeuN-immunoreactive neuronal distribution in the hippocampal CA1 was unchanged. This suggests that developmental DBDE-exposure caused irreversible white matter hypoplasia targeting oligodendrocytes from 100 ppm, accompanied with developmental hypothyroidism. The lowest-observed-adverse-effect level of DBDE was determined to be 10 ppm (0.7-2.4 mg/kg-body weight-d).


Index of permeability of large arteries to labeled albumin after administration of prostaglandin E2.
Prostaglandin (PG)E2 tends to increase the permeability to labeled albumin of the arterial walls of rabbits. The blood pressure decreases after administration of PGE2. The increase in permeability is probably due to direct effects of prostaglandin upon the endothelium, perhaps to an increase of cytopempsis or formation of leaks in the integrity of the cell layer.


Effects of rituximab and dexamethasone on regulatory and proinflammatory B-cell subsets in patients with primary immune thrombocytopenia.
To investigate the cytokine production and surface marker composition of B cells in adult patients with newly diagnosed primary immune thrombocytopenia (ITP) before and 12 months after treatment with rituximab + dexamethasone (RTX+DXM) or dexamethasone (DXM). Peripheral blood mononuclear cells were isolated from nine patients treated with RTX+DXM, seven patients treated with DXM, and seven healthy donors. Expression of the cell-surface markers CD5, CD27, CD25, and CD19, and intracellular content of IL-6 and IL-10 were measured by flow cytometry. PBMCs from ITP patients at baseline contained a lower proportion of IL-10+ B cells (P < .01) and IL-6+ B cells (P < .01) than healthy controls. All patients responded to therapy and levels were normalized at 12 months. The proportion of CD5+ B cells increased (P < .01) and CD27+ memory B cells decreased (P < .05) 12 months after treatment with RTX+DXM compared to baseline, with an inverse correlation between platelet numbers and the proportion of CD27+ B cells (R = -0.71; P < .05). Both treatment regimens normalized the frequencies of cytokine-producing B cells. The additional increase in CD5+ B cells after RTX+DXM is compatible with induction of Bregs.


Cell kinetics in the erythroid compartment of guinea pig bone marrow: a model based on 3H-TdR studies.
A model of steady-state erythropoiesis in the guinea pig is described. The model incorporates an unidentified progenitor compartment, as well as compartments representing proerythroblasts, basophilic, polychromatic and orthochromatic cells. A computer representation of the model permits a simulation of the labeling curves obtained in pulse and intermittent labeling regimes. It was found that a reasonable fit to the data can be achieved when the parameters for the various compartments are essentially identical. The results of a preliminary sensitivity analysis, carried out by perturbing the duration of S phase from the best fit value, are reported. The fit achieved to the data supports the hypothesis underlying the model that each compartment corresponds to one generation and that the flux within and between compartments is sequential.


PLX3397 inhibits the accumulation of intra-tumoral macrophages and improves bromodomain and extra-terminal inhibitor efficacy in melanoma.
Bromodomain and extra-terminal inhibitors (BETi) delay tumor growth, in part, through tumor cell intrinsic alterations and initiation of anti-tumor CD8+ T-cell responses. By contrast, BETi effects on pro-tumoral immune responses remain unclear. Here, we show that the next-generation BETi, PLX51107, delayed tumor growth to differing degrees in Braf V600E melanoma syngeneic mouse models. These differential responses were associated with the influx of tumor-associated macrophages during BETi treatment. Tumors that were poorly responsive to PLX51107 showed increased influx of colony-stimulating factor-1 receptor (CSF-1R)-positive tumor-associated macrophages. We depleted CSF-1R+ tumor-associated macrophages with the CSF-1R inhibitor, PLX3397, in combination with PLX51107. Treatment with PLX3397 enhanced the efficacy of PLX51107 in poorly responsive Braf V600E syngeneic melanomas in vivo. These findings suggest that tumor-associated macrophage accumulation limits BETi efficacy and that co-treatment with PLX3397 can improve response to PLX51107, offering a potential novel combination therapy for metastatic melanoma patients.


Postoperative fractures of the lingual plate after bilateral sagittal split osteotomies.
We encountered the unusual complication of postoperative fracture of the lingual plate in four patients after bilateral sagittal split osteotomy. We then did a retrospective review to identify possible risk factors. Over a 1-year period we did 52 bilateral split osteotomies. The patients' casenotes were examined and a number of variables were recorded, including surgical technique, and the patient's sex, age, presence or absence of third molars, and the height of the mandible in the region of the osteotomy. Significant risk factors were a vertical mandibular height of 2 cm or less distal to the last molar tooth (p=0.02), and a depth of 0.6 cm or less from the apex of last molar root or impacted third molar to the lower border (p=0.005).


Inhibitors of nitrofuran reduction in Escherichia coli: evidence for their existence, partial purification, binding of nitrofurantoin in vitro, and implications for nitrofuran resistance.
Nitrofurantoin (NF)-resistant mutants of Escherichia coli were isolated as described previously (18). One of the mutants (SSJ-2) was found to possess NF reductase activity equal to that of its parent (E. coli KL16). Two NF-resistant transductional derivatives, SSJ-2A and SSJ-2B, were isolated using SSJ-2 as the donor. SSJ-2 was found to be a double mutant carrying two mutations, nfnA and nfnB, while SSJ-2A (nfnA) and SSJ-2B (nfnB) carried these mutations individually. Heated extracts from SSJ-2A and SSJ-2B were found to inhibit the reduction of NF by unheated extracts of the NF-sensitive strain E. coli KL16 in vitro. Unheated extracts of these mutants reduced NF poorly relative to E. coli KL16. The poor reduction of NF by unheated extracts of SSJ-2A and SSJ-2B was greatly stimulated by heated extracts of SSJ-2B and SSJ-2A, respectively, and also by heated extracts of E. coli KL16. When heated extracts of SSJ-2A and SSJ-2B were mixed in a particular ratio and added to unheated extracts of E. coli KL16 they lost their inhibitory activity. Two proteins, designated inhibitor A and inhibitor B, have been partially purified from heated extracts of SSJ-2B and SSJ-2A, respectively. Their respective molecular weights, as determined by gel chromatography, were 37,000 and 20,500. The two inhibitors bound nitrofurantoin in vitro, and the NF-binding ability was lost when mixed in the molar ration of 3/1 (B/A). These observations were rationalized in terms of a hypothesis which explains (i) maximal NF reduction in wild-type cells, (ii) maximal NF reduction of nfnA-nfnB- double mutant, and (iii) poor NF reduction in nfnA- or nfnB- single mutants. The possible role of these inhibitors in nitrofurantoin resistance is also discussed.


Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease.
Transforming growth factor-β (TGF-β) is a key driver for liver fibrogenesis. TGF-β must be activated in order to function. Plasma kallikrein (PLK) is a TGF-β activator that cleaves the latency-associated protein (LAP) between arginine58 and lysine59 residues and releases active TGF-β from the latent TGF-β-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine58 (R58/LAP-DPs) and beginning from lysine59 (L59/LAP-DPs), reflects PLK-dependent TGF-β activation. However, the significance and details of TGF-β activation in patients with chronic liver disease (CLD) remain uncertain. We herein examined the PLK-dependent TGF-β activation in patients by detecting R58 and L59/LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R58/LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L59/LAP-DP concentration. R58/LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R58/LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L59/LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L59/LAP-DP showed no correlation with the levels of direct serum biomarkers of liver fibrosis; however, its changes during interferon-based therapy for chronic hepatitis C were significantly associated with virological responses. Our results suggest that PLK-dependent TGF-β activation occurs in the early stages of fibrosis and that its unique surrogate markers, R58 and L59/LAP-DPs, are useful for monitoring the clinical course of CLD.


MiR-450a-5p strengthens the drug sensitivity of gefitinib in glioma chemotherapy via regulating autophagy by targeting EGFR.
Glioma reported to be refractory to EGFR tyrosine kinase inhibitor is the most common malignant tumor in central nervous system. Our research showed the low expression of miR-450a-5p and high expression of EGFR in glioma tissues. MiR-450a-5p was also observed to synergize with gefitinib to inhibit the proliferation, migration and invasion and induce the apoptosis and autophagy of glioma cells. Furthermore, miR-450a-5p was demonstrated to target 3'UTR of EGFR, and regulated EGFR-induced PI3K/AKT/mTOR signaling pathway. Moreover, the above effects induced by miR-450a-5p in glioma cells were reversed by WIPI1 silencing. The inhibition role of miR-450a-5p on glioma growth was also confirmed in vivo by subcutaneous and intracranial tumor xenografts. Therefore, we conclude that miR-450a-5p synergizes with gefitinib to inhibit the glioma tumorigenesis through inducing autophagy by regulating the EGFR-induced PI3K/AKT/mTOR signaling pathway, thereby enhancing the drug sensitivity of gefitinib.


A comparison of clinical characteristics and long-term prognosis in asymptomatic and symptomatic patients with first-diagnosed atrial fibrillation: the Belgrade Atrial Fibrillation Study.
To investigate baseline characteristics and long-term prognosis of carefully characterized asymptomatic and symptomatic patients with atrial fibrillation (AF) in a 'real-world' cohort of first-diagnosed non-valvular AF over a 10-year follow-up period. We conducted an observational, non-interventional, and single-centre registry-based study of consecutive first-diagnosed AF patients. Of 1100 patients (mean age 52.7±12.2 years and mean follow-up 9.9±6.1 years), 146 (13.3%) had asymptomatic AF. Persistent or permanent AF, slower ventricular rate during AF (<100/min), CHA2DS2-VASc score of 0, history of diabetes mellitus and male gender were independent baseline risk factors for asymptomatic AF presentation (all p<0.01) with a good predictive ability of the multivariable model (c-statistic 0.86, p<0.001). Kaplan-Meier 10-year estimates of survival free of progression of AF (log-rank test=33.4, p<0.001) and ischemic stroke (log-rank test=6.2, p=0.013) were significantly worse for patients with asymptomatic AF compared to those with symptomatic arrhythmia. In the multivariable Cox regression analysis, intermittent asymptomatic AF was significantly associated with progression to permanent AF (Hazard Ratio 1.6; 95% CI, 1.1-2.2; p=0.009). In a 'real-world' setting, patients with asymptomatic presentation of their first-diagnosed AF could have different risk profile and long-term outcomes compared to those with symptomatic AF. Whether more intensive monitoring and comprehensive AF management including AF ablation at early stage following the incident episode of AF and increased quality of oral anticoagulation could alter the long-term prognosis of these patients requires further investigation.