Fallopian tube precursors of ovarian low- and high-grade serous neoplasms.
Traditionally, it was thought that ovarian high-grade serous carcinoma arises from the ovarian surface epithelium and epithelial inclusion glands and that the pathogenesis is de novo; nonetheless, a convincing precursor in the ovary or peritoneum has not been identified to date. During the last few years, however, there has been a dramatic shift in thinking, and a candidate precursor is now recognized in the fallopian tube, especially within the fimbriated end - serous tubal intra-epithelial carcinoma (STIC). Accordingly, STIC is probably the earliest histologically recognizable lesion in the pathogenesis of high-grade serous carcinoma, but steps in this pathway which precede STIC have also been proposed. With subsequent progression, STIC implants onto the ovary and then develops into an invasive high-grade serous carcinoma with rapid tumour growth. For invasive low-grade serous carcinoma, it is well-established that its pathogenesis begins with serous cystadenoma/adenofibroma, which develops sequentially into atypical proliferative serous tumour (typical serous borderline tumour), non-invasive micropapillary (low-grade) serous carcinoma (micropapillary serous borderline tumour) and then invasive low-grade serous carcinoma in a relatively slow stepwise process. It is presumed that cystadenoma/adenofibroma arises from epithelial inclusion glands in the ovary, but recent evidence suggests that epithelial inclusion glands originate in the fallopian tube. Alternatively, it has been proposed that the other early precursors in the low-grade pathway, including serous borderline tumours, non-invasive implants and endosalpingiosis, may also arise directly from tubal mucosa. Therefore, the precursor of most ovarian high-grade serous carcinomas originates in the fallopian tube, and that for low-grade serous tumours may also be derived from the tube. This review paper provides an overview of the fallopian tube's potential role in the pathogenesis of both types of serous neoplasms of the ovary.


[The effect of outpatient cost sharing on health care utilization of the elderly].
The purpose of this study was to analyze the effect of outpatient cost-sharing on health care utilization by the elderly. The data in this analysis was the health insurance claims data between July 1999 and December 2008 (114 months). The study group was divided into two age groups, namely 60-64 years old and 65-69 years old. This study evaluated the impact of policy change on office visits, the office visits per person, and the percentage of the copayment-paid visits in total visits. Interrupted time series and segmented regression model were used for statistical analysis. The results showed that outpatient cost-sharing decreased office visits, but it also decreased the percentage of copayment-paid visits, implying that the intensity of care increased. There was little difference in the results between the two age groups. But after the introduction of the coinsurance system for those patients under age 65, office visits and the percentage of copayment-paid visits decreased, and the 60-64 years old group had a larger decrease than the 65-69 years old group. This study evaluated the effects of outpatient cost-sharing on health care utilization by the aged. Cost sharing of the elderly had little effect on controlling health care utilization.


The Effect of Chronic Methamphetamine Exposure on the Hippocampal and Olfactory Bulb Neuroproteomes of Rats.
Nowadays, drug abuse and addiction are serious public health problems in the USA. Methamphetamine (METH) is one of the most abused drugs and is known to cause brain damage after repeated exposure. In this paper, we conducted a neuroproteomic study to evaluate METH-induced brain protein dynamics, following a two-week chronic regimen of an escalating dose of METH exposure. Proteins were extracted from rat brain hippocampal and olfactory bulb tissues and subjected to liquid chromatography-mass spectrometry (LC-MS/MS) analysis. Both shotgun and targeted proteomic analysis were performed. Protein quantification was initially based on comparing the spectral counts between METH exposed animals and their control counterparts. Quantitative differences were further confirmed through multiple reaction monitoring (MRM) LC-MS/MS experiments. According to the quantitative results, the expression of 18 proteins (11 in the hippocampus and 7 in the olfactory bulb) underwent a significant alteration as a result of exposing rats to METH. 13 of these proteins were up-regulated after METH exposure while 5 were down-regulated. The altered proteins belonging to different structural and functional families were involved in processes such as cell death, inflammation, oxidation, and apoptosis.


Investigating antiquities trafficking with generative pre-trained transformer (GPT)-3 enabled knowledge graphs: A case study.
Background: There is a wide variety of potential sources from which insight into the antiquities trade could be culled, from newspaper articles to auction catalogues, to court dockets, to personal archives, if it could all be systematically examined. We explore the use of a large language model, GPT-3, to semi-automate the creation of a knowledge graph of a body of scholarship concerning the antiquities trade. Methods: We give GPT-3 a prompt guiding it to identify knowledge statements around the trade. Given GPT-3's understanding of the statistical properties of language, our prompt teaches GPT-3 to append text to each article we feed it where the appended text summarizes the knowledge in the article. The summary is in the form of a list of subject, predicate, and object relationships, representing a knowledge graph. Previously we created such lists by manually annotating the source articles. We compare the result of this automatic process with a knowledge graph created from the same sources via hand. When such knowledge graphs are projected into a multi-dimensional embedding model using a neural network (via the Ampligraph open-source Python library), the relative positioning of entities implies the probability of a connection; the direction of the positioning implies the kind of connection. Thus, we can interrogate the embedding model to discover new probable relationships. The results can generate new insight about the antiquity trade, suggesting possible avenues of research. Results: We find that our semi-automatic approach to generating the knowledge graph in the first place produces comparable results to our hand-made version, but at an enormous savings of time and a possible expansion of the amount of materials we can consider. Conclusions: These results have implications for working with other kinds of archaeological knowledge in grey literature, reports, articles, and other venues via computational means.


Overactive bladder: achieving a differential diagnosis from other lower urinary tract conditions.
Overactive bladder (OAB) is a debilitating condition characterised by an urgent need to urinate (urgency), often with urinary frequency and, in some cases, urgency incontinence and nocturnal frequency. Patients often adopt complex adaptive behaviours to cope with their symptoms as OAB can compromise all dimensions of a patient's quality of life. Most OAB patients present initially to their primary care physician. Diagnosis is based on presenting symptomatology and does not require any invasive tests. Direct questioning about symptoms is important in achieving a differential diagnosis. The most common condition to be considered when working towards a differential diagnosis is a urinary tract infection (UTI). However, some physicians have expressed concerns about identifying the small number of cases where bladder cancer is a potential underlying aetiology for the symptoms of OAB. In this review, we examine the prevalence and patient profiles for these bladder conditions and their presenting symptomatology. We also review tests that may be recommended to exclude a diagnosis of UTI or bladder cancer and present a diagnostic algorithm suitable for office-based primary care practice.


Curcumin Delivery on Metal-Organic Frameworks: The Effect of the Metal Center on Pharmacokinetics within the M-MOF-74 Family.
Metal-organic frameworks (MOFs) have gained considerable attention as drug delivery platforms over the past decade owing to their tunable physiochemical properties, biodiversity, and capability to encapsulate sizable active compound loadings. Nevertheless, many fundamental properties pertaining to MOFs' pharmacokinetic performances as drug carriers have been poorly investigated. One such property is the relationship between the MOF metal center solubility and drug release rate. In this study, we investigated this relationship within the M-MOF-74 family by impregnating 30 or 50 wt % curcumin on either Mg-, Ni-, Zn-, or Co-MOF-74. The drug delivery performance of the materials was assessed in phosphate buffered saline solution by high-performance liquid chromatography over a time period of 0-24 h. From these experiments, it was determined that the 30 wt % curcumin loading led to increased drug delivery and kinetics compared to the 50 wt % loading regardless of the metal center, as the lower drug concentration did not hinder diffusion from the MOF pores. As such, the optimal curcumin loading within the M-MOF-74 family was concluded to be greater than 30 wt % but less than 50 wt %. These experiments also revealed that using Mg-MOF-74 as a drug carrier produced a twofold enhancement in the release rate from 0.15 to 0.30 h1/2 compared to the other three metal centers, where Mg-MOF-74's improved pharmacokinetics were attributed to the increased group II Mg solubility compared to Ni, Co, or Zn transition metals. On the basis of these findings, it was concluded that to promote rapid pharmacokinetics, it is essential to use MOFs with more soluble metal centers to promote dissolution of the nanocarrier. While this study focused on M-MOF-74, we expect that this conclusion has implications to other crystallites as well.


Exome sequencing in a Romanian Bardet-Biedl syndrome cohort revealed an overabundance of causal BBS12 variants.
Bardet-Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty-eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%-80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease-causing single nucleotide variants or small insertion-deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics.


A "grow-in-place" architecture and methodology for electrochemical synthesis of conducting polymer nanoribbon device arrays.
Fully enclosed horizontal nanochannels, in a prearranged array on a substrate and with built-in electrical contacts and chemical access regions, were used as growth templates for electrochemical synthesis of conducting polymer nanoribbons. In this "grow-in-place" approach, the nanochannel templates are part of the final array structure and remain after fabrication of the nanoribbons. The built-in electrical contacts, which provide the electrical potential for electrochemical polymerization, also remain and become contacts/interconnects to the array components. The grow-in-place architecture and methodology remove the need for template dissolution, any post-synthesis nanoribbon "grow-and-then-place" manipulation, and any post-synthesis electrical contacting. The fact that the templates are fully enclosed prohibits dendrite formation during growth, ensures precise dimensionality, and gives the encapsulation needed in any real device application. In this report the grow-in-place approach to electrochemical polymerization is used to produce polyaniline nanoribbons. These were found to be fibrils and not tubes and to grow from the central region of the growth-template cross-section and not from the template walls. Two-point and four-point electrical characterization of these polyaniline nanoribbons, obtained using the built-in electrodes, was employed to yield the true polyaniline conductivity and to assess the ohmicity of the contacting approach. Conductivity studies, done as a function of nanoribbon width, show conductivity increases as the width decreases. We also show that our grow-in-place approach may be used for chemical polymerization. However, at least for polyaniline, electrochemical polymerization is superior since it does not suffer from diffusion-limited growth and allows precise placement of the nanoribbons in the growth channel.


Filling-in void and sparse regions in protein sequence space by protein-like artificial sequences enables remarkable enhancement in remote homology detection capability.
Protein functional annotation relies on the identification of accurate relationships, sequence divergence being a key factor. This is especially evident when distant protein relationships are demonstrated only with three-dimensional structures. To address this challenge, we describe a computational approach to purposefully bridge gaps between related protein families through directed design of protein-like "linker" sequences. For this, we represented SCOP domain families, integrated with sequence homologues, as multiple profiles and performed HMM-HMM alignments between related domain families. Where convincing alignments were achieved, we applied a roulette wheel-based method to design 3,611,010 protein-like sequences corresponding to 374 SCOP folds. To analyze their ability to link proteins in homology searches, we used 3024 queries to search two databases, one containing only natural sequences and another one additionally containing designed sequences. Our results showed that augmented database searches showed up to 30% improvement in fold coverage for over 74% of the folds, with 52 folds achieving all theoretically possible connections. Although sequences could not be designed between some families, the availability of designed sequences between other families within the fold established the sequence continuum to demonstrate 373 difficult relationships. Ultimately, as a practical and realistic extension, we demonstrate that such protein-like sequences can be "plugged-into" routine and generic sequence database searches to empower not only remote homology detection but also fold recognition. Our richly statistically supported findings show that complementary searches in both databases will increase the effectiveness of sequence-based searches in recognizing all homologues sharing a common fold.


Eye movements disrupt episodic future thinking.
Remembering the past and imagining the future both rely on complex mental imagery. We considered the possibility that constructing a future scene might tap a component of mental imagery that is not as critical for remembering past scenes. Whereas visual imagery plays an important role in remembering the past, we predicted that spatial imagery plays a crucial role in imagining the future. For the purpose of teasing apart the different components underpinning scene construction in the two experiences of recalling episodic memories and shaping novel future events, we used a paradigm that might selectively affect one of these components (i.e., the spatial). Participants performed concurrent eye movements while remembering the past and imagining the future. These concurrent eye movements selectively interfere with spatial imagery, while sparing visual imagery. Eye movements prevented participants from imagining complex and detailed future scenes, but had no comparable effect on the recollection of past scenes. Similarities between remembering the past and imagining the future are coupled with some differences. The present findings uncover another fundamental divergence between the two processes.


DNA methylation patterns provide insight into epigenetic regulation in the Pacific oyster (Crassostrea gigas).
DNA methylation is an epigenetic mechanism with important regulatory functions in animals. While the mechanism itself is evolutionarily ancient, the distribution and function of DNA methylation is diverse both within and among phylogenetic groups. Although DNA methylation has been well studied in mammals, there are limited data on invertebrates, particularly molluscs. Here we characterize the distribution and investigate potential functions of DNA methylation in the Pacific oyster (Crassostrea gigas). Methylation sensitive PCR and bisulfite sequencing PCR approaches were used to identify CpG methylation in C. gigas genes and demonstrated that this species possesses intragenic methylation. In silico analysis of CpGo/e ratios in publicly available sequence data suggests that DNA methylation is a common feature of the C. gigas genome, and that specific functional categories of genes have significantly different levels of methylation. The Pacific oyster genome displays intragenic DNA methylation and contains genes necessary for DNA methylation in animals. Results of this investigation suggest that DNA methylation has regulatory functions in Crassostrea gigas, particularly in gene families that have inducible expression, including those involved in stress and environmental responses.


[Generalized tendomyopathy (fibromyalgia): differential diagnosis, therapy and prognosis].
The generalised tendomyopathy is one of the most variegated and fascinating disease of man. The unusual constellation and combination of symptoms constrain to the differential-diagnostic demarcation of a great number of rheumatic and non-rheumatic diseases. While the rheumatic polymyalgia and myositis are easily to be demarcated, the decision between a primary and secondary generalised tendomyopathy can be difficult. In individual cases a classical tendomyopathy can be accompanied by antinuclear factors and then it is at the earliest a "collagenosis the state of waiting". The therapy of tendomyopathy is altogether unsatisfactory. All forms of therapy (medicamentous, physical, psychotherapy) help at the utmost in 50%. Surprisingly, on the part of the medicaments the non-steroidal antiphlogistic drugs and the glucocorticoids in most cases completely fail, and also the physical therapy is frequently not tolerated and/or has only a short duration of effect. The more important are the influence on possible evoking factors, the optimization of the social background and the utilization of the possibilities of the "secondary prevention" (balneotherapy in a health resort, sauna bath, Kneipp's applications, change of the living and working conditions, easy sports activities). Since the disease is frequent, but not yet known in general, it should be made better acquainted among the physicians. The generalised tendomyopathy is and remains a cardinal problem not only of rheumatology, but of the physician's working-day in general.


Does overruling Roe discriminate against women (of colour)?
On 24 July 2022, the landmark decision Roe v. Wade (1973), that secured a right to abortion for decades, was overruled by the US Supreme Court. The Court decision in Dobbs v. Jackson Women's Health Organisation severely restricts access to legal abortion care in the USA, since it will give the states the power to ban abortion. It has been claimed that overruling Roe will have disproportionate impacts on women of color and that restricting access to abortion contributes to or amounts to structural racism. In this paper, we consider whether restricting abortion access as a consequence of overruling Roe could be understood as discrimination against women of color (and women in general). We argue that banning abortion is indirectly discriminatory against women of color and directly (but neither indirectly, nor structurally) discriminatory against women in general.


[Asthma epidemiology of based on a standard questionnaire].
Asthma is a common chronic airway disease in the world. Although the guidelines recommend the diagnostic criteria for asthma and have been widely used in clinical practice, the standardized asthma questionnaire is often recommended for prevalence surveys in large-scale epidemiological surveys of the population, because the standardized asthma questionnaire has the characteristics of high benefit, low cost and high response rate, and the results are also feasible for comparison between different populations or regions. There are currently four asthma epidemiological surveys in the world, including the European Community Respiratory Health Survey (ECRHS), the International Study of Asthma and Allergies in Childhood (ISAAC), the International Study of Wheezing in Infants (EISL) and World Health Survey (WHS). The above research results are also important data source for estimating the global prevalence of asthma in the Global Burden of Disease Study (GBD). In China, several national surveys have been conducted on the prevalence of asthma in children and adults, but the reported prevalence of asthma was not comparable with other countries because clinical diagnostic criteria for asthma were frequently used to define asthma in these previous studies. The China pulmonary health study (CPH) was a national cross-sectional study that enrolled a nationally representative sample of Chinese adults aged 20 years or older Using an asthma questionnaire derived from ECRHS, we reported that the prevalence of asthma with wheezing in Chinese adults was 4.2%, representing 45.7 million adult asthmatics. However, it is important to note that these data did not include people under the age of 20 years or those with atypical asthmatic symptoms. In addition, the study showed that asthma is largely under-diagnosed and undertreated in China, and these findings call for national efforts to improve the prevention, detection and treatment of asthma in China.


Influence of Risk Category and Screening Round on the Performance of an MR Imaging and Mammography Screening Program in Carriers of the BRCA Mutation and Other Women at Increased Risk.
Purpose To evaluate the real-life performance of a breast cancer screening program for women with different categories of increased breast cancer risk with multiple follow-up rounds in an academic hospital with a large screening population. Materials and Methods Screening examinations (magnetic resonance [MR] imaging and mammography) for women at increased breast cancer risk (January 1, 2003, to January 1, 2014) were evaluated. Risk category, age, recall for workup of screening-detected abnormalities, biopsy, and histopathologic diagnosis were recorded. Recall rate, biopsy rate, positive predictive value of recall, positive predictive value of biopsy, cancer detection rate, sensitivity, and specificity were calculated for first and follow-up rounds. Results There were 8818 MR and 6245 mammographic examinations performed in 2463 women. Documented were 170 cancers; of these, there were 129 screening-detected cancers, 16 interval cancers, and 25 cancers discovered at prophylactic mastectomy. Overall sensitivity was 75.9% including the cancers discovered at prophylactic mastectomy (95% confidence interval: 69.5%, 82.4%) and 90.0% excluding those cancers (95% confidence interval: 83.3%, 93.7%). Sensitivity was lowest for carriers of the BRCA1 mutation (66.1% and 81.3% when including and not including cancers in prophylactic mastectomy specimens, respectively). Specificity was higher at follow-up (96.5%; 95% confidence interval: 96.0%, 96.9%) than in first rounds (85.1%; 95% confidence interval: 83.4%, 86.5%) and was high for both MR imaging (97.1%; 95% confidence interval: 96.7%, 97.5%) and mammography (98.7%; 95% confidence interval: 98.3%, 99.0%). Positive predictive value of recall and positive predictive value of biopsy were lowest in women who had only a family history of breast cancer. Conclusion Screening performance was dependent on risk category. Sensitivity was lowest in carriers of the BRCA1 mutation. The specificity of high-risk breast screening improved at follow-up rounds. © RSNA, 2017 Online supplemental material is available for this article.


Long-Distance Effects of H-NS Binding in the Control of hilD Expression in the Salmonella SPI1 Locus.
Salmonella enterica serovar Typhimurium utilizes a type three secretion system (T3SS) carried on the Salmonella pathogenicity island 1 (SPI1) to invade intestinal epithelial cells and induce inflammatory diarrhea. HilA activates expression of the T3SS structural genes. Expression of hyper invasion locus A (hilA) is controlled by the transcription factors HilD, HilC, and RtsA, which act in a complex feed-forward regulatory loop. The nucleoid-associated protein H-NS is a xenogeneic silencer that has a major effect on SPI1 expression. In this work, we use genetic techniques to show that disruptions of the chromosomal region surrounding hilD have a cis effect on H-NS-mediated repression of the hilD promoter; this effect occurs asymmetrically over ∼4 kb spanning the prgH-hilD intergenic region. CAT cassettes inserted at various positions in this region are also silenced in relation to the proximity to the hilD promoter. We identify a putative H-NS nucleation site, and its mutation results in derepression of the locus. Furthermore, we genetically show that HilD abrogates H-NS-mediated silencing to activate the hilD promoter. In contrast, H-NS-mediated repression of the hilA promoter, downstream of hilD, is through its control of HilD, which directly activates hilA transcription. Likewise, activation of the prgH promoter, although in a region silenced by H-NS, is strictly dependent on HilA. In summary, we propose a model in which H-NS nucleates within the hilD promoter region to polymerize and exert its repressive effect. Thus, H-NS-mediated repression of SPI1 is primarily through the control of hilD expression, with HilD capable of overcoming H-NS to autoactivate. IMPORTANCE Members of the foodborne pathogen Salmonella rely on a type III secretion system to invade intestinal epithelial cells and initiate infection. This system was acquired through horizontal gene transfer, essentially creating the Salmonella genus. Expression of this critical virulence factor is controlled by a complex regulatory network. The nucleoid protein H-NS is a global repressor of horizontally acquired genomic loci. Here, we identify the critical site of H-NS regulation in this system and show that alterations to the DNA over a surprisingly large region affect this regulation, providing important information regarding the mechanism of H-NS action.


A general strategy for regiocontrol in nickel-catalyzed reductive couplings of aldehydes and alkynes.
A strategy for catalyst-controlled regioselectivity in aldehyde-alkyne reductive couplings has been developed. This strategy is the first where either regiochemical outcome may be selected for a broad range of couplings, without relying on substrate biases or directing effects. The complementary use of small cyclopropenylidene carbene ligands or highly hindered N-heterocyclic carbene ligands allows the regiochemical reversal with unbiased internal alkynes, aromatic internal alkynes, conjugated enynes, or terminal alkynes.


[Experience with the treatment of compression fractures of the vertebrae in children].
Based on an analysis of observation of 176 children with compressive fractures of vertebral bodies the authors consider the method of "evolutionary physical culture" in children with stable compressive fractures of vertebral bodies to be more physiological, convenient and endurable for patients. Most of the children followed up in the remote period (up to 6 years) showed a complete recovery of the structure and form of the injured vertebrae.


A combined three-dimensional in vitro-in silico approach to modelling bubble dynamics in decompression sickness.
The growth of bubbles within the body is widely believed to be the cause of decompression sickness (DCS). Dive computer algorithms that aim to prevent DCS by mathematically modelling bubble dynamics and tissue gas kinetics are challenging to validate. This is due to lack of understanding regarding the mechanism(s) leading from bubble formation to DCS. In this work, a biomimetic in vitro tissue phantom and a three-dimensional computational model, comprising a hyperelastic strain-energy density function to model tissue elasticity, were combined to investigate key areas of bubble dynamics. A sensitivity analysis indicated that the diffusion coefficient was the most influential material parameter. Comparison of computational and experimental data revealed the bubble surface's diffusion coefficient to be 30 times smaller than that in the bulk tissue and dependent on the bubble's surface area. The initial size, size distribution and proximity of bubbles within the tissue phantom were also shown to influence their subsequent dynamics highlighting the importance of modelling bubble nucleation and bubble-bubble interactions in order to develop more accurate dive algorithms.


The efficacy and safety of a controlled release formulation of salbutamol in the management of patients with asthma in Nairobi, Kenya.
The treatment of asthma in Africa is influenced by cultural and environmental factors as well as the availability of drugs. Poor compliance with regard to long-term maintenance treatment of chronic asthma is also a problem in Africa. The present study reports on 45 patients from 2 centres in Nairobi treated with 8 mg twice daily of an oral controlled release formulation of salbutamol ("Volmax"). The treatment produced a significant improvement in lung function measured by the PEFR compared with baseline data on previous therapy. Controlled release salbutamol was rated as effective or very effective by 84.2% of patients and for 81.6% of patients their physicians preferred this preparation to the therapy used before the study. Side effects were infrequent and usually occurred during the first few days of treatment. The study which is the first report in Africa to assess this novel formulation of salbutamol in a group of African patients, demonstrates that controlled release salbutamol 8 mg administered twice daily is safe and effective, offering benefits over current therapies in the treatment of asthma.


Long-term treatment in pediatric asthma: an update on chemical pharmacotherapy.
Asthma is the most common chronic disease in childhood, affecting approximately 10% of all children, and is the leading cause of hospitalization in developed countries. In this paper we aimed to review the evidence on chemical pharmacotherapy for long-term treatment of pediatric asthma, according to the latest updates. Area covered: Long-term treatment, essential for controlling symptoms and reducing future risks including exacerbations and decline in lung function, includes control agents such as inhaled corticosteroids, long-acting beta2-adrenergic agonists, and leukotriene modifiers. More recent strategies based on the use of a biological drug such as omalizumab, which is a monoclonal antibody directed against immunoglobulin E (IgE), can be considered in selected patients with severe asthma. Expert opinion: In the near future, the challenge of childhood asthma treatment will be to improve the chemical drugs that already exist as well as to carefully characterize the several different asthma subtypes, with special regard to children with severe disease. A better definition of patient features, made possible by the current advanced knowledge of the pathobiology of severe asthma, can ultimately allow the identification of specific phenotypes and endotypes of severe asthma, aimed to personalize pharmacological treatment.


CCA1 and ELF3 Interact in the control of hypocotyl length and flowering time in Arabidopsis.
The circadian clock is an endogenous oscillator with a period of approximately 24 h that allows organisms to anticipate, and respond to, changes in the environment. In Arabidopsis (Arabidopsis thaliana), the circadian clock regulates a wide variety of physiological processes, including hypocotyl elongation and flowering time. CIRCADIAN CLOCK ASSOCIATED1 (CCA1) is a central clock component, and CCA1 overexpression causes circadian dysfunction, elongated hypocotyls, and late flowering. EARLY FLOWERING3 (ELF3) modulates light input to the clock and is also postulated to be part of the clock mechanism. elf3 mutations cause light-dependent arrhythmicity, elongated hypocotyls, and early flowering. Although both genes affect similar processes, their relationship is not clear. Here, we show that CCA1 represses ELF3 by associating with its promoter, completing a CCA1-ELF3 negative feedback loop that places ELF3 within the oscillator. We also show that ELF3 acts downstream of CCA1, mediating the repression of PHYTOCHROME-INTERACTING FACTOR4 (PIF4) and PIF5 in the control of hypocotyl elongation. In the regulation of flowering, our findings show that ELF3 and CCA1 either cooperate or act in parallel through the CONSTANS/FLOWERING LOCUS T pathway. In addition, we show that CCA1 represses GIGANTEA and SUPPRESSOR OF CONSTANS1 by direct interaction with their promoters, revealing additional connections between the circadian clock and the flowering pathways.


Neurocognitive impairment influences quality of life in HIV-infected patients receiving HAART.
The objective of the study was to determine the association of neurocognitive impairment with health-related quality of life (HRQoL) in patients receiving highly active antiretroviral therapy (HAART). Seventy subjects were cross-sectionally analysed with a standardized neuropsychological test battery and a questionnaire including an Italian translation of the MOS-HIV Health Survey. The presence of neurocognitive impairment was significantly associated with lower HRQoL scores: pain (P = 0.03), physical functioning (P = 0.01), role functioning (P = 0.01), social functioning (P = 0.029), mental health (P = 0.001), energy (P = 0.036), health distress (P = 0.002), cognitive functioning (P = 0.05), current health perception (P <0.001), physical health summary score (PHS) (P = 0.005), mental health summary score (MHS) (P = 0.002). Years of education (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.65-0.96), PHS (OR 0.71; 95% CI 0.54-0.95) and MHS (OR 0.67; 95% CI 0.51-0.88) were also associated with cognitive impairment. Neurocognitive impairment in patients receiving HAART was associated with reduced HRQoL. Identifying cognitive impairment may provide motivation for additional treatment to help patients to compensate for deficits in functioning.


Assessing the Performance of Chat Generative Pretrained Transformer (ChatGPT) in Answering Andrology-Related Questions.
The internet and social media have become primary sources of health information, with men frequently turning to these platforms before seeking professional help. Chat generative pretrained transformer (ChatGPT), an artificial intelligence model developed by OpenAI, has gained popularity as a natural language processing program. The present study evaluated the accuracy and reproducibility of ChatGPT's responses to andrology-related questions. The study analyzed frequently asked andrology questions from health forums, hospital websites, and social media platforms like YouTube and Instagram. Questions were categorized into topics like male hypogonadism, erectile dysfunction, etc. The European Association of Urology (EAU) guideline recommendations were also included. These questions were input into ChatGPT, and responses were evaluated by 3 experienced urologists who scored them on a scale of 1 to 4. Out of 136 evaluated questions, 108 met the criteria. Of these, 87.9% received correct and adequate answers, 9.3% were correct but insufficient, and 3 responses contained both correct and incorrect information. No question was answered completely wrong. The highest correct answer rates were for disorders of ejaculation, penile curvature, and male hypogonadism. The EAU guideline-based questions achieved a correctness rate of 86.3%. The reproducibility of the answers was over 90%. The study found that ChatGPT provided accurate and reliable answers to over 80% of andrology-related questions. While limitations exist, such as potential outdated data and inability to understand emotional aspects, ChatGPT's potential in the health-care sector is promising. Collaborating with health-care professionals during artificial intelligence model development could enhance its reliability.


Structural roles of CTG repeats in slippage expansion during DNA replication.
CTG triplet repeat sequences have been found to form slipped-strand structures leading to self-expansion during DNA replication. The lengthening of these repeats causes the onset of neurodegenerative diseases, such as myotonic dystrophy. In this study, electrophoretic and NMR spectroscopic studies have been carried out to investigate the length and the structural roles of CTG repeats in affecting the hairpin formation propensity. Direct NMR evidence has been successfully obtained the first time to support the presence of three types of hairpin structures in sequences containing 1-10 CTG repeats. The first type contains no intra-loop hydrogen bond and occurs when the number of repeats is less than four. The second type has a 4 nt TGCT-loop and occurs in sequences with even number of repeats. The third type contains a 3 nt CTG-loop and occurs in sequences with odd number of repeats. Although stabilizing interactions have been identified between CTG repeats in both the second and third types of hairpins, the structural differences observed account for the higher hairpin formation propensity in sequences containing even number of CTG repeats. The results of this study confirm the hairpin loop structures and explain how slippage occurs during DNA replication.


The life experiences of Thai women and smoking: a phenomenological study.
Exploring and understanding the live experiences of women smokers as well as the conditions and the family/social context of Thai society. A phenomenological approach was used and conducted from July 2011 to April 2012. The informants were 25 Thai women smokers in Bangkok and peripheral areas. Data were collected from focus group discussions and indepth interviews and was analyzed using Diekelmann and Love thematic analysis. The informants ranged in age from 14 to 66 years. The highest education level was a Vocational Certificate and the lowest level was a primary education (Grade 4). The youngest began smoking at 12 years. The average duration of smoking behavior was 22.3 years; the longest of smoking duration was 52 years. They smoked 2.4 packs of cigarettes per day on average, 6 packs per day at the maximum. Within a family setting, the highest number of people smoking and living in the same household was 13 persons. Five themes were identified as follows: 1) the starting point of smoking:-the family environment triggers smoking; 2) the meaning of smoking:-smoking means 'cigarettes are like friends ', 3) femininity and smoking.:-smoking is an individual right and is not illegal; 4) smoking and health:-smoking-health linkage is not an immediate issue as the informants did not suffer from any serious illness; and 5) view on/intention to stop smoking:-the permanent cessation of smoking was not possible due to the current environment in which their friends or family members still smoked, and because some also chose to reduce their stress by smoking. Family environment and peer group influenced the informants smoking behavior Children see their grandmother mother or elder sister smoke, so smoking is perceived as normal behavior among women as well. Most of them had chosen cigarette smoking as a way to relieve themselves from stressful environments.


Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth.
Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer. Metabolism and therapeutic responses of murine pancreatic cancer were studied using KPC primary tumors and tumor chunk allografts. Mice on standard high-carbohydrate diet or ketogenic diet were treated with cytotoxic chemotherapy (nab-paclitaxel, gemcitabine, cisplatin). Metabolic activity was monitored with metabolomics and isotope tracing, including 2H- and 13C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry. Ketone bodies are unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate, which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose's concentration and tricarboxylic acid cycle contribution, enhances 3-hydroxybutyrate's concentration and tricarboxylic acid contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system. Ketogenic diet sensitizes murine pancreatic cancer tumors to cytotoxic chemotherapy. Based on these data, we have initiated a randomized clinical trial of chemotherapy with standard versus ketogenic diet for patients with metastatic pancreatic cancer (NCT04631445).


Itch associated with skin disease: advances in pathophysiology and emerging therapies.
Itch, also known as pruritus, is the major symptom in skin diseases with a variety of etiologies and pathophysiologies. Significant progress has been achieved in understanding the pathophysiology of itch in the last 5 years. Neurophysiological experiments in humans and animals have revealed that itch is carried by specific C nerve fibers. Recent studies have demonstrated that peripheral mediators other than histamine are involved in induction of itch. Mast cell tryptase seems to be an important mediator in itch by its activation of proteinase activated receptor 2 in the sensory nerves. Opioids have central and peripheral itch producing activity. Neuropeptides, such as substance P, induce itch by their effect on mast cells. Based upon our improved understanding of the neurophysiology of itch a clinical classification of itch has been proposed. The classification highlights differences between peripheral pruritoceptive itch, neuropathic itch (itch related to damage to afferent nerve fibers) and neurogenic itch (itch originating in the central nervous system without any evidence of nerve damage). Emerging therapies based on these findings include topical vanilloid receptor antagonists, topical antihistamines, and topical arachidonic acid inhibitors, as well as inhibitors of non-histamine inflammatory mediators, immunomodulators and strontium salts. Systemic therapies include thalidomide, opioid antagonists, phototherapy with narrow band UVB and experimental treatments with cutaneous field stimulation and vagal nerve stimulation. With the new information it seems we will be able to better help our dermatologic patients who have itch, however we are not closer to identifying a single agent specifically targetable to this symptom.


Pathophysiology of myocardial reperfusion.
The feasibility of myocardial reperfusion induced by coronary thrombolysis stimulated marked changes in the management of patients with acute myocardial infarction. Despite the demonstrable successful recanalization achieved in many patients, effective tissue reperfusion has not necessarily been achieved. Furthermore, factors defining the risk/benefit relationships of reperfusion, the extent to which salutary effects on jeopardized myocardium can be anticipated, and the ultimate long-term benefit conferred on the patient all require further definition. Widespread implementation of interventions utilized to induce myocardial reperfusion should be based on thorough characterization of the functional and metabolic responses of the heart to reperfusion. This selective review considers reperfusion within the context of an extensive body of information pertinent to the pathophysiological mechanisms underlying ischemic injury and discusses the potential favorable and unfavorable responses to reperfusion.


In-vitro comparison of different palatal sites for orthodontic miniscrew insertion: Effect of bone quality and quantity on primary stability.
This experiment was undertaken to assess the primary stability of orthodontic miniscrews inserted at different sites in human cadaveric palatal bone for temporary skeletal anchorage, and to determine the effect of bone quality and quantity on their primary stability using microcomputed tomography imaging. A total of 10 cadaveric maxillary hard palates were used for insertion of 130 orthodontic miniscrews (VectorTAS; Ormco, Orange, Calif; length, 6 mm; diameter, 1.4 mm). Upon insertion, maximal insertion torque (IT) was recorded. Imaging (microcomputed tomography) was performed before and after insertion for assessment of bone quality and quantity parameters (bone mineral density [BMD], bone thickness [BT], and length of screw engagement [LSE]). Differences in each parameter were assessed at the various insertion sites. Correlations between IT and measurements of BMD, BT, and LSE were evaluated. Significant differences (P < 0.001) were found among insertion sites for IT, BT, and LSE, but not for BMD (P = 0.004). Correlations were found between IT and BMD (rs = 0.42; P < 0.001), IT and BT (rs = 0.58; P < 0.001), and IT and LSE (rs = 0.58; P < 0.001). Most perforations of miniscrews into the nasal cavity occurred posterior to the permanent second premolars. The primary stability of orthodontic miniscrews in the palate is affected by bone quality and quantity, with higher primary stability obtained anterior to the second premolars and parasagittally at the level of the permanent first molars.


Prevention of DMBA-induced rat mammary carcinomas comparing leuprolide, oophorectomy, and tamoxifen.
Leuprolide, a gonadotropin releasing hormone agonist, is currently being evaluated in a pilot study of premenopausal women for the prevention of breast cancer. However, little data is available regarding the efficacy of leuprolide in experimental animal models of carcinoma when administered prior to the carcinogen. In the present study the capacity of leuprolide to prevent tumor development was evaluated by comparing its pretreatment effects in the DMBA-induced rat mammary carcinoma model to pretreatment with tamoxifen and oophorectomy. Fifty-five day old, female Sprague-Dawley rats were randomly allocated to one of four groups: 1) no treatment; 2) oophorectomy two weeks prior to DMBA; 3) leuprolide, 40 microg/kg/day; and 4) tamoxifen, 10 mg/kg/week. All animals received four 5 mg doses of DMBA for a total dose of 20 mg. Leuprolide and tamoxifen treatments began two weeks prior to DMBA and ended one week after DMBA administration. Animals were assessed weekly to determine palpable tumor onset, number, size, and volume. At the conclusion of the study (16 weeks), autopsies were performed and tumor tissue was collected for confirmation of malignancy. Seventy-eight percent of the untreated rats developed tumors. No tumors developed in the oophorectomy group, while the number of rats with tumors was significantly reduced (p<0.05) with both leuprolide (30%) and tamoxifen (21.9%) compared to controls (77.8%). There were no significant differences in the tumor number for each tumor-bearing rat or in tumor volume between treated and control groups. Using our dosage regimen, 'chemical oophorectomy' with leuprolide was not as effective as surgical oophorectomy in the prevention of chemical carcinogenesis by DMBA but was comparable to the results obtained with tamoxifen.


Physician assessment of ulcerative colitis activity correlates poorly with endoscopic disease activity.
Subjective physician assessment is the cornerstone of routine ulcerative colitis (UC) management. Endoscopic and histologic assessment of UC provides objective measures of inflammatory disease activity. The level of agreement between physician impression of UC activity and endoscopic disease activity has not been evaluated. The aim was to assess the level of agreement between physician's clinical impression of UC disease activity and endoscopic and histologic findings of inflammation. Using the Medical Archival Retrieval System at the University of Pittsburgh Medical Center, we reviewed clinical information on all UC patients between 1995 and 2008 who had clinic visits recorded prior to colonoscopy. Clinical UC disease activity was defined by the physician's clinical impression and the endoscopic and histologic activity by colonoscopy with biopsy. The level of agreement between colonoscopy assessment of UC with histologic and clinical assessment was determined by sensitivity, specificity, positive and negative predictive values, and the kappa coefficient. There were 369 UC patients who had a clinic visit proximate to a colonoscopy. The mean age of patients was 46 ± 16 years (50% female). The performance of clinical impression in recognizing disease activity, as determined by endoscopy, was relatively poor: sensitivity = 56.0%, predictive value negative = 56.8%, kappa coefficient = 0.35. In contrast, the performance of histological evaluation in recognizing disease activity was markedly better: sensitivity = 93.5%, predictive value negative = 89.1%, kappa coefficient = 0.70. The physician's clinical impression of UC activity shows poor agreement with endoscopy and histology, with over one-third of patients with chronic inflammation underrecognized by clinical impression. The consequences of underestimated UC activity by clinical assessment may include undertreatment of active disease and uncontrolled chronic inflammation.


AGAP2 regulates retrograde transport between early endosomes and the TGN.
The retrograde transport route links early endosomes and the TGN. Several endogenous and exogenous cargo proteins use this pathway, one of which is the well-explored bacterial Shiga toxin. ADP-ribosylation factors (Arfs) are approximately 20 kDa GTP-binding proteins that are required for protein traffic at the level of the Golgi complex and early endosomes. In this study, we expressed mutants and protein fragments that bind to Arf-GTP to show that Arf1, but not Arf6 is required for transport of Shiga toxin from early endosomes to the TGN. We depleted six Arf1-specific ARF-GTPase-activating proteins and identified AGAP2 as a crucial regulator of retrograde transport for Shiga toxin, cholera toxin and the endogenous proteins TGN46 and mannose 6-phosphate receptor. In AGAP2-depleted cells, Shiga toxin accumulates in transferrin-receptor-positive early endosomes, suggesting that AGAP2 functions in the very early steps of retrograde sorting. A number of other intracellular trafficking pathways are not affected under these conditions. These results establish that Arf1 and AGAP2 have key trafficking functions at the interface between early endosomes and the TGN.


SOLEIL shining on the solution-state structure of biomacromolecules by synchrotron X-ray footprinting at the Metrology beamline.
Synchrotron X-ray footprinting complements the techniques commonly used to define the structure of molecules such as crystallography, small-angle X-ray scattering and nuclear magnetic resonance. It is remarkably useful in probing the structure and interactions of proteins with lipids, nucleic acids or with other proteins in solution, often better reflecting the in vivo state dynamics. To date, most X-ray footprinting studies have been carried out at the National Synchrotron Light Source, USA, and at the European Synchrotron Radiation Facility in Grenoble, France. This work presents X-ray footprinting of biomolecules performed for the first time at the X-ray Metrology beamline at the SOLEIL synchrotron radiation source. The installation at this beamline of a stopped-flow apparatus for sample delivery, an irradiation capillary and an automatic sample collector enabled the X-ray footprinting study of the structure of the soluble protein factor H (FH) from the human complement system as well as of the lipid-associated hydrophobic protein S3 oleosin from plant seed. Mass spectrometry analysis showed that the structural integrity of both proteins was not affected by the short exposition to the oxygen radicals produced during the irradiation. Irradiated molecules were subsequently analysed using high-resolution mass spectrometry to identify and locate oxidized amino acids. Moreover, the analyses of FH in its free state and in complex with complement C3b protein have allowed us to create a map of reactive solvent-exposed residues on the surface of FH and to observe the changes in oxidation of FH residues upon C3b binding. Studies of the solvent accessibility of the S3 oleosin show that X-ray footprinting offers also a unique approach to studying the structure of proteins embedded within membranes or lipid bodies. All the biomolecular applications reported herein demonstrate that the Metrology beamline at SOLEIL can be successfully used for synchrotron X-ray footprinting of biomolecules.


The #IVF journey: content analysis of IVF videos on TikTok.
What patient populations and outcomes are depicted on IVF videos on the short-form video-sharing application 'TikTok'? This cross-sectional study investigated the 100 most-viewed videos utilizing the #IVF hashtag on TikTok. Only videos in English or Spanish were included in the analysis. An automated web-scraping platform was used to extract information from these videos. Standardized video coding was used to evaluate the featured subject(s), phase of care and IVF outcomes from the videos. Videos meeting the inclusion criteria (n=93) had 731 million views, 91 million likes and 893,000 shares. Patients' personal stories about IVF are over-represented relative to videos created by healthcare professionals. #IVF videos popular on TikTok disproportionately depict same-sex couples (38.1%), gestational carriers (14.0%), multiple gestations (60.0%) and live births (89.3%) relative to real-world data. Among the videos making scientific claims (n=16), nearly all were moderately to highly accurate (93.8%). Most videos had a positive (55.9%) or neutral (5.5%) tone towards IVF. Popular #IVF videos on TikTok contribute to public discourse about infertility, and highlight demographics that have traditionally been under-represented in health care. Videos rarely focused on health education or made informational claims, with low scores on measures of quality of information and actionability. This gap represents an opportunity for health providers and educators to create more engaging and educational content to reach patients considering IVF.


AKAP signaling in reinstated cocaine seeking revealed by iTRAQ proteomic analysis.
To identify candidate proteins in the nucleus accumbens (NAc) as potential pharmacotherapeutic targets for treating cocaine addition, an 8-plex iTRAQ (isobaric tag for relative and absolute quantitation) proteomic screen was performed using NAc tissue obtained from rats trained to self-administer cocaine followed by extinction training. Compared with yoked-saline controls, 42 proteins in a postsynaptic density (PSD)-enriched subfraction of the NAc from cocaine-trained animals were identified as significantly changed. Among proteins of interest whose levels were identified as increased was AKAP79/150, the rat ortholog of human AKAP5, a PSD scaffolding protein that localizes signaling molecules to the synapse. Functional downregulation of AKAP79/150 by microinjecting a cell-permeable synthetic AKAP (A-kinase anchor protein) peptide into the NAc to disrupt AKAP-dependent signaling revealed that inhibition of AKAP signaling impaired the reinstatement of cocaine seeking. Reinstatement of cocaine seeking is thought to require upregulated surface expression of AMPA glutamate receptors, and the inhibitory AKAP peptide reduced the PSD content of protein kinase A (PKA) as well as surface expression of GluR1 in NAc. However, reduced surface expression was not associated with changes in PKA phosphorylation of GluR1. This series of experiments demonstrates that proteomic analysis provides a useful tool for identifying proteins that can regulate cocaine relapse and that AKAP proteins may contribute to relapse vulnerability by promoting increased surface expression of AMPA receptors in the NAc.


The relationship between armed conflict and reproductive, maternal, newborn and child health and nutrition status and services in northeastern Nigeria: a mixed-methods case study.
Armed conflict between the militant Islamist group Boko Haram, other insurgents, and the Nigerian military has principally affected three states of northeastern Nigeria (Borno, Adamawa, Yobe) since 2002. An intensification of the conflict in 2009 brought the situation to increased international visibility. However, full-scale humanitarian intervention did not occur until 2016. Even prior to this period of armed conflict, reproductive, maternal, neonatal, and child health indicators were extremely low in the region. The presence of local and international humanitarian actors, in the form of United Nations agencies and non-governmental organizations, working in concert with concerned federal, state, and local entities of the Government of Nigeria, were able to prioritize and devise strategies for the delivery of health services that resulted in marked improvement of health status in the subset of the population in which this could be measured. Prospects for the future remain uncertain. Interviews were conducted with more than 60 respondents from government, United Nations agencies, and national and international non-governmental organizations. Quantitative data on intervention coverage indicators from publicly available national surveys (Demographic and Health Surveys (DHS), Multiple Indicator Cluster Surveys (MICS)), National Nutrition and Health Surveys (NNHS)) were descriptively analyzed. Overall, indicators of low reproductive, maternal, neonatal, and child health (RMNCH) status and intervention coverage were found in the pre-intervention period (prior to 2016) and important improvements were noted following the arrival of international humanitarian assistance, even while armed conflict and adverse conditions persisted. Security issues, workforce limitations, and inadequate financing were frequently cited obstacles. It is assumed that armed conflict would have a negative impact on the health status of the affected population, but pre-conflict indicators can be so depressed that this effect is difficult to measure. When this is the case, health sector intervention by the international community can often result in marked improvements in the accessible population. What might happen upon the departure of the humanitarian organizations cannot be predicted with an appreciable degree of certainty.


Biological activity of selenium: Revisited.
Selenium (Se) is an essential micronutrient that exerts multiple and complex effects on human health. Se is essential for human well-being largely due to its potent antioxidant, anti-inflammatory, and antiviral properties. The physiological functions of Se are carried out by selenoproteins, in which Se is specifically incorporated as the amino acid, selenocysteine. Importantly, both beneficial and toxic effects of Se have been reported suggesting that the mode of action of Se is strictly chemical form and concentration dependent. Additionally, there is a relatively narrow window between Se deficiency and toxicity and growing evidence suggests that Se health effects depend greatly on the baseline level of this micronutrient. Thus, Se supplementation is not an easy task and requires an individualized approach. It is essential that we continue to explore and better characterize Se containing compounds and mechanisms of action, which could be crucial for disease prevention and treatment.


Analysis of responses of garlic derivatives in the pulmonary vascular bed of the rat.
Allicin, an extract from garlic, has been shown to be a systemic and pulmonary arterial vasodilator that acts by an unknown mechanism. In the present experiments, pulmonary vascular responses to allicin (10-100 microg), allyl mercaptan (0.3-1 mg), and diallyl disulfide (0.3-1 mg) were studied in the isolated lung of the rat under constant-flow conditions. When baseline tone in the pulmonary vascular bed of the rat was raised to a high-steady level with the thromboxane A(2) mimic U-46619, dose-related decreases in pulmonary arterial pressure were observed. In terms of the mechanism of action of allicin vasodilator activity in the rat, responses to allicin were not significantly different after administration of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester, the K(ATP)(+) channel antagonist U-37883A, or the cyclooxygenase inhibitor sodium meclofenamate, or when lung ventilation was interrupted. These data show that allicin has significant vasodilator activity in the pulmonary vascular bed of the rat, whereas allyl mercaptan and diallyl disulfide produced no significant changes in pulmonary arterial perfusion pressure. The present data suggest that pulmonary vasodilator responses to allicin are independent of the synthesis of nitric oxide, ATP-sensitive K(+) channels, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the rat.


[Traditional medicine CDP and promoter demethylation in breast cancer cell lines].
To investigate the demethylation effect of CDP on P16 and E-CADHERIN genes. Breast cancer cell lines T47D and MDA-MB-435 were treated with CDP and DNA methyltransferase inhibitor 5-azacytidine (5-aza-C). The methylation of P16 and E-CADHERIN gene promoters were measured by methylation-specific PCR (MSP). The RNA transcription was determined by reverse transcription-PCR(RT-PCR). 1) The methylation-specific fragments of P16 gene promoter existed in T47D cells after 25, 50 and 75 micromol/L of CDP treatment for 6 days. An absolute demethylation on P16 gene occurred after treatment with 100 micromol/L of CDP. The unmethylation-specific fragments appeared in T47D cells after being treated with 25, 50, 75 and 100 micromol/L of CDP for 6 days. The RNA expression of P16 was detected after treatment with 75 and 100 micromol/L of CDP. 2) After being treated with 50 micromol/L of CDP, the methylation-specific fragments of CpG island in P16 gene promoter still existed in T47D cells. The unmethylation-specific fragments in T47D cells started to appear after 24 hours of treatment and lasted until 144 hour of treatment. The RNA expression was detected after 144 hours of treatment. 3) The demethylation on E-CADHERIN gene and genomic DNA or RNA transcription were not detected in MDA-MB-435 cells. CDP has concentration- and time-dependent demethylation effect on P16 gene in T47D cells, but not on E-CADHERIN gene in MDA-MB-435 cells, which indicates that CDP has substantial diversity in molecular activities.


Long-term effects of 2'-deoxycoformycin treatment on cytokine production in patients with hairy cell leukemia.
Deoxycoformycin (DCF) has been reported to cause immediate reduction and dysfunction of T lymphocytes, but the long-term effects on immune functions are still not known. As cytokine production is regulated by T helper-inducer lymphocytes and might represent a parameter for functional integrity of immunocompetent cells, we have measured the production of interleukin-2 (IL-2), tumor necrosis factor (TNF), and interferons (IFN) by peripheral mononuclear cells (PMNC) from 10 patients with hairy cell leukemia 11-24 months after end of therapy with DCF. The patients were in continuous remission at the time of study. Despite an absolute reduction in CD3+ and CD4+ lymphocytes. there were no significant differences in IL-2 or TNF release between patients and controls. Except for a significant reduction in IFN-alpha release stimulated by Newcastle disease virus (NDV), IFN productions induced by other mitogens (phytohemagglutinin, PHA; Concanavalin A, ConA; pokeweed mitogen, PWM) and viral antigens were within normal range. There was also a decrease in proliferative responsiveness to PHA, but responses to ConA, PWM, and other viral antigens were normal. In five of the patients, we have monitored closely the changes in IL-2, TNF, and IFN before, during, and after treatment and could demonstrate a rapid normalization of initially decreased IL-2 release in all cases and also of TNF if the initial production was reduced. This study shows that, even though the absolute number of T lymphocytes and helper cells are reduced in the long-term observation after DCF treatment, the capacity to produce IL-2, TNF, and IFN-gamma was within normal range. Parallel to this observation, no opportunistic infections or frequency of infectious complications occurred in these patients.


Validation of a 3D CT imaging method for quantifying implant migration following anatomic total shoulder arthroplasty.
Glenoid component loosening remains a common complication following anatomic total shoulder arthroplasty (TSA); however, plain radiographs are unable to accurately detect early implant migration. The purpose of this study was to validate the accuracy of a method of postoperative, three-dimensional (3D) computed tomography (CT) imaging with metal artifact reduction (MAR) to detect glenoid component migration following anatomic TSA. Tantalum bead markers were inserted into polyethylene glenoid components for implant detection on 3D CT. In-vitro validation was performed using a glenoid component placed into a scapula sawbone and incrementally translated and rotated, with MAR 3D CT acquired at each test position. Accuracy was evaluated by root mean square error (RMSE). In-vivo validation was performed on six patients who underwent anatomic TSA, with two postoperative CT scans acquired in each patient and marker-based radiostereometric analysis (RSA) performed on the same days. Glenoid component migration was calculated relative to a scapular coordinate system for both MAR 3D CT and RSA. Accuracy was evaluated by RMSE and paired Student's t-tests. The largest RMSE on in-vitro testing was 0.24 mm in translation and 0.11° in rotation, and on in-vivo testing was 0.47 mm in translation and 1.04° in rotation. There were no significant differences between MAR 3D CT and RSA measurement methods. MAR 3D CT imaging is capable of quantifying glenoid component migration with a high level of accuracy. MAR 3D CT imaging is advantageous over RSA because it is readily available clinically and can also be used to evaluate the implant-bone interface.


Improving fluorescent DNAzyme biosensors by combining inter- and intramolecular quenchers.
A previously reported DNAzyme-based biosensor for Pb(2+) has shown high sensitivity and selectivity at 4 degrees C. In the system, the substrate and the enzyme strand of the DNAzyme are labeled with a fluorophore and a quencher, respectively. In the presence of Pb(2+), the substrate strand is cleaved by the enzyme strand, and the release of the cleaved fragment results in significant fluorescence increase. However, the performance of the sensor decreases considerably if the temperature is raised to room temperature because of high background fluorescence. A careful analysis of the sensor system, including measurement of the melting curve and fluorescence resonance energy-transfer (FRET) study of the free substrate, suggests that a fraction of the fluorophore-labeled substrate strand is dissociated from the enzyme strand, resulting in elevated background fluorescence signals at room temperature. To overcome this problem, we designed a new sensor system by introducing both inter- and intramolecular quenchers. The design was aided by the FRET study that showed the dissociated substrate maintained a random coil conformation with an end-to-end distance of approximately 39 A, which is much shorter than that of the fully extended DNA. With this new design, the background fluorescence was significantly suppressed, with 660% increase of fluorescence intensity as compared to 60% increase for the previous design. This suppression of background fluorescence signals was achieved without losing selectivity of the sensor. The new design makes it possible to use the sensor for practical applications in a wide temperature range. The design principle presented here should be applicable to other nucleic acid-based biosensors to decrease background fluorescence.


Distinct mechanisms of bidirectional activity-dependent synaptic plasticity in superficial and deep layers of rat entorhinal cortex.
The entorhinal cortex plays a key role in processing memory information in the brain; superficial layers relay information to, and deep layers receive information from, the hippocampus. The cellular mechanisms of memory are thought to include a number that produce long-term potentiation (LTP) and depression (LTD) of synaptic strength. Our work presents evidence that LTP and LTD occur simultaneously at memory-relevant synapses. We report here that low frequency stimulation generates NMDA receptor-dependent LTD in Wistar rat superficial (layers II and III), and LTP in the deep entorhinal cortex layers (layers V and VI). LTP in deep layers is masked by simultaneously occurring voltage-gated calcium channel-dependent LTD. Our data support a novel mechanism for the sliding-threshold (BCM) model of synaptic plasticity: The sliding thresholds for induction of LTP and LTD in entorhinal cortex deep layers will be driven by the relative activation state of NMDA receptors and voltage-gated calcium channels. The co-expression of LTD and LTP at presynaptic sites in the entorhinal cortex deep layers reveals an intriguing mechanism for differential processing of synaptic information, which may underlie the vast dynamic capacity for information storage by this cortical structure.


Helminth Fauna of Spiny Tailed Lizard, Darevskia Rudis (Bedriaga, 1886) (Sauria: Lacertidae) from Turkey.
The present study investigated the composition of helminth parasites of Darevskia rudis, Spiny Tailed Lizard from Turkey. One hundred and two samples (49♀♀, 53♂♂) from the Tokat, Trabzon, Rize, Gümüşhane and Artvin Provinces were collected and examined for helminth parasites. New host and locality records were recorded. As a result of the present study, seven species of Nematoda, Skrjabinodon medinae, Spauligodon sp., Spauligodon carbonelli, Spauligodon aloisei, Skrjabinelazia hoffmanni, Strongyloides darevsky, Oswaldocruzia filiformis; one species of Cestoda, Mesocestoides spp. (tetrathyridium) and one species of Acanthocephala Sphaerirostris scanensis were reported from the lizard samples. Sp. carbonelli and Sphaerirostris scanensis are here recorded for the first time in Turkey. D. rudis is the new host recorded for Sk. medinae, Spauligodon sp., Sp. carbonelli, Sp. aloisei from Nematoda, Mesocestoides spp. from Cestoda and Sphaerirostris scanensis from Acanthocephala. This host has been studied for the first time for the helminth parasites from the Tokat and Gümüşhane Provinces. There is, to our knowledge, only one report of helminthes for D. rudis in Turkey.


Transforming vulnerability.
Asian American immigrant women engaged in filial caregiving are at special risk for health problems due to complex contextual factors related to immigration, cultural traditions, and role transition. This study examines the experience of two groups of immigrant Asian American women who are caring for older parents. A total of 41 women (22 Chinese American and 19 Filipino American) were interviewed in a study based on Strauss and Corbin's grounded theory methodology. The women were determined to be loyal to their traditional culture, which included strong filial values, while adapting to a new culture. Through the struggle of meeting role expectations and coping with paradox, the women mobilized personal and family resources to transform vulnerability into strength and well-being.


Influence of exercise order on the number of repetitions performed and perceived exertion during resistance exercise in women.
The purpose of this study was to investigate the influence of different resistance exercise orders on the number of repetitions performed to failure and on the ratings of perceived exertion (RPE) in trained women. Twenty-three women with a minimum of 2 years of resistance training experience volunteered to participate in the study (age, 24.2 +/- 4.5 years; weight, 56.9 +/- 4.7 kg; height, 162.3 +/- 5.9 cm; percent body fat, 18.2 +/- 2.9%; body mass index, 22.2 +/- 2 kg x m(-2)). Data were collected in 2 phases: (a) determination of a 1 repetition maximum (1RM) for the leg-press (LP), bench press (BP), leg extension (LE), seated machine shoulder press (SP), leg curl (LC), and seated machine triceps extension (TE); and (b) execution of 3 sets, with 2-minute rest intervals between sets and exercises, until fatigue using 80% of 1RM in 2 exercise sequences of the exact opposite order--Sequence A: BP, SP, TE, LP, LE, and LC, and Sequence B: LC, LE, LP, TE, SP, and BP. The RPE (Borg CR-10) was accessed immediately after each sequence and analyzed using a Wilcoxon test. A 2-way analysis of variance with repeated measurements, followed by a post hoc Fisher least significant difference test where indicated was used to analyze the number of repetitions per set of each exercise during the 2 sequences. The RPE was not significantly different between the sequences. The mean number of repetitions per set was always less when an exercise was performed later in the exercise sequence. The data indicate that in trained women, performance of both large- and small-muscle group exercises is affected by exercise sequence.


Safety and efficacy of iloprost for the treatment of ischaemic digits in paediatric connective tissue diseases.
We analysed our experience with the use of iloprost for the treatment of critical ischaemic digits (ID) in children with connective tissue diseases (CTD) in order to assess its safety and efficacy. This was a retrospective analysis of paediatric patients with CTD who were treated with iloprost for critical ID resistant to conventional therapy. Information on demographics, clinical and laboratory features, the regimen of iloprost treatment and outcome were collected. Fifteen patients (10 female, five male) treated one or more times with iloprost were included (total of 19 treatments). Six had juvenile systemic sclerosis, five had systemic lupus erythematosus, three had mixed connective tissue disease and one had cutaneous polyarteritis nodosa. Thirteen patients were already taking calcium channel blockers with no improvement; in two patients ID were the presenting signs of the disease without prior treatment. Eleven patients had more than two fingers involved; one child had involvement of all 10 fingers. Normal digital blood flow was achieved in 74% of treatments and significant improvement was noted in 26%. Fingertip necrosis was present in 11 patients (14 treatments). It healed completely in seven, improved in one and remained unchanged in six. Raynaud's phenomenon (RP) was present in 14 patients (17 treatments): in two no RP attack occurred during the follow-up period, eight improved both in the number of attacks per week and in the duration of each attack. Complete pain relief was observed in 10/17 treatments (59%) and there was a significant decrease in pain in the remaining seven. No major side-effects or withdrawal symptoms were reported. Minor side-effects reported include reversible headache (seven patients), hypotension or irritability (three), nausea/vomiting (two) and injection site reaction (one). Iloprost appears to be a safe and effective treatment for ischaemic digits and digital ulcers in children with CTD. In conjunction with immunosuppressive drugs, it has a potential role in preventing irreversible complications, such as digital gangrene and amputation.


Expression of Components of the Renin-Angiotensin System in Pyogenic Granuloma.
Background: There is a growing body of research demonstrating expression of the renin-angiotensin system (RAS) by a putative embryonic stem cell (ESC)-like population within vascular anomalies. This study investigated the expression of components of the RAS in relation to the putative ESC-like population within pyogenic granuloma (PG) that we have recently reported. Methods: PG samples from 14 patients were analyzed for the expression of components of the RAS: pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2), using 3,3-diaminobenzidine (DAB) immunohistochemical (IHC) staining. Immunofluorescence (IF) IHC staining was performed to localize these proteins on four of the PG samples. RT-qPCR was performed on two snap-frozen PG samples. Western blotting (WB) was performed on one snap-frozen PG sample and two PG-derived primary cell lines. Results: DAB IHC staining demonstrated the expression of ACE, PRR, ATIIR1, and ATIIR2 in all 14 PG tissue samples. RT-qPCR analysis confirmed abundant mRNA transcripts for PRR, ACE, AIITR1 and ATIIR2, relative to the housekeeping gene. WB confirmed the presence of PRR, ATIIR1, and ACE in the PG tissue sample, and PRR and ATIIR1, in the PG-derived primary cell lines. IF IHC staining demonstrated the expression of PRR, ACE, ATIIR1 on the primitive population that expressed NANOG and SOX2 on the ERG+ endothelium of the microvessels within PG. Conclusion: We have demonstrated the expression of PRR, ACE, and ATIIR1 by the putative the ESC-like population within PG.


Developing culturally sensitive interventions for Vietnamese health issues: an action research approach.
This article describes an action research approach to community development in Vietnam. An advisory committee worked with the researchers and identified the stigma of HIV/AIDS as a health issue of importance to it. The advisory committee consisted of representatives from the community. The selected issue was then explored in greater depth by individually interviewing infected persons, their family members, community members, and leaders. At the same time, focus groups were conducted for additional members of each of the above three cohorts. Through open-ended questions, the participants described the impacts of the stigma on their life, the possible causes of the stigma, and the relevant strategies to reduce these causes. Based on the findings, the advisory committee suggested interventions to reduce the stigma. This project demonstrated an effective way in which nurses can work with communities to help them to identify local solutions to their identified health issues.


Proline 68 enhances photoisomerization yield in photoactive yellow protein.
In proteins and enzymes, the local environment of an active cofactor plays an important role in controlling the outcome of a functional reaction. In photoactive yellow protein (PYP), it ensures photoisomerization of the chromophore, a prerequisite for formation of a signaling state. PYP is the prototype of a PAS domain, and the preferred model system for the studies of molecular mechanisms of biological light sensing. We investigated the effect of replacing proline-68, positioned near but not in direct contact with the chromophore, with other neutral amino acids (alanine, glycine, and valine), using ultrafast spectroscopy probing the visible and the mid-IR spectral regions, and molecular simulation to understand the interactions tuning the efficiency of light signaling. Transient absorption measurements indicate that the quantum yield of isomerization in the mutants is lower than the yield observed for the wild type. Subpicosecond mid-IR spectra and molecular dynamics simulations of the four proteins reveal that the hydrogen bond interactions around the chromophore and the access of water molecules in the active site of the protein determine the efficiency of photoisomerization. The mutants provide additional hydrogen bonds to the chromophore, directly and by allowing more water molecules access to its binding pocket. We conclude that proline-68 in the wild type protein optimizes the yield of photochemistry by maintaining a weak hydrogen bond with the chromophore, at the same time restraining the entrance of water molecules close to the alkylic part of pCa. This study provides a molecular basis for the structural optimization of biological light sensing.


Intraoral behaviour and biocompatibility of gold versus non precious alloys.
The costs of traditional dental gold alloys have increased rapidly over the last fifteen years, and numerous attempts have therefore been made to develop and produce less expensive alternatives for use in the manufacture of fixed dental appliances. A review is presented of the various types of alloys currently available in the western world, as well as of the biological, technical and clinical aspects of their use in dentistry. Special attention is paid to the possible risks of various types of pathological reactions associated with alternative alloys containing nickel, beryllium or cadmium. Technical aspects covered include constructional problems and those associated with casting, finishing and the clinical adjustment of fixed appliances produced by traditional and alternative alloys. In conclusion, it is stated that even if rapid progress in this area makes long-term predictions difficult there is no evidence at present to suggest that the costs of dental treatment have in general become noticably lower to the patients when alternative alloys have been used instead of traditional gold based ones.


Acute high-dose X-radiation-induced genomic changes in A549 cells.
Accidents with ionizing radiation often involve single, acute high-dose exposures that can lead to acute radiation syndrome and late effects such as carcinogenesis. To study such effects at the cellular level, we investigated acute ionizing radiation-induced chromosomal aberrations in A549 adenocarcinoma cells at the genome-wide level by exposing the cells to an acute dose of 6 Gy 240 kV X rays. One sham-irradiated clone and four surviving irradiated clones were recovered by minimal dilution and further expanded and analyzed by chromosome painting and tiling-path array CGH, with the nonirradiated clone 0 serving as the control. Acute X-ray exposure induced specific translocations and changes in modal chromosome number in the four irradiated clones. Array CGH disclosed unique and recurrent genomic changes, predominantly losses, and revealed that the fragile sites FRA3B and FRA16D were preferential regions of genomic alterations in all irradiated clones, which is likely related to radioresistant S-phase progression and genomic stress. Furthermore, clone 4 displayed an increased radiosensitivity at doses >5 Gy. Pairwise comparisons of the gene expression patterns of all irradiated clones to the sham-irradiated clone 0 revealed an enrichment of the Gene Ontology term "M Phase" (P = 6.2 × 10(-7)) in the set of differentially expressed genes of clone 4 but not in those of clones 1-3. Ionizing radiation-induced genomic changes and fragile site expression highlight the capacity of a single acute radiation exposure to affect the genome of exposed cells by inflicting genomic stress.


N2:O emissions from a cultivated Andisol after application of nitrogen fertilizers with or without nitrification inhibitor under soil moisture regime.
The aim of this work was to examine the emission of N2O from soils following addition of nitrogen fertilizer with a nitrification inhibitor (+inh) or without the nitrification inhibitor(-inh) at different soil water regime. Higher soil moisture contents increased the total N2O emissions in all treatments with total emissions being 7 times larger for the CK and > 20 times larger for the fertilizer treatments at 85% WFPS (soil water filled pore space) than at 40% WFPS. The rates of N2O emissions at 40% WFPS under all treatments were small. The maximum emission rate at 55% WFPS without the nitrification inhibitor (-inh) occurred later (day 11) than those of 70% WFPS (-inh) samples (day 8). The inhibition period was 4-22 d for 55% WFPS and 1-15 d for 70% WFPS comparing the rates of N2O emissions treated (+inh) with (-inh). The maximum emission rates at 85% WFPS were higher than those at the other levels of soil water content for all treatments. The samples (+inh) released less N2O than (-inh) samples at the early stage. Nevertheless, N2O emissions from (+inh) samples lasted longer than in the (-inh) treatment. Changes in mineral N at 55%, 70% and 85% WFPS followed the same pattern. NH4(+) -N concentrations decreased while NO3(-) -N concentrations increased from the beginning of incubation. NH4(+) -N concentrations from 40% WFPS treatment declined more slowly than those of the other three levels of soil water content. Nitrification was faster in the (-inh) samples with 100% NH4(+) -N nitrified after 22 d (50% WFPS) and 15 d (70% and 85% WFPS). N2O emissions increased with soil water content. Adding N-fertilizer increased emissions of N2O. The application of the nitrification inhibitor significantly reduced total N2O emissions from 30.5% (at 85% WFPS) to 43.6% (at 55% WFPS).


An experimental and ab initio study of the electronic spectrum of the jet-cooled F2BO free radical.
We have studied the B̃ (2)A1-X̃ (2)B2 laser-induced fluorescence (LIF) spectrum of the jet-cooled F2BO radical for the first time. The transition consists of a strong 0(0)(0)band at 446.5 nm and eight weak sequence bands to shorter wavelengths. Single vibronic level emission spectra obtained by laser excitation of individual levels of the B̃ state exhibit two electronic transitions: a very weak, sparse B̃-X̃ band system in the 450-500 nm region and a stronger, more extensive set of B̃ (2)A1-à (2)B1 bands in the 580-650 nm region. We have also performed a series of high level ab initio calculations to predict the electronic energies, molecular structures, vibrational frequencies, and rotational and spin-rotation constants in the X̃ (2)B2, à (2)B1 and B̃ (2)A1 electronic states as an aid to the analysis of the experimental data. The theoretical results have been used as input for simulations of the rotationally resolved B̃ (2)A1-X̃ (2)B2 0(0)(0) LIF band and Franck-Condon profiles of the LIF and single vibronic level emission spectra. The agreement between the simulations obtained with purely ab initio parameters and the experimental spectra validates the geometries calculated for the ground and excited states and the conclusion that the radical has C2v symmetry in the X̃, Ã, and B̃ states. The spectra provide considerable new information about the vibrational energy levels of the X̃ and à states, but very little for the B̃ state, due to the very restrictive Franck-Condon factors in the LIF spectra.


An association study between epicardial fat thickness and cognitive impairment in the elderly.
The amount of fat surrounding the heart, called epicardial adipose tissue (EAT), is a marker of cardiometabolic risk and correlates with the quantity of visceral adipose tissue (VAT). The amount of VAT is associated with an increased risk of cardiovascular and cerebrovascular disease and with cognitive impairment. We aimed to evaluate the association between EAT thickness as a measure of VAT and cognitive function. In 71 elderly subjects (mean age 72.7 ± 7.1 yr) we measured EAT thickness through transthoracic echocardiography, assessed the metabolic profile through evaluation of biochemical parameters, and estimated the cognitive function via the Mini Mental State Examination (MMSE). We found that greater EAT thickness was associated with lower cognitive performance evaluated by MMSE (P < 0.01) independently of the presence or absence of metabolic syndrome or obesity. Lower MMSE results were also associated with the presence of metabolic syndrome (P < 0.01), elevated HOMA index (P < 0.01), and high BMI values (P < 0.01). The results of mediation analysis confirmed that the total effect of metabolic syndrome, HOMA, and BMI on MMSE is mainly explained by an indirect effect through EAT thickness. In conclusion, increased EAT thickness assessed by transthoracic echocardiography is associated with deficient results of psychometric tests assessing cognitive performance and may consistently foresee impairment of cognition in the elderly.


Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity.
Cesarean section (CS) and antibiotic use during pregnancy may alter normal maternal-offspring microbiota exchange, thereby contributing to aberrant microbial colonization of the infant gut and increased susceptibility to obesity later in life. We hypothesized that (i) maternal use of antibiotics in the second or third trimester of pregnancy and (ii) CS are independently associated with higher risk of childhood obesity in the offspring. Of the 727 mothers enrolled in the Northern Manhattan Mothers and Children Study, we analyzed the 436 mother-child dyads followed until 7 years of age with complete data. We ascertained prenatal antibiotic use by a questionnaire administered late in the third trimester, and delivery mode by medical record. We derived age- and sex-specific body mass index (BMI) z-scores using the CDC SAS Macro, and defined obesity as BMI z⩾95th percentile. We used binary regression with robust variance and linear regression models adjusted for maternal age, ethnicity, pre-gravid BMI, maternal receipt of public assistance, birth weight, sex, breastfeeding in the first year and gestational antibiotics or delivery mode. Compared with children not exposed to antibiotics during the second or third trimester, those exposed had 84% (33-154%) higher risk of obesity, after multivariable adjustment. Second or third trimester antibiotic exposure was also positively associated with BMI z-scores, waist circumference and % body fat (all P<0.05). Independent of prenatal antibiotic usage, CS was associated with 46% (8-98%) higher offspring risk of childhood obesity. Associations were similar for elective and non-elective CS. In our cohort, CS and exposure to antibiotics in the second or third trimester were associated with higher offspring risk of childhood obesity. Future studies that address the limitations of our study are warranted to determine if prenatal antibiotic use is associated with offspring obesity. Research is also needed to determine if alterations in neonatal gut microbiota underlie the observed associations.


Early detection and treatment of neovascular age-related macular degeneration.
The neovascular form of age-related macular degeneration (AMD) can rapidly lead to severe loss of central vision and adversely affect the patient's quality of life. During the 1990s the only proven treatment for neovascular AMD was laser photocoagulation. Only a minority of patients are eligible to receive this treatment, however, and the treatment itself can cause acute retinal damage with immediate vision loss. Verteporfin therapy is a new treatment option involving photodynamic therapy that was recently shown to be relatively safe and effective in reducing the risk of vision loss in selected cases. Recent literature was reviewed on management of choroidal neovascularization caused by AMD that proved beneficial in large-scale randomized clinical trials. These studies were selected through a MEDLINE search of files from 1982 to the present using the keywords "randomized clinical trials," "choroidal neovascularization," and "age-related macular degeneration," as well as through personal knowledge of recently completed trials. Primary care physicians can effect good treatment outcomes by detecting early signs of AMD and educating patients about the necessity of prompt referral to an ophthalmologist. Immediate referral is increasingly important because, compared with laser photocoagulation, current photodynamic therapy with verteporfin is applicable to more patients. Greater patient awareness of neovascular AMD and the importance of self-testing of vision can also be communicated to patients in primary care.


Chebulagic acid from Terminalia chebula causes G1 arrest, inhibits NFκB and induces apoptosis in retinoblastoma cells.
Plants are the valuable source of natural products with important medicinal properties. Most of the approved anti cancer drugs have a natural product origin or are natural products. Retinoblastoma is the most common ocular cancer of children. Although chemotherapy is the preferred mode of therapy, a successful treatment for retinoblastoma requires enucleation. Chebulagic acid (CA) from Terminalia chebula was shown to have anti-proliferative properties in the studies on cancerous cell lines. Due to anti cancer properties of CA and due to limitation in treatment options for retinoblastoma, the present study is undertaken to understand the role of CA on the proliferation of retinoblastoma cells. Anti proliferative potential of CA was determined by MTT assay. The expression levels of various cell death mediators in retinoblastoma cells with CA treatment were assessed by Western blotting. Flowcytometer analysis was used to estimate the mitochondrial membrane potential (MMP) and to determine the percentage of cells undergoing apoptosis. The present study showed CA inhibited the proliferation of retinoblastoma cells in a dose dependent manner. CA modulated MMP, induced release of Cytochrome c, activated caspase 3 and shifted the ratio of BAX and Bcl2 towards cell death. G1 arrest, noticed in CA treated cells, is mediated by the increase in the expression of CDK inhibitor p27. CA treatment also decreased the levels of NFκB in the nucleus. This decrease is mediated by suppression in degradation of IκBα. CA has shown significant anti proliferative potential on retinoblastoma cells. Our findings clearly demonstrate that CA induces G1 arrest, inhibits NFκB and induces apoptosis of retinoblastoma cells.


Problem perception in Dutch university students using tobacco, alcohol and drugs.
When communicating about health behaviour with students, insight is needed in perceptions students have about their (un)healthy behaviour. We aimed to investigate associations between problem perception and perceived health, academic functioning in students using tobacco, alcohol or drugs. Students who were enrolled fulltime in Medicine, Economics, Occupational Therapy, History, Psychology or Information Studies in Amsterdam, the Netherlands (n = 8258), were invited for an internet-based questionnaire about perceived health, social support, study delay, and problem perception regarding tobacco, alcohol and drug use in October 2005 (response: 44%). Students using tobacco, alcohol and drugs with and without problem perception and non-users were compared (logistic regression). Problem perception in students using tobacco, alcohol or drugs was associated with worse health outcomes.


Toward Reducing Health Information Inequities in the Caribbean: Our Experience Building a Participatory Health Informatics Project.
Precision medicine seeks to leverage technology to improve the health for all individuals. Successful health information systems rely fundamentally on the integration and sharing of data from a range of disparate sources. In many settings, basic infrastructure inequities exist that limit the usefulness of health information systems. We discuss the work of the Yale Transdisciplinary Collaborative Center for Health Disparities focused on Precision Medicine, which aims to improve the health of people in the Caribbean and Caribbean diaspora by leveraging precision medicine approaches. We describe a participatory informatics approach to sharing data as a potential mechanism to reducing inequities in the existing data infrastructure.


[The reasons for complications in the use of metal-ceramic dentures].
A total of 262 patients aged 32 to 58 were examined and 246 patients aged 30 to 60 were treated. Of the 944 cermet crowns examined complications were found in 88 (9.34%). Ceramic fractures occurred in 20 crowns, inflammatory processes in the gingiva developed in 22 cases, functional overexercise of the periodontium in 21, failure of cement fixation in 18, apical periodontitis in 7 cases. The causes of these complications are analyzed and measures to prevent them worked out. If all preventive measures were adhered to in the treatment of 246 patients fitted with dentures, complications occurred three times more seldom (in only 3.14% of cases).


Synthesis, spectroscopic, and analyte-responsive behavior of a polymerizable naphthalimide-based carboxylate probe and molecularly imprinted polymers prepared thereof.
A naphthalimide-based fluorescent indicator monomer 1 for the integration into chromo- and fluorogenic molecularly imprinted polymers (MIPs) was synthesized and characterized. The monomer was equipped with a urea binding site to respond to carboxylate-containing guests with absorption and fluorescence changes, namely a bathochromic shift in absorption and fluorescence quenching. Detailed spectroscopic analyses of the title compound and various models revealed the signaling mechanism. Titration studies employing benzoate and Z-L-phenylalanine (Z-L-Phe) suggest that indicator monomers such as the title compound undergo a mixture of deprotonation and complex formation in the presence of benzoate but yield hydrogen-bonded complexes, which are desirable for the molecular imprinting process, with weakly basic guests like Z-l-Phe. Compound 1 could be successfully employed in the synthesis of monolithic and thin-film MIPs against Z-L-Phe, Z-L-glutamic acid, and penicillin G. Chromatographic assessment of the selectivity features of the monoliths revealed enantioselective discrimination and clear imprinting effects. Immobilized on glass coverslips, the thin-film MIPs of 1 displayed a clear signaling behavior with a pronounced enantioselective fluorescence quenching dependence and a promising discrimination against cross-analytes.