Chemicals as tumor-inducing agents.
Extract: There is overwhelming evidence that the majority of cancer deaths in Western countries are caused by exogenous factors such as tobacco, alcohol, diet, infections, and occupational exposures. Besides physical and biological factors, such as UV light or oncogenic viruses, chemicals were first considered as carcinogenic agents in the 18th century when two English physicians observed the occurrence of nose polyps or skin cancer due to exposure to snuff and soot. Today it has been established that a great range of chemicals and their mixtures present in our environment are carcinogenic in humans. Examples are metals such as nickel, cadmium or lead, aromatic amines, halogenated olefines (e.g., vinyl chloride) or paraffines, N-nitrosamines, aromatic compounds (e.g., benzo[a]pyrene; 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), estrogen-receptor agonists or antagonists with residual agonistic effects (e.g., tamoxifen), natural compounds (e.g., aflatoxins), and so forth.


Local translation in neuronal processes--in vivo tests of a "heretical hypothesis".
Intracellular trafficking and localization of mRNA is a fundamental feature of living cells, suggesting that localized mRNA translation should enable subcellular regulation of the proteome. Such localized regulation may be of particular importance in highly polarized cells such as neurons, where the requirement for a specific protein can be at a site far distant from the nucleus. Although dendritic and synaptic protein syntheses are well-established phenomena, the apparent paucity of ribosomes in early studies on mature vertebrate axons generated significant skepticism regarding the possibility of protein synthesis within axons. Here, we summarize recent findings in genetically engineered mouse models that support a role for local translation in axonal expression of β-actin and importin β1 in injured adult sensory neurons in vivo. These definitive confirmations of mammalian axonal protein synthesis in both transgenic and subcellular knockout models should direct further attention to the diverse roles suggested for local protein synthesis in axonal physiology.


Aloe vera: Potential candidate in health management via modulation of biological activities.
Treatment based on natural products is rapidly increasing worldwide due to the affordability and fewer side effects of such treatment. Various plants and the products derived from them are commonly used in primary health treatment, and they play a pivotal role in the treatment of diseases via modulation of biochemical and molecular pathways. Aloe vera, a succulent species, produces gel and latex, plays a therapeutic role in health management through antioxidant, antitumor, and anti-inflammatory activities, and also offers a suitable alternative approach for the treatment of various types of diseases. In this review, we summarize the possible mechanism of action and the therapeutic implications of Aloe vera in health maintenance based on its modulation of various biological activities.


Teaching Bioethics: just a passing fad?
Biomedical ethics is not taught as a subject in undergraduate or postgraduate studies in our country. Recently governing bodies have introduced the subject in medical school in a limited manner. A majority of doctors are unable to appreciate the importance of the subject in the curriculum. This article emphasises the importance of this subject by sharing the author's personal experiences after attaining a diploma in the subject.


A BEST example of channel structure annotation by molecular simulation.
An increasing number of ion channel structures are being determined. This generates a need for computational tools to enable functional annotation of channel structures. However, several studies of ion channel and model pores have indicated that the physical dimensions of a pore are not always a reliable indicator of its conductive status. This is due to the unusual behavior of water within nano-confined spaces, resulting in a phenomenon referred to as "hydrophobic gating". We have recently demonstrated how simulating the behavior of water within an ion channel pore can be used to predict its conductive status. In this addendum to our study, we apply this method to compare the recently solved structure of a mutant of the bestrophin chloride channel BEST1 with that of the wild-type channel. Our results support the hypothesis of a hydrophobic gate within the narrow neck of BEST1. This provides further validation that this simulation approach provides the basis for an accurate and computationally efficient tool for the functional annotation of ion channel structures.


MicroRNA-directed cleavage of HOXB8 mRNA.
MicroRNAs (miRNAs) are endogenous approximately 22-nucleotide RNAs, some of which are known to play important regulatory roles in animals by targeting the messages of protein-coding genes for translational repression. We find that miR-196, a miRNA encoded at three paralogous locations in the A, B, and C mammalian HOX clusters, has extensive, evolutionarily conserved complementarity to messages of HOXB8, HOXC8, and HOXD8. RNA fragments diagnostic of miR-196-directed cleavage of HOXB8 were detected in mouse embryos. Cell culture experiments demonstrated down-regulation of HOXB8, HOXC8, HOXD8, and HOXA7 and supported the cleavage mechanism for miR-196-directed repression of HOXB8. These results point to a miRNA-mediated mechanism for the posttranscriptional restriction of HOX gene expression during vertebrate development and demonstrate that metazoan miRNAs can repress expression of their natural targets through mRNA cleavage in addition to inhibiting productive translation.


Aging influence on pulmonary and systemic inflammation and neural metabolomics arising from pulmonary multi-walled carbon nanotube exposure in apolipoprotein E-deficient and C57BL/6 female mice.
Environmental exposures exacerbate age-related pathologies, such as cardiovascular and neurodegenerative diseases. Nanoparticulates, and specifically carbon nanomaterials, are a fast-growing contributor to the category of inhalable pollutants, whose risks to health are only now being unraveled. The current study assessed the exacerbating effect of age on multiwalled-carbon nanotube (MWCNT) exposure in young and old C57BL/6 and ApoE-/- mice. Female C57BL/6 and apolipoprotein E-deficient (ApoE-/-) mice, aged 8 weeks and 15 months, were exposed to 0 or 40 µg MWCNT via oropharyngeal aspiration. Pulmonary inflammation, inflammatory bioactivity of serum, and neurometabolic changes were assessed at 24 h post-exposure. Pulmonary neutrophil infiltration was induced by MWCNT in bronchoalveolar lavage fluid in both C57BL/6 and ApoE-/-. Macrophage counts decreased with MWCNT exposure in ApoE-/- mice but were unaffected by exposure in C57BL/6 mice. Older mice appeared to have greater MWCNT-induced total protein in lavage fluid. BALF cytokines and chemokines were elevated with MWCNT exposure, but CCL2, CXCL1, and CXCL10 showed reduced responses to MWCNT in older mice. However, no significant serum inflammatory bioactivity was detected. Cerebellar metabolic changes in response to MWCNT were modest, but age and strain significantly influenced metabolite profiles assessed. ApoE-/- mice and older mice exhibited less robust metabolite changes in response to exposure, suggesting a reduced health reserve. Age influences the pulmonary and neurological responses to short-term MWCNT exposure. However, with only the model of moderate aging (15 months) in this study, the responses appeared modest compared to inhaled toxicant impacts in more advanced aging models.


Genetic diversity and host associations in Campylobacter jejuni from human cases and broilers in 2000 and 2008.
Campylobacter jejuni is an important food-borne pathogen, with a global distribution. It can colonize numerous host species, including both domestic and wild animals, but is particularly associated with birds (poultry and wild birds). For human campylobacteriosis, poultry products are deemed the most significant risk factor for acquiring infection. We conducted a genotyping and host attribution study of a large representative collection of C. jejuni isolated from humans and broilers in Sweden in the years 2000 and 2008. In total 673 broiler and human isolates from 10 different abattoirs and 6 different hospitals were genotyped with multilocus sequence typing. Source attribution analyses confirmed the strong linkage between broiler C. jejuni and domestic human cases, but also indicated a significant association to genotypes more commonly found in wild birds. Genotype distributions did not change dramatically between the two study years, suggesting a stable population of infecting bacteria.


Albuminuria and rapid loss of GFR and risk of new hip and pelvic fractures.
The microvascular circulation plays an important role in bone health. This study examines whether albuminuria, a marker of renal microvascular disease, is associated with incident hip and pelvic fractures. This study reanalyzed data from the Ongoing Telmisartan Alone and in combination with Ramipril Global End Point Trial/Telmisartan Randomized Assessment Study in Angiotensin-Converting Enzyme Intolerant Subjects with Cardiovascular Disease trials, which examined the impact of renin angiotensin system blockade on cardiovascular outcomes (n=28,601). Albuminuria was defined as an albumin-to-creatinine ratio≥30 mg/g (n=4597). Cox proportional hazards models were used to determine the association of albuminuria with fracture risk adjusted for known risk factors for fractures, estimated GFR, and rapid decline in estimated GFR (≥5%/yr). There were 276 hip and pelvic fractures during a mean of 4.6 years of follow-up. Participants with baseline albuminuria had a significantly increased risk of fracture compared with participants without albuminuria (unadjusted hazard ratio=1.62 [1.22, 2.15], P<0.001; adjusted hazard ratio=1.36 [1.01, 1.84], P=0.05). A dose-dependent relationship was observed, with macroalbuminuria having a large fracture risk (unadjusted hazard ratio=2.01 [1.21, 3.35], P=0.007; adjusted hazard ratio=1.71 [1.007, 2.91], P=0.05) and microalbuminuria associating with borderline or no statistical significance (unadjusted hazard ratio=1.52 [1.10, 2.09], P=0.01; adjusted hazard ratio=1.28 [0.92, 1.78], P=0.15). Estimated GFR was not a predictor of fracture in any model, but rapid loss of estimated GFR over the first 2 years of follow-up predicted subsequent fracture (adjusted hazard ratio=1.47 [1.05, 2.04], P=0.02). Albuminuria, especially macroalbuminuria, and rapid decline of estimated GFR predict hip and pelvic fractures. These findings support a theoretical model of a relationship between underlying causes of microalbuminuria and bone disease.


Consensus statement on standard of care for congenital myopathies.
Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee's recommendations for symptom assessments and therapeutic interventions. It is the committee's goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome.


Systematic reviews of t'ai chi: an overview.
Several systematic reviews (SRs) have assessed the effectiveness of t'ai chi for many conditions including hypertension, osteoarthritis and fall prevention; however, their conclusions have been contradictory. The aim of this overview was to critically evaluate the SRs of t'ai chi for any improvement of medical conditions or clinical symptoms. English, Chinese and Korean electronic databases were searched for relevant articles, and data were extracted according to predefined criteria; 35 SRs met our inclusion criteria. They were related to the following conditions: cancer, older people, Parkinson's disease, musculoskeletal pain, osteoarthritis, rheumatoid arthritis (RA), muscle strength and flexibility, improving aerobic capacity, cardiovascular disease and risk factors, lowering resting blood pressure, osteoporosis or bone mineral density, type 2 diabetes, psychological health, fall prevention and improving balance, and any chronic conditions. In several instances, the conclusions of these articles were contradictory. Relatively clear evidence emerged to suggest that t'ai chi is effective for fall prevention and improving psychological health and was associated with general health benefits for older people. However, t'ai chi seems to be ineffective for the symptomatic treatment of cancer and RA. In conclusion, many SRs of t'ai chi have recently been published; however, the evidence is convincingly positive only for fall prevention and for improvement of psychological health.


Enhancing surface plasmon resonances of metallic nanoparticles by diatom biosilica.
Diatoms are single-celled algaes that make photonic-crystal-like silica shells or frustules with hierarchical micro- & nano-scale features consisting of two-dimensional periodic pores. This article reports the use of diatom frustules as an integration platform to enhance localized surface plasmon resonances of self-assembled silver nanoparticles (NPs) on the surface of diatom frustules. Theoretical and experimental results show enhanced localized surface plasmons due to the coupling with the guided-mode resonances of the frustules. We observed 2 × stronger optical extinction and over 4 × higher sensitivity of surface-enhanced Raman scattering of Rhodmine 6G from the NPs-on-diatom than the NPs-on-glass structure.


Parental influences on earliest memories.
Recently, independent lines of research have indirectly supported the notion that social variables, especially parent-child relationships, have a significant impact on adults' memories of their early life. In order to directly assess this Italian students were asked to recall as many memories involving parents as they could from before the age of 6 in a 3-minute timed recall task (i.e., memory fluency). They also filled out assessments about parental involvement in their lives as well as the quality of their relationships with their mothers and fathers. We found that, for males, the more involved the parents and the warmer the relationships between sons and both their mothers and their fathers, the more early memories, the more positive early memories, and the more episodic memories men recalled. For women, the warmer the relationship with their mothers, the earlier their earliest memory. Results are discussed in terms of gendered parent-child interactions as well as McAdam's emergent life-story theory.


Linkage analysis and molecular scanning of glucokinase gene in NIDDM families.
Mutations in the glucokinase gene are a major cause of maturity-onset diabetes of the young. To evaluate the contribution of this gene to the development of late-onset NIDDM, linkage analyses between DNA polymorphisms at the glucokinase locus and NIDDM were performed in 79 multigenerational French families. In addition, all exons and the islet promoter region of glucokinase gene from 1 affected member from each family as well as from 17 unrelated women with previous gestational diabetes were amplified by polymerase chain reaction and screened for mutations by single-strand conformational polymorphism and DNA sequencing. Linkage of glucokinase and NIDDM was significantly rejected under all models tested. However, in 1 family, the lod score was 2.30, and we found a nucleotide substitution at the position -30 in the islet promoter region that cosegregated with diabetes. The proband of this family was a gestational diabetic individual. No other mutation in glucokinase was found in the 79 NIDDM families. We identified a missense mutation (TGG257-->CGG257) in exon 7 of glucokinase gene from 1 of 17 women with gestational diabetes, which was present in all diabetic members of her family. This family is likely to be a cryptic maturity-onset diabetes of the young, as 4 younger members, carrying this mutation, were subsequently found to be hyperglycemic. In conclusion, no evidence was obtained to incriminate glucokinase as a major gene for late age of onset NIDDM. Diabetic families with mutations in glucokinase must be carefully investigated, to differentiate cryptic maturity-onset diabetes of the young from late-onset NIDDM. Furthermore, pregnancy reveals diabetes in women carrying a glucokinase defect.


Effects of Viewing Cute Pictures on Quiet Eye Duration and Fine Motor Task Performance.
We investigated if viewing cute pictures could improve fine motor skills and prolong quiet eye (QE) duration. QE is a gaze phenomenon, and its duration (i.e., the period between fixation onset preceding a critical movement and fixation offset) is thought to represent attention control. As it has been reported that QE duration is longer for expert athletes than for novice athletes in various sports and becomes shorter even for experts who choke under pressure during games, resulting in performance deterioration, QE prolongation is important to prevent choking under pressure. Separately, several studies have confirmed that viewing cute pictures can induce focal attention, thus improving performance in fine motor tasks. We hypothesized that viewing cute pictures may modulate attention control and prolong QE duration. We also tested if the beneficial effects of viewing cute pictures could be obtained in a high-pressure situation in which participant performance was evaluated by an experimenter. We used a fine-motor task requiring participants to use a pair of tweezers to remove 12 small pieces from holes in a game board. We randomly assigned participants to either the baby-animal pictures group or the adult-animal pictures group, based on pictures viewed prior to the task. Participants executed the task in a pre-test, post-test, and pressure test. In both the post-test and the pressure test, participants viewed seven photographs of either baby animals or adult animals before execution of the task. In accordance with previous research, task precision increased after viewing pictures of baby animals in both the post-test and pressure test. Furthermore, QE duration was also prolonged after viewing cute pictures in the post-test, but not in the pressure test. Neither performance improvement nor QE prolongation was found after viewing pictures of adult animals. These results suggested that simply viewing cute pictures could prolong QE duration without pressure and might provide a beneficial effect on performance, even in a high-pressure situation.


Occurrence, antimicrobial resistance and whole-genome sequencing analysis of Salmonella isolates from chicken carcasses imported into Iraq from four different countries.
Salmonella is a major cause of human foodborne illnesses worldwide; however, little is known about its occurrence and genomic characteristics in food sources in many developing countries. This study investigates the occurrence, serotypes distribution, antimicrobial resistance, and multilocus sequence types (ST) of Salmonella isolated from 400 imported frozen chicken carcasses sold in the markets of Thi-Qar, south-eastern Iraq. Salmonella was detected in 46 out of 400 tested samples [11.5% (95% confidence interval: 8.5%-15.0%)]. S. Typhimurium was the most abundant (30.4%) among 14 different serotypes recovered from the tested frozen carcasses. Antimicrobial resistance was most frequently detected against tetracycline (84.4%), nalidixic acid (80.4%), streptomycin (69.6%) and trimethoprim/sulfamethoxazole (65.2%). Whole-genome sequencing (WGS) analysis revealed that 18 isolates harbored four β-lactamase resistance genes, with blaCARB-2 was the most commonly (14/18) detected. It was possible to identify 8 multilocus sequence types from the WGS analysis of 40 out of the 46 Salmonella isolates; with ST-11 (among S. Enteritidis) and ST-19 (among S. Typhimurium) were the most frequently detected. These results add to our understanding of the global epidemiology of Salmonella. Our work stands as one of the first reports on WGS analysis of Salmonella from retail chicken in a Middle-Eastern country. Results from this study could be valuable for guiding an informed import risk analysis aiming at reducing the exposure risk from Salmonella through imported chicken carcasses into Iraq. This work demonstrates the value of WGS as a promising tool for supporting evidence-based food safety hazard characterization.


The level of inflammation in rheumatoid arthritis is determined early and remains stable over the longterm course of the illness.
To determine whether the level of inflammatory activity, determined by the erythrocyte sedimentation rate (ESR), changes over the longitudinal course of rheumatoid arthritis (RA); whether the level of inflammatory activity identified early in RA predicts longterm inflammatory status; and whether RA "bums out" after many years of inflammatory activity. A total of 21,866 consecutive ESR determinations from 1,897 patients with RA were analyzed to determine the association of inflammatory activity, as estimated by ESR, with duration of disease. Data were modeled by generalized estimating equations and random selection fractional polynomial regression models, controlling for age, sex, and calendar date. In a nonlinear fashion, ESR decreased by 4 mm/h over the first 10 years of disease, remained stable over the next 25 years, and increased slightly thereafter. Patients treated more recently had lower ESR values. Patients with recent onset of RA, when stratified in quartiles of ESR, maintained their position over time. Although ESR decreases by 4 mm/h over the first 10 years of disease, it remains stable or rises thereafter. The course of RA, as modeled by the ESR, appears to be "set" early in the disease and good and bad prognosis groups can be identified within the first 2 years. There is no evidence of general "burned out" RA or a lessening of disease activity with long duration of disease. Our findings tend to suggest that the ("usually treated") natural history of RA prior to introduction of antitumor necrosis factor agents is toward some degree of improvement in the early years. If the newer and combination therapies are indeed substantially better than what has been available, they must show a shifting of the curve downward, not just in the early years where it has occurred historically, but over the entire course of the illness.


Impact of combat and non-military trauma exposure on symptom reduction following treatment for veterans with posttraumatic stress disorder.
Military veterans with posttraumatic stress disorder (PTSD) frequently report exposure to multiple other traumas in addition to their military experiences. This study aimed to examine the impact of exposure-related factors for military veterans with PTSD on recovery after participation in a group-based treatment program. Subjects included 1548 military veterans with PTSD participating in specialist veterans' PTSD programs across Australia. The study included measures of PTSD, depression, anxiety and alcohol use. Analyses of variance found higher combat exposure was associated with more severe PTSD at intake. No differences in PTSD intake severity were evident in those with additional non-military trauma. Severity of combat exposure did not affect treatment outcomes, although those with low combat exposure and additional non-military trauma (which included high rates of molestation) did report reduced symptom improvement. These findings have implications for considerations of optimal interventions for those with lower levels of combat exposure and additional non-military trauma.


Wireless modification of the intraoperative examination monitor for awake surgery.
The dedicated intraoperative examination monitor for awake surgery (IEMAS) was originally developed by us to facilitate the process of brain mapping during awake craniotomy and successfully used in 186 neurosurgical procedures. This information-sharing device provides the opportunity for all members of the surgical team to visualize a wide spectrum of the integrated intraoperative information related to the condition of the patient, nuances of the surgical procedure, and details of the cortical mapping, practically without interruption of the surgical manipulations. The wide set of both anatomical and functional parameters, such as view of the patient's mimic and face movements while answering the specific questions, type of the examination test, position of the surgical instruments, parameters of the bispectral index monitor, and general view of the surgical field through the operating microscope, is presented compactly in one screen with several displays. However, the initially designed IEMAS system was occasionally affected by interruption or detachment of the connecting cables, which sometimes interfered with its effective clinical use. Therefore, a new modification of the device was developed. The specific feature is installation of wireless information transmitting technology using audio-visual transmitters and receivers for transfer of images and verbal information. The modified IEMAS system is very convenient to use in the narrow space of the operating room.


High-dimensional feature selection by feature-wise kernelized Lasso.
The goal of supervised feature selection is to find a subset of input features that are responsible for predicting output values. The least absolute shrinkage and selection operator (Lasso) allows computationally efficient feature selection based on linear dependency between input features and output values. In this letter, we consider a feature-wise kernelized Lasso for capturing nonlinear input-output dependency. We first show that with particular choices of kernel functions, nonredundant features with strong statistical dependence on output values can be found in terms of kernel-based independence measures such as the Hilbert-Schmidt independence criterion. We then show that the globally optimal solution can be efficiently computed; this makes the approach scalable to high-dimensional problems. The effectiveness of the proposed method is demonstrated through feature selection experiments for classification and regression with thousands of features.


Awareness of hepatitis C virus transmission routes among patients, their household contacts and health care staff: does perception match the reality?
The worldwide seroprevalence of hepatitis C virus infection is around 3%. Since there is no effective vaccine, a major effort should be given to counselling both HCV-infected patients and those at risk of infection. Our aim was to determine the awareness of the transmission routes of hepatitis C virus in health care staff (HC staff), HCV-infected patients and their household contacts. A reliable and valid self-report inquiry consisting of 14 questions was completed by 397 HC staff (75 first-year, 75 last-year medical students, 89 dentists, 71 pharmacists, 87 nurses), 68 HCV-infected patients and 62 household contacts. All subjects were asked about the various modes of transmission of hepatitis C virus. Ninety-seven percent of the HC staff, 85% of hepatitis C virus patients and 90% of household contacts were aware of the parenteral transmission of hepatitis C virus. Ninety percent of HC staff, 54% of hepatitis C virus patients and 66% of household contacts admitted the role of sexual transmission, with significant difference between the subgroups of HC staff (p<0.05). Fifteen percent of the first-year medical students did not consider sexual contact as a mode of transmission. Sharing personal items such as toothbrushes, razors and nail scissors were considered as risk factors for transmission by 94% of HC staff, 44% of hepatitis C virus patients and 71% of their household contacts. Skin contact, sharing clothes and using the same toilet were considered hazardous by 18%, 14% and 26% of the HC staff, respectively. Skin contact and using the same toilet were considered as risk factors (and/or were unknown) by 30% and 44% of the hepatitis C virus patients and by 36% and 51% of the household contacts, respectively. Transmission of hepatitis C virus by blood and blood products was better recognized in all groups tested, but the other means of infection were either overestimated (skin contact, sharing toilet and clothes) or under-recognized (blood-contaminated objects). More vigorous education programs are needed to increase awareness of hepatitis C virus in various risk groups in our country.


BayesTME: An end-to-end method for multiscale spatial transcriptional profiling of the tissue microenvironment.
Spatial variation in cellular phenotypes underlies heterogeneity in immune recognition and response to therapy in cancer and many other diseases. Spatial transcriptomics holds the potential to quantify such variation, but existing analysis methods are limited by their focus on individual tasks such as spot deconvolution. We present BayesTME, an end-to-end Bayesian method for analyzing spatial transcriptomics data. BayesTME unifies several previously distinct analysis goals under a single, holistic generative model. This unified approach enables BayesTME to deconvolve spots into cell phenotypes without any need for paired single-cell RNA-seq. BayesTME then goes beyond spot deconvolution to uncover spatial expression patterns among coordinated subsets of genes within phenotypes, which we term spatial transcriptional programs. BayesTME achieves state-of-the-art performance across myriad benchmarks. On human and zebrafish melanoma tissues, BayesTME identifies spatial transcriptional programs that capture fundamental biological phenomena such as bilateral symmetry and tumor-associated fibroblast and macrophage reprogramming. BayesTME is open source.


The Pellegrini-Stieda Lesion of the Knee: An Anatomical and Radiological Review.
The Pellegrini-Stieda lesion is a calcification on the medial side of the knee. The origin of this tissue is controversial. The purpose of our study is to investigate the origin of the Pellegrini-Stieda lesion using conventional radiography as to recreate the circumstances in which Pellegrini and Stieda had to study this pathology. Six nonpaired fresh-frozen cadaveric knees were used. A surgical approach to the medial side of the knee was performed using the layered approach. The origin of the gastrocnemius muscle (GM) (n = 3) or the superficial medial collateral ligament (sMCL) (n = 3) were marked with a radio-opaque fluid. X-ray analysis was performed by measuring the distance from the proximal part of the marking to the medial tibial plateau, multilayer views, and comparison to the original X-rays by Pellegrini-Stieda. Two out of three markings in both the GM and sMCL group were matched with the correct structure. The images were digitally processed so that the osseous structures became partly transparent. After overlaying the images, we found a random distribution of the markings. The Stieda/GM group had no overlap of the markings at all. Compared with the original images from the publications by Pellegrini and Stieda, no comparable position could be found between the original lesions and the markings in our specimens. Conventional X-ray of the knee could not reproduce a distinction between the sMCL and GM as origins for the Pellegrini-Stieda lesion as suggested by Pellegrini and Stieda.


Genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region.
Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrP(C)) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C) protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter.


Immune system evolution among anthropoid primates: parasites, injuries and predators.
In this study we investigate whether present-day variation in a key component of the immune system (baseline leucocyte concentrations) represents evolutionary adaptation to ecological factors. In particular, we test three hypotheses, namely that leucocyte concentrations will be positively related to one of the following: risk of disease transmission between hosts, which is related to host abundance (hypothesis 1), risk of disease infection from the environment due to parasite viability and abundance (hypothesis 2), and risk of injury and subsequent infection, for example following attacks by predators (hypothesis 3). No support was found for hypothesis 1: neither population density nor group size were associated with variation in leucocyte concentrations. Hypothesis 2 was supported: for both sexes, lymphocyte and phagocyte concentrations were positively correlated with annual rainfall, as predicted if interspecific variation in the immune system is related to parasite prevalence (primates suffer higher rates of parasitism in wetter habitats). Support was also provided for hypothesis 3: for both males and females, platelet concentrations were negatively related to body mass, as predicted if injury risk affects immune system evolution, because animals with larger body mass have a relatively lower surface area available to injury. Additional support was provided for hypothesis 3 by the finding that for males, the sex which plays the active role in troop defence and retaliation against predators, concentration of platelets was positively correlated with rate of predation. In conclusion, our analysis suggests that the risk of disease infection from the environment and the risk of injury have played a key role in immune system evolution among anthropoid primates.


AARC clinical practice guideline: blood gas analysis and hemoximetry: 2013.
We searched MEDLINE, CINAHL, and Cochrane Library database for articles published between January 1990 and December 2012. The update of this clinical practice guideline is based on 237 clinical trials, 54 reviews, and 23 meta-analyses on blood gas analysis (BGA) and hemoximetry. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation scoring system. BGA and hemoximetry are recommended for evaluating a patient's ventilatory, acid-base, and/or oxygenation status. BGA and hemoximetry are suggested for evaluating a patient's response to therapeutic interventions. BGA and hemoximetry are recommended for monitoring severity and progression of documented cardiopulmonary disease processes. Hemoximetry is recommended to determine the impact of dyshemoglobins on oxygenation. Capillary BGA is not recommended to determine oxygenation status. Central venous BGA and hemoximetry are suggested to determine oxygen consumption in the setting of early goal-directed therapies. For the assessment of oxygenation, a peripheral venous P(O2) is not recommended as a substitute for an arterial blood measurement (P(aO2)). It is not recommended to use venous P(CO2) and pH as a substitute for arterial blood measurement of P(aCO2) and pH. It is suggested that hemoximetry is used in the detection and evaluation of shunts during diagnostic cardiac catheterization.


Outlet strut fracture of Björk-Shiley convexo-concave valves: can valve-manufacturing characteristics explain the risk?
Björk-Shiley 60 degrees convexo-concave prosthetic heart valves (Shiley, Inc, Irvine, Calif, a subsidiary of Pfizer, Inc) continue to be a concern for approximately 35,000 nonexplanted patients worldwide, with approximately 600 events reported to the manufacturer to date. Fractures of the outlet struts of the valves began to appear in the early 1980s and have continued to the present, but their causes are only partially understood. A matched case-control study was conducted evaluating manufacturing records for 52 valves with outlet strut fractures and 248 control subjects matched for age at implantation, valve size, and valve position. In addition to the risk factors recognized as determinants of outlet strut fracture, the United Kingdom case-control study has observed 7- to 9-fold increased risk with performance of multiple hook deflection tests. This test was performed more than once, usually after rework on the valve. Six valves in this study underwent multiple hook deflection tests, of which 4 experienced an outlet strut fracture. Cracks and further rework were noted for these valves. Significant associations were also observed between outlet strut fracture and disc-to-strut gap measurements taken before the attachment of the sewing ring. It is our view that a combination of factors related to valve design, manufacturing process, and patient characteristics are responsible for outlet strut fractures of Björk-Shiley convexo-concave valves. Multiple hook deflection tests have emerged as a potential new risk factor for outlet strut fracture in both The Netherlands and the United Kingdom. This factor appears to be correlated with the presence of other abnormalities. A further study is needed to investigate the factors correlated with multiple hook deflection tests. On confirmation of risk, the presence of multiple hook deflection tests may be added to equations, quantifying the risk of outlet strut fracture for comparison against risk of mortality and serious morbidity from explant operations.


Multiscale spatial organization of RNA polymerase in Escherichia coli.
Nucleic acid synthesis is spatially organized in many organisms. In bacteria, however, the spatial distribution of transcription remains obscure, owing largely to the diffraction limit of conventional light microscopy (200-300 nm). Here, we use photoactivated localization microscopy to localize individual molecules of RNA polymerase (RNAP) in Escherichia coli with a spatial resolution of ∼40 nm. In cells growing rapidly in nutrient-rich media, we find that RNAP is organized in 2-8 bands. The band number scaled directly with cell size (and so with the chromosome number), and bands often contained clusters of >70 tightly packed RNAPs (possibly engaged on one long ribosomal RNA operon of 6000 bp) and clusters of such clusters (perhaps reflecting a structure like the eukaryotic nucleolus where many different ribosomal RNA operons are transcribed). In nutrient-poor media, RNAPs were located in only 1-2 bands; within these bands, a disproportionate number of RNAPs were found in clusters containing ∼20-50 RNAPs. Apart from their importance for bacterial transcription, our studies pave the way for molecular-level analysis of several cellular processes at the nanometer scale.


Adequacy of Some Locally Produced Complementary Foods Marketed in Benin, Burkina Faso, Ghana, and Senegal.
Adequate complementary foods are needed to help reduce the high prevalence of stunting in children in many Low and Middle Income Countries (LMICs). We assessed the availability, affordability, and nutrient adequacy of imported and locally produced processed cereal-based blends (PCBBs), marketed as complementary food for young children in Benin, Burkina Faso, Ghana, and Senegal. In total, 19 local producers and 275 points of sale in the four countries were surveyed to evaluate the quantities and accessibility of PCBBs. In addition, 32 PCBBs were analysed for their nutritional composition and packaging information. The results showed that only 7 out of 32 PCBBs could be classified as nutritionally satisfactory. Access to the products was insufficient in all surveyed settings. At the points of sale, the PCBB market was dominated by imported products, even though two out of four imported PCBBs were not nutritionally satisfactory. Imported PCBBs were two to three times more expensive than locally produced PCBBs. Labelling of the PCBBs was inadequate in many aspects. Technical support should be offered to local PCBB producers to ensure the adequate formulation and supply of an appropriate vitamin and mineral premix. The development of national specific regulations on PCBB composition and labelling is strongly recommended in these countries.


613 cases of splenic rupture without risk factors or previously diagnosed disease: a systematic review.
Rupture of the spleen in the absence of trauma or previously diagnosed disease is largely ignored in the emergency literature and is often not documented as such in journals from other fields. We have conducted a systematic review of the literature to highlight the surprisingly frequent occurrence of this phenomenon and to document the diversity of diseases that can present in this fashion. Systematic review of English and French language publications catalogued in Pubmed, Embase and CINAHL between 1950 and 2011. We found 613 cases of splenic rupture meeting the criteria above, 327 of which occurred as the presenting complaint of an underlying disease and 112 of which occurred following a medical procedure. Rupture appeared to occur spontaneously in histologically normal (but not necessarily normal size) spleens in 35 cases and after minor trauma in 23 cases. Medications were implicated in 47 cases, a splenic or adjacent anatomical abnormality in 31 cases and pregnancy or its complications in 38 cases. The most common associated diseases were infectious (n = 143), haematologic (n = 84) and non-haematologic neoplasms (n = 48). Amyloidosis (n = 24), internal trauma such as cough or vomiting (n = 17) and rheumatologic diseases (n = 10) are less frequently reported. Colonoscopy (n = 87) was the procedure reported most frequently as a cause of rupture. The anatomic abnormalities associated with rupture include splenic cysts (n = 6), infarction (n = 6) and hamartomata (n = 5). Medications associated with rupture include anticoagulants (n = 21), thrombolytics (n = 13) and recombinant G-CSF (n = 10). Other causes or associations reported very infrequently include other endoscopy, pulmonary, cardiac or abdominal surgery, hysterectomy, peliosis, empyema, remote pancreato-renal transplant, thrombosed splenic vein, hemangiomata, pancreatic pseudocysts, splenic artery aneurysm, cholesterol embolism, splenic granuloma, congenital diaphragmatic hernia, rib exostosis, pancreatitis, Gaucher's disease, Wilson's disease, pheochromocytoma, afibrinogenemia and ruptured ectopic pregnancy. Emergency physicians should be attuned to the fact that rupture of the spleen can occur in the absence of major trauma or previously diagnosed splenic disease. The occurrence of such a rupture is likely to be the manifesting complaint of an underlying disease. Furthermore, colonoscopy should be more widely documented as a cause of splenic rupture.


Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis.
Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.


Gut Microbial Ecosystem in Parkinson Disease: New Clinicobiological Insights from Multi-Omics.
Gut microbiome alterations in Parkinson disease (PD) have been reported repeatedly, but their functional relevance remains unclear. Fecal metabolomics, which provide a functional readout of microbial activity, have scarcely been investigated. We investigated fecal microbiome and metabolome alterations in PD, and their clinical relevance. Two hundred subjects (104 patients, 96 controls) underwent extensive clinical phenotyping. Stool samples were analyzed using 16S rRNA gene sequencing. Fecal metabolomics were performed using two platforms, nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry. Fecal microbiome and metabolome composition in PD was significantly different from controls, with the largest effect size seen in NMR-based metabolome. Microbiome and NMR-based metabolome compositional differences remained significant after comprehensive confounder analyses. Differentially abundant fecal metabolite features and predicted functional changes in PD versus controls included bioactive molecules with putative neuroprotective effects (eg, short chain fatty acids [SCFAs], ubiquinones, and salicylate) and other compounds increasingly implicated in neurodegeneration (eg, ceramides, sphingosine, and trimethylamine N-oxide). In the PD group, cognitive impairment, low body mass index (BMI), frailty, constipation, and low physical activity were associated with fecal metabolome compositional differences. Notably, low SCFAs in PD were significantly associated with poorer cognition and low BMI. Lower butyrate levels correlated with worse postural instability-gait disorder scores. Gut microbial function is altered in PD, characterized by differentially abundant metabolic features that provide important biological insights into gut-brain pathophysiology. Their clinical relevance further supports a role for microbial metabolites as potential targets for the development of new biomarkers and therapies in PD. ANN NEUROL 2021;89:546-559.


Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions.
Nine structurally modified apelin-13 analogues were assessed for their in vitro and acute in vivo antidiabetic potential. Stability was assessed in mouse plasma and insulinotropic efficacy tested in cultured pancreatic BRIN-BD11 cells and isolated mouse pancreatic islets. Intracellular Ca2+ and cAMP production in BRIN-BD11 cells was determined, as was glucose uptake in 3T3-L1 adipocytes. Acute antihyperglycemic effects of apelin analogues were assessed following i.p. glucose tolerance tests (ipGGT, 18 mmol/kg) in normal and diet-induced-obese (DIO) mice and on food intake in normal mice. Apelin analogues all showed enhanced in vitro stability (up to 5.8-fold, t½ = 12.8 h) in mouse plasma compared to native apelin-13 (t½ = 2.1 h). Compared to glucose controls, stable analogues exhibited enhanced insulinotropic responses from BRIN-BD11 cells (up to 4.7-fold, p < 0.001) and isolated mouse islets (up to 5.3-fold) for 10-7 M apelin-13 amide (versus 7.6-fold for 10-7 M GLP-1). Activation of APJ receptors on BRIN-BD11 cells increased intracellular Ca2+ (up to 3.0-fold, p < 0.001) and cAMP (up to 1.7-fold, p < 0.01). Acute ipGTT showed improved insulinotropic and glucose disposal responses in normal and DIO mice (p < 0.05 and p < 0.01, respectively). Apelin-13 amide and (pGlu)apelin-13 amide were the most effective analogues exhibiting acute, dose-dependent and persistent biological actions. Both analogues stimulated insulin-independent glucose uptake by differentiated adipocytes (2.9-3.3-fold, p < 0.05) and inhibited food intake (26-33%, p < 0.001), up to 180 min in mice, versus saline. In contrast, (Ala13)apelin-13 and (Val13)apelin-13 inhibited insulin secretion, suppressed beta-cell signal transduction and stimulated food intake in mice. Thus, stable analogues of apelin-13 have potential for diabetes/obesity therapy.


Racial and Gender Disparities in Incidence of Lung and Bronchus Cancer in the United States: A Longitudinal Analysis.
Certain population groups in the United States carry a disproportionate burden of cancer. This work models and analyzes the dynamics of lung and bronchus cancer age-adjusted incidence rates by race (White and Black), gender (male and female), and prevalence of daily smoking in 38 U.S. states, the District of Columbia, and across eight U.S. geographic regions from 1999 to 2012. Data, obtained from the U.S. Cancer Statistics Section of the Centers for Disease Control and Prevention, reflect approximately 77% of the U.S. population and constitute a representative sample for making inferences about incidence rates in lung and bronchus cancer (henceforth lung cancer). A longitudinal linear mixed-effects model was used to study lung cancer incidence rates and to estimate incidence rate as a function of time, race, gender, and prevalence of daily smoking. Between 1999 and 2012, age-adjusted incidence rates in lung cancer have decreased in all states and regions. However, racial and gender disparities remain. Whites continue to have lower age-adjusted incidence rates for this cancer than Blacks in all states and in five of the eight U.S. geographic regions. Disparities in incidence rates between Black and White men are significantly larger than those between Black and White women, with Black men having the highest incidence rate of all subgroups. Assuming that lung cancer incidence rates remain within reasonable range, the model predicts that the gender gap in the incidence rate for Whites would disappear by mid-2018, and for Blacks by 2026. However, the racial gap in lung cancer incidence rates among Black and White males will remain. Among all geographic regions, the Mid-South has the highest overall lung cancer incidence rate and the highest incidence rate for Whites, while the Midwest has the highest incidence rate for Blacks. Between 1999 and 2012, there was a downward trend in the prevalence of daily smokers in both genders. However, males have significantly higher rates of cigarette smoking than females at all time points. The highest and lowest prevalence of daily smoking are found in the Mid-South and New England, respectively. There was a significant correlation between lung cancer incidence rates and smoking prevalence in all geographic regions, indicating a strong influence of cigarette smoking on regional lung cancer incidence rates. Although age-adjusted incidence rates in lung cancer have decreased throughout the U.S., racial and gender disparities remain. This longitudinal model can help health professionals and policy makers make predictions of age-adjusted incidence rates for lung cancer in the U.S. in the next five to ten years.


Sleep and 24-h activity rhythms in relation to cortisol change after a very low-dose of dexamethasone.
The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in sleep. Nevertheless, the association of sleep and its 24-h organization with negative feedback control of the HPA axis has received limited attention in population-based studies. We explored this association in 493 middle-aged persons of the Rotterdam Study, a large population-based study (mean age 56 years, standard deviation: 5.3 years; 57% female). The negative feedback of the HPA axis was measured as the change in morning saliva cortisol after the intake of 0.25mg dexamethasone the night before. Actigraphy allowed us to measure the stability and fragmentation of the activity rhythm and to estimate total sleep time, sleep onset latency and wake after sleep onset. A sleep diary kept during the week of actigraphy was used to assess self-reported total sleep time, sleep onset latency, number of awakenings and perceived sleep quality. In our study, enhanced negative feedback of the HPA axis was found in association with unstable activity rhythms (B=0.106, 95% confidence interval (CI): 0.002; 0.210), total sleep time (B=0.108, 95%CI: 0.001; 0.215) and poor subjective sleep quality (B=0.107, 95%CI: 0.009; 0.206) after multivariate adjustment. These results indicated that the 24-h organization, duration and experience of sleep are all associated with the negative feedback control of the HPA axis.


Immune mechanisms in non-Hodgkin lymphoma: joint effects of the TNF G308A and IL10 T3575A polymorphisms with non-Hodgkin lymphoma risk factors.
Two common single nucleotide polymorphisms in immunoregulatory genes (TNF G308A, rs1800629 and IL10 T3575A, rs1800890) have been recently reported as risk factors for non-Hodgkin lymphoma (NHL) in a large pooled analysis. We systematically investigated the effects of other established NHL risk factors in relation to the tumor necrosis factor (TNF) G308A or interleukin 10 (IL10) T3575A genotypes. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) from 1,172 cases and 982 population-based controls in a U.S. multicenter study. We investigated NHL overall and two common subtypes [diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma]. NHL risks were increased among those with both an autoimmune condition and the TNF G308A GA/AA (OR(NHL), 2.1; 95% CI, 1.0-4.2) or the IL10 T3575A TA/AA genotype (OR(NHL), 1.6; 95% CI, 0.9-2.6) compared with individuals without an autoimmune condition and with the common TNF G308A GG or IL10 T3575A TT genotype, respectively; results were similar for DLBCL and follicular lymphoma. We found that elevated DLBCL risk associated with last-born status was more pronounced among those with TNF G308A GA/AA (OR(DLBCL), 2.7; 95% CI, 1.1-6.4) or IL10 T3575A TA/AA (OR(DLBCL), 2.9; 95% CI, 1.6-5.2). Similarly, elevated DLBCL risk associated with obesity (body mass index, > or = 35 versus <25 kg/m(2)) was observed only among those with TNF G308A GA/AA (OR(DLBCL), 2.5; 95% CI, 1.1-5.7) or IL10 T3575A TA/AA genotypes (OR(DLBCL), 2.0; 95% CI, 1.1-3.5). These exploratory results require replication but provide evidence that autoimmune conditions, late birth order, and obesity act partly through a common inflammatory pathway, posing a greater risk to individuals with variant TNF and IL10 genotypes than those with wild-type alleles.


Ion beam analysis (IBA) and instrumental neutron activation analysis (INAA) for forensic characterisation of authentic Viagra® and of sildenafil-based illegal products.
Illegal trafficking of pharmaceutical products by criminal organisations is a global threat for public health. Drugs for erectile dysfunction such as phosphodiesterase type 5 inhibitors are the most commonly counterfeited medicines in Europe. The search of possible toxic chemical substances in seized products is needed to provide early warning for public health. Furthermore, the elemental profile of the seized products can be useful in criminal investigations. For the first time an ion beam analysis (IBA) procedure to characterise authentic Viagra® tablets and sildenafil-based illegal products is described. Moreover, results are compared with the ones obtained by instrumental neutron activation analysis (INAA) on authentic Viagra® tablets in two reactors. IBA results showed that a combination of particle-induced X-ray emission (PIXE) and secondary ion mass spectrometry using primary ions with energies in the range of several MeV (MeV-SIMS) is a powerful tool to characterise different products in a straightforward manner, allowing discrimination between legal and illegal products. INAA allowed accurate elemental quantification and also showed a great potential for the future implementation of an inter-laboratory classification system.


Effect of a food supplementation and psychosocial stimulation trial for severely malnourished children on the level of maternal depressive symptoms in Bangladesh.
Maternal depression is associated with poor child development and growth in low-income countries. This paper evaluates the effect of a community-based trial providing psychosocial stimulation and food supplements to severely malnourished children on maternal depressive symptoms in Bangladesh. Severely underweight (weight-for-age Z-score < -3) hospitalized children aged 6-24 months (n = 507), were randomly assigned to: psychosocial stimulation (PS), food supplementation (FS), PS+FS, clinic control (CC) and hospital control (CH) at discharge. PS included play sessions with children and parental counselling to mothers during fortnightly follow-up visit at community clinics, conducted by trained play leaders for 6 months. FS involved cereal-based supplements (150-300 kcal/day) for 3 months. All groups received medical care, micronutrient supplements and growth monitoring. We used Bayley scales, Home Observation for Measurement of Environment (HOME) inventory and a parenting questionnaire to assess child development, home stimulation and mothers' child-rearing practices, respectively. We assessed mothers' depressive symptoms using a modified version of Centre for Epidemiologic Studies Depression Scale at baseline and at 6 months post intervention. Maternal depressive symptoms were significantly lower in the CH group at baseline (P = 0.014). After 6 months of intervention there was no significant effect of intervention after adjusting for baseline scores and all possible confounders. Maternal depressive symptoms were higher among poorer (P = 0.06), older (P = 0.057) and less educated (P = 0.019) mothers, who were housewives (P = 0.053), and whose husbands had more unstable jobs (P = 0.058). At 6 months post intervention, children's cognitive (P = 0.045) and motor (P = 0.075) development, HOME (P = 0.012) and mother's parenting score (P = 0.057) were higher among mothers with lower depressive symptoms. The study did not show a significant effect of the intervention on the level of maternal depressive symptoms. Interventions with higher intensity and/or of longer duration focusing directly on maternal psychosocial functioning are probably needed to reduce maternal depressive symptoms.


Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage.
Nuclear factor kappaB (NF-kappaB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-kappaB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMO(Delta hepa)) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMO(Delta hepa) mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMO(Delta hepa) livers. Interestingly, depletion of the NK1.1(+) cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMO(Delta hepa) mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)-mediated injury. The critical role of the NK cell/TRAIL axis in NEMO(Delta hepa) livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient(-/-) mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMO(Delta hepa) mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.


Expanding the phenotype of the X-linked BCOR microphthalmia syndromes.
Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.


Variable compensation technique for digital radiography of the chest.
The authors describe a new technique, variable compensation (VC) radiography, for digital radiography of the chest. It permits retrospective adjustment of image display while maintaining improved mediastinal signal-to-noise ratio (S/N) from aggressive x-ray equalization. A fraction of a logarithmic image representing the profile of the beam intensity incident on the patient is subtracted from a logarithmic equalized image. VC images of a chest phantom were generated with various weightings of the beam-profile image. Edge artifacts were substantially reduced with a weighting of greater than 0.5 and eliminated with a weighting of 1.0. The S/N properties of VC images were measured with a series of plastic squares placed over various regions of the chest phantom. The S/N of the squares in the dense sub-diaphragm were improved twofold compared with the S/N on unequalized radiographs, whereas the S/N in the lung was reduced by 30%. Studies of a volunteer revealed the ability to render images with aggressive equalization (for improved mediastinal visualization) and images with the appearance of traditional chest radiographs.


Improving access to primary care: eight case studies of introducing Advanced Access in England.
To examine the implementation of 'Advanced Access' as a means of improving access to primary care. Qualitative case studies of eight English general practices undertaken as part of a mixed method study. There was considerable variation in the interpretation and implementation of Advanced Access. Practices claiming to operate this system often did not follow its key principles. Differences between practice access systems centred on the use of 'same-day' appointments. The association of Advanced Access with same-day appointment systems was problematic as it both created antagonism to, and diverged from, the Advanced Access model. Practice staff did not necessarily share the conceptualisation of demand that underpinned Advanced Access. Other policies and targets provided further incentives to diverge from the model and these factors were compounded by informal organizational behaviours, notably the exercise of discretion, which led to adaptation. Advanced Access was diluted because it became confused with same-day appointment systems and other incentives and targets. Its guiding philosophy of 'manageable demand' appeared counter-intuitive to staff in the context of general practice, which made its implementation problematic. As a result, the system was adapted and modified.


An All-Recombinant Protein-Based Culture System Specifically Identifies Hematopoietic Stem Cell Maintenance Factors.
Hematopoietic stem cells (HSCs) are considered one of the most promising therapeutic targets for the treatment of various blood disorders. However, due to difficulties in establishing stable maintenance and expansion of HSCs in vitro, their insufficient supply is a major constraint to transplantation studies. To solve these problems we have developed a fully defined, all-recombinant protein-based culture system. Through this system, we have identified hemopexin (HPX) and interleukin-1α as responsible for HSC maintenance in vitro. Subsequent molecular analysis revealed that HPX reduces intracellular reactive oxygen species levels within cultured HSCs. Furthermore, bone marrow immunostaining and 3D immunohistochemistry revealed that HPX is expressed in non-myelinating Schwann cells, known HSC niche constituents. These results highlight the utility of this fully defined all-recombinant protein-based culture system for reproducible in vitro HSC culture and its potential to contribute to the identification of factors responsible for in vitro maintenance, expansion, and differentiation of stem cell populations.


Beyond sulfide-centric catalysis: recent advances in the catalytic cyclization reactions of sulfur ylides.
Great achievements in the asymmetric cyclization reactions of sulfur ylides have been reached by using chiral sulfides; however, this method usually suffers from the high loading of chiral sulfides. Over the past decade, new catalysis technologies beyond chiral sulfide-based catalysis have been gradually applied to the cyclizations of sulfur ylides. These technologies, including organocatalysis, organometallic catalysis and photocatalysis, can avoid the use of stoichiometric chiral pools and enable the development of new cyclization reactions of sulfur ylides. In this tutorial review, recent advances in this rapidly developing field will be highlighted with particular emphases on the catalytic mechanism and the development of new reactions, new reagents and new concepts.


Issues regarding the use of analgesia and sedation in critically ill neonates.
Attitudes and beliefs of physicians and nurses have shifted during the past decade, resulting in more frequent administration of analgesics and sedatives to neonates. However, nurses caring for critically ill newborns have difficulty in determining appropriate interventions because of the lack of clear and complete knowledge related to the use of analgesia and sedation in this patient population. This chapter presents current information on six key issues related to the use of analgesia and sedation in neonates. An algorithm for determining appropriate intervention for neonates with pain, distress, or agitation is proposed to provide a more systematic approach to the use of analgesics and sedatives.


Impact of Body Composition on Physical Performance Tasks in Older Obese Women Undergoing a Moderate Weight Loss Program.
Although obesity is a recognized risk factor for impaired physical function in older adults, there is still debate on whether older obese adults should undergo intentional weight loss due to concern of loss in lean body mass, including appendicular lean soft tissue mass. This may put them at risk for worsening muscle strength and mobility. Therefore, the purpose of this study was to examine the effect of a weight loss intervention on body composition and physical function in obese older women. Women were randomized into either a weight stable (WS) (n=20) or an intensive weight loss (WL) (n=26) group. The study setting was at a university research facility. Women (age, 67.8±1.3 yrs; BMI, 34.9 (0.7) kg/m2; mean±standard error of the mean) were recruited. The WL intervention was for 6 months and included moderate dietary energy restriction and aerobic and strength exercise training. Variables were obtained at baseline and 6-months and included body weight, dual energy x-ray absorptiometry (DXA), 6-minute walk distance, stair climb time, and concentric knee extension muscular strength. Estimated marginal means (SEM) for weight loss at 6-months was -8.5 (0.9)% for WL and +0.7 (1.0)% for WS. There was a significant loss of body fat mass, lean body mass, appendicular lean soft tissue mass, relative muscle mass, and skeletal muscle index for WL vs. WS at 6-months. However, improvements for WL vs. WS were seen in 6-minute walk distance and stair climb time, and trends for improved relative strength and leg muscle quality. Change in body fat mass was positively related to improved physical function and muscle strength and quality. These results further support the use of a sound intentional weight loss program incorporating moderate dietary energy restriction and exercise training in older obese women to improve physical function. Although lean soft tissue mass was lost, over the 6-month program there was no deleterious effect on muscle strength or muscle quality.


Simulation and Experiments To Identify Factors Allowing Synthetic Control of Structural Features of Polymeric Nanoparticles.
To develop a detailed picture of the microscopic structure of gelcore star polymers and to elucidate parameters of the synthetic process that might be exploited to control this structure, simulations of their synthesis were performed that were based on a particular synthetic approach. A range of results was observed from gelation at high reactant concentrations to the formation of various sizes and compositions of star polymers. Contrary to the prevailing experimental viewpoint, the simulations always suggest the production of a broad distribution of star polymer sizes. However, the GPC traces computed from simulation results are in good qualitative agreement with experiment. Topologically, the gelcore star polymers produced by simulation are not compact but, rather, sparse blobs loosely connected by filaments of linker when modeled in a good solvent. This is reflected in scaling relationships that relate polymer size (e.g., radius of gyration) and degree of polymerization. The arm-core composition is observed to be stoichiometric, strongly reflecting relative reactant concentrations during the synthesis. Reactions within star polymers that result in greater intramolecular cross-linking compete with those between star polymers that result in the production of larger star polymers from the joining of smaller ones. The balance in this competition can be controlled through the overall reactant concentration to limit and control resulting star polymer size. Therefore, the mean size, as well as the mean number of arms, can be controlled during synthesis by careful tuning of the overall ratio of the arm and linker reactant concentrations and the total reactant concentration.


Healthcare in a land called PeoplePower: nothing about me without me.
In a 5-day retreat at a Salzburg Seminar attended by 64 individuals from 29 countries, teams of health professionals, patient advocates, artists, reporters and social scientists adopted the guiding principle of 'nothing about me without me' and created the country of PeoplePower. Designed to shift health care from 'biomedicine' to 'infomedicine', patients and health workers throughout PeoplePower join in informed, shared decision-making and governance. Drawing, where possible, on computer-based guidance and communication technologies, patients and clinicians contribute actively to the patient record, transcripts of clinical encounters are shared, and patient education occurs primarily in the home, school and community-based organizations. Patients and clinicians jointly develop individual 'quality contracts', serving as building blocks for quality measurement and improvement systems that aggregate data, while reflecting unique attributes of individual patients and clinicians. Patients donate process and outcome data to national data banks that fuel epidemiological research and evidence-based improvement systems. In PeoplePower hospitals, constant patient and employee feedback informs quality improvement work teams of patients and health professionals. Volunteers work actively in all units, patient rooms are information centres that transform their shape and decor as needs and individual preferences dictate, and arts and humanities programmes nourish the spirit. In the community, from the earliest school days the citizenry works with health professionals to adopt responsible health behaviours. Communities join in selecting and educating health professionals and barter systems improve access to care. Finally, lay individuals partner with professionals on all local, regional and national governmental and private health agencies.


Treatment of adult acute lymphoblastic leukaemia (ALL) over a 16 year period.
Between 1972 and 1988 269 newly diagnosed adolescents and adults (age range 14-78 years) with ALL were managed with three protocols of increasing intensity (OPAL, HEAV'D, OPAL-HDAraC). The complete remission (CR) rate in 212 patients treated with OPAL and HEAV'D was 151/212 (71%), the median CR duration was 1.9 years. With a median follow-up of 9 years, 49 patients remain free of disease. On multivariate analysis age, blast cell count, and immunophenotype were found to correlate significantly with CR rate, remission duration and survival. CR was achieved in 38/57 (67%) patients subsequently treated with OPAL-HDAraC; however, although remission duration was longer in 'high risk' patients (T, B and Null phenotype irrespective of blast cout, cALLA+ve with blast count greater than 10 x 10(9)/l) as compared to the results achieved in similar patients with OPAL/HEAV'D, overall, the results were no better than those achieved previously. Indeed, patients in the 'standard risk' category (cALLA+ve, blast count less than 10 x 10(9)/l) fared better previously. Subsequently, neither treatment according to prognostic variables, or the addition of different pairs of drugs in rotation, to HEAV'D, have improved outcome in 63 other patients. Currently, further intensification of the early treatment is being evaluated.


Heteromultimerization of cannabinoid CB(1) receptor and orexin OX(1) receptor generates a unique complex in which both protomers are regulated by orexin A.
Agonist-induced internalization was observed for both inducible and constitutively expressed forms of the cannabinoid CB(1) receptor. These were also internalized by the peptide orexin A, which has no direct affinity for the cannabinoid CB(1) receptor, but only when the orexin OX(1) receptor was co-expressed along with the cannabinoid CB(1) receptor. This effect of orexin A was concentration-dependent and blocked by OX(1) receptor antagonists. Moreover, the ability of orexin A to internalize the CB(1) receptor was also blocked by CB(1) receptor antagonists. Remarkably, orexin A was substantially more potent in producing internalization of the CB(1) receptor than in causing internalization of the bulk OX(1) receptor population, and this was true in cells in which the CB(1) receptor was maintained at a constant level, whereas levels of OX(1) could be varied and vice versa. Both co-immunoprecipitation and cell surface, homogenous time-resolved fluorescence resonance energy transfer based on covalent labeling of N-terminal "SNAP" and "CLIP" tags present in the extracellular N-terminal domain of the receptors confirmed the capacity of these two receptors to heteromultimerize. These studies confirm the capacity of the CB(1) and OX(1) receptors to interact directly and demonstrate that this complex has unique regulatory characteristics. The higher potency of the agonist orexin A to regulate the CB(1)-OX(1) heteromer compared with the OX(1)-OX(1) homomer present in the same cells and the effects of CB(1) receptor antagonists on the function of orexin A suggest an interplay between these two systems that may modulate appetite, feeding, and wakefulness.


PspA, a surface protein of Streptococcus pneumoniae, is capable of eliciting protection against pneumococci of more than one capsular type.
Monoclonal antibodies against pneumococcal surface protein A (PspA) have been shown to protect mice from fatal pneumococcal infection. PspA is highly variable serologically, raising the possibility that PspA from one strain might not be able to elicit protective responses against strains which possess serologically different PspA. We have prepared a lambda gt11 library of pneumococcal genomic DNA and identified a clone expressing PspA. The recombinant PspA in this phage lysate elicited protection against pneumococcal infections with three strains of two different capsular serotypes. This finding demonstrated that PspA could elicit a protective response in the absence of other pneumococcal antigens. The observed protection was probably antibody mediated because it could be passively transferred with immune sera. Lambda lysates producing pneumococcal proteins other than PspA failed to elicit protection against fatal pneumococcal infection.


Impact of Dehydroamino Acids on the Structure and Stability of Incipient 310-Helical Peptides.
A comparative study of the impact of small, medium-sized, and bulky α,β-dehydroamino acids (ΔAAs) on the structure and stability of Balaram's incipient 310-helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a-c that maintained the 310-helical shape of 1. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a-c that preferred a β-sheet-like conformation. The impact of the ΔAA on peptide structure was independent of size, with small (ΔAla), medium-sized (Z-ΔAbu), and bulky (ΔVal) ΔAAs exerting similar effects. The proteolytic stabilities of 1 and its analogs were determined by incubation with Pronase. Z-ΔAbu and ΔVal increased the resistance of peptides to proteolysis when incorporated at the 3-position and had negligible impact on stability when placed at the 1-position, whereas ΔAla-containing peptides degraded rapidly regardless of position. Exposure of peptides 2a-c and 3a-c to the reactive thiol cysteamine revealed that ΔAla-containing peptides underwent conjugate addition at room temperature, while Z-ΔAbu- and ΔVal-containing peptides were inert even at elevated temperatures. These results suggest that both bulky and more accessible medium-sized ΔAAs should be valuable tools for bestowing rigidity and proteolytic stability on bioactive peptides.


A bilateral integrative health-care knowledge service mechanism based on 'MedGrid'.
Current health-care organizations are encountering impression of paucity of medical knowledge. This paper classifies medical knowledge with new scopes. The discovery of health-care 'knowledge flow' initiates a bilateral integrative health-care knowledge service, and we make medical knowledge 'flow' around and gain comprehensive effectiveness through six operations (such as knowledge refreshing...). Seizing the active demand of Chinese health-care revolution, this paper presents 'MedGrid', which is a platform with medical ontology and knowledge contents service. Each level and detailed contents are described on MedGrid info-structure. Moreover, a new diagnosis and treatment mechanism are formed by technically connecting with electronic health-care records (EHRs).


A 21-day Daniel fast with or without krill oil supplementation improves anthropometric parameters and the cardiometabolic profile in men and women.
The Daniel Fast is a vegan diet that prohibits the consumption of animal products, refined foods, white flour, preservatives, additives, sweeteners, flavorings, caffeine, and alcohol. Following this dietary plan for 21 days has been demonstrated to improve blood pressure, LDL-C, and certain markers of oxidative stress, but it has also been shown to lower HDL-C. Krill oil supplementation has been shown to increase HDL-C. We investigated the effects of following a Daniel Fast dietary plan with either krill oil supplementation (2 g/day) or placebo supplementation (coconut oil; 2 g/day) for 21 days. The subjects in this study (12 men and 27 women) were heterogeneous with respect to body mass index (BMI) (normal weight, overweight, and obese), blood lipids (normolipidemic and hyperlipidemic), blood glucose (normal fasting glucose, impaired fasting glucose, and type 2 diabetic), and blood pressure (normotensive and hypertensive). Krill oil supplementation had no effect on any outcome measure (all p > 0.05), and so the data from the krill oil group and the placebo group were collapsed and analyzed to examine the effects of following a 21-day Daniel Fast. Significant reductions were observed in LDL-C (100.6 ± 4.3 mg/dL vs. 80.0 ± 3.7 mg/dL), the LDL:HDL ratio (2.0 ± 0.1 vs. 1.7 ± 0.1), fasting blood glucose (101.4 ± 7.5 mg/dL vs. 91.7 ± 3.4 mg/dL), fasting blood insulin (7.92 ± 0.80 μU/mL vs. 5.76 ± 0.59 μU/mL), homeostasis model assessment of insulin resistance (HOMA-IR) (2.06 ± 0.30 vs. 1.40 ± 0.21), systolic BP (110.7 ± 2.2 mm Hg vs. 105.5 ± 1.7 mm Hg), and body weight (74.1 ± 2.4 kg vs. 71.5 ± 2.3 kg) (all p < 0.05). Following a Daniel Fast dietary plan improves a variety of cardiometabolic parameters in a wide range of individuals in as little as 21 days, and these improvements are unaffected by krill oil supplementation. Clinicaltrial.govNCT01378767.


Altered microRNA expression of nasal mucosa in long-term asthma and allergic rhinitis.
Asthma and allergic rhinitis (AR) commonly coexist and can be taken as manifestations of one syndrome. Evidence exists that microRNAs (miRNAs) are important in controlling inflammatory processes and they are considered promising biomarkers. However, little is known about the differences in miRNA expression in patients with chronic allergic airway disease. This study evaluated the inflammatory and miRNA profiles of the nasal mucosa of patients with long-term asthma with and without AR. We analyzed inflammatory cells, cytokines, and miRNAs in nasal biopsies and measured exhaled and nasal nitric oxide levels during the nonpollen season in 117 middle-aged men who had suffered mainly from allergic asthma for approximately 20 years and also in 33 healthy controls. The differences in the number of nasal eosinophils and cytokine expression levels were modest in nasal biopsies taken from asthmatics. Downregulation of miR-18a, miR-126, let-7e, miR-155, and miR-224 and upregulation of miR-498, miR-187, miR-874, miR-143, and miR-886-3p were observed in asthmatic patients in comparison to controls. The differences in miRNA expression were mainly similar in asthmatics with and without AR. With regard to asthma severity, a trend of increased miRNA expression in persistent asthma was seen, whereas the downregulation of certain miRNAs was most distinct in nonpersistent-asthma patients. Differences in miRNA expression in the nasal mucosa of subjects with long-term asthma and AR can be seen also when no markers of Th2-type inflammation are detected. Asthma severity had only a minor impact on miRNA expression.


Phosphorylation of nuclear and DNA-binding proteins in proliferating and quiescent mammalian cells.
The dependence of cell proliferation on nuclear protein phosphorylation was studied with exponential-phase and stationary-phase cultures of Chinese-hamster ovary cells. Nuclear proteins were fractionated, according to their DNA-binding affinities, by using sequential extractions of isolated nuclei with increasing concentrations of NaCl. When viable whole cells were labelled with H332PO4, phosphorylation of nuclear proteins was found to be lower in quiescent cells than in proliferating cells. Phosphorylation of nuclear proteins soluble in 0.30M-NaCl (less than 50% of these proteins bind to DNA) was greater than for those proteins soluble in higher salt concentrations (80-100% of these proteins bind to DNA). Cyclic AMP enhanced the phosphorylation of nuclear proteins soluble in 0.3 m-NaCl by 40-50%, and this stimulation was independent of cell growth. Cyclic AMP also increased the phosphorylation of nuclear proteins soluble in 0.6M-NaCl and 2.0M-NaCl by 40-50% in exponential-phase cultures, but not in stationary-phase cultures. Several examples of specific phosphorylation in response to cyclic AMP were observed, including a 35000-mol.wt. protein in the 0.30 M-NaCl-soluble fraction and several proteins larger than 100000 molecular weight within this fraction. A major peptide of molecular weight approx. 31000 extracted with 0.6M-NaCl was also phosphorylated. Its phosphorylation was independent of cyclic AMP in exponential-phase cultures, and it was not phosphorylated in plateau-phase cells. These changes in cell-growth-dependent phosphorylation occurred in the absence of any apparent qualitative changes in the nuclear protein molecular-weight distributions. These data demonstrate that (1) phosphorylation of nuclear proteins is dependent on the culture's proliferative status, (2) both cyclic AMP-dependent and cyclic AMP-independent specific phosphorylation occurs, and (3) the cyclic AMP-dependent growth-independent phosphorylation that occurs does not appear to be a modification of DNA-binding proteins, whereas the cyclic AMP-dependent growth-dependent phosphorylation does involve modification of DNA binding proteins.


Three dimensional in vitro models of cancer: Bioprinting multilineage glioblastoma models.
Three dimensional (3D) bioprinting of multiple cell types within optimised extracellular matrices has the potential to more closely model the 3D environment of human physiology and disease than current alternatives. In this study, we used a multi-nozzle extrusion bioprinter to establish models of glioblastoma made up of cancer and stromal cells printed within matrices comprised of alginate modified with RGDS cell adhesion peptides, hyaluronic acid and collagen-1. Methods were developed using U87MG glioblastoma cells and MM6 monocyte/macrophages, whilst more disease relevant constructs contained glioblastoma stem cells (GSCs), co-printed with glioma associated stromal cells (GASCs) and microglia. Printing parameters were optimised to promote cell-cell interaction, avoiding the 'caging in' of cells due to overly dense cross-linking. Such printing had a negligible effect on cell viability, and cells retained robust metabolic activity and proliferation. Alginate gels allowed the rapid recovery of printed cell protein and RNA, and fluorescent reporters provided analysis of protein kinase activation at the single cell level within printed constructs. GSCs showed more resistance to chemotherapeutic drugs in 3D printed tumour constructs compared to 2D monolayer cultures, reflecting the clinical situation. In summary, a novel 3D bioprinting strategy is developed which allows control over the spatial organisation of tumour constructs for pre-clinical drug sensitivity testing and studies of the tumour microenvironment.


A descriptive analysis of prevalent vs incident cervical intraepithelial neoplasia grade 3 following minor cytologic abnormalities.
Cervical intraepithelial neoplasia grade 3 (CIN 3) is the best proxy in research and screening for invasive cancer risk. Yet the timing of CIN 3 development is uncertain because of measurement errors integral to its diagnosis. We were interested in estimating the proportions of prevalent vs incident CIN 3 within 2 years of finding a minor cytologic abnormality. We estimate that only 17 (2.8%) of 613 CIN 3 cases diagnosed during the 2-year duration of the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS) were incident CIN 3 following an incident human papillomavirus (HPV) infection that persisted until the CIN 3 diagnosis was made. Using prevalent high-grade cytology as a marker of prevalent CIN 3, we estimated that another approximately 23% of CIN 3 cases were incident CIN 3 following a prevalently detected HPV infection that persisted until the CIN 3 diagnosis was made. We concluded that most CIN 3 cases diagnosed within the 2-year time frame were prevalent cases, and most incident CIN 3 cases followed a prevalently detected HPV infection.


Conduct disorder in adolescent females: current state of research and study design of the FemNAT-CD consortium.
Conduct disorder (CD) is a common and highly impairing psychiatric disorder of childhood and adolescence that frequently leads to poor physical and mental health outcomes in adulthood. The prevalence of CD is substantially higher in males than females, and partly due to this, most research on this condition has used all-male or predominantly male samples. Although the number of females exhibiting CD has increased in recent decades, the majority of studies on neurobiological measures, neurocognitive phenotypes, and treatments for CD have focused on male subjects only, despite strong evidence for sex differences in the aetiology and neurobiology of CD. Here, we selectively review the existing literature on CD and related phenotypes in females, focusing in particular on sex differences in CD symptoms, patterns of psychiatric comorbidity, and callous-unemotional personality traits. We also consider studies investigating the neurobiology of CD in females, with a focus on studies using genetic, structural and functional neuroimaging, psychophysiological, and neuroendocrinological methods. We end the article by providing an overview of the study design of the FemNAT-CD consortium, an interdisciplinary, multi-level and multi-site study that explicitly focuses on CD in females, but which is also investigating sex differences in the causes, developmental course, and neurobiological correlates of CD.


Computational Grounded Cognition: a new alliance between grounded cognition and computational modeling.
Grounded theories assume that there is no central module for cognition. According to this view, all cognitive phenomena, including those considered the province of amodal cognition such as reasoning, numeric, and language processing, are ultimately grounded in (and emerge from) a variety of bodily, affective, perceptual, and motor processes. The development and expression of cognition is constrained by the embodiment of cognitive agents and various contextual factors (physical and social) in which they are immersed. The grounded framework has received numerous empirical confirmations. Still, there are very few explicit computational models that implement grounding in sensory, motor and affective processes as intrinsic to cognition, and demonstrate that grounded theories can mechanistically implement higher cognitive abilities. We propose a new alliance between grounded cognition and computational modeling toward a novel multidisciplinary enterprise: Computational Grounded Cognition. We clarify the defining features of this novel approach and emphasize the importance of using the methodology of Cognitive Robotics, which permits simultaneous consideration of multiple aspects of grounding, embodiment, and situatedness, showing how they constrain the development and expression of cognition.


Effects of thermal stress on human performance.
Experimental evidence indicates that even relatively mild thermal stress may affect human performance. Tasks requiring manual dexterity and muscular strength are clearly impaired by cold exposure, while decrements in vigilance performance and endurance are well documented effects of heat stress. The considerable variation in results regarding the effects of thermal stress may, to some extent, be attributable to complex interactions between exposure conditions, task characteristics, and individual factors. In the present paper the relevance of some of the earlier research work on heat and cold stress is evaluated in the light of the practical and theoretical implications of more recent findings. Current work regarding the nature and extent of the effects of thermal stress on more complex performance is discussed. Attention is also focused on the significance of individual skill and training experience for performance under unfavorable conditions.


Urban legends: recurrent aphthous stomatitis.
Recurrent aphthous stomatitis (RAS) is the most common idiopathic intraoral ulcerative disease in the USA. Aphthae typically occur in apparently healthy individuals, although an association with certain systemic diseases has been reported. Despite the unclear etiopathogenesis, new drug trials are continuously conducted in an attempt to reduce pain and dysfunction. We investigated four controversial topics: (1) Is complex aphthosis a mild form of Behçet's disease (BD)? (2) Is periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome a distinct medical entity? (3) Is RAS associated with other systemic diseases [e.g., celiac disease (CD) and B12 deficiency]? (4) Are there any new RAS treatments? Results from extensive literature searches, including a systematic review of RAS trials, suggested the following: (1) Complex aphthosis is not a mild form of BD in North America or Western Europe; (2) Diagnostic criteria for PFAPA have low specificity and the characteristics of the oral ulcers warrant further studies; (3) Oral ulcers may be associated with CD; however, these ulcers may not be RAS; RAS is rarely associated with B12 deficiency; nevertheless, B12 treatment may be beneficial, via mechanisms that warrant further study; (4) Thirty-three controlled trials published in the past 6 years reported some effectiveness, although potential for bias was high.


Meloidogyne daklakensis n. sp. (Nematoda: Meloidogynidae), a new root-knot nematode associated with Robusta coffee (Coffea canephora Pierre ex A. Froehner) in the Western Highlands, Vietnam.
The root-knot nematode species Meloidogyne daklakensis n. sp. was discovered on the roots of Robusta coffee (Coffea canephora Pierre ex A. Froehner) in Dak Lak Province, Vietnam. This species is characterized by the females having rounded or oval perineal patterns, smooth, regular, continuous striae, and reduced lateral lines. The dorsal arch is low, rounded and encloses a quite distinct vulva and tail tip. The stylet is normally straight with well-developed and posteriorly sloped knobs. The males have a rounded cap that extends posteriorly into the lip region. The procorpus is outlined distinctly, and is three times longer than the metacorpus. The metacorpus is ovoid, with a strong valve apparatus. The species closely resembles M. marylandi, M. naasi, M. ovalis, M. panyuensis, M. lopezi, M. mali and M. baetica in the perineal pattern of the females, and the morphology of the males and the second-stage juveniles. Nonetheless, it can be differentiated from other species by a combination of morphometric, morphological and molecular characteristics. Phylogenetic analysis was conducted based on the internal transcribed spacer (ITS) and 28S rDNA as well as the region between the cytochrome c oxidase I (COI) and cytochrome c oxidase II (COII) mitochondrial genes. Herein, this nematode is described, illustrated, and designated as a new species, Meloidogyne daklakensis sp. n., based on morphometric, morphological and molecular analyses.


Enhanced expression of glutathione S-transferases in colorectal carcinoma compared to non-neoplastic mucosa.
Ten paired samples of primary human colorectal carcinoma and adjacent non-neoplastic mucosa were analysed for total glutathione S-transferase (GST) activities as determined by 1-chloro-2,4-dinitrobenzene assays. These tissues were also investigated for the expression of acidic (pi), basic (alpha) and neutral (mu) GSTs using Western blotting procedures and immunohistochemical staining. For each of the paired samples examined the total GST activity was higher in tumour than in adjacent non-neoplastic mucosa. Western blotting, using an antibody against acidic GST also showed strong immunoreactivity in all the samples with more intense reactions in tumour compared to mucosa in nine out of the ten paired samples. Low levels of basic GST were also expressed in all samples of tumour and mucosa. Neutral GST was not detectable in two samples of tumour and corresponding mucosa, but low levels of expression were demonstrated in the remaining eight. Immunohistochemical staining for acidic GST showed a dark brown reaction in all tumour cells; in non-neoplastic mucosa there was positive immunoreactivity for epithelial cells situated deep within the crypts and a negative reaction for surface epithelial cells. Immunohistochemical staining for basic GST was negative except for one sample of tumour and two of mucosa. Neutral GST was expressed only in two samples of tumour and two samples of mucosa. We therefore conclude that there is enhanced expression of GSTs, acidic GST being the predominant form, in tumour compared to normal mucosa, in keeping with a role for GSTs in colonic carcinogenesis and acquired or innate drug resistance.