IFT52 as a Novel Candidate for Ciliopathies Involving Retinal Degeneration.
Mutations in the intraflagellar transport protein 52 homolog (IFT52) gene are reported to interrupt ciliary function and cause short-rib thoracic dysplasia (SRTD), a specific form of skeletal ciliopathy. However, the roles of these mutations in retinal ciliopathy are inexplicit. We herein aim to study the impact of IFT52 mutations in retinopathies. A patient with syndromic ciliopathy, presenting mild SRTD (skeletal ciliopathy) and Liber congenital amaurosis (LCA; retinal ciliopathy), and nine unaffected family members were recruited. Comprehensive systemic evaluations, including ophthalmic tests, were received by the patient. Whole genome sequencing (WGS) was applied for genetic annotation. An in vitro cell system was employed to study the pathogenicity of the variant. WGS identified a homozygous missense variation in IFT52, c.556A>G (p.T186A), carried by the patient but absent in both unaffected siblings. In silico analysis supported the pathogenic nature of this highly conserved variant. Structural analysis suggested that this substitution could generate a novel hydrogen bond between the mutated residue 186 and proline at residue 192, thus potentially interrupting the tertiary structure and the stability of the IFT52 protein. In vitro cellular study indicated that this mutation might disturb the stability of encoded IFT52 protein and dramatically disrupt cilia elongation in hTERT-RPE1 cells in a loss-of-function manner. This report expands ocular phenotypes of IFT52 mutation-caused ciliopathy to include retinal ciliopathy and demonstrates its deleterious nature in interrupting primary ciliary function. Our study hence highlights the need for screening for IFT52 mutations in LCA patients and ophthalmic reviews of patients carrying IFT52 mutations.


Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease.
Systolic (Sa) and diastolic (Ea) myocardial velocities measured by tissue Doppler (TD) imaging (TDI) recently were shown to be decreased in subjects who have mutations causing hypertrophic cardiomyopathy (HCM) but who do not have left ventricular (LV) hypertrophy. By studying these subjects at a later date, we sought to determine whether TDI predicts the subsequent evolution of the HCM phenotype. Serial 2D and Doppler echocardiography were performed in 12 subjects (age range, 17 to 51 years) with HCM-causing mutations on 2 occasions: before development of hypertrophy and 2 years later. Twelve age- and gender-matched family members without mutations were included as control subjects. In those with mutations, mean septal thickness and LV mass were 1.07+/-0.14 cm and 103.0+/-11 g at baseline, respectively, and increased to 1.30+/-0.36 cm and 193.0+/-78 g at follow-up (P<0.01), with 6 subjects satisfying HCM diagnostic criteria. Sa and Ea velocities in those with mutations were lower compared with control subjects at baseline and follow-up (lateral Sa, 15+/-1.2 versus 8.2+/-2.1 cm/s; lateral Ea, 16.5+/-2.8 versus 8.1+/-2.3 cm/s; P<0.01). At 2 years, left atrial volume and pulmonary venous flow indices of LV filling pressures increased, whereas TD early and late diastolic velocities decreased (all P<0.05) in those with the mutations. Control subjects had no significant interval changes of the above parameters. Subsequent development of HCM in subjects with initially reduced TD velocities establishes TDI as a reliable method for early identification of HCM mutation carriers.


Methylation map genes can be critical in determining the methylome of intracranial aneurysm patients.
Aim: Intracranial aneurysm is often asymptomatic until the time of rupture. Elevated homocysteine is reported in vascular diseases. Identifying early events in homocysteine metabolism through methylation map genes may prevent fatality. Materials & methods: In the present study, we investigated the role of variants in methylation map genes in ethnically matched 480 individuals that can influence the homocysteine levels and promote development of aneurysm. Results: The study demonstrates that the genetic variants in folate cycle and methionine cycle genes such as MTHFR, MTRR, MTR, BHMT and DNMT1 are associated with the risk of aneurysm. Conclusion: The associated allelic variants in these genes have functional relevance and are predictive of decreased expression indicative of altered methylation levels that may result in elevated homocysteine.


Accumulation of metabolic cardiovascular risk factors in black and white young adults over 20 years.
Cross-sectional clustering of metabolic risk factors for cardiovascular disease in middle-aged adults is well described, but less is known regarding the order in which risk factors develop through young adulthood and their relation to subclinical atherosclerosis. A total of 3178 black and white women and men in the Coronary Artery Risk Development in Young Adults study were assessed to identify the order in which cardiovascular disease risk factors including diabetes, hypertension, dyslipidemia (low high-density lipoprotein cholesterol or high triglyceride levels), hypercholesterolemia (high total or low-density lipoprotein cholesterol), and obesity develop. Observed patterns of risk factor development were compared with those expected if risk factors accumulated randomly, given their overall distribution in the population. Over the 20 years of follow-up, 80% of participants developed at least 1 risk factor. The first factor to occur was dyslipidemia in 39% of participants, obesity in 20%, hypercholesterolemia in 11%, hypertension in 7%, and diabetes in 1%. Dyslipidemia was the only risk factor both to occur first and to be followed by additional risk factors more often than expected (P<0.001 for both). Order of risk factor accrual did not affect subclinical atherosclerosis at year 20. Results were similar by sex, race, and smoking status. Multiple patterns of cardiovascular risk factor development were observed from young adulthood to middle age. Dyslipidemia, a potentially modifiable condition, often preceded the development of other risk factors and may be a useful target for intervention and monitoring.


Video consultation use by Australian general practitioners: video vignette study.
There is unequal access to health care in Australia, particularly for the one-third of the population living in remote and rural areas. Video consultations delivered via the Internet present an opportunity to provide medical services to those who are underserviced, but this is not currently routine practice in Australia. There are advantages and shortcomings to using video consultations for diagnosis, and general practitioners (GPs) have varying opinions regarding their efficacy. The aim of this Internet-based study was to explore the attitudes of Australian GPs toward video consultation by using a range of patient scenarios presenting different clinical problems. Overall, 102 GPs were invited to view 6 video vignettes featuring patients presenting with acute and chronic illnesses. For each vignette, they were asked to offer a differential diagnosis and to complete a survey based on the theory of planned behavior documenting their views on the value of a video consultation. A total of 47 GPs participated in the study. The participants were younger than Australian GPs based on national data, and more likely to be working in a larger practice. Most participants (72%-100%) agreed on the differential diagnosis in all video scenarios. Approximately one-third of the study participants were positive about video consultations, one-third were ambivalent, and one-third were against them. In all, 91% opposed conducting a video consultation for the patient with symptoms of an acute myocardial infarction. Inability to examine the patient was most frequently cited as the reason for not conducting a video consultation. Australian GPs who were favorably inclined toward video consultations were more likely to work in larger practices, and were more established GPs, especially in rural areas. The survey results also suggest that the deployment of video technology will need to focus on follow-up consultations. Patients with minor self-limiting illnesses and those with medical emergencies are unlikely to be offered access to a GP by video. The process of establishing video consultations as routine practice will need to be endorsed by senior members of the profession and funding organizations. Video consultation techniques will also need to be taught in medical schools.


A national study of pain in the bleeding disorders community: a description of haemophilia pain.
The National Pain Study was a prospective, computer-based, descriptive survey of the pain experience of persons with a bleeding disorder conducted in the United States over a 28 month period from 2007 to 2009. The aim of this study was to (i) determine the language used by patients to describe and differentiate acute and persistent pain, (ii) describe pharmacological and non-pharmacological strategies utilized to control pain, (iii) assess the perceived effectiveness of current pain management on quality of life and, (iv) to determine who provides pain management to this population. One thousand, one hundred and four surveys were received. Only the responses of the 764 respondents who reported having hemophilia A or B were evaluated for this paper. Thirty nine percent of participants reported their pain was not well treated. The average acute pain score associated with a bleed reported was 5.97/10 while the average persistent pain score reported was 4.22/10. The most frequently reported word descriptors for acute pain were: throbbing, aching, sharp, tender and miserable. The most frequently reported word descriptors for persistent pain were aching, nagging, tiring, sharp, and tender. The most frequently reported pain strategies for acute and persistent pain included factor, rest, ice, elevation, and compression. Alcohol and illicit drugs were reportedly used to manage both acute pain as well as persistent pain. Primarily, short-acting opioids and acetaminophen were reported to treat both acute and persistent pain. Hematologists and primary care providers provide the majority of pain management for persons with hemophilia (PWH). Quality of life (QOL) scores were lowest in the domains of pain, energy/fatigue and physical problems indicating disruption of QOL. This substantiates under-recognition and under-treatment of pain in the hemophilia population when combined with the 39% of respondents who felt their pain was not well treated and literature in the general pain population of wide spread under-treatment of pain. The NPS is an initial step in recognizing the prevalence and description of pain in PWH. HTC providers should educate themselves in pain management techniques to better serve this population. Further research is necessary to develop specific pain management guidelines for the bleeding disorders population that include multimodal holistic treatment plans.


Evaluation of distraction implants for prosthetic treatment after vertical alveolar ridge distraction: a clinical investigation.
The purpose of this study was to clinically evaluate the mucosal condition and the esthetic and functional results of distraction implants loaded with fixed or removable implant-supported restorations. A total of 35 patients were treated with 62 distraction implants for correction of alveolar ridge deficiency. The distraction implants were loaded with prosthetic superstructures 4 to 6 months after distraction. Nine patients were provided with single-crown restorations, 16 received metal-ceramic fixed partial dentures, and 10 received removable overdentures. Recall was scheduled before and 3, 6, and 9 months after implant loading. Periotest values, periimplant probing depths, and radiographic marginal bone levels were recorded, along with any biologic or mechanical complications. Patients were followed for 9 months after implant loading. Two distraction implants were lost before abutment connection. After fabrication and placement of individual abutments, all implants were loaded with prosthetic superstructures. The results showed a decrease of the Periotest values, and thus an increase of implant stability, during the following 9 months. Periimplant probing depths also decreased in the first months after implant loading. Soft tissue around the superstructures and adjacent teeth was healthy. The distraction implant system has a high potential for osseointegration. Because of the gentle distraction technique and the possibility of using individual abutments at almost any angulation, satisfying esthetic and functional results are possible. The rate of complications was low in this short-term study.


A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics.
Pseudogenes are thought to be inactive gene sequences, but recent evidence of extensive pseudogene transcription raised the question of potential function. Here we discover and characterize the sets of mouse lncRNAs induced by inflammatory signaling via TNFα. TNFα regulates hundreds of lncRNAs, including 54 pseudogene lncRNAs, several of which show exquisitely selective expression in response to specific cytokines and microbial components in a NF-κB-dependent manner. Lethe, a pseudogene lncRNA, is selectively induced by proinflammatory cytokines via NF-κB or glucocorticoid receptor agonist, and functions in negative feedback signaling to NF-κB. Lethe interacts with NF-κB subunit RelA to inhibit RelA DNA binding and target gene activation. Lethe level decreases with organismal age, a physiological state associated with increased NF-κB activity. These findings suggest that expression of pseudogenes lncRNAs are actively regulated and constitute functional regulators of inflammatory signaling. DOI:http://dx.doi.org/10.7554/eLife.00762.001.


VARIABILITY IN THE ULTRASONOGRAPHIC APPEARANCE OF THE PANCREAS IN HEALTHY DOGS COMPARED TO DOGS WITH HYPERADRENOCORTICISM.
Anecdotally, an unusually hyperechoic pancreas can be found in seemingly healthy dogs on ultrasound examination and the prevalence and clinical significance of this finding is unknown. The objective of this study was to describe the prevalence of a hyperechoic and/or heterogenous pancreas in healthy dogs and correlate these findings to weight, age, and body condition score (BCS). An additional objective was to describe the prevalence of a hyperechoic and/or heterogenous pancreas in dogs with hyperadrenocorticism and compare this to the healthy dogs. Pancreata of 74 healthy dogs were evaluated prospectively and pancreatic echogenicity and echotexture were graded. Each dog's age, BCS, and weight were recorded. Dogs were screened for health by physical examination, serum chemistry panel, urine specific gravity, and a canine pancreatic lipase immunoreactivity assay. Pancreatic images for 92 dogs having hyperadrenocorticism were also reviewed and pancreatic echogenicity and echotexture were recorded. The prevalence of pancreatic hyperechogenicity in normal dogs was 7% (5 of 74) and heterogeneity was 40% (30 of 74). No correlation existed between pancreatic echogenicity and weight, age, or BCS (P > 0.1 for all sets). A statistically significant increase in the proportion of dogs having a hyperechoic pancreas was found in the hyperadrenocorticism sample of dogs (40%, 37 of 92, P < 0.0001). The underlying cause of pancreatic variability in the few healthy dogs and in dogs with hyperadrenocorticism is unknown and the varying appearance of the pancreas in these samples confounds interpretation of diseases such as chronic pancreatitis.


Electrical Probing and Tuning of Molecular Physisorption on Graphene.
The ability to tune the molecular interaction electronically can have profound impact on wide-ranging scientific frontiers in catalysis, chemical and biological sensor development, and the understanding of key biological processes. Despite that electrochemistry is routinely used to probe redox reactions involving loss or gain of electrons, electrical probing and tuning of the weaker noncovalent interactions, such as molecular physisorption, have been challenging, primarily due to the inability to change the work function of conventional metal electrodes. To this end, we report electrical probing and tuning of the noncovalent physisorption of polar molecules on graphene surface by using graphene nanoelectronic heterodyne sensors. Temperature-dependent molecular desorptions for six different polar molecules were measured in real-time to study the desorption kinetics and extract the binding affinities. More importantly, we demonstrate electrical tuning of molecule-graphene binding kinetics through electrostatic gating of graphene; the molecular desorption can be slowed down nearly three times within a gate voltage range of 15 V. Our results provide insight into small molecule-nanomaterial interaction dynamics and signify the ability to electrically tailor interactions, which can lead to rational designs of complex chemical processes for catalysis and drug discovery.


Structural evaluation of GM1-related carbohydrate-cholera toxin interactions through surface plasmon resonance kinetic analysis.
Surface plasmon resonance (SPR) can provide kinetic information about an interaction, and it can also be used to rapidly monitor dynamic processes, such as adsorption and degradation, without the need for sample labeling. Here, we employed SPR to analyze carbohydrate-protein interactions, particularly GM1-related carbohydrate-Vibrio cholera toxin interactions. The interaction between cholera toxin subunits A (ctxA) and B (ctxB) was similar to general ligand-receptor interactions. After the direct immobilization of thiol-containing GM1 pentasaccharide on a gold surface, the GM1-ctxB interaction kinetics were evaluated, and they showed a similar degree of kinetics as reported in previous reports. We found that ctxA had a high affinity for the GM1-ctxAB complex, although its equilibrium dissociation constant was 10 times lower than that of GM1-ctxB binding. Comparative analyses of GM1-related carbohydrate-ctxAB interactions were also conducted to determine the kinetic values of several GM1 analogues with different structures, although their kinetic values were one order of magnitude lower than those of the GM1-ctxAB interaction. The kinetic analysis results for the interactions of GM1 analogues and ctxAB indicated that the sialic acid thumb is important for recognition, and the terminal galactose and N-acetylgalactosamine fingers are required to stabilize the GM1-ctxAB interaction. Taken together, our results indicate that the direct immobilization of carbohydrate in an SPR-based analytical system can be used to evaluate the structural contribution of carbohydrate moieties in carbohydrate-protein interactions, as well as provide valuable information that can be used to understand the interactions.


Acute tryptophan depletion induced by a gelatin-based mixture impairs object memory but not affective behavior and spatial learning in the rat.
One manner to study the role of serotonin (5-HT) in behavioral functions is through nutritional manipulation of its precursor tryptophan (TRP). By means of the method of acute TRP depletion, plasma TRP levels can be reduced in a reversible way in both humans and rats. In the present study a TRP-free protein-carbohydrate mixture was used to investigate the behavioral effects of lowering TRP and 5-HT concentrations in adult male rats. These animals were tested in models of anxiety (open field, home cage emergence test), depression (forced swimming test) and cognition (object recognition test and Morris water escape test). The TRP-free protein-carbohydrate mixture substantially reduced the ratio TRP/SigmaLNAA within 2 and 4 h by 75 and 60%, respectively. It was found that 4 h after administration, the treatment did not affect anxiety-related behavior nor did it cause depressive-like behavior. Also, no treatment effect was found on spatial learning performance in a Morris water escape test. On the other hand, performance in an object recognition test was clearly impaired after TRP depletion. Taken together, these data suggest that acute lowered central 5-HT levels are not associated with changes in affective behavior (i.e. anxiety and depression), but do impair object memory in adult rats.


Epidemiology, microbiology and mortality associated with community-acquired bacteremia in northeast Thailand: a multicenter surveillance study.
National statistics in developing countries are likely to underestimate deaths due to bacterial infections. Here, we calculated mortality associated with community-acquired bacteremia (CAB) in a developing country using routinely available databases. Information was obtained from the microbiology and hospital database of 10 provincial hospitals in northeast Thailand, and compared with the national death registry from the Ministry of Interior, Thailand for the period between 2004 and 2010. CAB was defined in patients who had pathogenic organisms isolated from blood taken within 2 days of hospital admission without a prior inpatient episode in the preceding 30 days. A total of 15,251 CAB patients identified, of which 5,722 (37.5%) died within 30 days of admission. The incidence rate of CAB between 2004 and 2010 increased from 16.7 to 38.1 per 100,000 people per year, and the mortality rate associated with CAB increased from 6.9 to 13.7 per 100,000 people per year. In 2010, the mortality rate associated with CAB was lower than that from respiratory tract infection, but higher than HIV disease or tuberculosis. The most common causes of CAB were Escherichia coli (23.1%), Burkholderia pseudomallei (19.3%), and Staphylococcus aureus (8.2%). There was an increase in the proportion of Extended-Spectrum Beta-Lactamases (ESBL) producing E. coli and Klebsiella pneumoniae over time. This study has demonstrated that national statistics on causes of death in developing countries could be improved by integrating information from readily available databases. CAB is neglected as an important cause of death, and specific prevention and intervention is urgently required to reduce its incidence and mortality.


Dangers of bone graft substitutes: lessons from using GeneX.
Bone graft substitutes are widely used in spinal surgery. Here, serious complications associated with the bone graft substitute GeneX are presented. GeneX contains tri-calcium phosphate and calcium sulphate. GeneX was used in three patients who had spinal decompression and fusion. Mice were also injected with GeneX, demineralised bone matrix (DBX) or saline subcutaneously. After 24 h the extent of tissue damage and inflammation in tissue sections was quantified. To understand the licensing process for bone graft substitutes, the U.S. Food and Drug Administration (FDA) and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) websites were accessed. All patients developed sterile pus in soft tissues adjacent to the GeneX followed by skin breakdown in two and pharyngeal perforation in one. In mice, GeneX produced moderate or severe skin damage compared with no or mild skin damage after DBX (p<0.05) or saline (p<0.05) injection. GeneX caused more inflammation in mouse dermis (1704±193 leucocytes/mm2, mean ± SE) than DBX (537 ± 266, p<0.01) or saline (136 ± 19, p<0.01). The FDA and MHRA classify bone graft substitutes as medical devices. In contrast with drugs, medical devices do not need to undergo clinical safety tests before obtaining FDA 510(k) clearance for use in patients. GeneX may cause soft tissue inflammation and destruction and should not be placed next to thin walled structures, such as skin or pharynx, because it may erode through these tissues. Bone graft substitutes should undergo mandatory detailed safety testing prior to approval. This could be achieved by reclassifying them as drugs.


Antifungal Preservation of Food by Lactic Acid Bacteria.
Fungal growth and consequent mycotoxin release in food and feed threatens human health, which might even, in acute cases, lead to death. Control and prevention of foodborne poisoning is a major task of public health that will be faced in the 21st century. Nowadays, consumers increasingly demand healthier and more natural food with minimal use of chemical preservatives, whose negative effects on human health are well known. Biopreservation is among the safest and most reliable methods for inhibiting fungi in food. Lactic acid bacteria (LAB) are of great interest as biological additives in food owing to their Generally Recognized as Safe (GRAS) classification and probiotic properties. LAB produce bioactive compounds such as reuterin, cyclic peptides, fatty acids, etc., with antifungal properties. This review highlights the great potential of LAB as biopreservatives by summarizing various reported antifungal activities/metabolites of LAB against fungal growth into foods. In the end, it provides profound insight into the possibilities and different factors to be considered in the application of LAB in different foods as well as enhancing their efficiency in biodetoxification and biopreservative activities.


Protective Effects of Punicalagin on Osteoporosis by Inhibiting Osteoclastogenesis and Inflammation via the NF-κB and MAPK Pathways.
Postmenopausal osteoporosis is a worldwide disease characterized by reduced bone mineral density and increased fracture risk. Inflammatory bone loss due to excessive osteoclast bone resorption is significant in the pathogenesis and development of osteoporosis. Punicalagin (PUN) is a pomegranate fruit derivative and has potential anti-inflammatory effects. However, the effect of PUN on osteoporotic bone loss has yet to be clarified. In this study, we investigated the effect of PUN on RANKL-induced osteoclast formation and bone resorption in vitro, as well as its potential therapeutic effect on ovariectomized-induced bone loss in vivo. PUN was demonstrated to suppress osteoclast formation and bone resorptive function dose-dependently, while osteoclast-specific genes were also downregulated by PUN. In vivo micro-CT and histopathological staining showed that the OVX procedure led to significant bone loss characterized by decreased bone parameters and increased osteoclast numbers, while PUN treatment dramatically prevented these changes. Furthermore, PUN treatment effectively inhibited proinflammatory cytokine expression in vitro. Mechanistically, PUN maintained bone mass via suppressing nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway activation. Collectively, our observations provide evidence that PUN is a potential candidate for the treatment of osteoporosis.


Peyote use during pregnancy.
Peyote is a substance with varied potential. Used properly it may be a spiritual aid but used in excess, it can be a hallucinogenic agent with teratogenic potential. There is a growing community of devout people who use it as part of their religious observance. The active ingredient, mescaline, has been linked to a specific group of fetal abnormalities when the substance is used inappropriately.


Five- to fifteen-year follow-up after Fontan operation.
The purpose of this study was to estimate survival and quality of outcome and assess factors associated with outcome for patients out 5 to 15 years from their Fontan operation. We studied 352 patients who had the Fontan operation prior to 1985. The overall 1-, 5-, and 10-year survival was 77%, 70%, and 60%, respectively. The following factors were significantly associated with lower survival: univentricular heart or complex congenital anomalies other than tricuspid atresia, early calendar year of operation, heterotaxia syndromes, early age at operation, increased pulmonary artery pressure, atrioventricular valve dysfunction, and higher (worse) New York Heart Association class. Reoperations were necessary for 103 of the 352 patients. At least 20% of the survivors have or have had cardiac arrhythmias requiring antiarrhythmic medication or mechanical pacemaker insertion. Between 7% and 10% of the patients have had or had protein-losing enteropathy/hypoproteinemia. At 5 years postoperatively, 122 patients (34.7%) were alive with a better New York Heart Association functional classification than preoperatively. Fifty-eight patients (16.5%) were alive and in the same functional classification, but 126 (35.8%) died within the first 5 years or were in a worse functional classification. Thirty-nine patients were doing excellently and 29 patients poorly 5 years after the operation. Of the surviving patients, 43% can do as much exercise as their peers, whereas 3% are incapable of exercise. To assure good functional long-term outcome in addition to survival, clinicians must exclude from selection for Fontan operation patients known to be at high risk for death or poor outcome.


Connecting the dots: object connectedness deceives perception but not movement planning.
The perceptual system parses complex scenes into discrete objects. Parsing is also required for planning visually guided movements when more than one potential target is present. To examine whether visual perception and motor planning use the same or different parsing strategies, we used the connectedness illusion, in which observers typically report seeing fewer targets if pairs of targets are connected by short lines. We found that despite this illusion, when observers are asked to make speeded reaches toward targets in such displays, their reaches are unaffected by the presence of the connecting lines. Instead, their movement plans, as revealed by their movement trajectories, are influenced by the number of potential targets irrespective of whether connecting lines are present or not. This suggests that scene parsing for perception depends on mechanisms that are distinct from those that allow observers to plan rapid and efficient target-directed movements in situations with multiple potential targets.


[Impact of the internet on physician-patient relationship].
Internet became an inevitable phenomenon in the physician-patient relationship. The author analyzes it in two theoretical models: the effects on the medical profession and the interference with the decision making process. These will help to explain why patients search the internet for information about their illness, cure and their doctors. Some physicians dislike this, and they are not just worried about the patient, but about their own position and time. This fear is groundless, even if the internet patient can be hard to tackle in the daily routine. Internet can be seen not only as a necessary evil, but with proper communication skills physicians can benefit from their patients' passion to internet.


How doctors learn: physicians' self-directed learning episodes.
To qualitatively examine the self-directed learning activities of physicians in light of several lines of research on how doctors learn. Under the auspices of the Royal College of Physicians and Surgeons of Canada, the author elicited from physicians narratives about past learning experiences. He analyzed the narratives (1) seeking themes among the doctors' approaches and (2) examining those themes in light of the existing literature. The 32 physicians interviewed described learning experiences, confirming earlier research that two varieties of problems (specific and general) precipitate learning and that learning episodes follow definite stages: scanning for problems, deciding whether to pursue the learning task, acquiring new knowledge and skill, and gaining experience with what has been learned. The latter three stages have been described previously and are expanded upon here. This study produced an integrated and elaborated theory of learning in clinical practice with implications for both the education of physicians in training and physicians' continuing professional development. In particular, the theory points to problem areas in teaching medical students and residents to learn in clinical practice, and in matching the learning needs of physicians to organized continuing medical education activities.


The legacy of Homer W. Smith: mechanistic insights into renal physiology.
In 1945, Homer W. Smith published an article in the JCI that clearly demonstrated that para-aminohippuric acid is the most suitable agent for the evaluation of renal plasma flow in both humans and dogs; in addition, the paper provided detailed methodology that is still in use today. This paper is but one of many outstanding works performed by Smith and his colleagues that clearly established the clearance technique as a powerful noninvasive approach to gain mechanistic insights into intrarenal function.


Evaluation of cellular substrates for antinuclear antibody determinations.
The immunofluorescent technique was employed to evaluate the sensitivity of 10 human and animal cell monolayers and tissue sections as substrates for titering the antinuclear antibody content of serum samples. The highest mean ranks of sensitivity, the relative ability of each substrate to maintain its sensitivity rank when 21 selected positive sera were tested, were achieved by two fibroblast cell lines, baby hamster kidney (BHK 21/C13) and human lung (WI-38), respectively. The least sensitive substrates were commercial rat kidney and liver tissue sections.


[The rate of detection and diagnostic significance of antibodies to Borrelia burgdorferri in patients with eyes diseases of inflammatory nature].
The eyes diseases appear at any stage of Lyme borreliosis and clinical manifestations are polymorphic and non-specific. The study examined prevalence of B. burgdorferi s.l. infection in patients with different eyes diseases and evaluated diagnostic significance of antibodies to B. burgdorferi in clinical practice. The sampling included 57 patients with conjunctivitis, keratitis, uveitis, choreoretinitis, optical neuritis of unclear etiology. The blood serum of patients was analyzed to detect presence of IgM- and IgG-antibodies to B. burgdorferi s.l. The positive results were confirmed in Western blot (two-sweep method). The immune enzyme analysis detected antibodies to B. burgdorferi in 7 out of 57 examined patients (12.3%). The Western blot confirmed presence of antibodies only in 3 serums out of 57 (5.3%). The high rate of false positive results was established during immune enzyme analysis detecting IgM-antibodies to B. burgdorferi. On the basis of comprehensive examination ophtalmo-borreliosis was diagnosed in two out of three patients seropositive to B. burgdorferi. In one seropositive patient co-infection B. burgdorferi provoked exacerbation of chronic uveitis of unclear etiology. It is appropriate to include in plan of examination of patients with inflammatory eyes diseases of unclear genesis the detection of antibodies to B. burgdorferi using two-sweep test (study of serums with immune enzyme analysis, confirmation of positive results in Western blot).


Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application.
We aimed to assess the effect of ovariectomy on cartilage turnover and degradation, to evaluate whether ovariectomized (OVX) rats could form an experimental model of postmenopausal osteoarthritis. The effect of ovariectomy on cartilage was studied using two cohorts of female Sprague-Dawley rats, aged 5 and 7 months. In a third cohort, the effect of exogenous estrogen and a selective estrogen receptor modulator was analyzed. Knee joints were assessed by histological analysis of the articular cartilage after 9 weeks. Cartilage turnover was measured in urine by an immunoassay specific for collagen type II degradation products (CTX-II), and bone resorption was quantified in serum using an assay for bone collagen type I fragments (CTX-I). Surface erosion in the cartilage of the knee was more severe in OVX rats than in sham-operated animals, particularly in the 7-month-old cohort (P = 0.008). Ovariectomy also significant increased CTX-I and CTX-II. Both the absolute levels of CTX-II and the relative changes from baseline seen at week 4 correlated strongly with the severity of cartilage surface erosion at termination (r = 0.74, P < 0.01). Both estrogen and the selective estrogen receptor modulator inhibited the ovariectomy-induced acceleration of cartilage and bone turnover and significantly suppressed cartilage degradation and erosion seen in vehicle-treated OVX rats. The study indicates that estrogen deficiency accelerates cartilage turnover and increases cartilage surface erosion. OVX rats provide a useful experimental model for the evaluation of the chondroprotective effects of estrogens and estrogen-like substances and the model may be an in vivo representation of osteoarthritis in postmenopausal women.


Long-term cellular effects in humans chronically exposed to ionizing radiation.
The aim of the study was to investigate hematopoietic injury and recovery in residents of the Techa riverside villages who had been chronically exposed to radiation as a result of the activities of the Mayak Nuclear Facility, and evaluate late effects from chronic, low-dose radiation exposures. Whole blood samples were drawn from 338 unexposed individuals resident in noncontaminated villages, and 692 individuals chronically exposed externally (to primarily gamma radiation) and internally from Sr since 1949 at decreasing dose-rates which have currently reached the background levels. The mean cumulative dose in the exposed cohort was 0.62 Gy over the years 1949 to 2008 using the Techa River Dosimetry System (TRDS) 2000. The frequency of chromosome aberrations and mutations in peripheral lymphocytes, and other aspects indicative of cellular and molecular repair of radiation damage, were measured. The subjects were divided into two study groups: (a) 171 individuals who during the early exposure period (where the highest dose-rates were prevalent) were noted to manifest leucopenia and/or were diagnosed with chronic radiation syndrome (CRS), and (b) 521 exposed individuals without cytopenia and CRS. The first group demonstrated an increased frequency of micronuclei, dicentric chromosomes, somatic mutations (CD3-CD4+cells) in lymphocytes, and mutations in the TP53 gene. In addition, they demonstrated a lower Cu/Zn-SOD concentration, a significantly increased concentration of nitric oxide, and a greater apoptotic frequency in peripheral blood lymphocytes compared to exposed individuals without leucopenia. Similar to the unexposed individuals, the second group demonstrated "background levels" of mutational frequencies several years after their exposures, but they did show an increased number of cells with delayed cell cycles based on Chk-2 concentrations compared to the unexposed population. The data are consistent with the idea that a chronic radiation exposure within a dose range from 0.01 Gy to 1.96 Gy results in more severe late hematopoietic effects in a select cohort of highly radiosensitive individuals, rather than an overall increase in late effects in cells of each exposed individual. The authors state that radiation-exposed subjects demonstrating CRS showed an activation of barrier anti-oxidative stress mechanisms at late periods after radiation exposure, apparently in response to a more severe radiation damage than subjects exposed to similar radiation doses but not demonstrating CRS. Finally, the persistence of chromosome aberrations and somatic mutations in the CRS cohort is indicative of an exhaustion of the anti-oxidative stress mechanisms responding for so many years after the exposure, leading to genomic instability.


[Attention deficit hyperactivity disorder (ADHD) in children: neurobiological aspects, diagnosis and therapeutic approach].
The attention deficit hyperactivity disorder (ADHD) is usually associated to child development, presenting a strong neurobiological influence and being, thus, mostly common in childhood. This disorder is characterized by a persistent pattern of lack of attention and/or by hyperactivity and impulsivity. To conduct a systematic literature review on ADHD in children, focusing neurobiological aspects, diagnosis and therapeutic approaches. This is a literature review about ADHD in childhood, from 1994 through 2008. The neurobiological mechanisms that participate in ADHD are complex, involving the dopaminergic, noradrenergic and serotonergic systems. The diagnosis of ADHD must be based on the clinical behavior, since there is no biological marker defined. Metilfenidate is the main drug used for children's treatment. The search for relief of ADHD symptoms ought to be based on organic treatments, other specific treatments using medications or neurofeedbacks, as well as behavior therapies.


Peripheral autonomic nerves of human pineal organ terminate on vessels, their supposed role in the periodic secretion of pineal melatonin.
Nonvisual pineal and retinal photoreceptors are synchronizing circadian and circannual periodicity to the environmental light periods in the function of various organs. Melatonin of the pineal organ is secreted at night and represents an important factor of this periodic regulation. Night illumination suppressing melatonin secretion may result in pathological events like breast and colorectal cancer. Experimental works demonstrated the role of autonomic nerves in the pineal melatonin secretion. It was supposed that mammalian pineals have lost their photoreceptor capacity that is present in submammalians, and sympathetic fibers would mediate light information from the retina to regulate melatonin secretion. Retinal afferentation may reach the organ by central nerve fibers via the pineal habenulae as well. In our earlier works we have found that the pineal organ developing from lobular evaginations of the epithalamus differs from peripheral endocrine glands and is composed of a retina-like central nervous tissue that is comprised of cone-like pinealocytes, secondary pineal neurons and glial cells. Their autonomic nerves in submammalians as well as in mammalian animals do not terminate on pineal cells, rather, they run in the meningeal septa among pineal lobules and form vasomotor nerve endings. Concerning the adult human pineal there are no detailed fine structural data about the termination of autonomic fibers, therefore, in the present work we investigated the ultrastructure of the human pineal peripheral autonomic nerve fibers. It was found, that similarly to other parts of the brain, autonomic nerves do not enter the human pineal nervous tissue itself but separated by glial limiting membranes take their course in the meningeal septa of the organ and terminate on vessels by vasomotor endings. We suppose that these autonomic vasomotor nerves serve the regulation of the pineal blood supply according to the circadian and circannual changes of the metabolic activity of the organ and support by this effect the secretion of pineal neurohormones including melatonin.


Elevated plasma and urinary guanosine 3':5'-monophosphate and increased production rate in patients with neoplastic diseases.
The plasma and 24-hr urinary levels of cyclic adenosine 3':5'-monophosphate and of cyclic guanosine 3':5'-monophosphate (cGMP) were determined for 19 healthy normal patients, 54 patients with six types of nonneoplastic diseases (cholelithiasis, peptic ulcer, coronary heart disease, hypertension, regional ileitis, and cirrhosis), and 54 patients with five types of neoplastic disease (cancers of the lung, colon, and breast, acute myelocyte leukemia, and Hodgkin's disease). The cyclic adenosine 3':5'-monophosphate levels of urine and plasma in normal subjects, in noncancer subjects, and in cancer subjects did not differ significantly. The cGMP levels in the noncancer group were similarly unchanged from those in the normal group. However, mean cGMP levels in the urine and plasma of patients with neoplastic diseases were, respectively, 2- and 3-fold greater than the normal values (p less than 0.005 for urine and p less than 0.05 for plasma). Pharmacokinetic studies with [3H]cGMP in nine healthy controls and 15 patients with neoplasia showed that the mean production rate of this nucleotide in patients with metastatic cancer was elevated when compared to normal patients, but many values fell within the normal range. In acute leukemia, the production rate was seven times normal, with four of five patients having values clearly outside the normal range. The plasma clearance rate in patients with neoplasia was not decreased when compared to that in normal patients. It is proposed that an increased production rate, rather than any change in plasma clearance, accounts for the increased levels of cGMP in the plasma and urine of some patients with neoplastic disease.


Survey of Patients with Cervical Cancer in Hospital UniversitiSains Malaysia: Survival Data Analysis with Time-Dependent Covariate.
Cervical cancer is the third most common cancer among women in Malaysia. The objective of this study was to estimate the effect of explanatory variables on survival time of cervical cancer patients receiving treatment at a hospital in Malaysia. In this retrospective record review study, cervical cancer data obtained from Hospital UniversitiSains Malaysia (HUSM) was analysed. The data comprises of 120 patients who had been diagnosed as cervical cancer between 1(st) July 1995 and 30(th) June 2007, and obtained treatment from the hospital. The outcome variable was survival time (in months) from cervical cancer diagnosis to death. A stratified Weibull model was applied to study the effect of explanatory variable on survival time when there was time-dependent covariate in the model. Stage of disease and metastases were important prognostic variables. However, metastasis had been stratified because this variable did not satisfy the proportional hazard assumption. In without metastasis stratum, patients who were diagnosed at stage III & IV are at 2.30 times the risk of death as those in stage I & II. Meanwhile, in with metastasis stratum, patients in stage III & IV group had 3.53 times the hazard faced by patients in stage I & II. The prognosis of cervical cancer patients was dependent upon the stage at diagnosis, after the stratification of the metastasis variable. A poorer prognosis on survival was observed for patients in stage III & IV than those in stage I & II.


Prognostic significance of FA score based on plasma fibrinogen and serum albumin in patients with epithelial ovarian cancer.
To evaluate the significance of fibrinogen and albumin (FA) score based on preoperative peripheral blood plasma fibrinogen and serum albumin in the prognosis of patients with epithelial ovarian cancer (EOC). Patients' clinicopathological data of 186 cases of EOC were retrospectively collected, and these patients were divided into three groups according to their FA scores (both plasma fibrinogen and serum albumin abnormal were allocated a score of 2; one of them abnormal were allocated a score of 1; neither of them abnormal were allocated a score of 0; optimal cut-off point is taken as the critical point whether the value is abnormal or not). Correlation between FA score in patients with EOC as well as clinicopathological features and overall survival (OS) was analyzed. (1) Receiver operating characteristic curve showed that the optimal cut-off point of plasma fibrinogen in the preoperative peripheral blood of patients with EOC was 3.63 g/L. The optimal cut-off point for serum albumin level was 42.45 g/L. (2) There was no significant difference in age, tumor size, neutrophil count, lymphocyte count, C reactive protein and preoperative tumor marker CA125 between the three groups (FA score=0, FA score=1, FA score=2) (P>0.05). However, there was statistically significant difference in tumor grade, tumor stage and the presence of lymph node metastasis between different FA scoring groups (P<0.05). (3) Univariate and multivariate analyses showed that tumor size, tumor grade, tumor stage, plasma fibrinogen, serum albumin, FA score and tumor marker CA125 were statistically correlated with OS of EOC patients after surgery (P<0.05). The complex index FA score is superior to the single plasma fibrinogen and serum albumin when it comes to predicting prognosis. (4) FA score can better predict the prognosis of postoperative patients with EOC whose tumor size is ≥6 cm, whose EOC is advanced (stages III-IV) (P=0.0138) and whose tumor stage is medium or high grade (P=0.0005). FA score is closely related to the clinicopathological characteristics and OS of patients with EOC and is an independent risk factor indicating the prognosis of EOC patients.


Current status of anti-HBV chemotherapy.
In the past decade, significant progress has been achieved in the battle against hepatitis B virus. In addition to the immunomodulating agents such as interferon-alpha and thymosin, many novel antiviral agents have been discovered, among which nucleoside analogues are the mainstay. New-generation compounds such as 3TC and famciclovir have shown promise in the treatment of patients chronically infected by this virus, and are on the line for approval. However, viral rebound after cessation of therapy still remains a major problem. Additionally, the reports on the drug resistance to these antiviral agents suggest that combination therapy will be the eventual strategy (Bartholomew et al., 1997; Tipples et al., 1996). Therefore, developments of safe and effective antiviral agents which do not cross-resist with currently available antiviral drugs are still much needed.


Functional Neurophysiological Biomarkers of Early-Stage Alzheimer's Disease: A Perspective of Network Hyperexcitability in Disease Progression.
Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological indicator of Alzheimer's disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential indicator of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this readout. Several hypotheses have been put forward to explain the prevalence of NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD.


Effects of submucosal PRP injection on wound healing in endonasal surgeries: an experimental study.
To investigate the effects of submucosal platelet-rich plasma (PRP) injection on nasal mucosal wound healing after endoscopic sinus surgery. 24 New Zealand white rabbits were randomly divided into three groups. To mimic surgery, injury was created using 3-mm punch forceps on ventral turbinate mucosa for all groups. Submucosal PRP was injected to the damaged mucosa in the first group (PRP group, n = 8), where 0.9% saline solution to the second group (saline group, n = 8) and no injection to the third one (control group, n = 8). All the animals were sacrificed 14 days after surgery; histopathological examination and hydroxyproline measurements were performed on the mucosa of all groups. Neutrophils, goblet cells, and collagen intensity were found significantly lower (p < 0.05) in PRP group than the control group. Also, the number of ciliary and goblet cells, and collagen intensity were found significantly lower (p < 0.05) in PRP group, than the saline group. In PRP group, hydroxyproline levels were found (p < 0.05) significantly lower than the saline and the control group, and no significant difference was found between the saline group and the control group (p > 0.05). There are many studies in literature showing the positive effects of PRP on wound healing. The results of this study also demonstrated positive effects of PRP on the nasal mucosa. According to these results, PRP injection to the injured nasal mucosa showed anti-inflammatory, mucus-softening, and synechia-reducing effects. Therefore, submucosal PRP injection after endonasal surgeries can be considered an effective application for maintaining nasal physiology.


Functional consequences of morphological neuroglial changes in the magnocellular nuclei of the hypothalamus.
The supraoptic and paraventricular nuclei of the hypothalamus undergo reversible anatomical changes under conditions of intense neurohypophysial hormone secretion, such as lactation, parturition and chronic dehydration. This morphological remodelling includes a reduction in astrocytic coverage of neurones resulting in an increase in the number and extent of directly juxtaposed somatic and dendritic surfaces. There is a growing body of evidence indicating that such anatomical plasticity is of functional significance. Astrocytic-dependent clearance of electrolytes and neurotransmitters from the extracellular space appears to be altered under conditions where glial coverage of magnocellular neurones is reduced. Glutamate, for example, has been found to accumulate in the extracellular space in the supraoptic nucleus of lactating animals and cause a modulation of synaptic efficacy. On the other hand, the range of action of substances released from astrocytes and acting on adjacent magnocellular neurones is expected to be limited during such anatomical remodelling. It thus appears that the structural plasticity of the magnocellular nuclei does affect neuroglial interactions, inducing significant changes in signal transmission and processing.


Pathways to genetic parenthood for same-sex couples.
Researchers are pursuing various ways to synthesise human male and female gametes, which would be useful for people facing infertility. Some people are unable to conceive children with their partner because one of them is infertile in the sense of having an anatomical or physiological deficit. Other people-in same sex couples-may not be individually infertile but situationally infertile in relation to one another. Segers et al have described a pathway towards synthetic gametes that would rely on embryonic stem cells, rather than somatic cells. This pathway would be advantageous, they say, for same-sex couples even though it would not offer those couples 50%-50% shared genetics in their children but only 50%-25%. It is unclear, however, why this approach should be preferred morally speaking since it represents a falling off from the kind of shared genetics in children that are functionally a gold standard in parents' expectations generally. Despite raising concerns about whether genetic relatedness is necessary or sufficient as a condition of parental interest in children, Segers et al cede the sociocultural importance of that standard. If so, same-sex couples seem entitled to press a case for some measure of research priority that would offer the same level of access to that social good as everyone else.


Respiratory innate immune proteins differentially modulate the neutrophil respiratory burst response to influenza A virus.
Oxidants and neutrophils contribute to lung injury during influenza A virus (IAV) infection. Surfactant protein (SP)-D plays a pivotal role in restricting IAV replication and inflammation in the first several days after infection. Despite its potent anti-inflammatory effects in vivo, preincubation of IAV with SP-D in vitro strongly increases neutrophil respiratory burst responses to the virus. Several factors are shown to modify this apparent proinflammatory effect of SP-D. Although multimeric forms of SP-D show dose-dependent augmentation of respiratory burst responses, trimeric, single-arm forms either show no effect or inhibit these responses. Furthermore, if neutrophils are preincubated with multimeric SP-D before IAV is added, oxidant responses to the virus are significantly reduced. The ability of SP-D to increase neutrophil uptake of IAV can be dissociated from enhancement of oxidant responses. Finally, several other innate immune proteins that bind to SP-D and/or IAV (i.e., SP-A, lung glycoprotein-340 or mucin) significantly reduce the ability of SP-D to promote neutrophil oxidant response. As a result, the net effect of bronchoalveolar lavage fluids is to increase neutrophil uptake of IAV while reducing the respiratory burst response to virus.


Osmic acid in rheumatoid synovitis. A controlled study.
Ninety-nine adult RA patients with knee joint synovitis were randomized into two groups. The knee joints of the first group (52 patients) were treated with osmic acid and those of the second group (47 patients) with a placebo. After 6 months, the incidence of hydrops and pain was statistically less significant in joints treated with osmic acid. the result was better in joints without advanced radiological destruction. It is concluded that osmic acid is still of benefit in the local treatment of rheumatoid knee joint synovitis at an early stage.


Central Auditory Processing and Cognitive Functions in Children.
Introduction Nowadays, there is no consensus on whether central auditory processing disorder is a primary or a secondary deficit to other cognitive deficits. A better understanding of the association between cognitive functions and central auditory skills may help elucidate this dilemma. Objective To investigate possible associations between auditory abilities and cognitive functions in schoolchildren. Methods Fifty-eight schoolchildren, aged between 8 years and 0 months old and 11 years and 11 months old, who underwent the following tests: masking level difference, gaps in noise, pitch pattern sequence test, dichotic digits test, sustained auditory attention ability test, Wechsler intelligence scale for children - IV, junior Hayling test, five digits test, and behavior rating inventory of executive function. Results Significant correlations were found between the hearing ability of temporal resolution and executive functions, temporal ordering/sequencing, binaural integration and separation, and sustained auditory attention, operational memory, inhibitory control, and cognitive flexibility; binaural integration was also associated with intelligence. The statistically significant positive correlation found between the ability of binaural interaction and the components of emotional control and behavior regulation of the behavior rating inventory of executive function was unexpected. Conclusion The associations identified reinforce the complexity of the tasks involved in the evaluation of central auditory processing and the need for multidisciplinary evaluation for the differential diagnosis of auditory processing disorder. Confirmation of the presence or absence of comorbidities between different disorders allows directing the therapeutic behaviors and reducing the impact of possible auditory and/or cognitive deficits in the different daily life situations of children.


[Current status of dental English education in China].
The teaching of dental English for undergraduate students plays an important role in dental education. Most dental schools or colleges have set up the course of dental English education in China. However, this course lacks of a unified educational plans, contents and goals based on actual situation of dental students, which does not fully achieve the teaching purpose. This study was aimed to explore the developmental direction of the course of dental English education through comparison among different dental schools or colleges in China, in order to find out the teaching mode of dental English education, and promote the teaching effect and cultivation of international dental talents.


Scalable tight-binding model for graphene.
Artificial graphene consisting of honeycomb lattices other than the atomic layer of carbon has been shown to exhibit electronic properties similar to real graphene. Here, we reverse the argument to show that transport properties of real graphene can be captured by simulations using "theoretical artificial graphene." To prove this, we first derive a simple condition, along with its restrictions, to achieve band structure invariance for a scalable graphene lattice. We then present transport measurements for an ultraclean suspended single-layer graphene pn junction device, where ballistic transport features from complex Fabry-Pérot interference (at zero magnetic field) to the quantum Hall effect (at unusually low field) are observed and are well reproduced by transport simulations based on properly scaled single-particle tight-binding models. Our findings indicate that transport simulations for graphene can be efficiently performed with a strongly reduced number of atomic sites, allowing for reliable predictions for electric properties of complex graphene devices. We demonstrate the capability of the model by applying it to predict so-far unexplored gate-defined conductance quantization in single-layer graphene.


Greenhouse gas mitigation can reduce sea-ice loss and increase polar bear persistence.
On the basis of projected losses of their essential sea-ice habitats, a United States Geological Survey research team concluded in 2007 that two-thirds of the world's polar bears (Ursus maritimus) could disappear by mid-century if business-as-usual greenhouse gas emissions continue. That projection, however, did not consider the possible benefits of greenhouse gas mitigation. A key question is whether temperature increases lead to proportional losses of sea-ice habitat, or whether sea-ice cover crosses a tipping point and irreversibly collapses when temperature reaches a critical threshold. Such a tipping point would mean future greenhouse gas mitigation would confer no conservation benefits to polar bears. Here we show, using a general circulation model, that substantially more sea-ice habitat would be retained if greenhouse gas rise is mitigated. We also show, with Bayesian network model outcomes, that increased habitat retention under greenhouse gas mitigation means that polar bears could persist throughout the century in greater numbers and more areas than in the business-as-usual case. Our general circulation model outcomes did not reveal thresholds leading to irreversible loss of ice; instead, a linear relationship between global mean surface air temperature and sea-ice habitat substantiated the hypothesis that sea-ice thermodynamics can overcome albedo feedbacks proposed to cause sea-ice tipping points. Our outcomes indicate that rapid summer ice losses in models and observations represent increased volatility of a thinning sea-ice cover, rather than tipping-point behaviour. Mitigation-driven Bayesian network outcomes show that previously predicted declines in polar bear distribution and numbers are not unavoidable. Because polar bears are sentinels of the Arctic marine ecosystem and trends in their sea-ice habitats foreshadow future global changes, mitigating greenhouse gas emissions to improve polar bear status would have conservation benefits throughout and beyond the Arctic.


Prediagnostic intake of dairy products and dietary calcium and colorectal cancer survival--results from the EPIC cohort study.
We investigated whether prediagnostic reported intake of dairy products and dietary calcium is associated with colorectal cancer survival. Data from 3,859 subjects with colorectal cancer (42.1% male; mean age at diagnosis, 64.2 ± 8.1 years) in the European Investigation into Cancer and Nutrition cohort were analyzed. Intake of dairy products and dietary calcium was assessed at baseline (1992-2000) using validated, country-specific dietary questionnaires. Multivariable Cox regression models were used to calculate HR and corresponding 95% confidence intervals (CI) for colorectal cancer-specific death (n = 1,028) and all-cause death (n = 1,525) for different quartiles of intake. The consumption of total dairy products was not statistically significantly associated with risk of colorectal cancer-specific death (adjusted HR Q4 vs. Q1, 1.17; 95% CI, 0.97-1.43) nor that of all-cause death (Q4 vs. Q1, 1.16; 95% CI, 0.98-1.36). Multivariable-adjusted HRs for colorectal cancer-specific death (Q4 vs. Q1) were 1.21 (95% CI, 0.99-1.48) for milk, 1.09 (95% CI, 0.88-1.34) for yoghurt, and 0.93 (95% CI, 0.76-1.14) for cheese. The intake of dietary calcium was not associated with the risk of colorectal cancer-specific death (adjusted HR Q4 vs. Q1, 1.01; 95% CI, 0.81-1.26) nor that of all-cause death (Q4 vs. Q1, 1.01; 95% CI, 0.84-1.21). The prediagnostic reported intake of dairy products and dietary calcium is not associated with disease-specific or all-cause risk of death in patients diagnosed with colorectal cancer. The impact of diet on cancer survival is largely unknown. This study shows that despite its inverse association with colorectal cancer risk, the prediagnostic intake of dairy and dietary calcium does not affect colorectal cancer survival.


Measurement of Patients' Perceptions of the Quality of Acute Stroke Services: Development and Validation of the STROKE Perception Report.
Patients' perceptions of healthcare quality have become an important part of quality measurement. We explored patients' and family's lived experiences during acute stroke hospitalization to develop a quantitative instrument. Focus groups were conducted using open-ended scripted questions. Interview data were coded and analyzed using an inductive approach to thematic analysis. Symmetric patient and family instruments were developed based on qualitative domains and serially refined to a set of 30 survey items, 12 stroke knowledge test items, and 5 subject demographic fields. Scales were evaluated for internal consistency reliability using Cronbach α; construct validity with exploratory factor analysis using principal components with varimax rotation was performed to determine the extent to which items in a scale measure the same underlying factor. Feasibility of an electronic cloud-based survey was also tested. Three main themes emerged: fast action to diagnose and treat stroke, genuine caring, and education to prevent and respond to stroke. A total of 1029 subjects completed the final instrument with no differences in perception found by race, ethnicity, or length of stay. Scales showed satisfactory internal consistency reliability (Cronbach α scores, .89-.94); factor loadings across each scale ranged from 0.55 to 0.87. Data entry by electronic pad was perceived by 77% to be more confidential than paper surveys; median score for difficulty was 4 ("easy to use"). The STROKE Perception Report enables understanding of patients' and family's beliefs about the quality of acute stroke care in essential new domains never explored before.


Development of a miniaturized, reconnectable, and implantable multichannel connector.
Objective. Connectors for implantable neural prosthetic systems provide several advantages such as simplification of surgery, safe replacement of implanted devices, and modular design of the implant systems. With the rapid advancement of technologies for neural implants, miniaturized multichannel implantable connectors are also required. In this study, we propose a reconnectable and area-efficient multichannel implantable connector.Approach. A female-to-female adapter was fabricated using the thermal-press bonding of micropatterned liquid crystal polymer films. A bump inside the adapter enabled a reliable electrical connection by increasing the contact pressure between the contact pads of the adapter and the inserted cable. After connection, the adapter is enclosed in a metal case sealed with silicone elastomer packing. With different sizes of the packings, leakage current tests were performed under accelerated conditions to determine the optimal design for long-term reliability. Repeated connection tests were performed to verify the durability and reconnectability of the fabricated connector. The connector was implanted in rats, and the leakage currents were monitored to evaluate the stability of the connectorin vivo. Main results. The fabricated four- and eight-channel implantable connectors, assembled with the metal cases, had a diameter and length of 6 and 17 mm, respectively. Further, the contact resistances of the four- and eight-channel connectors were 53.2 and 75.2 mΩ, respectively. The electrical contact remained stable during repeated connection tests (50 times). The fabricated connectors with packings having 125%, 137%, and 150% volume ratios to the internal space of the metal case failed after 14, 88, and 14 d, respectively, in a 75 °C saline environment. In animal tests with rats, the connector maintained low leakage current levels for up to 92 d.Significance. An implantable and reconnectable multichannel connector was developed and evaluated. The feasibility of the proposed connector was evaluated in terms of electrical and mechanical characteristics as well as sealing performance. The proposed connector is expected to have potential applications in implantable neural prosthetic systems.


SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses.
Neddylation is a crucial post-translational modification that depends on the E3 cullin ring ligase (CRL). The E2-adapter component of the CRL, sensitive to apoptosis gene (SAG), is critical for the function of CRL-mediated ubiquitination; thus, the deletion of SAG regulates neddylation. We examined the role of SAG-dependent neddylation in T-cell-mediated immunity using multiple approaches: a novel T-cell-specific, SAG genetic knockout (KO) and chemical inhibition with small-molecule MLN4924. The KO animals were viable and showed phenotypically normal mature T-cell development. However, in vitro stimulation of KO T cells revealed significantly decreased activation, proliferation, and T-effector cytokine release, compared with WT. Using in vivo clinically relevant models of allogeneic bone marrow transplantation also demonstrated reduced proliferation and effector cytokine secretion associated with markedly reduced graft-versus-host disease. Similar in vitro and in vivo results were observed with the small-molecule inhibitor of neddylation, MLN4924. Mechanistic studies demonstrated that SAG-mediated effects in T cells were concomitant with an increase in suppressor of cytokine signaling, but not NF-κB translocation. Our studies suggest that SAG is a novel molecular target that regulates T-cell responses and that inhibiting neddylation with the clinically available small-molecule MLN4924 may represent a novel strategy to mitigate T-cell-mediated immunopathologies, such as graft-versus-host disease.


Evolutionary learning of hierarchical decision rules.
This paper describes an approach based on evolutionary algorithms, hierarchical decision rules (HIDER), for learning rules in continuous and discrete domains. The algorithm produces a hierarchical set of rules, that is, the rules are sequentially obtained and must therefore be tried until one is found whose conditions are satisfied. Thus, the number of rules may be reduced because the rules could be inside of one another. The evolutionary algorithm uses both real and binary coding for the individuals of the population. We tested our system on real data from the UCI repository, and the results of a ten-fold cross-validation are compared to C4.5s, C4.5Rules, See5s, and See5Rules. The experiments show that HIDER works well in practice.


Does the UKCAT predict performance in medical and dental school? A systematic review.
For the first time, this systematic review provides a summary of the literature exploring the relationship between performance in the UK Clinical Aptitude Test (UKCAT) and assessments in undergraduate medical and dental training. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, relevant studies were identified through systematic literature searches. Electronic searches were carried out on EBSCO, EMBASE, Educational Resources Information Centre, SCOPUS, Web of Knowledge. Studies which included the predictive validity of selection criteria including some element of the UKCAT were considered. 22 papers were identified for inclusion in the study. Four studies describe outcomes from dental programmes with limited results reported. 18 studies reported on relationships between the UKCAT and performance in undergraduate medical training. Of these, 15 studies reported relationships between the UKCAT cognitive tests and undergraduate medical assessments. Weak relationships (r=0.00-0.29) were observed in 14 of these studies; four studies reported some moderate relationships (r=0.30-0.49). The strongest relationships with performance in medical school were observed for the UKCAT total score and the verbal reasoning subtest. Relationships with knowledge-based assessments scores were higher than those for assessments of skills as the outcome. Relationships observed in small (single and double centre studies) were larger than those observed in multicentre studies. The results indicate that UKCAT scores predict performance in medical school assessments. The relationship is generally weak, although noticeably stronger for both the UKCAT total score and the verbal reasoning subtest. There is some evidence that UKCAT continues to predict performance throughout medical school. We recommend more optimal approaches to future studies. This assessment of existing evidence should assist medical/dental schools in their evaluation of selection processes.


Aberrant structural rich club organization in temporal lobe epilepsy with focal to bilateral tonic-clonic seizures.
The purpose of this study was to assess the differences of topological characteristic and rich club organization between temporal lobe epilepsy (TLE) patients with focal seizure (FS) only and those with focal to bilateral tonic-clonic seizures (FBTCS). We recruited 130 unilateral TLE patients, of which 57 patients with FS only and 73 patients with both FS and FBTCS, and 68 age- and gender-matched healthy controls (HC). Whole-brain networks were constructed based on diffusion weighted imaging data. Graph theory was applied to quantify the topological network metrics and rich club organization. Network-based statistic (NBS) analysis was administered to investigate the difference in edge-wise connectivity strength. The non-parametric permutation test was applied to evaluate the differences between groups. Benjamini-Hochberg FDR at the alpha of 5% was carried out for multiple comparations. In comparison with HC, both the FS and FBTCS group displayed a significant reduction in whole-brain connectivity strength and global efficiency. The FBTCS group showed lower connectivity strength both in the rich club and feeder connections compared to HC. The FS group had lower connectivity strength in the feeder and local connections compared to HC. NBS analysis revealed a wider range of decreased connectivity strength in the FBTCS group, involving 90% of the rich club regions, mainly affecting temporal-subcortical, frontal-parietal, and frontal-temporal lobe, the majority decreasing connections were between temporal lobe and stratum. While the decreased connectivity strength in the FS group were relatively local, involving 50% of rich club regions, mainly concentrated on the temporal-subcortical lobe. Network integration was reduced in TLE. TLE with FBTCS selectively disrupted the rich club regions, while TLE with FS only were more likely to affect the non-rich club regions, emphasizing the contribution of rich club organization to seizure generalization.


Risk factors for aseptic loosening of Müller-type straight stems: a registry-based analysis of 828 consecutive cases with a minimum follow-up of 16 years.
Background and purpose Even small differences in design variables for the femoral stem may influence the outcome of a hip arthroplasty. We performed a risk factor analysis for aseptic loosening of 4 different versions of cemented Müller-type straight stems with special emphasis on design modifications (2 shapes, MSS or SL, and 2 materials, CoNiCrMo (Co) or Ti-6Al-7Nb (Ti)). Methods We investigated 828 total hip replacements, which were followed prospectively in our in-house register. All stems were operated in the same setup, using Sulfix-6 bone cement and a second-generation cementing technique. Demographic and design-specific risk factors were analyzed using an adjusted Cox regression model. Results The 4 versions showed marked differences in 15-year stem survival with aseptic loosening as the endpoint: 94% (95% CI: 89-99) for MSS Co, 83% (CI: 75-91) for SL Co, 81% (CI: 76-87) for MSS Ti and 63% (CI: 56-71) for SL Ti. Cox regression analysis showed a relative risk (RR) for aseptic loosening of 3 (CI: 2-5) for stems made of Ti and of 2 (CI: 1-2) for the SL design. The RR for aseptic stem loosening increased to 8 (CI: 4-15) when comparing the most and the least successful designs (MSS Co and SL Ti). Interpretation Cemented Müller-type straight stems should be MSS-shaped and made of a material with high flexural strength (e.g. cobalt-chrome). The surface finish should be polished (Ra < 0.4 µm). These technical aspects combined with modern cementing techniques would improve the survival of Müller-type straight stems. This may be true for all types of cemented stems.


LINE-1 Hypomethylation Is Associated With Malignant Traits and Cell Proliferation in Lung Adenocarcinoma.
Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer. LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated. LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors. LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations.


Alterations in viability and CYP1A1 expression in SH SY5Y cell line by pollutants present in Madín Dam, Mexico.
Currently one of the problems facing global development is the availability of water. Although water is abundant the planet only a small portion is for human use and consumption. The problem is exacerbated due to different factors, mainly: meteorological phenomena, the presence of contaminants in the water and the increase in the number of inhabitants. Potential effects of pollutants not only can affect freshwater biota but also can be implicated in cancer development and neurodegenerative diseases in humans. The study was conducted in the Madín Dam, a reservoir of economic importance for the geographical area in which it is located, as well as catering to the population of nearby areas, and is a place where recreational activities such as fishing and kayaking are carried out. The aim of this study was to identify the toxic effects that the pollutants present in the water of the Madín Dam can generate on a human cell line (SH SY5Y) evaluating the cell viability and the participation of the Aril Hydrocarbon Receptor (AhR) and Pregnane X receptor (PXR) through of the expression of the CYP1A1 and CYP3A4 (canonical genes). In one of the five sites analyzed, cell viability was up to 50%, in this site a decrease in the normal expression of CYP1A1 was observed (p < 0.05) and the CYP3A4 gene was not expressed in the cells SH SY5Y. These results show that the SH SY5Y cell line is a good biomarker for assessing the human toxicity of environmental pollutants and relating it to neurodegenerative diseases.


Protection of the photosynthetic apparatus from extreme dehydration and oxidative stress in seedlings of transgenic tobacco.
A genetic program that in sunflower seeds is activated by Heat Shock transcription Factor A9 (HaHSFA9) has been analyzed in transgenic tobacco seedlings. The ectopic overexpression of the HSFA9 program protected photosynthetic membranes, which resisted extreme dehydration and oxidative stress conditions. In contrast, heat acclimation of seedlings induced thermotolerance but not resistance to the harsh stress conditions employed. The HSFA9 program was found to include the expression of plastidial small Heat Shock Proteins that accumulate only at lower abundance in heat-stressed vegetative organs. Photosystem II (PSII) maximum quantum yield was higher for transgenic seedlings than for non-transgenic seedlings, after either stress treatment. Furthermore, protection of both PSII and Photosystem I (PSI) membrane protein complexes was observed in the transgenic seedlings, leading to their survival after the stress treatments. It was also shown that the plastidial D1 protein, a labile component of the PSII reaction center, and the PSI core protein PsaB were shielded from oxidative damage and degradation. We infer that natural expression of the HSFA9 program during embryogenesis may protect seed pro-plastids from developmental desiccation.


Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives.
Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.


Risk factors associated with physical and mental distress in people who report a COPD diagnosis: latent class analysis of 2016 behavioral risk factor surveillance system data.
Challenges associated with COPD increase patients' risk of physical immobility and emotional distress, perpetuating a cycle of symptomatic living that hinders patients' self-management and adherence to a treatment regimen. There is limited evidence available on how discrete behavioral and health risk factors contribute to the physical and mental distress experienced by people living with COPD. This secondary data analysis of 2016 Behavioral Risk Factor Surveillance System (BRFSS) sought to identify subgroups of people with COPD who were at the highest risk for physical and mental distress. We selected 16 relevant risk indicators in four health-related domains - 1) health risk behaviors, 2) lack of preventive vaccinations, 3) limited health care access, and 4) comorbidities - as predictors of physical and mental health-related quality of life (HRQoL) in the COPD population. Latent class modeling (LCM) was applied to understand how various health-related indicators in these four health domains influenced reports of physical and/or mental distress. The majority of BRFSS respondents who reported a COPD diagnosis experienced physical (53.76%) and/or mental (58.23%) distress in the past 14 days. Frequent physical and mental distress were more common in females with COPD in the 45-64 years age group, who were also identified as white and in the lower socioeconomic group. Respondents with intermediate- to high-risk behaviors, intermediate to multiple comorbidities, limited access to health care, and intermediate to low use of preventive vaccinations were more likely to report frequent physical distress compared to the low-risk respondents. Similarly, respondents with high-risk behaviors, intermediate to multiple comorbidities, and low use of preventive vaccinations were more likely to report frequent mental distress than the low-risk group. This analysis of updated 2016 BRFSS data identified high-risk Americans with COPD who could benefit from disease management and secondary/tertiary health promotion interventions that may improve HRQoL. Future research should address noted disparities in risk factors, particularly among low socioeconomic populations living with COPD.


Metastatic myoepithelioma of the breast.
Myoepitheliomas are typically benign tumours arising from exocrine glands. There have only been five reports of malignant myoepitheliomas from breast origin previously published in the English literature. This report describes a patient with myoepithelioma arising in the breast which later metastasized despite the primary tumour having benign histological features. Impaired immune function due to end-stage renal failure and haemodialysis may have contributed to the malignant potential of her tumour. The literature regarding myoepithelial tumours is reviewed. All breast myoepitheliomas should be managed as potentially malignant tumours with appropriate surgical clearance and staging.


Evidence that poly(ADP-ribose) polymerase is involved in the loss of NAD from cultured rat liver cells.
Rat hepatocytes cultured from 24h lose 60% of their NAD content. By using the differential response to inhibitors of the two major enzymes that catabolize NAD in mammalian cells, it is shown that poly(ADP-ribose) polymerase is responsible for the loss of NAD. The relevance of this observation to the use of cultured hepatocytes for the study of DNA repair induced by carcinogens is discussed.


Fast image transforms using diophantine methods.
Many image transformations in computer vision and graphics involve a pipeline when an initial integer image is processed with floating point computations for purposes of symbolic information. Traditionally, in the interests of time, the floating point computation is approximated by integer computations where the integerization process requires a guess of an integer. Examples of this phenomenon include the discretization interval of rho and theta in the accumulator array in classical Hough transform, and in geometric manipulation of images (e.g., rotation, where a new grid is overlaid on the image). The result of incorrect discretization is a poor quality visual image, or worse, hampers measurements of critical parameters such as density or length in high fidelity machine vision. Correction techniques include, at best, anti-aliasing methods, or more commonly, a "kludge" to cleanup. In this paper, we present a method that uses the theory of basis reduction in Diophantine approximations; the method outperforms prior integer based computation without sacrificing accuracy (subject to machine epsilon).


Layer-by-layer assembly for rapid fabrication of thick polymeric films.
In the past two decades, layer-by-layer (LbL) assembly has been proven to be a convenient and versatile method to fabricate functional films. However, using traditional dipping LbL assembly to fabricate micrometer-thick films is time consuming. Compared with ultrathin films, micrometer-thick films prepared by LbL assembly possess enhanced mechanical stability, and allow deposition of a significantly increased amount of materials and the integration of multiple functions. These merits of thick films produced by LbL assembly can result in new functions and allow the functions of ultrathin films fabricated by LbL assembly to be optimized. In this tutorial review, the methods for rapid fabrication of thick polymeric films involving LbL assembly are reviewed. The functions of such films that are relevant to their micrometer thickness are discussed.


Population structure of Macrobrachium australiense (Decapoda: Palaemonidae) in Western Queensland, Australia: the role of contemporary and historical processes.
Rivers of Western Queensland, Australia, represent a discontinuous and variable aquatic habitat for the freshwater fauna of the region. Rivers periodically fluctuate between being highly fragmented, with numerous disconnected waterholes and ephemeral channels, and being highly connected by a dominant system of anastomosing channels. We used mitochondrial sequences to investigate the genetic structure and inferred patterns of dispersal associated with this flow regime for the freshwater prawn, Macrobrachium australiense (Decapoda: Palaemonidae), sampling 28 localities throughout eight catchments. Based on a 505 base pair fragment of mitochondrial cytochrome c oxidase subunit I, we identified 98 haplotypes in a sample of 402 individuals. The haplotypes clustered into two main clades corresponding geographically to the major drainages: the Lake Eyre and Murray-Darling basins. Populations of M. australiense inhabiting the two basins appear to have diverged around 800,000 years ago (estimated sequence divergence of 1.6%). Analysis of population differentiation indicated contemporary high levels of genetic subdivision and restricted gene flow among populations within and among catchments. Phylogenetic analysis detected a series of historical range expansions in the region and we suggest that climate fluctuations during the Pleistocene have resulted in extensive floods that have promoted historical movements of aquatic organisms across catchment boundaries.


Near-specular acoustic scattering from a buried submarine mud volcano.
Submarine mud volcanoes are objects that form on the seafloor due to the emission of gas and fluidized sediment from the Earth's interior. They vary widely in size, can be exposed or buried, and are of interest to the underwater acoustics community as potential sources of active sonar clutter. Coincident seismic reflection data and low frequency bistatic scattering data were gathered from one such buried mud volcano located in the Straits of Sicily. The bistatic data were generated using a pulsed piston source and a 64-element horizontal array, both towed over the top of the volcano. The purpose of this work was to appropriately model low frequency scattering from the volcano using the bistatic returns, seismic bathymetry, and knowledge of the general geoacoustic properties of the area's seabed to guide understanding and model development. Ray theory, with some approximations, was used to model acoustic propagation through overlying layers. Due to the volcano's size, scattering was modeled using geometric acoustics and a simple representation of volcano shape. Modeled bistatic data compared relatively well with experimental data, although some features remain unexplained. Results of an inversion for the volcano's reflection coefficient indicate that it may be acoustically softer than expected.


Efficient Aflatoxin B1 Sequestration by Yeast Cell Wall Extract and Hydrated Sodium Calcium Aluminosilicate Evaluated Using a Multimodal In-Vitro and Ex-Vivo Methodology.
In this work, adsorption of the carcinogenic mycotoxin aflatoxin B1 (AFB1) by two sequestrants-a yeast cell wall-based adsorbent (YCW) and a hydrated sodium calcium aluminosilicate (HSCAS)-was studied across four laboratory models: (1) an in vitro model from a reference method was employed to quantify the sorption capabilities of both sequestrants under buffer conditions at two pH values using liquid chromatography with fluorescence detection (LC-FLD); (2) in a second in vitro model, the influence of the upper gastrointestinal environment on the mycotoxin sorption capacity of the same two sequestrants was studied using a chronic AFB1 level commonly encountered in the field (10 µg/L and in the presence of feed); (3) the third model used a novel ex vivo approach to measure the absorption of 3H-labelled AFB1 in the intestinal tissue and the ability of the sequestrants to offset this process; and (4) a second previously developed ex vivo model readapted to AFB1 was used to measure the transfer of 3H-labelled AFB1 through live intestinal tissue, and the influence of sequestrants on its bioavailability by means of an Ussing chamber system. Despite some sorption effects caused by the feed itself studied in the second model, both in vitro models established that the adsorption capacity of both YCW and HSCAS is promoted at a low acidic pH. Ex vivo Models 3 and 4 showed that the same tested material formed a protective barrier on the epithelial mucosa and that they significantly reduced the transfer of AFB1 through live intestinal tissue. The results indicate that, by reducing the transmembrane transfer rate and reducing over 60% of the concentration of free AFB1, both products are able to significantly limit the bioavailability of AFB1. Moreover, there were limited differences between YCW and HSCAS in their sorption capacities. The inclusion of YCW in the dietary ration could have a positive influence in reducing AFB1's physiological bioavailability.


Ultrasonic scanning of the pancreas.
The use of ultrasonic scanning in diagnosis of pancreatic disease is reviewed. A procedure for the examination of the pancreas with a compound scanning technique and the ultrasonic appearance of the normal and diseased pancreas is described. Diffuse or localized enlargement can be demonstrated and the latter be differentiated as to whether it is solid or cystic lesion. Percutaneous fine needle aspiration biopsy of solid lesions and percutaneous puncture of cysts can be performed with great accuracy under the guidance of ultrasound. Differential diagnosis and liminations in pancreatic scanning are discussed.


The influence of nutritional factors on prostate cancer incidence and aggressiveness.
There is an increasing evidence for a link between nutrition, lifestyle and prostate cancer (PCa) development and/or progression of disease. The objective of this study was to examine the association between dietary factors and PCa incidence and aggressiveness in a case-control study. After the analysis of the anatomic pathology, subjects were classified in patients with PCa (n = 157) and controls (n = 158). Clinical data including Gleason score, PSA values and biopsy results, were compiled. Frequencies of food consumption and sociodemographic data were also obtained. The results showed that physical activity was significantly higher in control (p < .022). It was also found that some nutritional habits offer a protective effect among studied subjects, like high nuts (p = .041) and fish (p = .041) intakes. Moreover, there was a significant reduction in risk (p = .029) in cases with a higher fruits and vegetables intakes. A decreased risk of aggressive PCa was associated with fruits, vegetables, legumes and fish intakes. However, these relationships were not statistically significant when data were adjusted for covariates. In conclusion, this study found an inverse association between PCa risk and the intake of fruits and vegetables, fish and nuts. The results suggested that a diet with higher intakes of these foods as Mediterranean diet may lower the risk of PCa in the studied population. As dietary factors are modifiable, identifying food groups or dietary patterns that modulate the risk of PCa and its aggressiveness can offer effective and practical strategies for its primary prevention.


Diagnostics and prognostics of inflammatory bowel disease with fecal neutrophil-derived biomarkers calprotectin and lactoferrin.
Crohn's disease (CD), ulcerative colitis (UC), and colitis unclassified, collectively defined as inflammatory bowel disease (IBD), are the consequence of chronic inflammatory reactions in the gastrointestinal tissue. Endoscopy with biopsies is the mainstay in the diagnosis of this inflammation and is also important in the assessment of disease activity and monitoring of treatment. Furthermore, mucosal healing is increasingly becoming a therapeutic target for treatment of IBD and the golden standard of assessing it is endoscopy. However, due to the costs, invasiveness, and to limited endoscopic capacity, the need is strong for reliable surrogate markers of intestinal inflammation. Bowel contents, being in close contact with intestinal mucosa, can take up molecules that are measurable from stool samples and thus can serve as markers of inflammation. The fecal neutrophil-derived biomarkers, especially calprotectin and lactoferrin, have several features of an ideal test for detecting intestinal inflammation: they are noninvasive, simple, and low in cost. The utility of these biomarkers in distinguishing IBD from noninflammatory conditions such as irritable bowel syndrome is well documented. They correlate closely with endoscopic activity both in CD and UC. They allow serial monitoring of disease activity and of treatment success, and can even serve in predicting clinical relapse in unsymptomatic patients or sustained remission after induction with TNF-α-blocking agents. In this review an overview will be given to the role of fecal neutrophil-derived biomarkers calprotectin and lactoferrin in diagnostics and prognostics of IBD.