Sustained Dorzolamide Release Prevents Axonal and Retinal Ganglion Cell Loss in a Rat Model of IOP-Glaucoma.
To determine if one injection of a sustained release formulation of dorzolamide in biodegradable microparticles (DPP) reduces retinal ganglion cell (RGC) loss in a rat model of glaucoma. We injected either DPP or control microparticles intravitreally in rats. Two days later, unilateral ocular hypertension was induced by translimbal, diode laser treatment by a surgeon masked to treatment group. IOP and clinical exams were performed until sacrifice 6 weeks after laser treatment. RGC loss was measured by masked observers in both optic nerve cross-sections and RGC layer counts from retinal whole mounts. Cumulative IOP exposure was significantly reduced by DPP injection (49 ± 48 mm Hg × days in treated versus 227 ± 191 mm Hg × days in control microparticle eyes; P = 0.012, t-test). While control-injected eyes increased in axial length by 2.4 ± 1.7%, DPP eyes did not significantly enlarge (0.3 ± 2.2%, difference from control, P = 0.03, t-test). RGC loss was significantly less in DPP eyes compared with control microparticle injection alone (RGC axon count reduction: 21% vs. 52%; RGC body reduction: 25% vs. 50% [beta tubulin labeling]; P = 0.02, t-test). A single injection of sustained release DPP protected against RGC loss and axial elongation in a rat model of IOP glaucoma. Sustained release IOP-lowering medications have the potential to stop glaucoma progression.


A digital workflow for design and fabrication of bespoke orthoses using 3D scanning and 3D printing, a patient-based case study.
This study demonstrates the development and application of a novel workflow for designing and fabricating orthoses, using a combination of 3D scanning and 3D printing technologies. The workflow is applied to a clinically relevant translational case study in a patient with a neurological disorder and complex clinical needs. All traditional and commercial approaches to helping the patient's cervical instability and resulting 'head-drop' had previously failed, with associated progressive deterioration in the patient's clinical state and posture. The workflow was developed to design and fabricate a bespoke device for this patient with no viable alternative therapy. The workflow was developed to generate 3D printable geometry from obtained 3D scan data. The workflow includes algorithms to relax geometry, distribute material efficiently and for variational cutting of orthosis padding material. The 3D patient scan was validated against actual measurements to ensure accuracy of measurements. A total of four prototypes were produced with each iteration being improved based on patient and clinical feedback. There was a progressive improvement in subjective feedback through each iteration at sites of discomfort and overall comfort score. There was a marked improvement in the patient's posture with correction at the cervical and lumbar spine with the 3D-printed padded collar being worn for 4 hour periods. This study has implications for the rapid production of personalised orthoses which can help reduce patient waiting time, improve patient compliance, reduce pain and reduce further deterioration. The workflow could form the basis for an integrated process, whereby a single hospital visit results in a bespoke orthosis optimised and personalised for each patient.


Microglia Receptors in Animal Models of Traumatic Brain Injury.
Microglia have been implicated as a key mediator of chronic inflammation following traumatic brain injury (TBI). The animal models of TBI vary significantly based on the type of brain injury (focal versus diffuse). This has made it extremely difficult to assess the role of microglia and the window of microglia activation. Hence, the focus of this review is to summarize the time course of microglia activation in various animal models of TBI. The review explores the repertoire of secondary injury mechanisms such as aberrant neurotransmitter release, oxidative stress, blood-brain barrier disruption, and production of pro-inflammatory cytokines that follow microglia activation. Since receptors act as sensors for activation, we highlight certain microglia receptors that have been implicated in TBI pathology, including fractalkine receptor (CX3CR1), purinergic receptor (P2Y12R), Toll-like receptor (TLR4), scavenger receptors, tumor necrosis factor receptor (TNF-1R), interleukin receptor (IL-1R), complement receptors, and peroxisome proliferator-activated receptor (PPAR). In addition to describing their downstream signaling pathways in TBI, we describe the functional consequences of their activation and the implication in behavioral outcomes. Taken together, this review will provide a holistic view of the role of microglia and its receptors in TBI based on animal studies.


Comparative analysis of radiative transfer approaches for calculation of diffuse reflectance of plane-parallel light-scattering layers.
We present an analysis of a number of different approximations for the diffuse reflectance (spherical and plane albedo) of a semi-infinite, unbounded, plane-parallel, and optically homogeneous layer. The maximally wide optical conditions (from full absorption to full scattering and from fully forward to fully backward scattering) at collimated, diffuse, and combined illumination conditions were considered. The approximations were analyzed from the point of view of their physical limitations and compared to the numerical radiative transfer solutions, whenever it was possible. The main factors impacting the spherical and plane albedo were revealed for the known and unknown scattering phase functions. The main criterion for inclusion of the models in analysis was the possibility of practical use, i.e., approximations were well parameterized and only included easily measured or estimated parameters. We give a detailed analysis of errors for different models. An algorithm for recalculation of results under combined (direct and diffuse) illumination also has been developed.


Investigating brain response to music: a comparison of different fMRI acquisition schemes.
Functional magnetic resonance imaging (fMRI) in auditory experiments is a challenge, because the scanning procedure produces considerable noise that can interfere with the auditory paradigm. The noise might either mask the auditory material presented, or interfere with stimuli designed to evoke emotions because it sounds loud and rather unpleasant. Therefore, scanning paradigms that allow interleaved auditory stimulation and image acquisition appear to be advantageous. The sparse temporal sampling (STS) technique uses a very long repetition time in order to achieve a stimulus presentation in the absence of scanner noise. Although only relatively few volumes are acquired for the resulting data sets, there have been recent studies where this method has furthered remarkable results. A new development is the interleaved silent steady state (ISSS) technique. Compared with STS, this method is capable of acquiring several volumes in the time frame between the auditory trials (while the magnetization is kept in a steady state during stimulus presentation). In order to draw conclusions about the optimum fMRI procedure with auditory stimulation, different echo-planar imaging (EPI) acquisition schemes were compared: Continuous scanning, STS, and ISSS. The total acquisition time of each sequence was adjusted to about 12.5 min. The results indicate that the ISSS approach exhibits the highest sensitivity in detecting subtle activity in sub-cortical brain regions.


Treatment of lymphocele in renal allograft recipients.
Retroperitoneal lymphoceles developed in 12 renal allograft recipients during the last nine years. The interval between transplantation and the development of symptoms averaged seven months. The specific syndrome suggesting the presence of a lymphocele included lower abdominal swelling, weight gain, and, occasionally, fever without an obvious source of infection. Although these symptoms mimicked allograft rejection, diagnosis was easily made by ultrasound and intravenous pyelogram. Surgical marsupialization of the lymphocele with drainage into the peritoneal cavity proved to be an effective treatment.


Chronic fatigue syndrome: la bête noire of the Belgian health care system.
The World Health Organization acknowledges Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) to be a medical illness. ME/CFS is characterized by disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways. In 2002, the Belgian government started with the development of CFS "Reference Centers", which implement a "psychosocial" model. The medical practices of these CFS Centers are defined by the Superior Health Council, e.g. treatment should be based upon Cognitive Behavioral Therapy (CBT) and Graded Exercise Therapy (GET); and biological assessments and treatments of ME/CFS should not be employed. Recently, the Belgian government has evaluated the outcome of the treatments at the CFS Centers. They concluded that a "rehabilitation therapy" with CBT/GET yielded no significant efficacy in the treatment of ME/CFS and that CBT/GET cannot be considered to be curative therapies. In case reports, we have shown that patients who were "treated" at those CFS centers with CBT/GET in fact suffered from IO&NS disorders, including intracellular inflammation, an increased translocation of gram-negative enterobacteria (leaky gut), autoimmune reactions and damage by O&NS. Considering the fact that these findings are exemplary for ME/CFS patients and that GET may even be harmful, it means that many patients are maltreated by the Belgian CFS Centers. Notwithstanding the above, the government and the CFS Centers not only continue this unethical and immoral policy, but also reinforce their use of CBT/GET in patients with ME/CFS treated at those Centers.


Distribution of the transposable elements bilbo and gypsy in original and colonizing populations of Drosophila subobscura.
Transposable elements (TEs) constitute a substantial amount of all eukaryotic genomes. They induce an important proportion of deleterious mutations by insertion into genes or gene regulatory regions. However, their mutational capabilities are not always adverse but can contribute to the genetic diversity and evolution of organisms. Knowledge of their distribution and activity in the genomes of populations under different environmental and demographic regimes, is important to understand their role in species evolution. In this work we study the chromosomal distribution of two TEs, gypsy and bilbo, in original and colonizing populations of Drosophila subobscura to reveal the putative effect of colonization on their insertion profile. Chromosomal frequency distribution of two TEs in one original and three colonizing populations of D. subobscura, is different. Whereas the original population shows a low insertion frequency in most TE sites, colonizing populations have a mixture of high (frequency > or = 10%) and low insertion sites for both TEs. Most highly occupied sites are coincident among colonizing populations and some of them are correlated to chromosomal arrangements. Comparisons of TE copy number between the X chromosome and autosomes show that gypsy occupancy seems to be controlled by negative selection, but bilbo one does not. These results are in accordance that TEs in Drosophila subobscura colonizing populations are submitted to a founder effect followed by genetic drift as a consequence of colonization. This would explain the high insertion frequencies of bilbo and gypsy in coincident sites of colonizing populations. High occupancy sites would represent insertion events prior to colonization. Sites of low frequency would be insertions that occurred after colonization and/or copies from the original population whose frequency is decreasing in colonizing populations. This work is a pioneer attempt to explain the chromosomal distribution of TEs in a colonizing species with high inversion polymorphism to reveal the putative effect of arrangements in TE insertion profiles. In general no associations between arrangements and TE have been found, except in a few cases where the association is very strong. Alternatively, founder drift effects, seem to play a leading role in TE genome distribution in colonizing populations.


A motion illusion reveals mechanisms of perceptual stabilization.
Visual illusions are valuable tools for the scientific examination of the mechanisms underlying perception. In the peripheral drift illusion special drift patterns appear to move although they are static. During fixation small involuntary eye movements generate retinal image slips which need to be suppressed for stable perception. Here we show that the peripheral drift illusion reveals the mechanisms of perceptual stabilization associated with these micromovements. In a series of experiments we found that illusory motion was only observed in the peripheral visual field. The strength of illusory motion varied with the degree of micromovements. However, drift patterns presented in the central (but not the peripheral) visual field modulated the strength of illusory peripheral motion. Moreover, although central drift patterns were not perceived as moving, they elicited illusory motion of neutral peripheral patterns. Central drift patterns modulated illusory peripheral motion even when micromovements remained constant. Interestingly, perceptual stabilization was only affected by static drift patterns, but not by real motion signals. Our findings suggest that perceptual instabilities caused by fixational eye movements are corrected by a mechanism that relies on visual rather than extraretinal (proprioceptive or motor) signals, and that drift patterns systematically bias this compensatory mechanism. These mechanisms may be revealed by utilizing static visual patterns that give rise to the peripheral drift illusion, but remain undetected with other patterns. Accordingly, the peripheral drift illusion is of unique value for examining processes of perceptual stabilization.


[Personality disorders in older adults: a Delphi-study conducted among Dutch and Belgian experts concerning specific diagnostic and therapeutic aspects].
In psychiatry for older adults (> 60 years) personality disorders play an important part in diagnosis and treatment and in the advice given to health professionals and carers on how to deal with this age group. So far, however, research in this area has been inadequate. To investigate age-related diagnostic and therapeutic aspects of personality disorders occurring in adults over the age of 60. A Delphi-study was conducted among 35 Dutch and Belgian experts in the field of personality disorders in older adults. This multidisciplinary panel consisted of psychiatrists, psychologists, psychotherapists, geriatricians and psychiatric nurses. In four rounds 21 gerontological statements to be assessed on a 5-point Likert scale were presented to the panel of experts. Agreement was said to be reached when at least two thirds of the experts agreed or fully agreed with a statement.RESULTS Satisfactory agreement was reached in the case of 20 of the 21 diagnostic and/or therapeutic statements about older adults with personality disorders. CONCLUSION There seem to be various age-specific aspects in the diagnosis and treatment of personality disorders in older adults. Therefore, it is advisable to pay more attention to this highly complex group of older adults when guidelines and protocols are being drawn up and scientific research is being planned or conducted.


CrossCheck: Integrating self-report, behavioral sensing, and smartphone use to identify digital indicators of psychotic relapse.
This purpose of this study was to describe and demonstrate CrossCheck, a multimodal data collection system designed to aid in continuous remote monitoring and identification of subjective and objective indicators of psychotic relapse. Individuals with schizophrenia-spectrum disorders received a smartphone with the monitoring system installed along with unlimited data plan for 12 months. Participants were instructed to carry the device with them and to complete brief self-reports multiple times a week. Multimodal behavioral sensing (i.e., physical activity, geospatials activity, speech frequency, and duration) and device use data (i.e., call and text activity, app use) were captured automatically. Five individuals who experienced psychiatric hospitalization were selected and described for instructive purposes. Participants had unique digital indicators of their psychotic relapse. For some, self-reports provided clear and potentially actionable description of symptom exacerbation prior to hospitalization. Others had behavioral sensing data trends (e.g., shifts in geolocation patterns, declines in physical activity) or device use patterns (e.g., increased nighttime app use, discontinuation of all smartphone use) that reflected the changes they experienced more effectively. Advancements in mobile technology are enabling collection of an abundance of information that until recently was largely inaccessible to clinical research and practice. However, remote monitoring and relapse detection is in its nascence. Development and evaluation of innovative data management, modeling, and signal-detection techniques that can identify changes within an individual over time (i.e., unique relapse signatures) will be essential if we are to capitalize on these data to improve treatment and prevention. (PsycINFO Database Record


Update on limbal stem cell transplantation.
Limbal epithelial stem cells are the primary source of corneal epithelial cell regeneration. Limbal stem cell deficiency (LSCD) can develop in traumatic, immunologic, or genetic diseases that affect the ocular surface. LSCD leads to conjunctivalization, with corneal vascularization and opacification and subsequent loss of vision. Limbal stem cell transplantation is a surgical treatment to address LSCD and restore a corneal epithelial phenotype. Based on the source of cells, limbal transplant can be autologous or allogenic. Many surgical techniques are defined according to the source of the stem cells and the carrier tissues that are used. More recently, ex vivo expanded bioengineered epithelial cells have been used to reconstruct the corneal surface using autologous cells to eliminate the risk of rejection. Before transplantation, a systematic exam of the lids, eyelashes, fornices, and aqueous tears is mandatory and every effort should be made to optimize ocular surface health and control inflammation to enhance the chances of graft survival. Postoperative care is also another major determinant of success. Any factor that destabilizes the ocular surface needs to be addressed. In addition, systemic and topical immunosuppressants are also needed in all allograft recipients. In addition to pre-operative and postoperative care and the surgery itself, the etiology of LSCD also has an impact on the outcome. The prognosis of inflammatory diseases such as Stevens-Johnson syndrome is the worst among disorders causing LSCD.


Would school closure for the 2009 H1N1 influenza epidemic have been worth the cost?: a computational simulation of Pennsylvania.
During the 2009 H1N1 influenza epidemic, policy makers debated over whether, when, and how long to close schools. While closing schools could have reduced influenza transmission thereby preventing cases, deaths, and health care costs, it may also have incurred substantial costs from increased childcare needs and lost productivity by teachers and other school employees. A combination of agent-based and Monte Carlo economic simulation modeling was used to determine the cost-benefit of closing schools (vs. not closing schools) for different durations (range: 1 to 8 weeks) and symptomatic case incidence triggers (range: 1 to 30) for the state of Pennsylvania during the 2009 H1N1 epidemic. Different scenarios varied the basic reproductive rate (R(0)) from 1.2, 1.6, to 2.0 and used case-hospitalization and case-fatality rates from the 2009 epidemic. Additional analyses determined the cost per influenza case averted of implementing school closure. For all scenarios explored, closing schools resulted in substantially higher net costs than not closing schools. For R(0) = 1.2, 1.6, and 2.0 epidemics, closing schools for 8 weeks would have resulted in median net costs of $21.0 billion (95% Range: $8.0 - $45.3 billion). The median cost per influenza case averted would have been $14,185 ($5,423 - $30,565) for R(0) = 1.2, $25,253 ($9,501 - $53,461) for R(0) = 1.6, and $23,483 ($8,870 - $50,926) for R(0) = 2.0. Our study suggests that closing schools during the 2009 H1N1 epidemic could have resulted in substantial costs to society as the potential costs of lost productivity and childcare could have far outweighed the cost savings in preventing influenza cases.


Application of cognitive rehabilitation theory to the development of smart prompting technologies.
Older adults with cognitive impairments often have difficulty performing instrumental activities of daily living (IADLs). Prompting technologies have gained popularity over the last decade and have the potential to assist these individuals with IADLs in order to live independently. Although prompting techniques are routinely used by caregivers and health care providers to aid individuals with cognitive impairment in maintaining their independence with everyday activities, there is no clear consensus or gold standard regarding prompt content, method of instruction, timing of delivery, or interface of prompt delivery in the gerontology or technology literatures. In this paper, we demonstrate how cognitive rehabilitation principles can inform and advance the development of more effective assistive prompting technologies that could be employed in smart environments. We first describe cognitive rehabilitation theory (CRT) and show how it provides a useful theoretical foundation for guiding the development of assistive technologies for IADL completion. We then use the CRT framework to critically review existing smart prompting technologies to answer questions that will be integral to advancing development of effective smart prompting technologies. Finally, we raise questions for future exploration as well as challenges and suggestions for future directions in this area of research.


Positive association between conflicts of interest and reporting of positive results in randomized clinical trials in dentistry.
The relationship between industry funding and study results has been explored widely in medicine but not in dentistry. The authors aimed to assess the relationship between conflicts of interest (COIs) and study results. The authors assessed all randomized clinical trials (RCTs) published between July 2010 and June 2012 in the 10 dental journals with the highest impact factors in dentistry. The authors used three definitions of COI and explored their associations with positive study results. Depending on the definition of COI, the odds ratio for reporting positive results varied between 2.40 (95 percent confidence interval [CI], 1.16-5.13) and 9.19 (95 percent CI, 1.71-170.64). The authors found no association between positive study results and journal of publication or area of practice. RCTs in which authors have some type of COI are more likely to have results that support the intervention being assessed. When reviewing the results of RCTs, clinicians need to be aware of the association between reporting positive study results and the type of COI disclosure and be even more careful when critically appraising and applying their results.


Enhancement of Hippocampal CA3 Neuronal Dendritic Arborization by Glycyrrhiza glabra root extract Treatment in Wistar Albino Rats.
In the traditional system of medicine, the roots and rhizomes of Glycyrrhiza glabra (Gg) (family: Leguminosae) have been in clinical use for centuries. In the present study, we investigated the role of aqueous extract of root of Gg treatment on the dendritic morphology of hippocampal Cornu Ammonis area three (CA3) neurons, one of the regions concerned with learning and memory, in 1- month- old male Wistar albino rats. The aqueous extract of root of Gg was administered orally in four doses (75, 150, 225 and 300 mg/kg) for 4 weeks. After the treatment period, all experimental animals were subjected to spatial learning (Morris water maze, Hebb-William's maze and elevated plus maze) tests. At the end of the spatial memory tests, the rats were deeply anesthetized with Pentobarbitone and killed their brains were removed rapidly and fixed in rapid Golgi fixative. Hippocampal CA3 neurons were traced using camera lucida, and dendritic arborization and intersections were quantified. These data were compared to those of age-matched control rats. The aqueous root extract of Gg in the dose of 150 and 225 mg/kg/p.o showed a significant (P < 0.01) enhancement of dendritic arborization (dendritic branching points) and dendritic intersections along the length of both apical and basal dendrites in hippocampal (CA3) pyramidal neurons is comparable to control. Based on our results obtained, we conclude that constituents present in aqueous root extract of Gg have neuronal dendritic growth stimulating properties.


Evaluation of diagnosis techniques used for spinal injury related back pain.
Back pain is a prevalent condition affecting much of the population at one time or the other. Complications, including neurological ones, can result from missed or mismanaged spinal abnormalities. These complications often result in serious patient injury and require more medical treatment. Correct diagnosis enables more effective, often less costly treatment methods. Current diagnosis technologies focus on spinal alterations. Only approximately 10% of back pain is diagnosable, with current diagnostic technologies. The objective of this paper is to investigate and evaluate based on specific criteria current diagnosis technique. Nine diagnostic techniques were found in the literature, namely, discography, myelography, single photon emission computer tomography (SPECT), computer tomography (CT), combined CT & SPECT, magnetic resonance imaging (MRI), upright and kinematic MRI, plain radiography and cineradiography. Upon review of the techniques, it is suggested that improvements can be made to all the existing techniques for diagnosing back pain. This review will aid health service developers to focus on insufficient areas, which will help to improve existing technologies or even develop alternative ones.


High-Intensity Drinking in Adult Australian Twins.
Many adult drinkers consume far beyond the binge threshold. This "high-intensity drinking" (HID), defined as 2 (HID-2) and 3 (HID-3) times the binge threshold, is of public health interest due to its role in acute alcohol-related harms. Research on HID has mostly been limited to college-aged young adults, focused on contextual factors, and neglected the potential role of genetic influences on the propensity to engage in HID. Structured diagnostic interviews assessing past-year alcohol involvement were conducted with 3,785 individuals (1,365 men, 2,420 women; Mage = 32, range = 21 to 46), including 3,314 twins and 471 nontwin siblings from the Australian Twin Registry. Multinomial logistic regression analyses were conducted to compare HID-2 and HID-3 to binge drinking on demographic correlates, drinking characteristics, and drinking-related consequences. Biometric modeling was conducted to estimate the role of genetic, common, and individual-specific environmental factors in HID propensity. Among past-year drinkers, the prevalence of HID-2 and HID-3 was both 22%, with men disproportionally represented. The frequencies of drinking, intoxication, and binge drinking significantly increased across the heavier drinking categories, which also evidenced higher average consumption quantities and higher rates of alcohol-related consequences. The propensity to engage in HID was significantly heritable (A = 37% [95% CI: 28 to 46%]), with individual-specific environmental influences accounting for the remainder of the variance. This study convincingly demonstrates that HID is not restricted to college-aged young adults, but also can be highly prevalent among those of working age, and that the propensity to engage in HID is partially explained by genetic influences.


Recent outbreaks of foot and mouth disease in countries of east Asia.
Japan regained the status of freedom from foot and mouth disease (FMD) without vaccination in September 2000 and the Republic of Korea likewise obtained this status in September 2001. However, new outbreaks of FMD caused by the pan-Asian topotype have occurred in pigs in the Republic of Korea since May 2002. Taipei China has not experienced an outbreak of FMD since February 2001 and the country is currently implementing an eradication programme. These countries had been free from FMD for many decades when in 1997, the FMD virus (FMDV) once again invaded the region, particularly in 2000; this resulted in widespread occurrence of the disease. The types of FMDV were investigated by genome analysis, and in each case the virus concerned was found to be a member of the pan-Asian O lineage. The authors present the recent situations and the characteristics of FMD in countries of east Asia.


The mechanism of activation of hormone-sensitive lipase in human adipose tissue.
A partially purified hormone-sensitive triglyceride lipase of human adipose tissue was found to be activated twofold by the addition of cyclic 3',5'-AMP, ATP, and magnesium ions. Lipase activities against diolein and monoolein were not affected. Addition of protein kinase inhibitor at zero time completely inhibited activation, and this inhibition was prevented by prior addition of an excess of exogenous protein kinase (from rabbit skeletal muscle). Addition of protein kinase inhibitor during the activation step blocked the activation process without a time lag, suggesting that protein kinase operates directly on hormone-sensitive lipase. Further purification yielded a fraction free of protein kinase, and lipase activation in this fraction depended absolutely on addition of exogenous kinase. Incubation of human fat with epinephrine or isoproterenol stimulated lipolysis and caused conversion of nonactivated hormone-sensitive lipase to its activated form, as indicated by a decrease in the activation subsequently obtainable in fractions prepared from such hormone-treated tissues. These findings strongly suggest that the stimulation of lipolysis by hormonal treatment is the consequence of the activation of hormone-sensitive triglyceride lipase by cyclic 3',5'-AMP-dependent protein kinase.


Enzymatic markers of gallstone-induced pancreatitis identified by ROC curve analysis, discriminant analysis, logistic regression, likelihood ratios, and information theory.
We investigated the diagnostic utility of frequent serial determinations of aspartate aminotransferase, alanine aminotransferase (ALT), lipase, amylase, and the lipase/amylase (L/A) ratio for distinguishing patients with acute pancreatitis due to biliary obstruction from those with acute pancreatitis due to other pathogenesis. Analyzed were enzyme activities obtained at admission and peak enzyme activities identified retrospectively from serial measurements in 53 patients with acute pancreatitis due to various causes. We evaluated the data with multiple statistical tools. Discriminant analysis and logistic regression revealed the diagnostic significance of ALT at initial and peak values, and the maximum information provided by peak ALT was confirmed by both logistic regression and stratum-specific likelihood ratios. Stratum-specific likelihood ratios showed peak ALT > 150 U/L was highly diagnostic of biliary pancreatitis. The L/A ratio, either at admission or at peak, was the only other significant variable for identifying patients with acute pancreatitis due to biliary obstruction. A multivariate logistic discriminant function including ALT and the L/A ratio significantly discriminated biliary acute pancreatitis from pancreatitis due to other causes. Evaluation of initial and peak enzyme data by information theory revealed that the optimal test depended on disease prevalence. Initial ALT activities were the test of choice for identifying biliary pancreatitis, up to a disease prevalence of approximately 0.75. At disease prevalence > 0.75, the initial L/A ratio provided the greatest amount of diagnostic information.


A pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report.
The pharmacological treatment for autism spectrum disorders is often poorly tolerated and has traditionally targeted associated conditions, with limited benefit for the core social deficits. We describe the novel use of a cannabidiol-based extract that incidentally improved core social deficits and overall functioning in a patient with autism spectrum disorder, at a lower dose than has been previously reported in autism spectrum disorder. The parents of a 15-year-old boy, of South African descent, with autism spectrum disorder, selective mutism, anxiety, and controlled epilepsy, consulted a medical cannabis physician to trial cannabis extract to replace seizure medications. Incidentally, at a very low cannabidiol-based extract dose, he experienced unanticipated positive effects on behavioral symptoms and core social deficits. This case report provides evidence that a lower than previously reported dose of a phytocannabinoid in the form of a cannabidiol-based extract may be capable of aiding in autism spectrum disorder-related behavioral symptoms, core social communication abilities, and comorbid anxiety, sleep difficulties, and weight control. Further research is needed to elucidate the clinical role and underlying biological mechanisms of action of cannabidiol-based extract in patients with autism spectrum disorder.


Induction and maintenance of ethanol self-administration in cynomolgus monkeys (Macaca fascicularis): long-term characterization of sex and individual differences.
Investigations of oral ethanol self-administration in nonhuman primates have revealed important parallels with human alcohol use and abuse, yet many fundamental questions concerning the individual risk to, and the biological basis of, excessive ethanol consumption remain unanswered. Moreover, many conditions of access to ethanol in nonhuman primate research are largely unexplored. This set of experiments extends within- and across-session exposure to ethanol to more fully characterize individual differences in oral ethanol self-administration. Eight male and eight female adult cynomolgus monkeys (Macaca fascicularis) were exposed to daily oral ethanol self-administration sessions for approximately 9 months. During the first 3 months, a fixed-time (FT) schedule of food delivery was used to induce the consumption of an allotted dose of ethanol in 16-hr sessions. Subsequently, the FT schedule was suspended, and ethanol was available ad libitum for 6 months in 16- or 22-hr sessions. Cynomolgus monkeys varied greatly in their propensity to self-administer ethanol, with sex and individual differences apparent within 10 days of ethanol exposure. Over the last 3 months of ethanol access, individual average ethanol intakes ranged from 0.6 to 4.0 g/kg/day, resulting in blood ethanol concentrations from 5 to 235 mg/dl. Males drank approximately 1.5-fold more than females. In addition, heavy-, moderate-, and light-drinking phenotypes were identified by using daily ethanol intake and the percentage of daily calories obtained from ethanol as criteria. Cynomolgus monkeys displayed a wide intersubject range of oral ethanol self-administration with a procedure that used a uniform and prolonged induction that restricted early exposure to ethanol and subsequently allowed unlimited access to ethanol. There were sex and stable individual differences in the propensity of monkeys to consume ethanol, indicating that this species will be important in characterizing risk factors associated with heavy-drinking phenotypes.


A 3-in-1 perineal care washcloth impregnated with dimethicone 3% versus water and pH neutral soap to prevent and treat incontinence-associated dermatitis: a randomized, controlled clinical trial.
We compared the effectiveness of a 3-in-1 perineal care washcloth versus standard of care (water and pH neutral soap) to prevent and treat incontinence-associated dermatitis (IAD). The product under study was a soft, premoistened washcloth, including a 3% dimethicone formula, with cleansing, moisturizing, and barrier protection properties. Randomized, controlled clinical trial. The study sample comprised a random sample of 11 nursing home wards (6 experimental and 5 control) in a convenience sample of 4 nursing homes in Belgium. The sample included nursing home residents at risk for and/or affected by IAD defined as incontinent of urine, feces, urine/feces, and/or having erythema of the perineal skin (not caused by pressure/shear), and/or having an edematous skin in the genital area. Participants in the experimental group were treated according to a standardized protocol, including the use of a 3-in-1 perineal care washcloth impregnated with a 3% dimethicone skin protectant. Participants in the control group received perineal skin care with water and pH neutral soap, the standard of care in Belgian nursing homes. The study period was 120 days. Data were collected between February and May 2010. Incontinence-associated dermatitis prevalence and severity were assessed using the IAD Skin Condition Assessment Tool. The surface (cm), redness, and depth of the perineal lesion were assessed daily by the nurses. This tool generates a cumulative severity score (maximum score = 10) based on area of skin affected, degree of redness, and depth of erosion. Four hundred sixty-four nursing home residents were assessed and 32.9% (n = 141) met the criteria for inclusion, including 73 subjects in the experimental group and 68 in the control group. Baseline IAD prevalence was comparable in both groups (experimental: 22.3% vs control: 22.8%, P = .76). Baseline IAD severity was 6.9/10 in the experimental group and 7.3/10 in the control group. A significant intervention effect on IAD prevalence was found (experimental: 8.1% vs control: 27.1%, F = 3.1, P = .003). A nonsignificant effect on IAD severity could be determined (experimental: 3.8/10 vs control: 6.9/10, F = 0.8, P = .06). The use of a 3-in-1 washcloth, impregnated with a 3% dimethicone formula, resulted in a significantly reduced prevalence of IAD and a trend toward less severe lesions. These findings provide indicative evidence for the use of 3-in-1 perineal care washcloth as an effective intervention against the use of water and a pH neutral soap to prevent and/or treat IAD.


Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer.
Colorectal cancer (CRC) tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN) and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS) and is historically considered to be chromosomally unstable (CIN+). However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-). MSS CIN- tumors have not been assessed for telomere attrition. MSS rectal cancers from patients ≤50 years old with Stage II (B2 or higher) or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]). Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH. Tumors were classified as chromosomally stable (CIN-) and chromosomally instable (CIN+) by degree of DNA copy number changes. CIN- tumors (35%; n=6) had fewer copy number changes (<17% of their clones with DNA copy number changes) than CIN+ tumors (65%; n=13) which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066) and in those in which telomerase was not activated (p=0.004). Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040); and tended to be CIN+ (p=0.0949). MSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.


Ellagic acid-borax fluorescence interaction: application for novel cyclodextrin-borax nanosensors for analyzing ellagic acid in food samples.
The food industry needs cheap, fast and sensitive methods to increase the number of analyses that are routinely carried out; for this reason, new methods are constantly being sought. This paper describes a novel fluorescent nanosensor based on cyclodextrin (CD) to determine ellagic acid (EA). The encapsulation of EA in the presence of borax was studied. Firstly, the complexation of EA-borax was tested. The stoichiometry of the EA-borax complex showed a 1 : 2 complex, with KF1 = 2548 ± 127 M-1 and KF2 = 302 ± 15 M-1. Different CDs were used to obtain a 1 : 1 : 1 CD-EA-borax complex with γ-CD providing the best complexation constant (KF3 = 364 ± 18 M-1). Furthermore, when the accuracy and sensitivity of the nanosensor were tested using a crude blueberry extract, the CD/borax mixture provided an 18 times stronger signal than with the crude extract alone and 7 times stronger than that obtained using borax alone.


Collagen peptide supplementation in combination with resistance training improves body composition and increases muscle strength in elderly sarcopenic men: a randomised controlled trial.
Protein supplementation in combination with resistance training may increase muscle mass and muscle strength in elderly subjects. The objective of this study was to assess the influence of post-exercise protein supplementation with collagen peptides v. placebo on muscle mass and muscle function following resistance training in elderly subjects with sarcopenia. A total of fifty-three male subjects (72·2 (sd 4·68) years) with sarcopenia (class I or II) completed this randomised double-blind placebo-controlled study. All the participants underwent a 12-week guided resistance training programme (three sessions per week) and were supplemented with either collagen peptides (treatment group (TG)) (15 g/d) or silica as placebo (placebo group (PG)). Fat-free mass (FFM), fat mass (FM) and bone mass (BM) were measured before and after the intervention using dual-energy X-ray absorptiometry. Isokinetic quadriceps strength (IQS) of the right leg was determined and sensory motor control (SMC) was investigated by a standardised one-leg stabilisation test. Following the training programme, all the subjects showed significantly higher (P<0·01) levels for FFM, BM, IQS and SMC with significantly lower (P<0·01) levels for FM. The effect was significantly more pronounced in subjects receiving collagen peptides: FFM (TG +4·2 (sd 2·31) kg/PG +2·9 (sd 1·84) kg; P<0·05); IQS (TG +16·5 (sd 12·9) Nm/PG +7·3 (sd 13·2) Nm; P<0·05); and FM (TG -5·4 (sd 3·17) kg/PG -3·5 (sd 2·16) kg; P<0·05). Our data demonstrate that compared with placebo, collagen peptide supplementation in combination with resistance training further improved body composition by increasing FFM, muscle strength and the loss in FM.


Intracellular trafficking of Notch receptors and ligands.
The Notch pathway represents a highly conserved signaling network, which regulates the formation and maintenance of various organ systems along development and during adulthood. Direct cell-cell contacts between ligand- and receptor-expressing cells underlie activation of the Notch pathway. Notch signaling requires endocytosis in both signal emitting and receiving cells. Recent findings on the roles of a number of modulators show that they act either on the maintenance of an active receptor at the membrane, or on the production of active ligand, or on signal transduction after activation.


MPBoot: fast phylogenetic maximum parsimony tree inference and bootstrap approximation.
The nonparametric bootstrap is widely used to measure the branch support of phylogenetic trees. However, bootstrapping is computationally expensive and remains a bottleneck in phylogenetic analyses. Recently, an ultrafast bootstrap approximation (UFBoot) approach was proposed for maximum likelihood analyses. However, such an approach is still missing for maximum parsimony. To close this gap we present MPBoot, an adaptation and extension of UFBoot to compute branch supports under the maximum parsimony principle. MPBoot works for both uniform and non-uniform cost matrices. Our analyses on biological DNA and protein showed that under uniform cost matrices, MPBoot runs on average 4.7 (DNA) to 7 times (protein data) (range: 1.2-20.7) faster than the standard parsimony bootstrap implemented in PAUP*; but 1.6 (DNA) to 4.1 times (protein data) slower than the standard bootstrap with a fast search routine in TNT (fast-TNT). However, for non-uniform cost matrices MPBoot is 5 (DNA) to 13 times (protein data) (range:0.3-63.9) faster than fast-TNT. We note that MPBoot achieves better scores more frequently than PAUP* and fast-TNT. However, this effect is less pronounced if an intensive but slower search in TNT is invoked. Moreover, experiments on large-scale simulated data show that while both PAUP* and TNT bootstrap estimates are too conservative, MPBoot bootstrap estimates appear more unbiased. MPBoot provides an efficient alternative to the standard maximum parsimony bootstrap procedure. It shows favorable performance in terms of run time, the capability of finding a maximum parsimony tree, and high bootstrap accuracy on simulated as well as empirical data sets. MPBoot is easy-to-use, open-source and available at http://www.cibiv.at/software/mpboot .


Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review.
Silymarin, an extract from milk thistle seeds, has been used for centuries to treat hepatic conditions. Preclinical data indicate that silymarin can reduce oxidative stress and consequent cytotoxicity, thereby protecting intact liver cells or cells not yet irreversibly damaged. Eurosil 85® is a proprietary formulation developed to maximize the oral bioavailability of silymarin. Most of the clinical research on silymarin has used this formulation. Silymarin acts as a free radical scavenger and modulates enzymes associated with the development of cellular damage, fibrosis and cirrhosis. These hepatoprotective effects were observed in clinical studies in patients with alcoholic or non-alcoholic fatty liver disease, including patients with cirrhosis. In a pooled analysis of trials in patients with cirrhosis, silymarin treatment was associated with a significant reduction in liver-related deaths. Moreover, in patients with diabetes and alcoholic cirrhosis, silymarin was also able to improve glycemic parameters. Patients with drug-induced liver injuries were also successfully treated with silymarin. Silymarin is generally very well tolerated, with a low incidence of adverse events and no treatment-related serious adverse events or deaths reported in clinical trials. For maximum benefit, treatment with silymarin should be initiated as early as possible in patients with fatty liver disease and other distinct liver disease manifestations such as acute liver failure, when the regenerative potential of the liver is still high and when removal of oxidative stress, the cause of cytotoxicity, can achieve the best results.


Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations.
Previously, we demonstrated with the use of microsatellite markers that a 2-cM haplotype on chromosome 15q containing the fibrillin 1 gene (FBN1) was strongly associated with systemic sclerosis (SSc) in the Choctaw, a population with high SSc prevalence. In this study, all 69 known FBN1 exons were sequenced to ascertain the presence of changes that might show associations with SSc in the Choctaw and Japanese SSc patients and controls. Screening of FBN1 exons was accomplished by polymerase chain reaction-based fluorescence sequencing of genomic DNA using single-nucleotide polymorphism (SNP) haplotypes, and their frequencies were determined with a new algorithm that recognizes past recombination events between sites. Haplotype phylogenies were inferred using the median-joining network analysis. Five SNPs were identified in FBN1. They are located in the 5'-untranslated region (SNP-1), exon 15 (SNP-2), intron 17 (SNP-3), exon 27 (SNP-4), and intron 27 (SNP-5). Only SNP-1 (T-->C) demonstrated an association with SSc in the Choctaw. Eleven FBN1 SNP haplotypes were ascertained in the Choctaw population, 2 of which (SNPs 5 and 6) were found only in the SSc patients. These same FBN1 SNP haplotypes were associated with SSc in the Japanese. A SNP in the 5'-untranslated region of FBN1 (SNP-1, C allele) was strongly associated with SSc in the Choctaw. Furthermore, this polymorphism is present on 2 unique FBN1 haplotypes found only in Choctaw SSc patients. The same 2 haplotypes demonstrate associations with SSc in the Japanese. These data extend the earlier microsatellite studies and are consistent with the hypothesis that FBN1 or a nearby gene on chromosome 15q is involved in SSc susceptibility in the Choctaw and the Japanese.


Fine-scale spatial climate variation and drought mediate the likelihood of reburning.
In many forested ecosystems, it is increasingly recognized that the probability of burning is substantially reduced within the footprint of previously burned areas. This self-limiting effect of wildland fire is considered a fundamental emergent property of ecosystems and is partly responsible for structuring landscape heterogeneity (i.e., mosaics of different age classes), thereby reducing the likelihood of uncharacteristically large fires in regions with active fire regimes. However, the strength and longevity of this self-limiting phenomenon is not well understood in most fire-prone ecosystems. In this study, we quantify the self-limiting effect in terms of its strength and longevity for five fire-prone study areas in western North America and investigate how each measure varies along a spatial climatic gradient and according to temporal (i.e., annual) climatic variation. Results indicate that the longevity (i.e., number of years) of the self-limiting effect ranges between 15 yr in the warm and dry study area in the southwestern United States to 33 yr in the cold, northern study areas in located in northwestern Montana and the boreal forest of Canada. We also found that spatial climatic variation has a strong influence on wildland fire's self-limiting capacity. Specifically, the self-limiting effect within each study area was stronger and lasted longer in areas with low mean moisture deficit (i.e., wetter and cooler settings) compared to areas with high mean moisture deficit (warmer and drier settings). Last, our findings show that annual climatic variation influences wildland fire's self-limiting effect: drought conditions weakened the strength and longevity of the self-limiting effect in all study areas, albeit at varying magnitudes. Overall, our study provides support for the idea that wildland fire contributes to spatial heterogeneity in fuel ages that subsequently mediate future fire sizes and effects. However, our findings show that the strength and longevity of the self-limiting effect varies considerably according to spatial and temporal climatic variation, providing land and fire managers relevant information for effective planning and management of fire and highlighting that fire itself is an important factor contributing to fire-free intervals.


Simulations of vibrational spectra from classical trajectories: calibration with ab initio force fields.
An algorithm allowing simulating vibrational spectra from classical time-dependent trajectories was applied for infrared absorption, vibrational circular dichroism, Raman, and Raman optical activity of model harmonic systems. The implementation of the theory within the TINKER molecular dynamics (MD) program package was tested with ab initio harmonic force fields in order to determine the feasibility for more extended MD simulations. The results suggest that sufficiently accurate frequencies can be simulated with integration time steps shorter than about 0.5 fs. For a given integration time step, lower vibrational frequencies ( approximately 0-2000 cm(-1)) could be reproduced with a higher accuracy than higher-frequency vibrational modes (e.g., O-H and C-H stretching). In principle, the algorithm also provides correct intensities for ideal systems. In applied simulations, however, the intensity profiles are affected by an unrealistic energy distribution between normal modes and a slow energy relaxation. Additionally, the energy fluctuations may cause weakening of the intensities on average. For ab initio force fields, these obstacles could be overcome by an arbitrary normal mode energy correction. For general MD simulations, averaging of many shorter MD trajectories started with randomly distributed atomic velocities provided the best spectral shapes. alpha-pinene, D-gluconic acid, formaldehyde dimer, and the acetylprolineamide molecule were used in the tests.


Innate immunity mediates follicular transport of particulate but not soluble protein antigen.
Ag retention on follicular dendritic cells (FDCs) is essential for B cell activation and clonal selection within germinal centers. Protein Ag is deposited on FDCs after formation of immune complexes with specific Abs. In this study, by comparing the same antigenic determinant either as soluble protein or virus-like particle (VLP), we demonstrate that VLPs are transported efficiently to murine splenic FDCs in vivo in the absence of prior immunity. Natural IgM Abs and complement were required and sufficient to mediate capture and transport of VLPs by noncognate B cells. In contrast, soluble protein was only deposited on FDCs in the presence of specifically induced IgM or IgG Abs. Unexpectedly, IgG Abs had the opposite effect on viral particles and inhibited FDC deposition. These findings identify size and repetitive structure as critical factors for efficient Ag presentation to B cells and highlight important differences between soluble proteins and viral particles.


Aldose reductase inhibition prevents colon cancer growth by restoring phosphatase and tensin homolog through modulation of miR-21 and FOXO3a.
We have shown earlier that inhibition of aldose reductase (AR), an oxidative stress-response protein, prevents colon cancer cell growth in vitro and in vivo. Changes in microribonucleic acid (miR) expression can contribute to cancer by modulating the functional expression of critical genes involved in cancer growth and metastasis. However, the molecular mechanisms by which AR regulates miR expression and their dependent mitogenic effects in cancer cells are not known. Therefore, we investigated how AR regulates growth factor-induced expression of miRs and growth of colon cancer cells. Inhibition of AR significantly downregulated growth factor-induced miR-21 expression in human colon cancer cells, HT29, SW480, and Caco-2. Further, AR inhibition also increased phosphatase and tensin homolog (PTEN) (a direct target of miR-21) and forkhead box O3A (FOXO3a) in colon cancer cells. Our results obtained with HT29 cells ablated with FOXO3a siRNA showed increased activator protein-1 (AP-1) activation and miR-21 expression, indicating that FOXO3a represses miR-21 via AP-1 inactivation. Inhibition of AR also prevented the epidermal growth factor-induced phosphorylation of phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), c-Jun, c-Fos, PTEN, and FOXO3a, and deoxyribonucleic acid (DNA)-binding activity of AP-1. More importantly, in human colon adenocarcinoma xenograft tissues, miR-21 expression was lower, and PTEN and FOXO3a levels were significantly higher in AR inhibitor-treated mice compared to controls. These findings demonstrate a novel role of AR in the regulation of miR-21 and its target PTEN in growth factor-induced colon cancer cell growth. Collectively, these results show a novel role of AR in mediation of growth factor-induced colon cancer growth by modulating miR-21, PTEN, and FOXO3a expression through reactive oxygen species (ROS)/PI3K/AKT/AP-1.


Para-chlorophenylalanine prevents feeding induced by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT).
The effects of para-chlorophenylalanine pre-treatment (PCPA, 150 mg/kg IP daily for 3 days) on feeding and stereotyped behaviour elicited by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in rats were investigated. PCPA depleted brain serotonin and 5-hydroxyindoleacetic acid concentrations by 90% and increased feeding during a 2-h day-time test. 8-OH-DPAT (60-4000 micrograms/kg SC) increased food intake in control animals but decreased it in PCPA-treated animals during the 2-h test. PCPA treatment had no effect on 8-OH-DPAT-induced locomotion or serotonin-related stereotyped behaviour (i.e. forepaw treading, headweaving, wet dog shakes, etc). Since PCPA prevents the operation of pre-synaptic serotonergic mechanisms, the failure of 8-OH-DPAT to increase food intake in PCPA-treated rats suggests that 8-OH-DPAT-induced hyperphagia is autoreceptor mediated.


Cross-species virus transmission and the emergence of new epidemic diseases.
Host range is a viral property reflecting natural hosts that are infected either as part of a principal transmission cycle or, less commonly, as "spillover" infections into alternative hosts. Rarely, viruses gain the ability to spread efficiently within a new host that was not previously exposed or susceptible. These transfers involve either increased exposure or the acquisition of variations that allow them to overcome barriers to infection of the new hosts. In these cases, devastating outbreaks can result. Steps involved in transfers of viruses to new hosts include contact between the virus and the host, infection of an initial individual leading to amplification and an outbreak, and the generation within the original or new host of viral variants that have the ability to spread efficiently between individuals in populations of the new host. Here we review what is known about host switching leading to viral emergence from known examples, considering the evolutionary mechanisms, virus-host interactions, host range barriers to infection, and processes that allow efficient host-to-host transmission in the new host population.


Low message sensation health promotion videos are better remembered and activate areas of the brain associated with memory encoding.
Greater sensory stimulation in advertising has been postulated to facilitate attention and persuasion. For this reason, video ads promoting health behaviors are often designed to be high in "message sensation value" (MSV), a standardized measure of sensory intensity of the audiovisual and content features of an ad. However, our previous functional Magnetic Resonance Imaging (fMRI) study showed that low MSV ads were better remembered and produced more prefrontal and temporal and less occipital cortex activation, suggesting that high MSV may divert cognitive resources from processing ad content. The present study aimed to determine whether these findings from anti-smoking ads generalize to other public health topics, such as safe sex. Thirty-nine healthy adults viewed high- and low MSV ads promoting safer sex through condom use, during an fMRI session. Recognition memory of the ads was tested immediately and 3 weeks after the session. We found that low MSV condom ads were better remembered than the high MSV ads at both time points and replicated the fMRI patterns previously reported for the anti-smoking ads. Occipital and superior temporal activation was negatively related to the attitudes favoring condom use (see Condom Attitudes Scale, Methods and Materials section). Psychophysiological interaction (PPI) analysis of the relation between occipital and fronto-temporal (middle temporal and inferior frontal gyri) cortices revealed weaker negative interactions between occipital and fronto-temporal cortices during viewing of the low MSV that high MSV ads. These findings confirm that the low MSV video health messages are better remembered than the high MSV messages and that this effect generalizes across public health domains. The greater engagement of the prefrontal and fronto-temporal cortices by low MSV ads and the greater occipital activation by high MSV ads suggest that that the "attention-grabbing" high MSV format could impede the learning and retention of public health messages.


Construction of a polyproline structure with hydrophobic exterior using octahydroindole-2-carboxylic acid.
The proline analogue (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic) has been previously applied as a proline substitute in pharmocologically active peptides and as a structural component of the antihypertensive drug Perindopril. Herein, we describe the formation of an oligoproline structure by an Oic oligomer. A series of Oic oligomers were investigated to show the structural and energetic contribution of appended residues to the structure. NMR investigation of these oligomers revealed an all-trans amide bond structure, and we provide evidence that a cascade-like mechanism is responsible for the all-trans folding cooperativity. X-ray crystallography of the Oic-hexapeptide clearly demonstrates that the all-trans structure of the Oic oligomer is a polyproline II helix. Thus, as a hydrophobic proline analog with a highly stable trans-amide bond, Oic represents an ideal building block for hydrophobic sites of polyproline II structures in biologically relevant contexts.


Comparison of energy metabolism in human normal and neoplastic (Burkitt's lymphoma) lymphoid cells.
In order to detect possible differences in the energy metabolism between normal and neoplastic lymphoid cells, we studied purified normal human lymphocytes (FL) and transformed lymphoblastoid cell lines derived from umbilical cord blood (CL) and compared them to cell lines derived from American Burkitt's lymphoma (BL). The total adenosine triphosphate production rate by these cells was estimated by measuring O2 consumption and lactic acid production rates. O2 consumption (nmol/min/mg protein) was 4.9 +/- 0.3 (S.D.) in CL, 4.4 +/- 0.3 in FL, and 4.9 +/- 0.3 in BL. Lactic acid production (nmol/min/mg protein) was 30.9 +/- 3.0 in CL, 29.9 +/- 3.0 in FL, and 23.4 +/- 4.0 in BL. Using these values of O2 consumption and lactic acid production, the average adenosine triphosphate production rates (nmol/min/mg protein) were calculated to be 60 in CL, 56 in FL, and 53 in BL. We conclude that the BL do not have more aerobic glycolysis than do normal lymphoid cells, suggesting that the lactic acidosis seen in American Burkitt's lymphoma is not due to a preferential glycolytic metabolism of the tumor. More likely, the lactic acidosis is simply due to the large total mass of these neoplastic cells and not due to a modification of their energy metabolism.


Endoscopic intracranial craniofacial and monobloc osteotomies with the aid of a malleable high-speed pneumatic drill: a cadaveric and clinical study.
Endoscopic techniques are now an accepted part of the surgical armamentarium and are used routinely in a number of aesthetic and reconstructive procedures. Endoscopic techniques are now being used commonly by plastic surgeons in forehead and face lifts. In both craniofacial surgery and in neurosurgery, the application of endoscopy potentially allows the surgical team to perform wide dissection of the dura mater in a minimally invasive fashion, thereby potentially reducing the risk of dural and brain injury. Also reduced by this surgical approach is potential injury to the major venous structures, such as the sagittal sinus, along with overall reduced bleeding. After an extensive laboratory study of 10 cadaveric dissections, the authors have refined a new endoscopic technique for completing an endoscopic intracranial craniofacial osteotomy. This study was conducted in the Department of Pathology at the University of Brno (Czech Republic), and was performed as a cooperative multicenter project between the University of Palermo, the Albert Einstein College of Medicine/ Montefiore Medical Center, the Hospital Infantil de Mexico, "Federico Gomez," and the Medtronic Midas Rex Institute, (Fort Worth, TX). During this cadaveric anatomic study and using small trephinations and skin incisions the authors were able to develop several different craniofacial and endoscopic monobloc procedures. To accomplish intracranial and facial osteotomies, a new malleable high-speed drill was designed for use in the endoscopic craniofacial approach. Using these newly developed cadaveric techniques and instrumentation, the authors performed two intracranial craniofacial procedures on children with congenital craniofacial anomalies. There would appear to be several significant advantages for the craniofacial patient as result of these new techniques: reduced surgical trauma, operative bleeding, surgical time, and hospitalization, along with a reduced risk of infection. It became quickly apparent, as a result of these cadaveric studies, that the learning curve for this endoscopic procedure is quite steep. Tutino M, Chico F, Tutino M, Goodrich JT, Ortiz Monasterio F. Endoscopic intracranial craniofacial and monobloc osteotomies with the aid of a malleable high-speed pneumatic drill: a cadaveric and clinical study.


The unaided recovery of marathon-induced serum metabolome alterations.
Endurance athlete performance is greatly dependent on sufficient post-race system recovery, as endurance races have substantial physiological, immunological and metabolic effects on these athletes. To date, the effects of numerous recovery modalities have been investigated, however, very limited literature exists pertaining to metabolic recovery of athletes after endurance races without the utilisation of recovery modalities. As such, this investigation is aimed at identifying the metabolic recovery trend of athletes within 48 h after a marathon. Serum samples of 16 athletes collected 24 h before, immediately after, as well as 24 h and 48 h post-marathon were analysed using an untargeted two-dimensional gas chromatography time-of-flight mass spectrometry metabolomics approach. The metabolic profiles of these comparative time-points indicated a metabolic shift from the overall post-marathon perturbed state back to the pre-marathon metabolic state during the recovery period. Statistical analyses of the data identified 61 significantly altered metabolites including amino acids, fatty acids, tricarboxylic acid cycle, carbohydrates and associated intermediates. These intermediates recovered to pre-marathon related concentrations within 24 h post-marathon, except for xylose which only recovered within 48 h. Furthermore, fluctuations in cholesterol and pyrimidine intermediates indicated the activation of alternative recovery mechanisms. Metabolic recovery of the athletes was attained within 48 h post-marathon, most likely due to reduced need for fuel substrate catabolism. This may result in the activation of glycogenesis, uridine-dependent nucleotide synthesis, protein synthesis, and the inactivation of cellular autophagy. These results may be beneficial in identifying more efficient, targeted recovery approaches to improve athletic performance.


Surgical reduction and stabilization for repair of femoral capital physeal fractures in cats: 13 cases (1998-2002).
To evaluate anatomic reduction and surgical stabilization of femoral capital physeal fractures in cats. Retrospective study. 13 cats. Medical records of cats with unilateral or bilateral femoral capital physeal fractures evaluated from 1998 to 2002 were reviewed. Age and weight of cats at the time of surgery; breed; sex; concurrent injuries; severity of lameness before and 1, 2, 4, 6, and 8 weeks after surgery; the amount of fracture reduction achieved and number of Kirschner wires (K-wires) used; degree of degenerative joint disease of the hip joint and lysis of the femoral neck and head observed after surgery; whether K-wires were removed after surgery; and complications after surgery were evaluated. Thirteen cats with 16 capital physeal fractures were identified. There was significant improvement in the severity of clinical lameness in all cats from weeks 1 through 4 after surgery. There was no correlation between the scores of the individuals who evaluated radiographs for fracture reduction and placement of K-wires. Results suggested that surgical stabilization and repair of femoral capital physeal fractures facilitate a short recovery period and a good prognosis for return to normal function in cats.


Human immunodeficiency virus infection in hemophilic children.
The following groups were compared: (1) children less than 18 years old who have hemophilia-associated acquired immunodeficiency syndrome (AIDS) with other children with AIDS and with adults who have hemophilia-associated AIDS and (2) asymptomatic HIV-infected hemophilic children with asymptomatic HIV-infected hemophilic adults. Children with hemophilia-associated AIDS were older than other children with AIDS (medians 13 and 1 years, respectively) and less frequently had lymphocytic interstitial pneumonitis (5% v 48%) but had similar incidences of Pneumocystis carinii pneumonia (51% v 53%) and similar case to fatality ratios (59% v 61%). Children with hemophilia-associated AIDS had P carinii pneumonia significantly less often than did adults with hemophilia-associated AIDS, but both had similar case to fatality ratios (adults 72% with P carinii pneumonia, 68% dead). Significantly more hemophilic children than adults with AIDS were nonwhite (30% v 14%) and resided in the tristate area of New York/New Jersey/Pennsylvania (43% v 25%). The immune effects of human immunodeficiency virus (HIV) to date on asymptomatic pediatric and adult hemophiliacs are similar but may be more severe in adults. It is concluded that, although some of the clinical manifestations of AIDS (eg, lymphocytic interstitial pneumonitis) occurring or not occurring in older children infected through blood factor products differ from those of other children with AIDS, disease outcome to date is equally poor. The reasons for the differences between hemophilic children and hemophilic adults with and without AIDS warrant further investigation.


The clinical feasibility of deep hyperthermia treatment in the head and neck: new challenges for positioning and temperature measurement.
To apply high-quality hyperthermia treatment to tumours at deep locations in the head and neck (H&N), we have designed and built a site-specific phased-array applicator. Earlier, we demonstrated its features in parameter studies, validated those by phantom measurements and clinically introduced the system. In this paper we will critically review our first clinical experiences and demonstrate the pivotal role of hyperthermia treatment planning (HTP). Three representative patient cases (thyroid, oropharynx and nasal cavity) are selected and discussed. Treatment planning, the treatment, interstitially measured temperatures and their interrelation are analysed from a physics point of view. Treatments lasting 1 h were feasible and well tolerated and no acute treatment-related toxicity has been observed. Maximum temperatures measured are in the range of those obtained during deep hyperthermia treatments in the pelvic region but mean temperatures are still to be improved. Further, we found that simulated power absorption correlated well with measured temperatures illustrating the validity of our treatment approach of using energy profile optimizations to arrive at higher temperatures. This is the first data proving that focussed heating of tumours in the H&N is feasible. Further, HTP proved a valuable tool in treatment optimization. Items to improve are (1) the transfer of HTP settings into the clinic and (2) the registration of the thermal dose, i.e. dosimetry.


Lessons learned from engaging men in sexual and reproductive health as clients, partners and advocates of change in the Hoima district of Uganda.
This study examined the impact of a three-year intervention project conducted in the Hoima district of Uganda, which sought to engage men in sexual and reproductive health as clients, equal partners and advocates of change. Structured surveys with 164 self-reported heterosexual men aged 18-54 years were used to assess knowledge and attitudes towards sexual and reproductive health. Data from these were analysed using Stata and SPSS. Additionally, five focus groups were conducted with the female partners and male beneficiaries of the project and with project peer educators. Four interviews were conducted with project staff and male beneficiaries. Data from these and the focus groups were analysed using a thematic approach. Following the intervention, a significantly greater number of men accessed, and supported their partners in accessing sexual health services services, had gained sexual and reproductive health awareness, reported sharing domestic duties and contraceptive decision-making, and displayed a decreased tolerance for domestic violence. It was more difficult to assess men's involvement and behaviours as advocates of change, which sheds light on the complexities of a gender transformative project and the importance of evaluating such projects from both men's and their partners' perspectives and at different levels of the male involvement model in sexual and reproductive health.


A chromosome-level sequence assembly reveals the structure of the Arabidopsis thaliana Nd-1 genome and its gene set.
In addition to the BAC-based reference sequence of the accession Columbia-0 from the year 2000, several short read assemblies of THE plant model organism Arabidopsis thaliana were published during the last years. Also, a SMRT-based assembly of Landsberg erecta has been generated that identified translocation and inversion polymorphisms between two genotypes of the species. Here we provide a chromosome-arm level assembly of the A. thaliana accession Niederzenz-1 (AthNd-1_v2c) based on SMRT sequencing data. The best assembly comprises 69 nucleome sequences and displays a contig length of up to 16 Mbp. Compared to an earlier Illumina short read-based NGS assembly (AthNd-1_v1), a 75 fold increase in contiguity was observed for AthNd-1_v2c. To assign contig locations independent from the Col-0 gold standard reference sequence, we used genetic anchoring to generate a de novo assembly. In addition, we assembled the chondrome and plastome sequences. Detailed analyses of AthNd-1_v2c allowed reliable identification of large genomic rearrangements between A. thaliana accessions contributing to differences in the gene sets that distinguish the genotypes. One of the differences detected identified a gene that is lacking from the Col-0 gold standard sequence. This de novo assembly extends the known proportion of the A. thaliana pan-genome.


Schedule and magnitude of reproductive investment under immune trade-offs explains sex differences in immunity.
Sex differences in immunity are found in many species. Known immune mechanisms in birds and mammals suggest that pathogen detection may be amplified in females, whereas in males, pathogen killing is amplified. We show that these immunological profiles emerge as distinct peaks on a fitness landscape defined by sensitivity-specificity and infection-immunopathology immune tradeoffs. What selection pressures might drive males and females towards separate peaks? Surprisingly, modeling immune trade-offs alone results in a pattern of sex differences that is the reverse of what is observed. By integrating these trade-offs into a life-history framework, where the schedule and magnitude of reproductive investment differs between the sexes, we find that increased age-specific infection and mortality risks during parental investment can push females towards the peak that aligns with empirical observations. Overall, our model suggests enhanced pathogen detection (in females) versus enhanced pathogen killing (in males) is best explained if shared immune tradeoffs interact with sex-specific reproductive schedules and risks. We suggest ways to test this framework empirically.


The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data.
The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.


Impact of exposure to phenols during early pregnancy on birth weight in two Canadian cohort studies subject to measurement errors.
It is of interest to know whether early pregnancy exposure to phenols such as bisphenol-A (BPA) or triclosan (TCS) negatively impacts birth weight outcomes. Exposure to these chemicals is widespread in the Canadian population but obtaining accurate measurements of average exposure is difficult because these chemicals are rapidly excreted from the body, causing body levels to fluctuate both within and between days, as observed in a recent Canadian study (P4). This measurement error can attenuate the estimated effects of exposures. Data from two Canadian cohort studies, the Plastics and Personal-care Products use in Pregnancy (P4) Study and the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, such that all participants with complete BPA or TCS exposure and outcome data were used (MIREC n = 1822, P4 n = 68). We used regression calibration to correct for the attenuating effects of exposure measurement error when modeling the effect of first trimester BPA or TCS exposure on four birth weight outcomes: birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and large for gestational age (LGA). Specific gravity, time of day, and time since last urine void were also controlled in the analysis. TCS exposure has a marginally significant association with SGA only with odds ratio 0.87 and 95% confidence interval (0.74, 1.00). It also has a marginally significant association with LGA in male offspring with odds ratio 1.11 and 95% confidence interval (1.00, 1.25). The effects of BPA on the four birth outcomes were insignificant. Increased TCS exposure during pregnancy is marginally associated with decreased odds of having SGA offspring. It is possibly associated with decreased BW in males and decreased odds of LBW, though these associations were not present in measurement error corrected models. TCS is possibly associated with increased odds in male offspring of being LGA, though this relationship was not present in models not corrected for measurement error. The study finds no significant effects of BPA on birth weight outcomes, which may be due to more severe measurement error in a single observation of BPA.


Web-based communications and management of a multi-center clinical trial: the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project.
While efficient methods of communication are known to be essential in conducting large multicenter clinical trials, very little information is provided on actual methods that can be implemented to improve communication. An integrated technology-based communication system was developed for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project, which prospectively defines treatments that are most effective for participants with a diagnosis of a nonpsychotic major depressive disorder (MDD) who report an unsatisfactory clinical outcome to an initial and, if necessary, subsequent treatment(s). This web-based communication system is comprised of a multi-faceted study Web site, including a help desk, document sharing, a project directory and reports. In addition, automated reporting via e-mail and an online data correction mechanism are also available. The STAR*D communication system improves communication between study personnel and improves the quality of the study's data through the integration of system elements, the integration of those elements with traditional forms of communication,, by filling the gaps not addressed by those traditional methods and by reducing the staff workload burden.


Molecular mechanisms of in vitro betulin-induced apoptosis of Leishmania donovani.
Although leishmanial infections of humans occur globally, the major health impact lies in developing nations, thus, leishmaniases remain "neglected" diseases for new drugs development. Multidrug resistance has been documented in most countries where leishmaniases is endemic. Betulin is a widely available and affordable natural product exerting leishmanicidal activity at micromolar concentration. In this study, the molecular mechanisms of death that contribute to the anti-leishmanial activity of betulin are investigated. In promastigotes, betulin stimulated reactive oxygen species generation at micromolar concentrations in Leishmania. Apoptosis was observed in betulin-treated promastigotes using flow cytometric analysis of treated cells stained with annexin V-FITC and propidium iodide. Furthermore, betulin treatment of promastigotes led to mitochondrial membrane damage, activation of caspase-like proteases, and DNA fragmentation in Leishmania donovani promastigotes. Betulin treatment of amastigotes cultured within macrophages, resulted in a reduced number of amastigotes, with no substantive cytotoxic damage to the host macrophage cells at leishmanicidal drug concentrations.


Global analysis of gene expression changes during retinoic acid-induced growth arrest and differentiation of melanoma: comparison to differentially expressed genes in melanocytes vs melanoma.
The incidence of malignant melanoma has significantly increased over the last decade. Some of these malignancies are susceptible to the growth inhibitory and pro-differentiating effects of all-trans-retinoic acid (RA). The molecular changes responsible for the biological activity of RA in melanoma are not well understood. In an analysis of sequential global gene expression changes during a 4-48 h RA treatment of B16 mouse melanoma cells, we found that RA increased the expression of 757 genes and decreased the expression of 737 genes. We also compared the gene expression profile (no RA treatment) between non-malignant melan-a mouse melanocytes and B16 melanoma cells. Using the same statistical test, we found 1495 genes whose expression was significantly higher in melan-a than in B16 cells and 2054 genes whose expression was significantly lower in melan-a than in B16 cells. By intersecting these two gene sets, we discovered a common set of 233 genes whose RNA levels were significantly different between B16 and melan-a cells and whose expression was altered by RA treatment. Within this set, RA treatment altered the expression of 203 (87%) genes toward the melan-a expression level. In addition, hierarchical clustering showed that after 48 h of RA treatment expression of the 203 genes was more closely related to the melan-a gene set than any other RA treatment time point. Functional analysis of the 203 gene set indicated that RA decreased expression of mRNAs that encode proteins involved in cell division/cell cycle, DNA replication, recombination and repair, and transcription regulation. Conversely, it stimulated genes involved in cell-cell signaling, cell adhesion and cell differentiation/embryonic development. Pathway analysis of the 203 gene set revealed four major hubs of connectivity: CDC2, CHEK1, CDC45L and MCM6. Our analysis of common genes in the 48 h RA-treatment of B16 melanoma cells and untreated B16 vs. melan-a data set show that RA "normalized" the expression of genes involved in energy metabolism, DNA replication, DNA repair and differentiation. These results are compatible with the known growth inhibitory and pro-differentiating effects of RA. Pathway analysis suggests that CDC2, CHEK1, CDC45L and MCM6 are key players in mediating the biological activity of RA in B16 melanoma cells.


Impact of peanuts and tree nuts on body weight and healthy weight loss in adults.
Nuts (ground and tree) are rich sources of multiple nutrients and their consumption is associated with health benefits, including reduced cardiovascular disease risk. This has prompted recommendations to increase their consumption. However, they are also high in fat (albeit largely unsaturated) and are energy dense. The associations between these properties, positive energy balance, and body weight raise questions about such recommendations. This issue is addressed through a review of the literature pertaining to the association between nut consumption and energy balance. Epidemiological studies document an inverse association between the frequency of nut consumption and BMI. Clinical trials reveal little or no weight change with inclusion of various types of nuts in the diet over 1-6 mo. Mechanistic studies indicate this is largely attributable to the high satiety property of nuts, leading to compensatory responses that account for 65-75% of the energy they provide. Limited data suggest chronic consumption is associated with elevated resting energy expenditure resulting in dissipation of another portion of the energy they provide. Additionally, due to poor bioaccessibility, there is limited efficiency of energy absorption from nuts. Collectively, these mechanisms offset much of the energy provided by nuts. The few trials contrasting weight loss through regimens that include or exclude nuts indicate improved compliance and greater weight loss when nuts are permitted. This consistent literature suggests nuts may be included in the diet, in moderation, to enhance palatability and nutrient quality without posing a threat for weight gain.


Characteristics of good diagnostic studies.
Whether or not patients are better off from undergoing a diagnostic test will depend on how test information is used to guide subsequent decisions on starting, stopping, or modifying treatment. Consequently, the practical value of a diagnostic test can only be assessed by taking into account subsequent health outcomes. In the appraisal of diagnostic test studies, it is essential to discriminate between studies that report on the accuracy of a diagnostic test and studies that report on health outcomes of strategies that incorporate diagnostic tests. In a study that reports on diagnostic accuracy, a cohort of patients is subjected to at least two diagnostic tests: the index test and the reference test, the latter usually being the best method available to detect the target condition. The accuracy of the index test can be expressed in terms of sensitivity, specificity, or likelihood ratios. Studies that compare two or more strategies that incorporate diagnostic tests as well as therapeutic interventions should be approached differently. Such studies do not require expression of test accuracy in terms of sensitivity and specificity. The merit of diagnostic tests evaluated in such studies can be expressed by comparing relevant outcomes of both strategies. The effectiveness of such strategies can be compared similarly as the effectiveness of treatment. However, due to the fact that the effect of a diagnostic test on health outcome is not as direct as the effect of treatment on health outcome, the design of outcome studies reporting on diagnostic tests requires special attention. It is important to establish a clear link between the result of the test under study and subsequent therapeutic management. Furthermore, trial efficiency can be improved by moving the point of randomization from the decision point, whether or not to test, to the point where a decision has to be made regarding what to do with the positive test results.


Creation of line defects in holographic photonic crystals by a double-exposure thresholding method.
Recording of periodic variations of amplitude and phase by the interference of coherent laser beams in a hologram offers a natural means for creating one-, two-, and three-dimensional photonic crystals. For device applications such as waveguides in optical communications, one usually needs to create defects in photonic crystals. We present an analysis and an experimental demonstration of a double-exposure method for creating photonic crystals with line defects. The idea is based on the principle of superposition of holographic grating patterns of different spatial periods while the recording medium is held stationary and on the application of a threshold to the recording medium. We use the same symmetrical optical architecture to achieve nondefective and defective holographic photonic crystals. The technique may be extended to the creation of defects based on functional synthesis by means of Fourier series, by use of light sources of other wavelengths with an appropriate high-contrast recording material.


A consideration of ambient solar ultraviolet radiation in the interpretation of studies of the aetiology of melanoma.
Values of ambient solar ultraviolet radiation and estimated hourly radiation for both erythemal (UVB) and UVA radiation are presented for the latitudes where the major studies of human cutaneous melanoma have been performed; 50-55 degrees N (Denmark and Western Canada), 30-34 degrees S (Western Australia) and 15-27 degrees N (Queensland). Comparisons are made for exposure patterns relating to constant and to intermittent exposure, and combinations of these. The results show that the wavelength distribution of solar ultraviolet radiation varies with latitude and exposure pattern. At higher latitudes, the contribution of exposure at peak periods is more marked. The comparison or combination or results from epidemiological studies at different locations will be aided by this consideration of the variation in different aspects of solar radiation, and tables are given for this purpose.


Prevalence of inherited ataxias in the province of Padua, Italy.
Few population studies are available on epidemiological indexes of hereditary ataxias. An investigation on the prevalence rate of these movement disorders is in progress for the Veneto region, the main area of northeast Italy with a population of 4,490,586 inhabitants. The first results of this epidemiological survey concern the province of Padua, which numbers 845,203 residents (January 1, 2002). The prevalence rate of inherited ataxias has been estimated at 93.3 cases per million inhabitants. The most common types appeared to be the autosomal dominant forms, namely spinocerebellar ataxia type 1 and 2, with a prevalence of 24 per 1,000,000. In the same population, with a prevalence rate of 6 per 1,000,000, Friedreich's ataxia was defined as the prominent recessive autosomal form. There were very rare cases of ataxia telangiectasia, ataxia with vitamin E deficiency and cerebellar ataxia with congenital muscular dystrophy, a recently identified autosomal recessive disease.


Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.
Crohn's disease (CD) is a chronic relapsing inflammatory condition and maintenance of remission is a major issue as many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues such as azathioprine (AZA) and 6-mercaptopurine (6-MP) have been used to maintain surgically-induced remission in CD, but the effectiveness, tolerability and safety of these agents remains controversial. To assess the efficacy and safety of purine analogues (AZA and 6-MP) for maintenance of surgically-induced remission in CD. We searched PubMed, MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 26 July 2018 (and from inception to 31 July 2019). In addition, we searched reference lists of all included studies and relevant reviews, conference proceedings and trials registers. Randomised controlled trials (RCTs) with a duration of at least three months that enrolled adults and children with surgically-induced remission of CD and compared AZA or 6-MP to no treatment, placebo or any other active intervention were considered for inclusion. Two authors independently assessed trial eligibility, extracted data, assessed the risk of bias and assessed the certainty of the evidence using GRADE. The primary outcome was clinical relapse. Secondary outcomes included endoscopic relapse, radiologic and surgical relapse, adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs and health-related quality of life. Ten RCTs with a total of 928 participants were included. Study participants were adults recruited from university clinics and gastroenterology hospitals who received interventions post-surgery for a duration between 12 to 36 months. Most study participants were recruited less than three months after surgery in all except one study where participants were recruited between 6 to 24 months post-surgery. One study was rated as low risk of bias, six studies were rated high risk of bias and three were rated unclear risk of bias.There was moderate certainty evidence that purine analogues are more efficient for preventing clinical relapse than placebo. At 12 to 36 months, 51% (109/215) of AZA/6-MP participants relapsed compared to 64% (124/193) of placebo participants (RR 0.79; 95% CI 0.67 to 0.92; 408 participants; 3 studies; I² = 0%; moderate certainty evidence). The certainty of the evidence regarding the efficacy of AZA or 6-MP for maintaining postoperative clinical remission compared to 5-ASA compounds was low. At 12 to 24 months , 64% (113/177) of purine analogue participants relapsed compared to 59% (101/170) of 5-ASA participants (RR 1.05; 95% CI 0.89 to 1.24; 347 participants; 4 studies; I² = 8%; low certainty evidence). The certainty of evidence that purine analogues are inferior for preventing postsurgical clinical relapse compared to tumour necrosis factor alpha agents (anti-TNF-α) was very low. At 12 to 24 months, 43% (29/67) of AZA participants relapsed compared to 14% (10/72) of anti-TNF-α participants (RR 2.89; 95% CI 1.50 to 5.57; 139 participants; 3 studies; I² = 0%; very low certainty evidence).The effect of purine analogues compounds on AEs compared to placebo or any active treatment was uncertain, as the quality of evidence ranged from very low to low. After 12 to 24 months, 14% (12/87) of purine analogue participants experienced an AE compared to 10% (8/81) of placebo participants (RR 1.36; 95% CI 0.57 to 3.27; 168 participants; 2 studies; I² = 0%; low certainty evidence). The effect of purine analogues on AEs compared to 5-ASA agents was uncertain. After 12 to 24 months, 41% (73/176) of purine analogue participants had an AE compared to 47% (81/171) of 5-ASA participants (RR 0.89; 95% CI 0.74 to 1.07; 346 participants; 4 studies; I² = 15%; low certainty evidence). The effect of purine analogues on AEs in comparison to anti TNF-α agents was uncertain. At 12 to 24 months, 57% (32/56) of AZA participants had an AE compared to 51% (31/61) of anti-TNF-α participants (RR 1.13; 95% CI 0.83 to 1.53; 117 participants; 2 studies; I² = 0%; low certainty evidence). Purine analogue participants were more like than 5-ASA participants to have a SAE (RR 3.39, 95% CI 1.26 to 9.13, 311 participants; 3 studies; I² = 9%; very low certainty evidence), or to withdraw due to an AE (RR 2.21, 95% CI 1.28 to 3.81; 425 participants; 5 studies; I² = 0%; low certainty evidence). Commonly reported AEs across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, nasopharyngitis and flatulence. Moderate certainty evidence suggests that AZA and 6-MP may be superior to placebo for maintenance of surgically-induced remission in participants with CD. There was no clear difference in the number of clinical relapses when purine analogues were compared with 5-ASA agents, however this is based on low certainty evidence. There was very low certainty evidence that AZA and 6-MP are more likely to result in more serious adverse events (SAEs) and withdrawals due to an AE (low certainty) when compared to 5-ASA agents. Very low certainty evidence suggests that purine analogues may be inferior to anti-TNF-α agents, however, no firm conclusions can be drawn. Further research investigating the efficacy and safety of AZA and 6-MP in comparison to other active medications in surgically-induced remission of CD is warranted.