Using molecular epidemiology to track Toxoplasma gondii from terrestrial carnivores to marine hosts: implications for public health and conservation.
Environmental transmission of the zoonotic parasite Toxoplasma gondii, which is shed only by felids, poses risks to human and animal health in temperate and tropical ecosystems. Atypical T. gondii genotypes have been linked to severe disease in people and the threatened population of California sea otters. To investigate land-to-sea parasite transmission, we screened 373 carnivores (feral domestic cats, mountain lions, bobcats, foxes, and coyotes) for T. gondii infection and examined the distribution of genotypes in 85 infected animals sampled near the sea otter range. Nested PCR-RFLP analyses and direct DNA sequencing at six independent polymorphic genetic loci (B1, SAG1, SAG3, GRA6, L358, and Apico) were used to characterize T. gondii strains in infected animals. Strains consistent with Type X, a novel genotype previously identified in over 70% of infected sea otters and four terrestrial wild carnivores along the California coast, were detected in all sampled species, including domestic cats. However, odds of Type X infection were 14 times higher (95% CI: 1.3-148.6) for wild felids than feral domestic cats. Type X infection was also linked to undeveloped lands (OR = 22, 95% CI: 2.3-250.7). A spatial cluster of terrestrial Type II infection (P = 0.04) was identified in developed lands bordering an area of increased risk for sea otter Type II infection. Two spatial clusters of animals infected with strains consistent with Type X (P ≤ 0.01) were detected in less developed landscapes. Differences in T. gondii genotype prevalence among domestic and wild felids, as well as the spatial distribution of genotypes, suggest co-existing domestic and wild T. gondii transmission cycles that likely overlap at the interface of developed and undeveloped lands. Anthropogenic development driving contact between these cycles may increase atypical T. gondii genotypes in domestic cats and facilitate transmission of potentially more pathogenic genotypes to humans, domestic animals, and wildlife.


Systemic immunotherapy delays photoreceptor cell loss and prevents vascular pathology in Royal College of Surgeons rats.
Degenerative retinopathies, including retinitis pigmentosa, age-related retinal degeneration, autoimmune retinopathy, and related diseases affect millions of people around the world. Currently, there is no effective treatment for most of those diseases. We investigated systemic recombinant T-cell receptor ligand (RTL) immunotherapy for preventing retinal degeneration and vascular damage in the Royal College of Surgeons (RCS) rat model of retinal degeneration. RCS rats were treated with RTL220 tethered to interphotoreceptor retinoid binding protein (IRBP) peptide or control RTL101 without peptide by subcutaneous administration starting at the onset of photoreceptor degeneration or after the degenerative process began daily or every other day and performed for a 13-week period. The retinal cross sections and whole mounts were prepared to determine histopathology, leaking vessels, and formation of vascular complexes. Immunofluorescent studies evaluated microglia and monocyte chemoattractant protein-1 chemokine in treated retinas. Optokinetic studies were performed to determine visual acuity. Systemic treatment with RTL220 prevented decreases in outer nuclear layer (ONL) thickness and showed a significantly higher number of nuclei than control rats treated with RTL101 or vehicle. RTL220 was also effective in protecting retinal vasculature from leakage and the formation of abnormal vascular complexes even when the treatment was administered after the degenerative process was initiated. Visual acuity measurement showed that rats treated with RTL220 performed significantly better than those with RTL101 and untreated age-matched controls at P60 and P90. Biodistribution studies showed that RTL220 cleared slowly from the administration site. Moreover, RTL220-treated retinas had a significantly reduced number of activated microglia in the subretinal space, decreased monocyte chemoattractant protein-1 production in the retina, inhibited T-cell responses, and reduced anti-interphotoreceptor retinoid binding protein autoantibody titers. Treatment with the control RTL101 (without a specific peptide tethered) or vehicle alone did not inhibit microglia activation or protect photoreceptors or vasculature. RTL therapy augmented photoreceptor cell survival, protected vasculature, and increased visual function in the RTL rat. Targeting chronic autoimmunity with RTLs can be an effective therapeutic alternative in delaying retinal degeneration. Subcutaneous delivery of RTLs alone or combined with other drugs could be an attractive option for long-term therapy for retinal degenerative diseases.


Vascular COX-2 modulates blood pressure and thrombosis in mice.
Prostacyclin (PGI(2)) is a vasodilator and platelet inhibitor, properties consistent with cardioprotection. More than a decade ago, inhibition of cyclooxygenase-2 (COX-2) by the nonsteroidal anti-inflammatory drugs (NSAIDs) rofecoxib and celecoxib was found to reduce the amount of the major metabolite of PGI(2) (PGI-M) in the urine of healthy volunteers. This suggested that NSAIDs might cause adverse cardiovascular events by reducing production of cardioprotective PGI(2). This prediction was based on the assumption that the concentration of PGI-M in urine likely reflected vascular production of PGI(2) and that other cardioprotective mediators, especially nitric oxide (NO), were not able to compensate for the loss of PGI(2). Subsequently, eight placebo-controlled clinical trials showed that NSAIDs that block COX-2 increase adverse cardiovascular events. We connect tissue-specific effects of NSAID action and functional correlates in mice with clinical outcomes in humans by showing that deletion of COX-2 in the mouse vasculature reduces excretion of PGI-M in urine and predisposes the animals to both hypertension and thrombosis. Furthermore, vascular disruption of COX-2 depressed expression of endothelial NO synthase and the consequent release and function of NO. Thus, suppression of PGI(2) formation resulting from deletion of vascular COX-2 is sufficient to explain the cardiovascular hazard from NSAIDs, which is likely to be augmented by secondary mechanisms such as suppression of NO production.


Interventions for paracetamol (acetaminophen) overdose.
Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites. To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews. Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens. Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software. We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults. These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.


Skeletal robustness and bone strength as measured by anthropometry and ultrasonography as a function of physical activity in young adults.
During the last 10 years, skeletal robustness in children has generally decreased. The reasons for this phenomenon, as well as its outcomes, are undetermined so far. The present study explores the association between anthropometric skeletal measurements, bone quality measurements, and physical activity in young adults. 118 German young men (N = 68; 19-25 years old) and women (N = 50; 19-24 years old) were investigated by anthropometric methods (i.e., height, weight, shoulder, elbow breadth, and pelvic breadth) and quantitative ultrasound measurement (QUS). Strength and stability of Os calcis have been determined by speed of sound (in m/s) and broadband ultrasound attenuation (in dB/Mhz); individual physical activity was analyzed by a pedometer and by questionnaire. The results show a correlation between sports hours per week and bone quality index in males. But no correlation exists between anthropometric data and QUSs for either sexes, as well as no correlation between total steps per day and internal bone quality or external bone dimensions. These results are discussed in the context of generally decreasing physical activity, the outcomes of prevention programs as well as evolutionary adaptation of human phenotypic plasticity in a changing environment.


Use of simultaneous radiation boost achieves high treatment response rate in patients with metastatic gastric cancer.
Intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) could improve local control rates at different anatomic sites. However, little is known for its use in metastatic gastric cancer. Our study aimed to compare the treatment response rates of IMRI-SIB and conformal radiotherapy (CRT) in patients with metastatic gastric cancer. We retrospectively identified twenty patients with metastatic gastric cancer from 2013 to 2015, 12 given IMRT-SIB, and eight given CRT. Treatment response and toxicities were evaluated for all patients. The radiation target included peritoneal lymph nodes. RECIST criteria were used to assess the treatment response. Three patients of eight in the CRT group died before the end of treatment due to the progression of diseases in the field. For the IMRT-SIB group, the median dose of high dose field was 60.8 Gy (50-64.4 Gy), and the median dose of low-dose field was 45 Gy (36-50.4 Gy). For the CRT group, the median dose of the total dose was 50 Gy (41.4-60 Gy). IMRT-SIB could elevate local dose significantly, compared to the CRT group. One patient of 12 in the IMRT-SIB group achieved complete response, and nine patients achieved partial response (PR), whereas no patient achieved CR in the CRT group. Two of five patients achieved PR (40%) in the CRT group. IMRT-SIB improved the treatment response rate significantly (odds ratio 8.33, 95% confidence interval: 1.03-67.14, P = 0.046). Two patients of 12 in the IMRT-SIB group developed enteritis, whereas two patients of five developed enteritis in the CRT group. IMRT-SIB could escalate the local dose and improve the treatment response rates in patients with metastatic gastric cancer and with acceptable toxicities. Further study with a larger population to validate our data is underway.


Immunoenzymatic quantitation of antibodies to Bothrops asper myotoxins after polyvalent antivenom administration in mice.
1. Two quantitative enzyme-immunoassays (EIA) for Bothrops asper myotoxin and anti-myotoxin antibodies, respectively, were utilized to study their in vivo distribution in mice (Swiss, 18 to 20 g). 2. After polyvalent antivenom (0.4 ml) administration by the iv route, there was an immediate peak in plasma anti-myotoxin antibodies which declined rapidly during the first hour, and then decreased more gradually. Anti-myotoxin antibodies were detected in muscular tissue (gastrocnemius) following iv injection of antivenom. After im injection of antivenom (0.4 ml), a slow and steady increase in plasma anti-myotoxin levels was observed, with a peak at 24 h. 3. Mice that received antivenom (0.4 ml) by the iv or im route 15 min after im injection of B. asper venom (100 micrograms) had lower levels of plasma anti-myotoxin antibodies than controls injected with antivenom only, suggesting that at least a fraction of the antibodies combines with myotoxins in vivo. 4. Myotoxin was not detected in plasma at any time after venom injection by the im (100 micrograms) or ip (40 micrograms) route. Following iv injection of 50 micrograms of purified myotoxin II, all plasma samples were also negative, at a detection limit of 10 ng/ml. 5. It was demonstrated that myotoxin II binds to mouse erythrocytes in vitro, a fact that could partially explain its rapid in vivo disappearance from plasma. 6. The present results on the distribution of anti-myotoxin antibodies in vivo are in agreement with previous experimental studies reporting the poor neutralization of myotoxicity induced by B. asper venom when antivenom is injected im, in comparison to i.v. injection.


Draft Genome Sequence of Acidobacteria Group 1 Acidipila sp. Strain EB88, Isolated from Forest Soil.
Here, we present the genome sequence of a member of the group I Acidobacteria, Acidipila sp. strain EB88, which was isolated from temperate forest soil. Like many other members of its class, its genome contains evidence of the potential to utilize a broad range of sugars.


Clinical prognostic factors in multiple sclerosis: a natural history review.
This Review summarizes the natural history studies on multiple sclerosis (MS) that have evaluated prognostic factors. Reassessment of prognostic factors is warranted, as our ability to offer patients a reliable prognosis is limited, yet we rely on this knowledge to appropriately design clinical trials and interpret their results. The selection criteria for studies to review included a geographical referral base, duration of at least 9 years, prospective design, and populations of at least 100 patients with MS. For all forms of MS combined, negative prognostic factors included progressive disease, and disability at 2 and 5 years. In relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) combined, negative prognostic factors were the onset of progression, a higher relapse rate, greater disability in the first 5 years, a shorter interval to the second relapse, and the involvement of more systems. Additional negative factors include a shorter time to progression in SPMS and a faster rate of disability in the first 2 and 5 years in primary progressive MS (PPMS). Onset of progression, relapse rate and disability in the initial 5 years could be fruitful therapeutic targets; however, longer-term clinical trials will be required to justify these end points.


Influence of water-soluble channeling agents on the release of diclofenac sodium from Irvingia malayana wax matrix tablets.
Irvingia malayana wax (IW) is majorly composed of esters of medium chain fatty acids. Its melting point is low and closed to the body temperature. This study aimed at investigating the potential of IW as a matrix-forming agent and evaluate the effect of soluble channeling agents on the release of diclofenac sodium (DS) from IW matrix tablets. The preformulation study by infrared spectroscopy and differential scanning calorimetry showed no incompatibility between IW and DS or soluble channeling agents, namely PEG 4000, PEG 6000 and lactose. IW retarded the release of DS from the matrix tablets more efficiently than carnauba wax due to its greater hydrophobicity and its ability to become partial molten wax at 37° C. Factors affecting the release of DS from IW matrix were drug concentrations, and types and concentrations of channeling agents. The release of DS significantly improved when DS concentration reached approximately 33%. The fast dissolving channeling agent, lactose, could enhance the drug release rate more effectively than PEG 4000 and PEG 6000, respectively. The linear relationship between the DS release rate and the concentration of the chosen channeling agent, PEG 6000, was found (r2=0.9866).


Staphylococcus aureus and the ecology of the nasal microbiome.
The human microbiome can play a key role in host susceptibility to pathogens, including in the nasal cavity, a site favored by Staphylococcus aureus. However, what determines our resident nasal microbiota-the host or the environment-and can interactions among nasal bacteria determine S. aureus colonization? Our study of 46 monozygotic and 43 dizygotic twin pairs revealed that nasal microbiota is an environmentally derived trait, but the host's sex and genetics significantly influence nasal bacterial density. Although specific taxa, including lactic acid bacteria, can determine S. aureus colonization, their negative interactions depend on thresholds of absolute abundance. These findings demonstrate that nasal microbiota is not fixed by host genetics and opens the possibility that nasal microbiota may be manipulated to prevent or eliminate S. aureus colonization.


Insights into hydrogen bonding and stacking interactions in cellulose.
In this quantum chemical study, we explore hydrogen bonding (H-bonding) and stacking interactions in different crystalline cellulose allomorphs; namely, cellulose I(β) and cellulose III(I). We consider a model system representing a cellulose crystalline core made from six cellobiose units arranged in three layers with two chains per layer. We calculate the contributions of intrasheet and intersheet interactions to the structure and stability in both cellulose I(β) and cellulose III(I) crystalline cores. Reference structures for this study were generated from molecular dynamics simulations of water-solvated cellulose I(β) and III(I) fibrils. A systematic analysis of various conformations describing different mutual orientations of cellobiose units is performed using the hybrid density functional theory with the M06-2X with 6-31+G(d,p) basis sets. We dissect the nature of the forces that stabilize the cellulose I(β) and cellulose III(I) crystalline cores and quantify the relative strength of H-bonding and stacking interactions. Our calculations demonstrate that individual H-bonding interactions are stronger in cellulose I(β) than in cellulose III(I); however, the total H-bonding contribution to stabilization is larger in cellulose III(I) because of the highly cooperative nature of the H-bonding network. In addition, we observe a significant contribution from cooperative stacking interactions to the stabilization of cellulose I(β). The theory of atoms-in-molecules (AIM) has been employed to characterize and quantify these intermolecular interactions. AIM analyses highlight the role of nonconventional CH···O H-bonding in the cellulose assemblies. Finally, we calculate molecular electrostatic potential maps for the cellulose allomorphs that capture the differences in chemical reactivity of the systems considered in our study.


Rehabilitation after arthroscopy of an acetabular labral tear.
Over the past few years, arthroscopy of the hip joint is becoming more common as a technique in both the diagnosis and treatment of hip pain. A frequent cause of hip and groin pain is a tear of the acetabular labrum. Patients with labral tears complain of pain in the groin region and pain with clicking in the hip without a history of pain prior to the original onset. Once a patient presents with signs and symptoms of hip pain that are greater than four weeks in conjunction with indicative findings of a labral tear by way of MRI, he or she may be considered a good candidate for arthroscopy of the hip joint. Little evidence exists in the current literature on rehabilitative procedures performed after arthroscopy of the acetabular labrum. The purpose of this clinical commentary is to suggest a rehabilitation protocol after acetebular labral debridement or repair.


Origins of clustered frequency combs in Kerr microresonators.
Recent experiments have demonstrated the generation of widely spaced parametric sidebands that can evolve into "clustered" optical frequency combs in Kerr microresonators. Here we describe the physics that underpins the formation of such clustered comb states. In particular, we show that the phase matching required for the initial sideband generation is such that (at least) one of the sidebands experiences anomalous dispersion, enabling the sideband to drive frequency comb formation via degenerate and non-degenerate four-wave mixing. We validate our proposal through a combination of experimental observations made in a magnesium-fluoride microresonator and corresponding numerical simulations. We also investigate the coherence properties of the resulting clustered frequency combs. Our findings provide valuable insights on the generation and dynamics of widely spaced parametric sidebands and clustered frequency combs in Kerr microresonators.


A new in vitro model to study cellular responses after thermomechanical damage in monolayer cultures.
Although electrosurgical instruments are widely used in surgery to cut tissue layers or to achieve hemostasis by coagulation (electrocautery), only little information is available concerning the inflammatory or immune response towards the debris generated. Given the elevated local temperatures required for successful electrocautery, the remaining debris is likely to contain a plethora of compounds entirely novel to the intracorporal setting. A very common in vitro method to study cell migration after mechanical damage is the scratch assay, however, there is no established model for thermomechanical damage to characterise cellular reactions. In this study, we established a new in vitro model to investigate exposure to high temperature in a carefully controlled cell culture system. Heatable thermostat-controlled aluminium stamps were developed to induce local damage in primary human umbilical vein endothelial cells (HUVEC). The thermomechanical damage invoked is reproducibly locally confined, therefore allowing studies, under the same experimental conditions, of cells affected to various degrees as well as of unaffected cells. We show that the unaffected cells surrounding the thermomechanical damage zone are able to migrate into the damaged area, resulting in a complete closure of the 'wound' within 48 h. Initial studies have shown that there are significant morphological and biological differences in endothelial cells after thermomechanical damage compared to the mechanical damage inflicted by using the unheated stamp as a control. Accordingly, after thermomechanical damage, cell death as well as cell protection programs were activated. Mononuclear cells adhered in the area adjacent to thermomechanical damage, but not to the zone of mechanical damage. Therefore, our model can help to understand the differences in wound healing during the early phase of regeneration after thermomechanical vs. mechanical damage. Furthermore, this model lends itself to study the response of other cells, thus broadening the range of thermal injuries that can be analysed.


POLIOMYELITIS IN THE CYNOMOLGUS MONKEY : I. COMPARISON OF THE UPPER PORTION OF THE ALIMENTARY TRACT WITH ITS LOWER, GASTROINTESTINAL PORTION AS A PORTAL OF ENTRY, WITH SPECIAL REFERENCE TO THE PERIPHERAL GANGLIA.
1. Cynomolgus monkeys were subjected to a series of non-traumatic exposures of the mucous membranes of the alimentary tract, designed to test the relative permeability to poliomyelitis virus of its upper and lower portions. 2. In the first stage, dried poliomyelitis virus of tested potency was administered in fat-covered capsules to 26 monkeys in such a way as to avoid contamination of the oropharynx but to permit thorough exposure of the gastro-intestinal mucosae. No clinical evidence of poliomyelitic infection appeared. 3. Subsequent application of small amounts of virus to the tongues of 18 of the same monkeys caused paralytic poliomyelitis in one of them. 4. Virus given subsequently by enema to 11 of the monkeys caused no clinical manifestations of poliomyelitis. 5. Of 7 monkeys later treated with virus by oronasal spraying, one developed typical preparalytic signs of infection, and the distribution of lesions indicated that entry had occurred through the afferent nerves of the oropharynx and, possibly, the esophagus. 6. The 6 surviving monkeys were exposed to virus by inhalation. One of them developed paralytic poliomyelitis by olfactory entry. The others appeared to have acquired some resistance to infection. 7. The 5 surviving monkeys were inoculated intracerebrally, as a test of immunity. One of them developed paralytic poliomyelitis. The other 4 showed no clinical signs of infection, but all had typical lesions of varying extent and intensity in the central nervous system. 8. A histological examination of the peripheral nervous ganglia in 12 of the exposed monkeys sacrificed at various stages of the experiments revealed lesions compatible with poliomyelitis in all. Ganglia connected with the head alone (Gasserian, cervical sympathetic) were more constantly and, on the average, more severely involved than the celiac, which is connected only with the intestine. 9. While the celiac ganglion was involved in 7 cases, no evidence was found of the spread of infection from it to the spinal cord.


Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics.
Crohn's disease, ulcerative colitis, and pouchitis are caused by overly aggressive immune responses to a subset of commensal (nonpathogenic) enteric bacteria in genetically predisposed individuals. Clinical and experimental studies suggest that the relative balance of aggressive and protective bacterial species is altered in these disorders. Antibiotics can selectively decrease tissue invasion and eliminate aggressive bacterial species or globally decrease luminal and mucosal bacterial concentrations, depending on their spectrum of activity. Alternatively, administration of beneficial bacterial species (probiotics), poorly absorbed dietary oligosaccharides (prebiotics), or combined probiotics and prebiotics (synbiotics) can restore a predominance of beneficial Lactobacillus and Bifidobacterium species. Current clinical trials do not fulfill evidence-based criteria for using these agents in inflammatory bowel diseases (IBD), but multiple nonrigorous studies and widespread clinical experience suggest that metronidazole and/or ciprofloxacin can treat Crohn's colitis and ileocolitis (but not isolated ileal disease), perianal fistulae and pouchitis, whereas selected probiotic preparations prevent relapse of quiescent ulcerative colitis and relapsing pouchitis. These physiologic approaches offer considerable promise for treating IBD, but must be supported by rigorous controlled therapeutic trials that consider clinical disease before their widespread clinical acceptance. These agents likely will become an integral component of treating IBD in combination with traditional anti-inflammatory and immunosuppressive agents.


Preschoolers at risk for attention-deficit hyperactivity disorder and oppositional defiant disorder: family, parenting, and behavioral correlates.
This community study assigned 129 4-year-olds to groups at risk for attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), both ADHD and ODD, or no problems. Mothers of children at risk for ODD reported more family dysfunction, felt less competent as parents, suggested fewer solutions to child behavior problems, demonstrated a less assertive approach to child management, and reported more child internalizing problems than did mothers of children not elevated on ODD symptoms. Mothers of children at risk for ADHD reported higher personal depression scores than did those of the non-ADHD subgroup. Children at risk for ADHD evidenced the most difficulties in school where teachers reported more social behavior, classroom management, and internalizing problems relative to other children not at risk for ADHD. When solving child management problems, mothers of children in all groups suggested twice as many controlling/negative management strategies as positive/preventive strategies. In addition, faced with oppositional and conduct problems, mothers of children in all groups increased controlling/negative suggestions and decreased positive/preventive suggestions. Mothers of girls at risk for ADHD, ODD, and ADHD/ODD gave more rewards per positive behavior than did mothers of boys.


Impact of Growth Hormone on Cystatin C.
Cystatin C (CysC) is an alternative marker to creatinine for estimation of the glomerular filtration rate (GFR). Hormones such as thyroid hormones and glucocorticoids are known to have an impact on CysC. In this study, we examined the effect of growth hormone (GH) on CysC in patients with acromegaly undergoing transsphenoidal surgery. Creatinine, CysC, GH and insulin-like growth factor-1 (IGF-1) were determined in 24 patients with acromegaly before and following transsphenoidal surgery. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. In all patients, surgical debulking resulted in decreased clinical disease activity and declining GH/IGF-1 levels. Postoperatively, biochemical cure was documented in 20 out of 24 patients. Creatinine levels (mean ± SEM) increased from 72 ± 3 to 80 ± 3 µmol/l (p = 0.0004) and concurrently, estimated GFR decreased from 99 ± 3 to 91 ± 3 ml/min (p = 0.0008). In contrast to creatinine, CysC levels decreased from 0.72 ± 0.02 to 0.68 ± 0.02 mg/l (p = 0.0008). Our study provides strong evidence for discordant effects of GH on creatinine and CysC in patients with acromegaly undergoing transsphenoidal surgery, thus identifying another hormone that influences CysC independent of renal function.


Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2007 and 2011 staging systems: a pooled analysis of individual patient data.
There is no universal consensus on the best staging system for chronic obstructive pulmonary disease (COPD). Although documents (eg, the Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2007) have traditionally used forced expiratory volume in 1 s (FEV1) for staging, clinical parameters have been added to some guidelines (eg, GOLD 2011) to improve patient management. As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aimed to investigate how individual patients were categorised by GOLD 2007 and 2011, and compare the prognostic accuracy of the staging documents for mortality. We searched reports published from Jan 1, 2008, to Dec 31, 2014. Using data from cohorts that agreed to participate and had a minimum amount of information needed for GOLD 2007 and 2011, we did a patient-based pooled analysis of existing data. With use of raw data, we recalculated all participant assignments to GOLD 2007 I-IV classes, and GOLD 2011 A-D stages. We used survival analysis, C statistics, and non-parametric regression to model time-to-death data and compare GOLD 2007 and GOLD 2011 staging systems to predict mortality. We collected individual data for 15 632 patients from 22 COPD cohorts from seven countries, totalling 70 184 person-years. Mean age of the patients was 63·9 years (SD 10·1); 10 751 (69%) were men. Based on FEV1 alone (GOLD 2007), 2424 (16%) patients had mild (I), 7142 (46%) moderate (II), 4346 (28%) severe (III), and 1670 (11%) very severe (IV) disease. We compared staging with the GOLD 2007 document with that of the new GOLD 2011 system in 14 660 patients: 5548 (38%) were grade A, 2733 (19%) were grade B, 1835 (13%) were grade C, and 4544 (31%) were grade D. GOLD 2011 shifted the overall COPD severity distribution to more severe categories. There were nearly three times more COPD patients in stage D than in former stage IV (p<0·05). The predictive capacity for survival up to 10 years was significant for both systems (p<0·01) but area under the curves were only 0·623 (GOLD 2007) and 0·634 (GOLD 2011), and GOLD 2007 and 2011 did not differ significantly. We identified the percent predicted FEV1 thresholds of 85%, 55% and 35% as better to stage COPD severity for mortality, which are similar to the ones used previously. Neither GOLD COPD classification schemes have sufficient discriminatory power to be used clinically for risk classification at the individual level to predict total mortality for 3 years of follow-up and onwards. Increasing intensity of treatment of patients with COPD due to their GOLD 2011 reclassification is not known to improve health outcomes. Evidence-based thresholds should be searched when exploring the prognostic ability of current and new COPD multicomponent indices. None.


Second-look US: how to find breast lesions with a suspicious MR imaging appearance.
Breast magnetic resonance (MR) imaging has high sensitivity in breast cancer diagnosis. The probability of malignancy for additional detected lesions is higher in patients with breast cancer than in the population without malignancy, which is why biopsy or further study should be considered for additional detected lesions. Because of the shortcomings of MR imaging-guided biopsy, second-look ultrasonography (US) may be the preferred next step. Detecting target lesions at second-look US and correlating lesions between the two modalities may be challenging. Using axial MR imaging to localize the lesion with respect to the nipple and the lesion-to-nipple distance can narrow the scan range at US. Evaluating the lesion's location relative to the mammary zones and surrounding tissues, as well as noting its depth, characteristics, and nearby landmarks, will aid in lesion correlation. Doppler imaging, tissue harmonic imaging, and other US techniques can be used to identify subtle lesions. Although malignant breast lesions may appear probably benign at second-look US, decision making for biopsy must be based primarily on MR imaging findings. In sonographically occult, MR imaging-detected lesions with suspicious MR imaging features, the probability of malignancy is much higher than 2%, and MR imaging-guided biopsy must be performed.


Investigation of self-phase modulation based optical regeneration in single mode As2Se3 chalcogenide glass fiber.
We investigate the feasibility of all-optical regeneration based on self-phase modulation in single mode As2Se3 chalcogenide fiber. By combining the chalcogenide fiber with a bandpass filter, we achieve a near step-like power transfer function with no pulse distortion. The device is shown to operate with 5.8 ps duration pulses, thus demonstrating the feasibility of this device operating with high bit-rate data signals. These results are achieved with pulse peak powers <10 W in a fully passive device, including only 2.8 m of chalcogenide fiber. We obtain an excellent agreement between theory and experiment and show that both the high nonlinearity of the chalcogenide glass along with its high normal dispersion near 1550 nm enables a significant device length reduction in comparison with silica-based devices, without compromise on the performance. We find that even for only a few meters of fiber, the large normal dispersion of the chalcogenide glass inhibits spectral oscillations that would appear with self-phase modulation alone. We measure the two photon absorption attenuation coefficient and find that it advantageously affects the device transfer function.


Plasmodium DEH is ER-localized and crucial for oocyst mitotic division during malaria transmission.
Cells use fatty acids (FAs) for membrane biosynthesis, energy storage, and the generation of signaling molecules. 3-hydroxyacyl-CoA dehydratase-DEH-is a key component of very long chain fatty acid synthesis. Here, we further characterized in-depth the location and function of DEH, applying in silico analysis, live cell imaging, reverse genetics, and ultrastructure analysis using the mouse malaria model Plasmodium berghei DEH is evolutionarily conserved across eukaryotes, with a single DEH in Plasmodium spp. and up to three orthologs in the other eukaryotes studied. DEH-GFP live-cell imaging showed strong GFP fluorescence throughout the life-cycle, with areas of localized expression in the cytoplasm and a circular ring pattern around the nucleus that colocalized with ER markers. Δdeh mutants showed a small but significant reduction in oocyst size compared with WT controls from day 10 postinfection onwards, and endomitotic cell division and sporogony were completely ablated, blocking parasite transmission from mosquito to vertebrate host. Ultrastructure analysis confirmed degeneration of Δdeh oocysts, and a complete lack of sporozoite budding. Overall, DEH is evolutionarily conserved, localizes to the ER, and plays a crucial role in sporogony.


Nerve regeneration across a 2-cm gap in the rat median nerve using a resorbable nerve conduit filled with Schwann cells.
In a rat model, nerve regeneration was evaluated across a 2-cm defect in the median nerve by using a resorbable artificial nerve conduit. The aim of this study was to develop an artificial, biocompatible nerve guide to induce regeneration in the peripheral nervous system. The authors compared a nerve conduit of trimethylenecarbonate-co-epsilon-caprolactone (TMC/CL) filled with autologous Schwann cells with both an empty hollow conduit and an autologous nerve graft. Animals that did not undergo surgery served as the control group. Nerve regeneration was evaluated with the grasping test, histological analysis of the nerve, muscle weight analysis (flexor digitorum superficialis muscle), and electrophysiological examination. After an observation period of 9 months, regeneration occurred only in animals that had received an autologous graft or a Schwann cell containing nerve conduit. No signs of regeneration were found in animals supplied with the empty conduit. Results of this study reveal the important role of Schwann cells in the regeneration process across a 2-cm defect in the rat median nerve. Furthermore, Schwann cell-filled nerve conduits induced functional recovery, as demonstrated in the grasping test, that was comparable with that of the autologous graft 9 months after implantation.


Molecular and serological evidence of flea-associated typhus group and spotted fever group rickettsial infections in Madagascar.
Rickettsiae are obligate intracellular bacteria responsible for many febrile syndromes around the world, including in sub-Saharan Africa. Vectors of these pathogens include ticks, lice, mites and fleas. In order to assess exposure to flea-associated Rickettsia species in Madagascar, human and small mammal samples from an urban and a rural area, and their associated fleas were tested. Anti-typhus group (TGR)- and anti-spotted fever group rickettsiae (SFGR)-specific IgG were detected in 24 (39%) and 21 (34%) of 62 human serum samples, respectively, using indirect ELISAs, with six individuals seropositive for both. Only two (2%) Rattus rattus out of 86 small mammals presented antibodies against TGR. Out of 117 fleas collected from small mammals, Rickettsia typhi, a TGR, was detected in 26 Xenopsylla cheopis (24%) collected from rodents of an urban area (n = 107), while two of these urban X. cheopis (2%) were positive for Rickettsia felis, a SFGR. R. felis DNA was also detected in eight (31%) out of 26 Pulex irritans fleas. The general population in Madagascar are exposed to rickettsiae, and two flea-associated Rickettsia pathogens, R. typhi and R. felis, are present near or in homes. Although our results are from a single district, they demonstrate that rickettsiae should be considered as potential agents of undifferentiated fever in Madagascar.


Severe toxicity from checkpoint protein inhibitors: What intensive care physicians need to know?
Checkpoint protein inhibitor antibodies (CPI), including cytotoxic T-lymphocyte-associated antigen 4 inhibitors (ipilimumab, tremelimumab) and the programmed cell death protein 1 pathway/programmed cell death protein 1 ligand inhibitors (pembrolizumab, nivolumab, durvalumab, atezolizumab), have entered routine practice for the treatment of many cancers. They improve the outcome for many cancers, and more patients will be treated with CPI in the future. Although CPI can lead to adverse events (AE) less frequently than for chemotherapy, their use can require intensive care unit admission in case of severe immune-related adverse events (IrAE). Moreover, some of these events, particularly late events, are poorly documented, so a high level of suspicion should be maintained for patients receiving CPI. Intensivists should be aware in general of the known complications and appropriate management of these AE. Nevertheless, a multidisciplinary collaboration remains essential for their diagnosis and management. This review described the most severe complications related to CPI.


A satellite repeat-derived piRNA controls embryonic development of Aedes.
Tandem repeat elements such as the diverse class of satellite repeats occupy large parts of eukaryotic chromosomes, mostly at centromeric, pericentromeric, telomeric and subtelomeric regions1. However, some elements are located in euchromatic regions throughout the genome and have been hypothesized to regulate gene expression in cis by modulating local chromatin structure, or in trans via transcripts derived from the repeats2-4. Here we show that a satellite repeat in the mosquito Aedes aegypti promotes sequence-specific gene silencing via the expression of two PIWI-interacting RNAs (piRNAs). Whereas satellite repeats and piRNA sequences generally evolve extremely quickly5-7, this locus was conserved for approximately 200 million years, suggesting that it has a central function in mosquito biology. piRNA production commenced shortly after egg laying, and inactivation of the more abundant piRNA resulted in failure to degrade maternally deposited transcripts in the zygote and developmental arrest. Our results reveal a mechanism by which satellite repeats regulate global gene expression in trans via piRNA-mediated gene silencing that is essential for embryonic development.


Calibration between the Estimated Probability of the Risk Assessment Chart of Japan Atherosclerosis Society and Actual Mortality Using External Population: Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN).
In Japan Atherosclerosis Society guidelines for the prevention of atherosclerotic cardiovascular diseases 2012 (JAS2012), NIPPON DATA80 risk assessment chart (ND80RAC) was adopted to estimate the 10-year probability of coronary artery disease (CAD) mortality. However, there was no comparison between the estimated mortality calculated by ND80RAC and actual mortality in external populations. Accordingly, we used the large pooled database of cohorts in Japan, EPOCH-JAPAN, as an external population. The participants of EPOCH-JAPAN without a history of cardiovascular disease (15,091 men and 18,589 women aged 40-74 years) were analyzed based on sex. The probability of a 10-year risk of CAD/stroke mortality was estimated by ND80RAC. The participants were divided into both decile of their estimated mortality and three categories according to JAS2012. The calibration between the mean estimated mortality and the actual mortality was performed by the Hosmer and Lemeshow (H-L) test. In both sexes, the estimated CAD mortality was higher than the actual mortality, particularly in higher deciles of estimated mortality, and the estimated stroke mortality was almost concordant with the actual mortality in low/moderate deciles of estimated mortality. As for the categories according to JAS2012, the estimated CAD mortality was higher than the actual mortality in both sexes; actual mortality in Category III was lower than that in Category II in women. However, it increased in the ascending order of category when we excluded the presence of diabetes from Category III. The estimated CAD mortality by ND80RAC tended to be higher than the actual mortality in the population in which the baseline survey was more recently performed.


Transient growth factor delivery sustains regenerated axons after spinal cord injury.
Growth factors influence the topography of axonal projections during nervous system development and facilitate axonal sprouting and regeneration after injury in the adult. However, in the absence of target reinnervation and reestablishment of synaptic activity, we hypothesized that continuing delivery of neurotrophins would be required to sustain regenerating axons for prolonged times points after neurotrophin-induced axon growth after spinal cord injury (SCI) in the adult. Using tetracycline-inducible expression of brain-derived neurotrophic factor by genetically modified fibroblasts, we were able to extensively and significantly turn growth factor expression "on" or "off" in vitro and in vivo within sites of SCI. Notably, we find that transient growth factor delivery is sufficient to sustain regenerated axons for prolonged time periods within spinal cord lesion sites. Immunohistochemical analysis demonstrated an absence of neuronal targets or synapses within transient growth factor expressing grafts but the persistent presence of Schwann cells. Thus, the adult CNS appears capable of sustaining axons that have extended after transient growth factor delivery, an effect potentially attributable to the persistence of Schwann cells in lesion/graft sites.


Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium.
GRP78/BiP has recently emerged as a novel biomarker for aggressive prostate cancer. Here, we report that homozygous deletion of Grp78 specifically in mouse prostate epithelium suppresses prostate tumorigenesis without affecting postnatal prostate development and growth. Mouse prostates with double conditional knockout of Grp78 and Pten exhibit normal histology and cytology, in contrast to the invasive adenocarcinoma in mouse prostates with Pten inactivation. AKT activation in Pten null prostate epithelium is inhibited by Grp78 homozygous deletion, corresponding with suppression of AKT phosphorylation by GRP78 knockdown in prostate cancer cell line. Thus, inactivation of GRP78 may represent a previously undescribed approach to stop prostate cancer and potentially other cancers resulting from the loss of PTEN tumor suppression and/or activation of the oncogenic AKT.


Voluntary exercise delays progressive deterioration of markers of metabolism and behavior in a mouse model of Parkinson's disease.
Although a good deal is known about the genetics and pathophysiology of Parkinson's disease (PD), and information is emerging about its cause, there are no pharmacological treatments shown to have a significant, sustained capacity to prevent or attenuate the ongoing neurodegenerative processes. However, there is accumulating clinical results to suggest that physical exercise is such a treatment, and studies of animal models of the dopamine (DA) deficiency associated with the motor symptoms of PD further support this hypothesis. Exercise is a non-pharmacological, economically practical, and sustainable intervention with little or no risk and with significant additional health benefits. In this study, we investigated the long-term effects of voluntary exercise on motor behavior and brain biochemistry in the transgenic MitoPark mouse PD model with progressive degeneration of the DA systems caused by DAT-driven deletion of the mitochondrial transcription factor TFAM in DA neurons. We found that voluntary exercise markedly improved behavioral function, including overall motor activity, narrow beam walking, and rotarod performance. There was also improvement of biochemical markers of nigrostriatal DA input. This was manifested by increased levels of DA measured by HPLC, and of the DA membrane transporter measured by PET. Moreover, exercise increased oxygen consumption and, by inference, ATP production via oxidative phosphorylation. Thus, exercise augmented aerobic mitochondrial oxidative metabolism vs glycolysis in the nigrostriatal system. We conclude that there are clear-cut physiological mechanisms for beneficial effects of exercise in PD.


Spread of contraction in rabbit ear artery preparations in response to stimulation by norepinephrine.
To investigate the spread of contraction in the rabbit ear artery, changes in segment diameter were measured after local stimulation. No spread of contraction was produced by direct current or local application of norepinephrine (NE). Repetitive electrical stimulation caused contraction which spread far from the point of excitation. Since 2 x 10(-7) g/ml tetrodotoxin (TTX) or 10(-5) M phentolamine prevented this spread of contraction, we concluded that it depends on normal function of periarterial nerves and of the alpha-adrenergic receptors at the site of the smooth muscle cells. To check this conclusion and exclude the possibility of myogenic propagation, which normally is due to the conduction of action potentials, the relation between membrane potential of smooth muscle cells and the rapid phase of the contractile response after rapid addition of NE was investigated. In both polarized and depolarized tissues NE induces a biphasic contractile response with no difference in latency. Membrane potential does not change during mechanical latency after the rapid addition of 5 x 10(-9) - 5 x 10(-6) g/ml NE. There are only slight differences in contraction amplitude and maximum rate of tension development when strips from polarized and depolarized tissues incubated in Ca2+-free solution are stimulated by NE. These findings support the conclusion that spread of contraction is not due to myogenic propagation.


Global and local disturbances interact to modify seagrass palatability.
Global change, such as warming and ocean acidification, and local anthropogenic disturbances, such as eutrophication, can have profound impacts on marine organisms. However, we are far from being able to predict the outcome of multiple interacting disturbances on seagrass communities. Herbivores are key in determining plant community structure and the transfer of energy up the food web. Global and local disturbances may alter the ecological role of herbivory by modifying leaf palatability (i.e. leaf traits) and consequently, the feeding patterns of herbivores. This study evaluates the main and interactive effects of factors related to global change (i.e. elevated temperature, lower pH levels and associated ocean acidification) and local disturbance (i.e. eutrophication through ammonium enrichment) on a broad spectrum of leaf traits using the temperate seagrass Cymodocea nodosa, including structural, nutritional, biomechanical and chemical traits. The effect of these traits on the consumption rates of the generalist herbivore Paracentrotus lividus (purple sea urchin) is evaluated. The three disturbances of warming, low pH level and eutrophication, alone and in combination, increased the consumption rate of seagrass by modifying all leaf traits. Leaf nutritional quality, measured as nitrogen content, was positively correlated to consumption rate. In contrast, a negative correlation was found between feeding decisions by sea urchins and structural, biomechanical and chemical leaf traits. In addition, a notable accomplishment of this work is the identification of phenolic compounds not previously reported for C. nodosa. Our results suggest that global and local disturbances may trigger a major shift in the herbivory of seagrass communities, with important implications for the resilience of seagrass ecosystems.


Identification of airborne bacterial and fungal community structures in an urban area by T-RFLP analysis and quantitative real-time PCR.
This study explores the characteristics of bacterial and fungal communities of total suspended particles (TSP) in the atmosphere by using various molecular methods. TSP samples were collected on a glass fiber filter at an urban location in the middle of the Korean Peninsula (Seoul) between middle autumn and early winter in 2007. From the aerosol samples, DNA could be extracted and DNA sequences were determined for bacteria and fungi. Terminal restriction length polymorphism (T-RFLP) analysis was applied to analyze the community structure of them. To estimate the concentration of DNA originating from bacterial and fungal communities, we used the quantitative real-time polymerase chain reaction (Q-PCR). Sequence analyses were also used to determine the identity of biological organisms. The number of bacteria and fungi in the air were between 5.19x10(1) and 4.31x10(3) cellsm(-3) and from 9.56x10(1) to 4.22x10(4) cellsm(-3), respectively and bacterium/fungus ratios ranged from 0.09 to 0.76 across the seven sampling dates. Most of the bacterial sequences found in our TSP samples were from Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes. The fungal sequences were characteristic for Ascomycota, Basidiomycota, and Glomeromycota which are known to actively discharge spores into the atmosphere. The plant sequences could be also detected. We found that large shifts in the community structure of bacteria and fungi were present in our TSP samples collected on different dates. The results demonstrated that in our TSP samples collected at the urban site; (1) there were very diverse bacterial and fungal groups including potential pathogens and allergens and (2) there were temporal shifts in both bacterial and fungal communities in terms of both diversity and abundances across an inter-seasonal period.


Food preparation by young adults is associated with better diet quality.
To describe food-preparation behaviors, cooking skills, resources for preparing food, and associations with diet quality among young adults. Cross-sectional analyses were performed in a sample of young adults who responded to the second wave of a population-based longitudinal study. Measures pertaining to food preparation were self-reported and dietary intake was assessed by a food frequency questionnaire, both by a mailed survey. Males (n = 764) and females (n = 946) ages 18 to 23 years. Cross-tabulations and chi2 tests were used to examine associations between food preparation, skills/resources for preparing foods, and characteristics of young adults. Mixed regression models were used to generate expected probabilities of meeting the Healthy People 2010 dietary objectives according to reported behaviors and skills/resources. Food-preparation behaviors were not performed by the majority of young adults even weekly. Sex (male), race (African American), and living situation (campus housing) were significantly related to less frequent food preparation. Lower perceived adequacy of skills and resources for food preparation was related to reported race (African American or Hispanic) and student status (part-time or not in school). The most common barrier to food preparation was lack of time, reported by 36% of young adults. Young adults who reported frequent food preparation reported less frequent fast-food use and were more likely to meet dietary objectives for fat (P < 0.001), calcium (P < 0.001), fruit (P < 0.001), vegetable (P < 0.001), and whole-grain (P = 0.003) consumption. To improve dietary intake, interventions among young adults should teach skills for preparing quick and healthful meals.


Plasma CRH measurement at 16 to 20 weeks' gestation does not predict preterm delivery in women at high-risk for preterm delivery.
The purpose of this study was to examine the utility of a single second-trimester plasma corticotropin-releasing hormone measurement as a marker for preterm delivery in women at high risk for preterm delivery. This is an analysis of data from a multicenter placebo-controlled trial designed to evaluate the role of 17 alpha hydroxyprogesterone caproate (17P) in the prevention of recurrent preterm birth. Women with a documented history of a previous spontaneous preterm birth at <37 weeks were enrolled (16-20 wks) and randomly assigned in a 2 to 1 ratio to weekly injections of 17P or matching placebo. Blood was collected before treatment in 170 patients (113 assigned 17P and 57 placebo) who were enrolled at 11 of the 19 centers. Plasma levels of corticotropin-releasing hormone were compared between those who delivered preterm and those delivering at term. Data were analyzed using the Wilcoxon rank-sum test. The overall rates of preterm birth in this cohort of 170 patients were 35.9% at <37 weeks (31.9% progesterone, 43.9% placebo), and 19.4% at <35 weeks (18.6% vs 21.1%). The median levels of corticotropin-releasing hormone were similar between those delivering at <37 weeks and those delivering > or = 37 weeks (0.39 ng/mL vs 0.37 ng/mL, P = .08). In addition, there were no differences in corticotropin-releasing hormone levels among those who delivered at <35 weeks or > or = 35 weeks (0.36 vs 0.38, P = .90). Moreover, there were no differences in corticotropin-releasing hormone levels among those in the placebo group who delivered at <37 or > or = 37 weeks (0.40 vs 0.41, P = .72) and at <35 or > or = 35 weeks (P = .64). A single measurement of corticotropin-releasing hormone at 16 to 20 weeks' gestation is not a good biomarker for recurrent preterm delivery in patients at high risk for this complication.


Expression of active iron regulatory factor from a full-length human cDNA by in vitro transcription/translation.
Iron regulatory factor (IRF), also called iron responsive element-binding protein (IRE-BP), is a cytoplasmic RNA-binding protein which regulates post-transcriptionally transferrin receptor mRNA stability and ferritin mRNA translation. By using the polymerase chain reaction (PCR) and the sequence published by Rouault et al. (1990) a probe was derived which permitted the isolation of three human IRF cDNA clones. Hybridization to genomic DNA and mRNA, as well as sequencing data indicated a single copy gene of about 40 kb specifying a 4.0 kb mRNA that translates into a protein of 98,400 dalton. By in vitro transcription of a assembled IRF cDNA coupled to in vitro translation in a wheat germ extract, we obtained full sized IRF that bound specifically to a human ferritin IRE. In vitro translated IRF retained sensitivity to sulfhydryl oxidation by diamide and could be reactivated by beta-mercaptoethanol in the same way as native placental IRF. An IRF deletion mutant shortened by 132 amino acids at the COOH-terminus was no longer able to bind to an IRE, indicating that this region of the protein plays a role in RNA recognition. Placental IRF has previously been shown to migrate as a doublet on SDS-polyacrylamide gels. After V8 protease digestion the heterogeneity was located in a 65/70 kDa NH2-terminal doublet. The liberated 31 kDa COOH-terminal polypeptide was found to be homogeneous by amino acid sequencing supporting the conclusion of a single IRF gene.


Monte-Carlo-based model for the extraction of intrinsic fluorescence from turbid media.
A Monte-Carlo-based model of fluorescence is developed that is capable of extracting the intrinsic fluorescence properties of tissue, which are independent of the absorption and scattering properties of tissue. This model is flexible in its applicability to different illumination-collection geometries and is also valid for a wide range of optical properties, representative of tissue in the UV-visible spectrum. This is potentially useful in a variety of biomedical applications, including cancer diagnostics and monitoring the physiological response to therapy. The model is validated using phantoms composed of hemoglobin (absorber), polystyrene spheres (scatterer), and furan-2 (fluorophore). It is found that this model is able to retrieve the intrinsic fluorescence spectra of the tissue phantoms and recover the intrinsic fluorescence intensity of furan within the phantoms to within a mean error of less than 10%.


Regulated expression of Ly-6A.2 is important for T cell development.
Ly-6A.2 is a surface protein on T cells that may play a role in lymphocyte activation. The regulation of Ly-6A.2 expression during T cell lymphopoiesis has been intriguing. It is one of the earliest markers expressed on pluripotent hemopoietic stem cells and is present on both primitive and mature T cells, but its expression is extinguished in the thymus during key developmental stages. To determine whether Ly-6A.2 is active on developing T cells, as well as the significance of its developmental regulation, Ly-6A.2 was expressed throughout T cell development under control of the T cell-specific human CD2 enhancer in transgenic mice. The constitutive overexpression of Ly-6A.2 in vivo led to a marked impairment in the generation of thymocytes. Development was arrested at the time in thymic development when Ly-6A.2 expression is normally turned off. These results indicate that the regulated expression of Ly-6A.2 in thymocytes may be important for normal development. Moreover, these findings demonstrate that Ly-6A.2 is active in the thymic microenvironment.


Active and inactive forms of biotin synthase occur in Heterodera glycines.
Heterodera glycines, the soybean cyst nematode (SCN), is a plant-parasitic nematode capable of manipulating host plant biochemistry and development. Many studies have suggested that the nematode has acquired genes from bacteria via horizontal gene transfer events (HGTs) that have the potential to enhance nematode parasitism. A recent allelic imbalance analysis identified two candidate virulence genes, which also appear to have entered the SCN genome through HGTs. One of the candidate genes, H. glycines biotin synthase (HgBioB), contained sequence polymorphisms between avirulent and virulent inbred SCN strains. To test the function of these HgBioB alleles, a complementation experiment using biotin synthase-deficient Escherichia coli was conducted. Here, we report that avirulent nematodes produce an active biotin synthase while virulent ones contain an inactive form of the enzyme. Moreover, sequencing analysis of HgBioB genes from SCN field populations indicates the presence of diverse mixture of HgBioB alleles with the virulent form being the most prevalent. We hypothesize that the mutations in the inactive HgBioB allele within the virulent SCN could result in a change in protein function that in some unknown way bolster its parasitic lifestyle.


Innate immunity and monocyte-macrophage activation in atherosclerosis.
Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.


Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice.
The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.


A Service User Perspective Informing the Role of Occupational Therapy in School Transition Practice for High School Learners with TBI: An African Perspective.
In the South African context, there are no specific guidelines regarding how to prepare and support adolescents for the transition from a health care to a high school setting post TBI. This raises questions about the relevance and responsiveness of the current transition practices in occupational therapy in terms of adequately preparing and supporting these adolescents to participate in school and hence exercise their right to a quality education. This study explored adolescents and other key role players' perspectives on and experiences of the high school transition (i.e., school reentry and continued school participation) post TBI. It was anticipated that this would provide an increased understanding of the enablers and barriers to high school reentry and participation post TBI. This served as a basis to explore the main aim of this study which was to help occupational therapists identify where efforts in terms of service delivery are needed. This study was situated in the interpretivist qualitative paradigm and used a multicase study design, which included semistructured interviews with eight adolescent learners with TBI, their primary caregivers, teachers, and principals as well as observations and documentation review. This paper will focus on a central theme in the research, namely, the nature and extent of support needed to facilitate the high school transition of adolescents with TBI within a developing context. Similar to the findings of studies conducted in developed contexts, participants highlighted that they felt that adolescents need support at various stages of the school transition. Participants further alluded to support that should be collaborative, coordinated, flexible, and monitored to ensure it is relevant and responsive to these adolescents' changing needs. The study findings conclude that occupational therapists have a crucial role in fostering an enabling environment (directly and indirectly) through fulfilling various roles including that of a facilitator, intermediary, coach, collaborator, supporter, and advocator.


VCAM-1 targeted alpha-particle therapy for early brain metastases.
Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti-VCAM-1 antibody (212Pb-αVCAM-1). Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.


Myogenic cell lineages.
For many years the mechanisms by which skeletal muscles in higher vertebrates come to be composed of diverse fiber types distributed in distinctive patterns has interested cell and developmental biologists. The fiber composition of skeletal muscles varies from class to class and from muscle to muscle within the vertebrates. The developmental basis for these events is the subject of this review. Because an individual multinucleate vertebrate skeletal muscle fiber is formed by the fusion of many individual myoblasts, more attention, in recent times, has been directed toward the origins and differences among myoblasts, and more emphasis has been placed on the lineal relationship of myoblasts to fibers. This is a review of studies related to the concepts of myogenic cell lineage in higher vertebrate development with emphases on some of the most challenging problems of myogenesis including the embryonic origins of myogenic precursor cells, the mechanisms of fiber type diversity and patterning, the distinctions among myoblasts during myogenesis, and the current hypotheses of how a variety of factors, intrinsic and extrinsic to the myoblast, determine the definitive phenotype of a muscle fiber.


Evaluating the Effect of Phosphorylation on the Structure and Dynamics of Hsp27 Dimers by Means of Ion Mobility Mass Spectrometry.
The quaternary structure and dynamics of the human small heat-shock protein Hsp27 are linked to its molecular chaperone function and influenced by post-translational modifications, including phosphorylation. Phosphorylation of Hsp27 promotes oligomer dissociation and can enhance chaperone activity. This study explored the impact of phosphorylation on the quaternary structure and dynamics of Hsp27. Using mutations that mimic phosphorylation, and ion mobility mass spectrometry, we show that successive substitutions result in an increase in the conformational heterogeneity of Hsp27 dimers. In contrast, we did not detect any changes in the structure of an Hsp27 12-mer, representative of larger Hsp27 oligomers. Our data suggest that oligomer dissociation and increased flexibility of the dimer contribute to the enhanced chaperone activity of phosphorylated Hsp27. Thus, post-translational modifications such as phosphorylation play a crucial role in modulating both the tertiary and quaternary structure of Hsp27, which is pivotal to its function as a key component of the proteostasis network in cells. Our data demonstrate the utility of ion mobility mass spectrometry for probing the structure and dynamics of heterogeneous proteins.


Genetic variation in XPD predicts treatment outcome and risk of acute myeloid leukemia following chemotherapy.
The xeroderma pigmentosum group D (XPD) gene encodes a DNA helicase that functions in nucleotide excision repair of chemotherapy-induced DNA damage, the efficiency of which is predicted to be affected by a lysine to glutamine variant at codon 751. We hypothesized that this constitutive genetic variant may modify clinical response to chemotherapy, and we have examined its association with outcome following chemotherapy for acute myeloid leukemia (AML) in 341 elderly patients entered into the United Kingdom Medical Research Council AML 11 trial, and with the risk of developing chemotherapy-related AML. Among subjects treated for AML, disease-free survival at one year was 44% for lysine homozygotes, compared with 36% for heterozygotes and 16% for glutamine homozygotes (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.01-1.70; P = .04). Similarly, overall survival at one year was 38% for lysine homozygotes, 35% for heterozygotes, and 23% for glutamine homozygotes (HR, 1.18; 95% CI, 0.99-1.41; P = .07). Furthermore, homozygosity for the XPD codon 751 glutamine variant was associated with a significantly increased risk of developing AML after chemotherapy (odds ratio, 2.22 for Gln/Gln vs Lys/Lys; 95% CI, 1.04-4.74). These data suggest that the XPD codon 751 glutamine variant protects against myeloid cell death after chemotherapy.


Variation in Laboratory Test Naming Conventions in EHRs Within and Between Hospitals: A Nationwide Longitudinal Study.
Electronic health records provide clinically rich data for research and quality improvement work. However, the data are often unstructured text, may be inconsistently recorded and extracted into centralized databases, making them difficult to use for research. We sought to quantify the variation in how key laboratory measures are recorded in the Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) across hospitals and over time. We included 6 laboratory tests commonly drawn within the first 24 hours of hospital admission (albumin, bilirubin, creatinine, hemoglobin, sodium, white blood cell count) from fiscal years 2005-2015. We assessed laboratory test capture for 5,454,411 acute hospital admissions at 121 sites across the VA. The mapping of standardized laboratory nomenclature (Logical Observation Identifiers Names and Codes, LOINCs) to test results in CDW varied within hospital by laboratory test. The relationship between LOINCs and laboratory test names improved over time; by FY2015, 109 (95.6%) hospitals had >90% of the 6 laboratory tests mapped to an appropriate LOINC. All fields used to classify test results are provided in an Appendix (Supplemental Digital Content 1, http://links.lww.com/MLR/B635). The use of electronic health record data for research requires assessing data consistency and quality. Using laboratory test results requires the use of both unstructured text fields and the identification of appropriate LOINCs. When using data from multiple facilities, the results should be carefully examined by facility and over time to maximize the capture of data fields.


Filamin repeat segments required for photosensory signalling in Dictyostelium discoideum.
Filamin is an actin binding protein which is ubiquitous in eukaryotes and its basic structure is well conserved - an N-terminal actin binding domain followed by a series of repeated segments which vary in number in different organisms. D. discoideum is a well established model organism for the study of signalling pathways and the actin cytoskeleton and as such makes an excellent organism in which to study filamin. Ddfilamin plays a putative role as a scaffolding protein in a photosensory signalling pathway and this role is thought to be mediated by the unusual repeat segments in the rod domain. To study the role of filamin in phototaxis, a filamin null mutant, HG1264, was transformed with constructs each of which expressed wild type filamin or a mutant filamin with a deletion of one of the repeat segments. Transformants expressing the full length filamin to wild type levels completely rescued the phototaxis defect in HG1264, however if filamin was expressed at lower than wild type levels the phototaxis defect was not restored. The transformants lacking any one of the repeat segments 2-6 retained defective phototaxis and thermotaxis phenotypes, whereas transformants expressing filaminDelta1 exhibited a range of partial complementation of the phototaxis phenotype which was related to expression levels. Immunofluorescence microscopy showed that filamin lacking any of the repeat segments still localised to the same actin rich areas as wild type filamin. Ddfilamin interacts with RasD and IP experiments demonstrated that this interaction did not rely upon any single repeat segment or the actin binding domain. This paper demonstrates that wild type levels of filamin expression are essential for the formation of functional photosensory signalling complexes and that each of the repeat segments 2-6 are essential for filamins role in phototaxis. By contrast, repeat segment 1 is not essential provided the mutated filamin lacking repeat segment 1 is expressed at a high enough level. The defects in photo/thermosensory signal transduction caused by the absence of the repeats are due neither to mislocalisation of filamin nor to the loss of RasD recruitment to the previously described photosensory signalling complex.


Obesity inhibits the osteogenic differentiation of human adipose-derived stem cells.
Craniomaxillofacial defects secondary to trauma, tumor resection, or congenital malformations are frequent unmet challenges, due to suboptimal alloplastic options and limited autologous tissues such as bone. Significant advances have been made in the application of adipose-derived stem/stromal cells (ASCs) in the pre-clinical and clinical settings as a cell source for tissue engineering approaches. To fully realize the translational potential of ASCs, the identification of optimal donors for ASCs will ensure the successful implementation of these cells for tissue engineering approaches. In the current study, the impact of obesity on the osteogenic differentiation of ASCs was investigated. ASCs isolated from lean donors (body mass index <25; lnASCs) and obese donors (body mass index >30; obASCs) were induced with osteogenic differentiation medium as monolayers in an estrogen-depleted culture system and on three-dimensional scaffolds. Critical size calvarial defects were generated in male nude mice and treated with scaffolds implanted with lnASCs or obASCs. lnASCs demonstrated enhanced osteogenic differentiation in monolayer culture system, on three-dimensional scaffolds, and for the treatment of calvarial defects, whereas obASCs were unable to induce similar levels of osteogenic differentiation in vitro and in vivo. Gene expression analysis of lnASCs and obASCs during osteogenic differentiation demonstrated higher levels of osteogenic genes in lnASCs compared to obASCs. Collectively, these results indicate that obesity reduces the osteogenic differentiation capacity of ASCs such that they may have a limited suitability as a cell source for tissue engineering.


Neuronal increase in various areas of the nervous system of the guppy, Lebistes.
The numbers of 1) dorsal root ganglion cells in the 2nd spinal segment, 2) ventral horn cells in the 2nd spinal segment, 3) Purkinje cells of the cerebellum, and 4) neurons in the nucleus glomerulosus were counted and correlated with age and size in the guppy, Lebistes. The findings were that the neuronal numbers in all these areas increased throughout much of the life of the animal. These data, combined with the previously demonstrated increases in retinal neurons in goldfish and sensory and spinal neurons in stingrays, suggest that neurons are added to many areas of the nervous system of fish as the animal ages and grows. In this respect, the nervous systems of fish differ from the nervous systems of other vertebrates. We offer the suggestion that the comparatively greater ability of fish to regenerate their nervous system after injury may be related in part to their ability to add neurons to various parts of the nervous system throughout life.


The role of CD4+ helper T cells in the destruction of microencapsulated islet xenografts in nod mice.
Islet transplants for large numbers of patients with diabetes will require xenografts. Microencapsulation is an appealing method for islet xenografting. However, graft function has been limited by a cellular reaction, particularly intense in spontaneously diabetic, NOD mice. The purpose of this study was to elucidate the mechanism of this reaction. Poly-1-lysine-alginate microcapsules containing 4000-12,000 dog or 1800-2000 rat islets were xenografted intraperitoneally into streptozotocin (SZN)-diabetic C57BL/6J and NOD mice, with or without recipient treatment with GK 1.5 (anti-CD4 monoclonal antibody) (20-30 microliters i.p. every 5 days, begun on day -7. Grafts were considered technically successful if random blood glucose (BG) was normalized (less than 150 mg/dl) within 36 hr. Graft failure was defined as BG greater than 250 mg/dl. Dog and rat islets in microcapsules normalized BG in both SZN and NOD mice within 24 hr routinely. Empty microcapsules and GK 1.5 treatments alone did not affect BG. NODs destroyed both microencapsulated dog and rat islets more rapidly than did SZN-diabetic mice (P less than .01). Graft biopsies showed an intense cellular reaction, composed of lymphocytes, macrophages and giant cells, and no viable islets. GK 1.5 treatment significantly prolonged both dog-to-NOD and rat-to-NOD grafts (P less than 0.01). Biopsies of long-term functioning grafts (on days 65-85) demonstrated viable islets and no cellular reaction around microcapsules; 1/4 rat and 1/8 dog islet xenografts continued to function indefinitely in NOD recipients, even after cessation of GK 1.5 therapy. Prediabetic NODs receiving encapsulated dog or rat islets mounted a moderate cellular reaction to grafts. Empty microcapsules excited no cellular reaction in diabetic or prediabetic NODs. We conclude that the NOD reaction to microencapsulated xenogeneic islets is helper T cell-dependent, and that the target of this reaction is not the microcapsule itself, but the donor cells within.


Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction.
To clarify which rheumatoid arthritis (RA) patients benefit most from the anti-receptor activator of nuclear factor-κB ligand antibody denosumab to reduce the progression of joint destruction. We pooled patient data from the 12-month, double-blind, placebo-controlled DRIVE (phase II) and DESIRABLE (phase III) studies. In DRIVE, concomitant treatment was limited to methotrexate, salazosulfapyridine and bucillamine. In DESIRABLE, patients could receive any disease-modifying antirheumatic drug. RA patients were randomised to denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or placebo. Efficacy was assessed by van der Heijde-modified total Sharp score (mTSS), bone erosion score (ES) and joint space narrowing score (JSNS). Change in mTSS was assessed in subgroups stratified by risk factors for radiographic damage if the interaction factor was significant. The pooled analysis included 909 patients. Denosumab reduced worsening of mTSS (mean (SD)) at 12 months in the Q6M (0.88 (3.30), p=0.0024) and Q3M (0.66 (2.16), p=0.0002) groups versus placebo (1.50 (3.73)). This reduction in mTSS progression was due to the change in ES (Q6M, 0.44 (1.89), p=0.0006; Q3M, 0.20 (0.86), p<0.0001) versus placebo (0.98 (2.54)); no effect was observed on JSNS. Anti-cyclic citrullinated peptide (CCP) antibodies, glucocorticoid use and baseline ES showed a significant interaction. Denosumab was particularly effective in patients who were anti-CCP antibody positive (p<0.05). Changes in mTSS versus placebo were observed in all denosumab dose groups, regardless of glucocorticoid use and baseline ES. Denosumab broadly reduced the progression of joint destruction in RA patients with risk factors for radiographic damage such as especially anti-CCP antibody positivity.


WFSBP * and IAWMH ** Guidelines for the treatment of alcohol use disorders in pregnant women.
These practice guidelines for the treatment of alcohol use disorders during pregnancy were developed by members of the International Task Force of the World Federation of Societies of Biological Psychiatry and the International Association for Women's Mental Health. We performed a systematic review of all available publications and extracted data from national and international guidelines. The Task Force evaluated the data with respect to the strength of evidence for the efficacy and safety of each medication. There is no safe level of alcohol use during pregnancy. Abstinence is recommended. Ideally, women should stop alcohol use when pregnancy is planned and, in any case, as soon as pregnancy is known. Detecting patterns of alcohol maternal drinking should be systematically conducted at first antenatal visit and throughout pregnancy. Brief interventions are recommended in the case of low or moderate risk of alcohol use. Low doses of benzodiazepines, for the shortest duration, may be used to prevent alcohol withdrawal symptoms when high and chronic alcohol intake is stopped and hospitalisation is recommended. Due to the low level of evidence and/or to low benefit/risk ratio, pharmacological treatment for maintenance of abstinence should not be used during pregnancy. At birth, foetal alcohol spectrum disorders must be searched for, and alcohol metabolites should be measured in meconium of neonates in any doubt of foetal alcohol exposure.


Fatal secondary increase in serum S-100B protein after severe head injury. Report of three cases.
The S-100B protein is a small cytosolic protein that is found in astroglial or Schwann cells. It is highly specific for brain tissue and is increasingly being investigated as a diagnostic tool to assess the neurological damage after head injury, stroke, subarachnoid hemorrhage, and cardiopulmonary bypass. The authors report on three patients with severe head injury with otherwise normal cerebral perfusion pressure, SaO2, PaCO2, and controlled intracranial pressure (ICP), in whom a secondary excessive increase in serum S-100B was observed. In all cases, the S-100B increase was followed by an increase in ICP. All three patients died within 72 hours after the excessive increase in S-100B. These findings indicate that major secondary brain damage may occur at a cellular level without being identified by current neuromonitoring techniques.


Inter-Species/Host-Parasite Protein Interaction Predictions Reviewed.
Host-parasite protein interactions (HPPI) are those interactions occurring between a parasite and its host. Host-parasite protein interaction enhances the understanding of how parasite can infect its host. The interaction plays an important role in initiating infections, although it is not all host-parasite interactions that result in infection. Identifying the protein-protein interactions (PPIs) that allow a parasite to infect its host has a lot do in discovering possible drug targets. Such PPIs, when altered, would prevent the host from being infected by the parasite and in some cases, result in the parasite inability to complete specific stages of its life cycle and invariably lead to the death of such parasite. It therefore becomes important to understand the workings of host-parasite interactions which are the major causes of most infectious diseases. Many studies have been conducted in literature to predict HPPI, mostly using computational methods with few experimental methods. Computational method has proved to be faster and more efficient in manipulating and analyzing real life data. This study looks at various computational methods used in literature for host-parasite/inter-species protein-protein interaction predictions with the hope of getting a better insight into computational methods used and identify whether machine learning approaches have been extensively used for the same purpose. The various methods involved in host-parasite protein interactions were reviewed with their individual strengths. Tabulations of studies that carried out host-parasite/inter-species protein interaction predictions were performed, analyzing their predictive methods, filters used, potential protein-protein interactions discovered in those studies and various validation measurements used as the case may be. The commonly used measurement indexes for such studies were highlighted displaying the various formulas. Finally, future prospects of studies specific to human-plasmodium falciparum PPI predictions were proposed. We discovered that quite a few studies reviewed implemented machine learning approach for HPPI predictions when compared with methods such as sequence homology search and protein structure and domain-motif. The key challenge well noted in HPPI predictions is getting relevant information. This review presents useful knowledge and future directions on the subject matter.


Passenger car collision fatalities--with special emphasis on collisions with heavy vehicles.
Between 1995 and 2004, 293 passenger car occupants died in collisions with other vehicles in northern Sweden (annual incidence: 3.3 per 100,000 inhabitants, 6.9 per 100,000 cars, or 4.8 per 10(9)km driven); half of these deaths involved heavy vehicles. The annual number of passenger car occupant deaths per 100,000 cars in car-truck/bus collisions has remained unchanged since the 1980s, but in car-car collisions it has decreased to one third of its former level. As crash objects, trucks and buses killed five times as many car occupants per truck/bus kilometer driven as did cars. The collisions were characterized by crashes in the oncoming vehicle's lane, under icy, snowy, or wet conditions; crashes into heavy vehicles generally occurred in daylight, on workdays, in winter, and on 90 and 70 km/h two-lane roads. Head and chest injuries accounted for most of the fatal injuries. Multiple fatal injuries and critical and deadly head injuries characterized the deaths in collisions with heavy vehicles. An indication of suicide was present in 4% of the deaths; for those who crashed into trucks, this percentage was doubled. Among the driver victims, 4% had blood alcohol levels above the legal limit of 0.2g/L. Frontal collision risks might be reduced by a mid-barrier, by building less injurious fronts on trucks and buses, by efficient skid prevention, and by use of flexible speed limits varying with road and light conditions.


Continuing Medical Education: an international reality.
We are all aware today of the growing interest in continuing medical education (CME) programmes in many European Countries and it is important to understand why and how CME could become an international reality. It is obvious that patients need a good doctor--the best possible--as far as medical knowledge, attention to the patient's quality of life and cost-control is concerned. All European health care systems have to take into consideration everything that causes patient dissatisfaction, risk management and unjustified expenses. An example is the increase of claims and complaints against doctors and the strong attention of patients to medical procedures. In other words, medicine worldwide is becoming a service industry and has to consider quality and quantity of performances as well as to pay attention to personal responsibility. The object of our work is to evaluate the CME systems present in Europe, to show the work done on CME by the CME Committee of the European Academy of Allergology and Clinical Immunology and to highlight the Consensus Report on CME approved by an international panel of CME experts.


Predictors of venous thromboembolism in patients with advanced common solid cancers.
There is uncertainty about risk heterogeneity for venous thromboembolism (VTE) in older patients with advanced cancer and whether patients can be stratified according to VTE risk. We performed a retrospective cohort study of the linked Medicare-Surveillance, Epidemiology, and End Results cancer registry in older patients with advanced cancer of lung, breast, colon, prostate, or pancreas diagnosed between 1995-1999. We used survival analysis with demographics, comorbidities, and tumor characteristics/treatment as independent variables. Outcome was VTE diagnosed at least one month after cancer diagnosis. VTE rate was highest in the first year (3.4%). Compared to prostate cancer (1.4 VTEs/100 person-years), there was marked variability in VTE risk (hazard ratio (HR) for male-colon cancer 3.73 (95% CI 2.1-6.62), female-colon cancer HR 6.6 (3.83-11.38), up to female-pancreas cancer HR 21.57 (12.21-38.09). Stage IV cancer and chemotherapy resulted in higher risk (HRs 1.75 (1.44-2.12) and 1.31 (1.0-1.57), resp.). Stratifying the cohort by cancer type and stage using recursive partitioning analysis yielded five groups of VTE rates (nonlocalized prostate cancer 1.4 VTEs/100 person-years, to nonlocalized pancreatic cancer 17.4 VTEs/100 patient-years). In a high-risk population with advanced cancer, substantial variability in VTE risk exists, with notable differences according to cancer type and stage.